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CONTEMPOR ARY OB/GYN SEPTEMBER 2014, Vol. 59, No. 9 Expert Advice for Today’s Ob/Gyn For Doctors by Doctors ContemporaryOBGYN.net ULTR ASOUND TRIAGE OF POSTMENOPAUSAL BLEEDING ◾ POSTMENOPAUSAL HT UPDATE ◾ NIPT TECHNOLOGIES Ultrasound Triage of Postmenopausal Bleeding James M. Shwayder, MD, JD PEG laxatives like MiraLAX® are now recommended as a first-line constipation therapy by the AGA 1 One product. Two benefits. MiraLAX® is the osmotic laxative with dual benefits—it relieves constipation and softens stool. Rethinking hormones in menopause Two expert opinions LEGALLY SPEAKING Recommend MiraLAX today and see why it is the #1 GI recommended laxative.2 Fibroid—or sarcoma? GME at a crossroads For more information, please visit www.MiraLAXMD.com Reference: 1. American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013;144:211-217. 2. IMS data. IMS National Disease & Therapeutic Index. 2011. SEPTEMBER 2014 | VOLUME 59, NUMBER 9 APRIL 2014 Use as directed. | VOLUME 59, NUMBER 4 facebook.com/ContempOBGY © 2014 MSD Consumer Care, Inc. All rights reserved. twitter.com/ContempOBGYN CONTEMPOR ARY OB / GYN SEPTEMBER 2014, Vol. 59, No. 9 Expert Advice for Today’s Ob/Gyn For Doctors by Doctors ContemporaryOBGYN.net ULTR ASOUND TRIAGE OF POSTMENOPAUSAL BLEEDING ◾ POSTMENOPAUSAL HT UPDATE ◾ NIPT TECHNOLOGIES Ultrasound Triage of Postmenopausal Bleeding James M. Shwayder, MD, JD Rethinking hormones in menopause Two expert opinions LEGALLY SPEAKING Fibroid—or sarcoma? GME at a crossroads SEPTEMBER 2014 magenta cyan yellow black | VOLUME 59, NUMBER 9 ES495995_obgyn0914_cv1.pgs 08.29.2014 22:25 ADV magenta cyan yellow black ES496832_OBGYN0914_CV2_FP.pgs 09.01.2014 18:09 ADV magenta cyan yellow black ES496825_OBGYN0914_001_FP.pgs 09.01.2014 18:09 ADV DEPUTY EDITOR EDITOR IN CHIEF Charles J Lockwood, MD, MHCM Jon I Einarsson, MD, PhD, MPH Senior Vice President, USF Health Dean, Morsani College of Medicine Associate Professor of Obstetrics and Gynecology Harvard Medical School University of South Florida Director, Division of Minimally Invasive Gynecologic Surgery Brigham and Women’s Hospital TAMPA, FL BOSTON, MA YOUR EDITORIAL BOARD Haywood L Brown, MD Paula J Adams Hillard, MD Sharon T Phelan, MD Roy T. Parker Professor and Chair, Division of Maternal Fetal Medicine Professor, Department of Obstetrics and Gynecology, Chief, Division of Gynecologic Specialties Professor, Department of Obstetrics and Gynecology Stanford University School of Medicine ALBUQUERQUE, NM Duke University Medical Center DURHAM, NC University of New Mexico STANFORD, CA Ilana Cass, MD Sarah J Kilpatrick, MD, PhD Joe Leigh Simpson, MD Vice Chair, Associate Clinical Professor, Department of Obstetrics and Gynecology Helping Hand Endowed Chair, Department of Obstetrics and Gynecology Cedars-Sinai Medical Center Cedars-Sinai Medical Center Executive Associate Dean for Academic Affairs, Professor of Obstetrics and Gynecology, and Human and Molecular Genetics LOS ANGELES, CA LOS ANGELES, CA Florida International University College of Medicine MIAMI, FL Joshua A Copel, MD Professor, Obstetrics, Gynecology, and Reproductive Sciences, and Pediatrics Yale University School of Medicine NEW HAVEN, CT Elliott K Main, MD FOUNDING EDITOR Director, California Maternal Quality Care Collaborative, Chair and Chief, Department of Obstetrics and Gynecology John T Queenan, MD California Pacific Medical Center WASHINGTON, DC Professor of Obstetrics and Gynecology Georgetown University School of Medicine SAN FRANCISCO, CA John O DeLancey, MD Norman F Miller Professor of Gynecology, Director, Pelvic Floor Research, Group Director, Fellowship in Female Pelvic Medicine and Reconstructive Surgery University of Michigan Medical School Laurie J McKenzie, MD Director of Oncofertility, Houston IVF, Director Houston Oncofertility Preservation and Education (H.O.P.E.) HOUSTON, TX ANN ARBOR, MI OUR MISSION For nearly a half century, busy practitioners have trusted Contemporary OB/GYN to translate the latest research into outstanding patient care. We are dedicated to providing them with evidence-based information on scientific advances in a clinically useful format. 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Ext. 121 AUDIENCE DEVELOPMENT Joy Puzzo Don Berman Corporate Director [email protected] Executive Vice President 440-891-2778, [email protected] Business Director, eMedia 212-951-6745, [email protected] Christine Shappell Ken Sylvia Meg Benson Director [email protected] Special Projects Director 732-346-3039, [email protected] Joe Martin Vice President, Group Publisher 732-346-3017, [email protected] 2 magenta cyan yellow black CONTEMPORARYOBGYN.NET Chief Executive Officer Joe Loggia Executive Vice-President, Chief Administrative Officer & Chief Financial Officer Tom Ehardt Executive Vice-President Georgiann DeCenzo Executive Vice-President Chris DeMoulin Executive Vice-President, Business Systems Rebecca Evangelou Executive Vice-President, Human Resources Julie Molleston Sr Vice-President Tracy Harris Vice-President, General Manager Pharm/Science Group Dave Esola Vice-President, Legal Michael Bernstein Vice-President, Media Operations Francis Heid Vice-President, Treasurer & Controller Adele Hartwick Manager [email protected] SEPTEMBER 2014 ES495029_obgyn0914_002.pgs 08.29.2014 02:32 ADV “My income more than tripled after adding aesthetic laser treatments.” DR. MICHAEL SINCLAIR, MD FA M I LY P R A C T I T I O N E R Add revenue. Improve patient care. Aesthetic treatments for skin revitalization and hair removal make the perfect complement to your practice. Your patients will love it because it builds their confdence. You’ll love it because it builds your business. And it couldn’t be easier. We can have you trained and up in running faster than you think. Stop worrying about your practice and start growing it. With Cynosure. Learn more at startwithaesthetics.com © 2014 Cynosure, Inc. All rights reserved. Cynosure is a registered trademark magenta cyan yellow black ES496807_OBGYN0914_003_FP.pgs 09.01.2014 18:08 ADV CONTEMPORARYOBGYN.NET VOL. 59, NO. 9 SEPTEMBER 2014 GRAND ROUNDS triage 24 Ultrasound of postmenopausal bleeding JAMES M. SHWAYDER, MD, JD Ultrasound-based evaluation is less costly than an endometrial biopsy and also allows for evaluation of the adnexa and bladder. 34 Hormone therapy in menopause HUGH S. TAYLOR, MD AND HOLLY M. THACKER, MD, FACP, CCD, NCMP Two experts give their opinions on HT use in postmenopausal patients in light of new information. TECH TOOLS 46 NIPT update BRIAN A. LEVINE, MD, MS, AND DAN GOLDSCHLAG, MD, FACOG 24 The Tech Tools columnists report on the latest advancements in noninvasive prenatal testing. 20 Uterine fibroid—or sarcoma? 5 OB/GYN STAT BITE 56 Health tracking for patients PAULA J. ADAMS HILLARD, MD Nearly two-thirds of US adults keep track of at least one personal health indicator. CHARLES J. LOCKWOOD, MD, MHCM Should graduate medical education be funded by the federal government? ANDREW I. KAPLAN, ESQ A plaintiff claims that her ob/gyn attributed her complaints to a fibroid rather than uterine cancer. EDITORIAL 9 16 50 55 WOMEN’S HEALTH UPDATE LETTERS TO THE EDITOR CLASSIFIEDS CALENDAR/AD INDEX CONTEMPORARY OB/GYN (Print ISSN#0090-3159, DIGITAL ISSN#2150-6264), is published monthly by Advanstar Communications, Inc, 131 West First St, Duluth, MN 55806-2065. One-year subscription rates: $110.00 per year (USA and Possessions); $140.00 per year (elsewhere). Single copies (prepaid only) $12.00 in the USA; $18.00 per copy elsewhere. Include $6.50 per order plus $2.00 for US postage and handling. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to Contemporary OB/GYN, PO Box 6084, Duluth, MN 55806-6084. Return Undeliverable Canadian Addresses to: IMEX Global Solutions, PO Box 25542, London, ON N6C 6B2, CANADA. Canadian GST number: R-124213133RT001. Publications Mail Agreement Number 40612608. Printed in USA. Subscription inquiries/address changes: toll-free 888-527-7008, or dial direct 218-740-6477. ©2014 Advanstar Communications Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/educational or personal use of specific clients is granted by Advanstar Communications Inc for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr, Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://www. copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept, fax 440-756-5255 or email: [email protected]. 4 magenta cyan yellow black CONTEMPORARYOBGYN.NET ILLUSTRATION BY ALEX BAKER, DNA ILLUSTRATIONS, INC. LEGALLY SPEAKING SEPTEMBER 2014 ES495972_obgyn0914_004.pgs 08.29.2014 22:23 ADV EDITORIAL bY cHarLes J. LocKWooD, mD, mHcm Graduate medical education at the crossroads a recent institute of Medicine report suggests changing how GME is funded and may ultimately lead to a shortage of physicians. I f we want to ensure that future generations of medical students have access to first-rate ob/gyn training, we need to join the growing debate over graduate medical education (GME) funding. If you are like me, you had no idea who provided the money to pay your salary as a resident. I just assumed it was my hospital. But the federal government spends more than $15 billion per year on residency and fellowship training, and many are asking why physicians deserve this special largesse denied other professionals. A recent Institute of Medicine (IOM) report called for a complete restructuring of federal GME payments to achieve greater transparency and accountability in meeting the nation’s physician workforce needs.1 Critics contend that adopting the IOM recommendations would lead to major cuts in GME funding, threatening the world’s best training programs and jeopardizing patient care.2 What are the issues behind this debate—and should we be concerned about the viability of future ob/gyn training? Federal support for GME Hospitals with accredited GME programs receive $6.8 billion in indirect medical education (IME) and $2.8 billion in direct graduate medical education (DGME) funding from Medicare.1 The former is doled out to hospitals as part of their Medicare prospective payment system remuneration using a complex formula derived from outdated 1980s cost data and designed to cover debatable “indirect” expenses accruing from resident training. We should be concerned about the viability of future ob/gyn training. In contrast, DGME funds are used to directly support the salaries and benefits of residents, program directors, and select faculty. Both IME and DGME payments are dependent on a hospital’s volume of Medicare inpatients, disadvantaging programs with large pediatric, obstetric, and non-elderly adult populations. Most states also provide Medicaid GME, matched by the federal government, totaling about $4 billion. The Veterans Health Administration (VA) and the Health Resources and Services Administration (HRSA) supply an additional $1.44 billion and $464 million, respectively, in GME funds. The VA keeps its IME payments and provides DGME funds to affiliated academic GME sponsors, while HRSA funds are used to support children’s hospital residency programs, primary care loan repayment programs, and, more recently, community-based family medicine training programs. However, both VA and HRSA funds depend on politically unreliable Congressional discretionary appropriations, rather than Medicare’s mandatory appropriations. The Department of Defense sponsors 200 GME programs with 3200 trainees, but the exact costs of these programs are not available. In addition, an unknown level of support is provided by hospitals, physician groups, philanthropy, and even industry, but the preponderance of financial support for GME comes from the federal government. Federal GME funding under scrutiny Federal funding of GME has been under intense scrutiny for more than WE WANT TO HEAR FROM YOU Send your feedback to: [email protected]. september 2014 magenta cyan yellow black contemporary ob/gyn 5 ES496160_obgyn0914_005.pgs 08.30.2014 01:42 ADV Editorial 2 decades. The primary question is why Medicare serves as the chief underwriter of resident and fellowship training when Medicare patients account for a minority of most physicians’ practices. And, why does the bulk of such funding go toward specialist and subspecialist training, when there is a clear national shortage of primary care providers (PCPs)? Why do hospitals receive virtually all Medicare funding when future physicians will predomi- and other professional societies and hospital trade groups. The controversial IOM recommendations The IOM Committee on Governance and Financing of GME was formed at the behest of stakeholders including 11 US senators. The Committee assessed workforce assumptions, funding sources, and the quality of current GME training. They concluded that the the government has reduced IME funding several times during the past 30 years. nately work in ambulatory settings? It is also legitimate to wonder why most funding goes to urban hospitals, given the surfeit of physicians in affluent urban areas and their dearth in rural locales. Partly in response to these concerns, but mostly to save money, the federal government “capped” residency slots as part of the 1997 Balanced Budget Act, paying hospitals for the number of residents and fellows they had on December 31, 1996. This “cap” has had the perverse effect of perpetuating geographical and specialty imbalances, though so-called virgin institutions may request new Medicare GME funding with these slots capped after 5 years. Also in response to critics’ complaints that IME formulas overestimated trainee-related hospital costs, the government has reduced IME funding several times during the past 30 years. More recently, both the White House and House Republicans proposed substantial reductions in GME funding, which were blocked only after a massive lobbying effort led by the Association of American Medical Colleges (AAMC) 6 magenta cyan yellow black contemporaryobgyn.net current GME system is neither transparent nor accountable, has too many specialists and too few PCPs, and is not producing physicians willing to work in rural and underserved areas. They argued that GME programs are too focused on inpatient rather than community and ambulatory care and that they lack proper emphasis on coordination and cost of care, health information technologies, and cultural competency. The IOM recommended that there be no further increases in Medicare GME funding and that IME and DGME funding streams be merged and used to directly fund all residents and fellows at a geographic- and inflationadjusted national per resident amount. The IOM also recommended dividing this funding into operational and transformational components. The former would cover current training programs and the latter would be used to experiment with new GME models. Operational funds would be progressively reduced by up to 30% to fund transformational projects. The IOM also called for creating a new bureaucracy to oversee GME payments and policies, collect data, and issue reports. They also opined that GME funds should no longer be distributed to hospitals based on Medicare inpatient volume but to the actual sponsors (eg, medical schools, federally qualified health centers, and academic medical centers) responsible for maintaining accreditation, thus addressing the disconnect between those receiving Medicare funds and those responsible for the academic integrity of GME programs. After a 10-year transition all Medicare GME payments would reward performance and reflect national, regional, and local workforce needs. The stakes could not be higher In response to an impending shortage of an estimated 130,000 physicians by 2025,2 the number of US medical students has risen 28% over the past decade from 80,180 to 104,498. During that time there has been a 12.8% increase in the number of new US allopathic medical schools, from 125 to 141, and a 17.5% increase in the number of allopathic medical students.1 The number of new osteopathic schools has increased 70% from 20 to 34, with a 90.2% increase in the number of osteopathic medical students.1 And even more new medical schools are planned. Over the same interval, despite the Medicare cap, the number of Accreditation Council for Graduate Medical Education (ACGME)-approved GME slots has increased 17.5%, from 100,176 to 117,717, though the number of new first-year positions has increased only 13.6%.1 There are another 7498 trainees in osteopathic residencies. Thus, the concern is that at some point in the not-too-distant future the rising number of US medical students will exceed the number of available US september 2014 ES496161_obgyn0914_006.pgs 08.30.2014 01:42 ADV Innovation is in our DNA so you can provide insight into theirs From basic to complex, trust Quest Diagnostics for prenatal genetic testing that is truly innovative. Quest Diagnostics uses the most advanced technologies, including: • High-resolution chromosomal microarrays • Advanced sequencing using next-generation platforms • Cutting-edge automated platforms In addition to innovative technology, Quest Diagnostics has a team of genetic counselors available for physician consultation at 866-GENE-INFO (866-436-3463). Find out what a difference our innovation makes at QuestDiagnostics.com /DNA © 2014 Quest Diagnostics Incorporated. All rights reserved. 02/2014 magenta cyan yellow black ES496880_OBGYN0914_007_FP.pgs 09.01.2014 18:17 ADV Editorial GME slots. Moreover, many experts worry that implementation of the IOM recommendations could exacerbate the problem by reducing the number of GME slots just as this wave of needed new physicians is graduating.2 For their part, the IOM Committee disputes claims of an impending physician shortage, arguing that they do not take into account likely future improvements in productivity from increased use of physician assistants and advanced practice nurses as well as improved efficiencies resulting from new health information technologies and telemedicine. They argue that these productivity improvements— coupled with reduced physician demand resulting from new medical payment systems such as capitation and patient-centered medical homes— will mitigate future shortages. The Committee also notes that hospitals increased GME slots, as noted above, despite the Medicare cap. The essential problem with the IOM position is that if their estimates of increased productivity and decreased physician demand are wrong, and/or if hospitals can’t continue to increase self-funded GME slots in the face of anticipated historic revenue shortfalls, there will be not only many disappointed US medical student graduates unable to find residency slots, but also many patients with reduced or no access to physicians. On the other hand, if the IOM Committee’s critics are wrong, and GME slots are needlessly increased, there will be a surplus of physicians, reducing market demand and potentially reducing costs. Which bet would you make? Take-home message The IOM report makes many compelling arguments and has stimulated a 8 magenta cyan yellow black contemporaryobgyn.net much-needed debate. The IOM Committee makes some excellent suggestions including eliminating distinct IME and DGME payment streams in favor of a simple, transparent per-resident amount. It also favors funding GME sponsors responsible for maintaining accreditation rather than hospitals that directly benefit from trainee work and receive hard-to-justify IME payments. But at the heart of the debate is the question of how we reconcile national workforce needs with the freedom of students to choose their own career paths. The IOM argues that Medicare should continue to fund GME because we should not squander this “leverage” for GME reform. I find that argument unconvincing. Indeed, economists contend that there is no economic rationale for taxpayer support of GME because it fails to meet the definition of a public good.3 This argument rings hollow as well since access to effective health care is an obvious public good. Moreover, since all patients and payers ultimately benefit from having a well-trained, competent, and diverse physician workforce, all payers should cover GME costs. Thus, whether the GME program is based in a rural community health center or quaternary care urban teaching hospital, all payments received from all insurers (private and public) for all patient services rendered at these sites should include a specified component to cover GME costs. These funds should then go to the academic GME sponsor who pays the trainees’ salaries and covers legitimate administrative and teaching costs. As to the number of GME slots available and their allocation by specialty, these decisions should be left to the free market—rather than some government agency’s central planning efforts—as far as is practicable. As we move to consumer-directed healthcare plans, traditional labor market supply-and-demand forces will do a far better job of meeting future physician workforce needs. And where the free market falters, the government can provide incentives through loan forgiveness programs, scholarships, and generous bonuses to encourage graduating medical students to enter primary care fields and serve in rural and under-resourced urban settings. As for ob/gyns, for many reasons there will be high and sustained market demand for resident graduates for years to come and as long as the government doesn’t interfere, the market will ensure an adequate number of training programs and graduating residents. Dr. LockwooD, Editor-in-Chief, is dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South Florida, tampa. He can be reached at [email protected]. references 1. Eden J, Berwick d, Wilensky G. Graduate Medical Education That Meets the Nation’s Health Needs. Institute of Medicine of the National Academies. Washington, dC: the National academies Press; 2014. 2. association of american Medical Colleges. ioM’s vision of GME will not meet real-world patient needs. www.aamc.org/newsroom/ newsreleases/381882/07292014.html. accessed august 21, 2014. 3. the New York times. the teaching of future doctors doesn’t necessarily deserve your tax dollars. www.nytimes.com/2014/08/23/ upshot/the-teaching-of-future-doctorsdoesnt-necessarily-deserve-your-tax-dollars. html?abt=0002&abg=1. accessed august 21, 2014. september 2014 ES496162_obgyn0914_008.pgs 08.30.2014 01:42 ADV WOMEN’S HEALTH UPDATE ‘gOHO’ course teams residents with ultrasound leaders pHotos CoURtesY KImBeRlY aBRUZese, Rdms T he GOHO course returned to the Icahn School of Medicine at Mount Sinai in New York City for its second year last month, bringing learning from ultrasound’s leaders to enthusiastic ob/gyn residents. It’s the second year for the free program, hosted by The Gottesfeld-Hohler (GOHO) Memorial Foundation, a nonprofit organization dedicated to improving education and research in ultrasound for ob/gyns. Speakers at the program, which at t rac te d 63 s e c ond-ye a r residents, included Contemporary OB/GYN Editorial Board member Joshua A. Copel, MD, John Hobbins, MD, Larry Platt, MD, Lynn Simpson, MD, Joanne Stone, MD, Ilan Timor, MD, and Mark Sauer, MD. Spanning a f ull weekend, t he 2-day course afforded the students the opportunity for 3 hours of hands-on scanning per day— twice the amount as last year. Attendees rotated through six rooms equipped with ultrasound machines on which they performed biometric scans on live models and two with simulators on which to practice transvaginal ultrasound and view cases involving gynecologic pathology. T he GOHO prog ra m wa s supported by the American College of Obstetricians and Gynecologists (ACOG) Council on Resident Education in Obstetrics and Gynecology (CREOG), and utilized educational materials developed along with the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), and the American Institute of Ultrasound in Medicine (AIUM). “I am thrilled that Mount Sinai was selected to host the GOHO resident ultrasound course for the second year in a row,” said Dr. Stone, who is Director of Maternal-Fetal Medicine at Mount Sinai Hospital. “The turnout was incredible. The residents really seemed to learn so much from both the hands-on sessions and the ultrasound lectures. Every september 2014 contemporary ob/gyn magenta cyan yellow black 9 ES496118_obgyn0914_009.pgs 08.30.2014 01:03 ADV Women’s HealtH Update second-year resident in the country should be able to attend this course.” The Gottesfeld-Hohler Memorial Foundation honors the memory of Kenneth Gottesfeld and Charles Hohler, two early pioneers of ob/ gyn ultrasound. The organization has cosponsored a research award with ACOG, run “think tanks” and provides grants for other ultrasound education activities. Faculty for the GOHO program receive only expense reimbursements and no honoraria. Dr. Copel, who is the g roup’s t reasurer, repor ts t hat more than 98% of the money the organization raises goes to support scholarly activities. The ultrasound program is the organization’s way of leveraging its limited assets to support its educational goals. Corporate sponsors for this year’s event were GE, Philips, and Samsung; Medaphor and Sonosim also participated in the event. Money is also raised through a continuing education ultrasound course the Foundation offers every year in December. Information on that course is available at www. cmebyplaza.com. Is there an unmet need for post-mastectomy reconstruction? 16.8% underwent delayed reconstruction, for a total of 41.6%. Factors significantly associated with not undergoing reconstruction were black race, lower educational level, increased age, major comorbidity, and having undergone chemotherapy. Only 13.3% of women were dissatisfied with the reconstruction decision-making process, but ost women who undergo mastectomy following this dissatisfaction was higher among nonwhite patients breast cancer do not then undergo breast (adjusted odds ratio, 2.87 [95% CI, 1.27-6.51]; P = .03). reconstruction. In light of this, a team of researchers The most common reasons for not having breast recently conducted a survey to determine if women reconstruction that women reported were are satisfied with their choices concerning reconstruction. Specifically, they set out to The most common the desire to avoid additional surgery (48.5%), fear of implants (33.8%), and the “examine correlates of breast reconstruction patient-reported belief that reconstruction was not important after mastectomy and to determine if a reasons for not (36.3%). Reasons for avoiding reconstruction significant unmet need for reconstruction having breast exists.” reconstruction were: varied by race, and reported barriers to reconstruction were more common among The research team included specialists % nonwhite respondents. Residual demand in radiation oncology, plastic surgery, breast desire to avoid for reconstruction at 4 years was low, with surgery, public health, preventative medicine, additional surgery only 30 of 263 patients who did not undergo and general medicine. reconstruction still considering the procedure. The team sent a survey to a sample of % The resea rchers concluded t hat 3252 women aged 20 to 79 years diagnosed fear of implants reconstruction rates largely reflect patient as having ductal carcinoma in situ or stages demand and that most patients are satisfied I to III invasive breast cancer. Black and % with the decision-making process about Latina women were oversampled to ensure belief that it is not reconstruction. They recommended developing adequate representation of minorities. Of important specific approaches to address lingering the women who received the initial survey patient-level and system factors with a negative effect a median of 9 months after diagnosis, 2290 completed on reconstruction among minority women. it. Those who remained disease-free were surveyed 4 The study was published online by JAMA Surgery on years later; 1536 completed the follow-up survey. Four August 20. hundred and eighty-five women who remained disease free at follow-up underwent analysis. Of the 485 patients who reported on the initial survey morrow m, li Y, alderman aK, et al. access to breast reconstruction after that they had undergone mastectomy and remained disease mastectomy and patient perspectives on reconstruction decision making. Jama surg. 2014 aug 20. doi: 10.1001/jamasurg.2014.548. [epub ahead of print] free, 24.8% underwent immediate reconstruction and M 48.5 33.8 36.3 10 magenta cyan yellow black contemporaryobgyn.net september 2014 ES496117_obgyn0914_010.pgs 08.30.2014 01:03 ADV Women’s HealtH Update ICD-10 traInIng Complications of pregnancy A s phys ic i a n s a nd c o de r s transition to the International Classification of Diseases—10th Revision—Clinical Management (ICD-10-CM), several coding and documentation issues related to complications of pregnancy need to be addressed. Codes for reporting complications of pregnancy, childbirth, and the puerperium are in chapter 15 of ICD10-CM and begin with the letter O. Including the trimester in which the condition occurs, and seventh digits to identify the fetus affected (when necessary) are the main structural changes. The episode-ofcare designations used in ICD-9-CM are no longer an axis of classification in ICD-10-CM. For complications of pregnancy, the trimester during which the compl icat ion occu rs is pa r t of the code selection in ICD-10-CM. The number of weeks of gestation determines the code selection. ICD10-CM has no fifth-digit classification for episode of care. The trimester is included as part of the complete code description. Chapter-level instructions note that an additional code from category Z3A, “Weeks of gestation,” should be assigned to identify the specific week of the pregnancy, and is used only on the maternal record. Fo r s o m e c o m p l i c a t i o n o f pregnancy codes, seventh character extensions are required to complete a valid, reportable code. These seventh character extensions identify the fetus affected. The seventh character ‘0’ is for single gestations and multiple gestations in which the fetus affected is unspecified. The seventh characters 1 to 9 are for cases of multiple gestations to identify the fetus to which the code applies. Further coding instructions may also require that a code from category O30, “Multiple gestation,” be assigned when reporting a code with a seventh character. The 2 classification systems for reporting diabetes mellitus (DM) in pregnancy have been greatly expanded in ICD-10-CM. For complications of pregnancy, the trimester during which the complication occurs is part of the code selection in ICD-10-CM. In ICD-9-CM DM complicating pre g n a nc y, ch i ldbi r t h, or t he p ue r p e r iu m i s r e p or te d w it h 648.0x, and gestational diabetes is reported with 648.8x, “Abnormal glucose tolerance.” Each requires a fifth digit of 0-4 for the episode of care. ‘DM in pregnancy, childbirth, and the puerperium,’ category O24, has 6 subcategories, each with further subclassified codes for valid reporting. The subcategories are “Pre-existing DM, type 1;” “Preexisting DM, type 2;” “Unspecified pre-ex isting DM;” “Gestational DM;” “Other pre-existing DM;” and “Unspecified DM.” Each subcategories provides codes specifying the trimester of pregnancy, in childbirth, and in the puerperium. Both systems require the use of additional codes to further specify the manifestations. “Unspecified pre-existing DM” (O24.3-) is reported when the patient had diabetes before pregnancy. However, the type is not specified. Any additional diabetes codes reported from the endocrine chapter used to further identify the particular manifestations must be selected from category E11 for type 2 as the default. “Unspecified DM” (O24.9-) is reported when it is not known whether the diabetes arose during pregnancy or before. “Other pre-existing DM” (O24.8-) is used when the patient had DM due to another underlying condition, such as Cushing’s syndrome; drugor chemical-induced DM; DM due to genetic disorders/defects; or other secondary (post-procedural) DM prior to pregnancy. Additional codes reported with O24.8- for the particular diabetic manifestations must be selected from the category in the endocrine chapter that reflects the appropriate type of other (pre-existing) diabetes. These will be from category E08, E09 or E13. In both classification systems, a code for long-term (current) use of insulin is also provided. Gestational diabetes codes in ICD-10-CM have a slightly different structure than that of the pre-existing or unspecified DM in pregnancy codes. Gestat iona l d iabetes is subdivided into codes that specify whether it is diet-controlled, insulincontrolled, or unspecified control in pregnancy. september 2014 contemporary ob/gyn magenta cyan yellow black 11 ES496116_obgyn0914_011.pgs 08.30.2014 01:03 ADV A NOVEL TREATMENT WITH AN ALTERNATIVE TO A PROGESTIN FOR YOUR POSTMENOPAUSAL PATIENTS WITH A UTERUS1 Help her put moderate to severe hot flashes as well as bone loss in their place2 The first and only treatment of its kind1 DUAVEE combines conjugated estrogens (CEs) with the SERM* bazedoxifene (BZA): • CEs provide significant relief of moderate to severe hot flashes due to menopause and prevent postmenopausal osteoporosis2 • BZA helps protect the uterine lining from endometrial hyperplasia associated with estrogen-alone treatment2 Purposeful pairing of with the SERM CONJUGATED ESTROGENS BAZEDOXIFENE instead of a progestin IMPORTANT SAFETY INFORMATION Women taking DUAVEE should not take progestins, additional estrogens, or additional estrogen agonists/antagonists. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. DUAVEE contains bazedoxifene, an estrogen agonist/antagonist that reduces the risk of endometrial hyperplasia that can occur with estrogens and which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT). Should either of these occur or be suspected, DUAVEE should be discontinued immediately. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older. Estrogen agonists/antagonists, including bazedoxifene, and estrogens individually are known to increase the risk of venous thromboembolism (VTE). magenta cyan yellow black ES496851_OBGYN0914_012_FP.pgs 09.01.2014 18:10 ADV DUAVEE is indicated in women with a uterus for the treatment of moderate to severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis. Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically, as clinically appropriate, to determine if treatment is still necessary. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis, and non-estrogen medication should be carefully considered. DUAVEE should not be used in women with undiagnosed abnormal uterine bleeding; known, suspected, or past history of breast cancer or estrogen-dependent neoplasia; active or past history of venous or arterial thromboembolism; hypersensitivity to estrogens, bazedoxifene, or any ingredients; known hepatic impairment or disease; known thrombophilic disorders. Women who are or may become pregnant and nursing mothers should not use DUAVEE. The use of estrogen alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. The effect of treatment with DUAVEE on the risk of breast and ovarian cancer is unknown. Estrogens increase the risk of gallbladder disease. Discontinue estrogen if loss of vision, severe hypertriglyceridemia, or cholestatic jaundice occurs. Monitor thyroid function in women on thyroid replacement therapy, because estrogen increases thyroid binding globulin (TBG) levels. Adverse reactions more common in the DUAVEE treatment group in four placebo-controlled studies were muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain. Please see brief summary of Full Prescribing Information, including Boxed Warning, on the following pages. *Selective estrogen receptor modulator, also known as an estrogen agonist/antagonist. †Based on eligibility. ‡ Terms and conditions apply. References: 1. Kharode Y, Bodine PVN, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology. 2008;149(12):6084-6091. 2. DUAVEE [package insert]. New York, NY: Pfizer Inc; 2013. ORDER SAMPLES† AND SAVINGS CARDS‡ AT DUAVEEHCP.COM © 2014 Pfizer Inc. magenta cyan yellow black All rights reserved. Printed in USA/July 2014 APC660613-01 ES496850_OBGYN0914_013_FP.pgs 09.01.2014 18:10 ADV BRIEF SUMMARY: This is only a brief summary of prescribing information. For current Full Prescribing Information, please visit www.duaveehcp.com. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, AND PROBABLE DEMENTIA Women taking DUAVEE should not take additional estrogens [see Warnings and Precautions]. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. DUAVEE has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions]. Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions]. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) (0.625 mg)-alone, relative to placebo [see Warnings and Precautions]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. INDICATIONS AND USAGE DUAVEE is indicated in women with a uterus for the treatment of moderate to severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis. Important Limitations of Use Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered. CONTRAINDICATIONS DUAVEE is contraindicated in women with any of the following conditions: • Undiagnosed abnormal uterine bleeding • Known, suspected, or past history of breast cancer • Known or suspected estrogen-dependent neoplasia • Active DVT, pulmonary embolism (PE), or history of these conditions • Active arterial thromboembolic disease (for example, stroke, myocardial infarction) or history of these conditions • Hypersensitivity (for example, anaphylaxis, angioedema) to estrogens, bazedoxifene, or any ingredients • Known hepatic impairment or disease • Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders • Pregnancy, women who may become pregnant, and nursing mothers. DUAVEE may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus WARNINGS AND PRECAUTIONS Drugs Containing Progestins, Estrogens or Estrogen Agonist/Antagonists DUAVEE contains CE and bazedoxifene, an estrogen agonist/antagonist. Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists. Cardiovascular Disorders Estrogen agonist/antagonists (including bazedoxifene, a component of DUAVEE) and estrogens individually are known to increase the risk of venous thromboembolism (VTE). An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, DUAVEE should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). Should a stroke occur or be suspected, DUAVEE should be discontinued immediately [see Contraindications]. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent myocardial infarction, or CHD death) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years). Venous Thromboembolism (VTE) In the WHI estrogen-alone substudy, the risk of VTE [DVT and PE] was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years. If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization. Malignant Neoplasms Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more of treatment. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. black DUAVEE contains an estrogen agonist/antagonist. This component reduces the risk of endometrial hyperplasia that can occur with the CE component. Endometrial hyperplasia may be a precursor to endometrial cancer. Women taking DUAVEE should not take additional estrogens as this may increase the risk of endometrial hyperplasia. Clinical surveillance of all women taking DUAVEE is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Breast Cancer The most important randomized clinical study providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80). The use of estrogen-alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. The effect of treatment with DUAVEE on the risk of breast cancer is unknown. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Ovarian Cancer In some epidemiological studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. The effect of treatment with DUAVEE on the risk of ovarian cancer is unknown. Probable Dementia In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years [see Use in Specific Populations]. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, DUAVEE should be permanently discontinued. Elevated Blood Pressure In a small number of case reports in women receiving estrogens, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical study, a generalized effect of estrogens on blood pressure was not seen. Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, treatment with estrogens may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of DUAVEE if pancreatitis occurs. Hepatic Impairment and Past History of Cholestatic Jaundice DUAVEE has not been studied in women with impaired liver function or past history of cholestatic jaundice. Estrogens may be poorly metabolized in women with impaired liver function. On average, women with hepatic impairment treated with bazedoxifene alone showed a 4.3-fold increase in overall exposures compared with controls [see Use in Specific Populations]. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised; and in the case of recurrence, DUAVEE should be discontinued. Use of DUAVEE in patients with hepatic impairment is contraindicated [see Contraindications]. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Fluid Retention Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as cardiac dysfunction or renal impairment, warrant careful observation when estrogens are prescribed. Use of DUAVEE in patients with renal impairment is not recommended [see Use in Specific Populations]. Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Exacerbation of Other Conditions Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Premenopausal Women There is no indication for premenopausal use of DUAVEE. The efficacy and safety of DUAVEE in premenopausal women have not been established, and its use is not recommended. Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms. Drug-Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance. ES496827_OBGYN0914_014.pgs 09.01.2014 18:09 ADV ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiovascular Disorders [see Warnings and Precautions] • Malignant Neoplasms [see Warnings and Precautions] • Gallbladder Disease [see Warnings and Precautions] • Hypertriglyceridemia [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of CE/bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6,210 postmenopausal women age 40 to 75 years (mean age 55 years). A total of 1,224 patients were treated with DUAVEE and 1,069 patients received placebo. Women enrolled in Studies 1 and 2 received calcium (600-1200 mg) and vitamin D (200-400 IU) daily, while women in Studies 3 and 4 received no calcium and vitamin D supplementation as part of the protocol. The incidence of all-cause mortality was 0.0% in the DUAVEE group and 0.2% in the placebo group. The incidence of serious adverse reactions was 3.5% in the DUAVEE group and 4.8% in the placebo group. The percentage of patients who withdrew from treatment due to adverse reactions was 7.5% in the DUAVEE group and 10.0% in the placebo group. The most common adverse reactions leading to discontinuation were hot flush, abdominal pain upper, and nausea. The most commonly observed adverse reactions (incidence ≥ 5%) more frequently reported in women treated with DUAVEE than placebo are summarized in the following table. ADVERSE REACTIONS (INCIDENCE ≥ 5%) MORE COMMON IN THE DUAVEE TREATMENT GROUP IN PLACEBO-CONTROLLED TRIALS DUAVEE (N=1224) Placebo (N=1069) n (%) n (%) Gastrointestinal disorders Nausea 100 (8) 58 (5) Diarrhea 96 (8) 57 (5) Dyspepsia 84 (7) 59 (6) Abdominal pain upper 81 (7) 58 (5) Musculoskeletal and connective tissue disorders Muscle spasms 110 (9) 63 (6) Neck pain 62 (5) 46 (4) Nervous system disorders Dizziness 65 (5) 37 (3) Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 80 (7) 61 (6) Venous thromboembolism : In the clinical studies with DUAVEE, the reporting rates for venous thromboembolism (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis) were low in all treatment groups. Adverse reactions of venous thromboembolism were reported in 0.0% of patients treated with DUAVEE and 0.1% of patients treated with placebo. Due to the low rate of events in both groups, it is not possible to conclude that the risk of venous thromboembolism with DUAVEE is different from that seen with other estrogen therapies [see Warnings and Precautions]. DRUG INTERACTIONS No drug interaction studies were conducted with DUAVEE. Results from in vitro and in vivo studies and clinical studies conducted with the CE or bazedoxifene components of DUAVEE are noted below: Cytochrome P450 (CYP) In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s Wort (Hypericum perforatum ) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase the exposure of CE resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors (>30 days) concurrently administered with DUAVEE, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Bazedoxifene undergoes little or no cytochrome P450 (CYP)-mediated metabolism. Bazedoxifene does not induce or inhibit the activities of major CYP isoenzymes. In vitro data suggest that bazedoxifene is unlikely to interact with co-administered drugs via CYP-mediated metabolism. Uridine Diphosphate Glucuronosyltransferase (UGT) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampin, phenobarbital, carbamazepine, and phenytoin. A reduction in bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Atorvastatin Concomitant administration of bazedoxifene (40 mg daily) and atorvastatin (20 mg, single-dose) to healthy postmenopausal women did not affect the pharmacokinetics of bazedoxifene, atorvastatin or its active metabolites. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category X [see Contraindications] DUAVEE must not be used in women who are or may become pregnant. No studies were performed on animals to evaluate the effects on reproduction with CE/bazedoxifene. Administration of bazedoxifene to rats at maternally toxic dosages ≥ 1 mg/kg/day (≥ 0.3 times the human area under the curve (AUC) at the 20 mg dose) resulted in reduced numbers of live fetuses and/or reductions in fetal body weights. No fetal developmental anomalies were observed. In studies conducted with pregnant rabbits treated with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of ≥ 0.5 mg/kg/day (2 times the human AUC at the 20 mg dose). Nursing Mothers DUAVEE should not be used by lactating women [see Contraindications]. It is not known whether this drug is excreted in human milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving CE. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. © 2014 Pfizer Inc. black All rights reserved. Pediatric Use DUAVEE is not indicated for use in children [see Indications and Usage]. Geriatric Use DUAVEE is not recommended for use in women greater than 75 years of age. Of the total number of women in phase 3 clinical studies who received DUAVEE, 4.60% (n=224) were 65 years and over. DUAVEE was not studied in women aged 75 and over. No overall differences in safety or effectiveness were observed between women 65-74 years of age and younger women, and other reported clinical experience has not identified differences in responses between the elderly and younger women, but greater sensitivity of some older women cannot be ruled out. An increased risk of probable dementia in women over 65 years of age was reported in the WHIMS ancillary studies of the WHI using daily CE (0.625 mg). Renal Impairment DUAVEE is not recommended for use in patients with renal impairment. The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with renal impairment. Hepatic Impairment DUAVEE is contraindicated in patients with hepatic impairment [see Contraindications]. The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with hepatic impairment. In a pharmacokinetics study of bazedoxifene 20 mg alone, the Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, in women with mild hepatic impairment (Child Pugh Class A), compared to healthy women. The Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, in women with moderate hepatic impairment (Child Pugh Class B). The Cmax and AUC of bazedoxifene increased 20% and 268%, respectively, in women with severe hepatic impairment (Child Pugh Class C). No pharmacokinetic studies with CE were conducted in women with hepatic impairment. Use in Women with Body Mass Index (BMI) > 27 kg/m2 A 17% reduction in bazedoxifene exposure was predicted in women with BMI > 27 kg/m2 (N=144) compared to those with BMI ≤ 27 kg/m2 (N=93) after administration of DUAVEE, based on a population pharmacokinetic model using data from four Phase 1 studies. A reduction in bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia. Regardless of BMI, adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Venous Thromboembolic Events Advise patients to immediately report to their physician any signs or symptoms related to venous thrombosis and thromboembolic events [see Warnings and Precautions]. Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions]. Possible Serious Adverse Reactions with Estrogen Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions]. Possible Less Serious Adverse Reactions with DUAVEE Inform postmenopausal women of possible less serious but common adverse reactions of DUAVEE therapy such as muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, throat pain, dizziness and neck pain. Calcium and Vitamin D Intake Advise patients to add supplemental calcium and/or vitamin D to the diet if daily intake is inadequate. This brief summary is based on the DUAVEE full prescribing information LAB-0582-1.0, October 2013. Printed in USA/July 2014 APC660613-02 ES496830_OBGYN0914_015.pgs 09.01.2014 18:09 ADV LETTERS TO THE EDITOR EDITORIAL READERS’ RESPONSES TO Dr. Charles J. Lockwood’s August 2014 editorial thAnk you, thAnk you, thAnk you. At last someone has the courage and the intelligence to speak out against the idea that most of what we ob/gyns have always done for our patients is now irrelevant or even harmful [‘Whither the bimanual examination?’ August 2014 Contemporary OB/GYN]. You don’t need me to tell you about all the asymptomatic breast masses and pelvic masses I have discovered in 35 years of practice. I thought that it could go no farther, after debasing the value of the annual Pap, but at least that had a bit of validity with HPV cotesting. Hopefully, our patients will raise their voices when we are told not to order annual mammograms or recommend DEXAs or colonoscopies. It had better be the patients who raise those voices, since the majority of my colleagues just go along like sheep in accepting so-called guidelines. This is also not to mention the lack of support we get from our so-called representative organizations. Joseph s. Ferroni, MD Via email I AgrEE WIth your PoInts and in addition I would like to add 16 magenta cyan yellow black ContEMPorAryoBgyn.nEt the 3 cases of vaginal melanoma that I’ve found over the years on “routine” pelvic exams. I also think that the unique intimate nature of the exam and the trusted doctorpatient relationship that develops because of those yearly visits with “the laying on of hands” leads to discussions that would otherwise go unspoken about all sorts of topics like physical abuse, sexual function and dysfunction, and rectal issues that have translated into appropriate referrals and treatment. Dr. Dave Posted on ContemporaryoBGYN.net Dr. loCkWooD’s DIsCussIon Is rEAsonABlE, if not scientifically grounded, based on the current literature until adding “free” ultrasound to the annual visit. One of the foci of the ACP position is the amount of benign “disease” we find that is not clinically relevant to the patient’s long-term well being but elicits worry, increased medical workup, and often unwarranted surgical exploration. The increased risk to the asymptomatic patient cannot be ignored. And the specious argument that this service BY cHa rLeS J. LocK Woo D, mD, mHc m Whither the bimanual exam ination? the abs ence of evidence for benefit is no evidence of abs t the same as ence of benefi t. R ecently, Qaseem and colleagues publ ished an to assess the accu Ame rican Colracy, benefits, and lege of Physician harms of scree whose conclusio ning pelvic exam s (ACP) Clinins have robu inacal Guideline tions. They defin st statistical support, advising again ed a pelvic exam this study had pelvic exam inati st as a “combination” none of those elem ons for the detec of speculum and ents. tion of patholog bimanual exam First the autho ical cond ition inati on not including rs focused only s in asymptomatic, cervical canc on ovar ian cancer nonpregnant, er scree ning. and detection adult women.1 of bacteria l vaginosis because those This advisory were the only conditions has generated much about which there commentar y in the blogosphe were sufficient publi re and shed data to draw particularly amon tangential conc g ob/g yns. Man lusions. (Wha women, upon y t is the old line abou hear ing news t the inebr iated repor ts concerning the fellow looking for his ACP guidelines keys under the , will assume these lamp post because that recom mendation is where the light s are valid and that shining?) As such is they no longe r need , the authors failed annual pelvic exams. Moreover, to address the myriad of other some women may assu reaso ns ob/g yns carry me that since out bimanual they no longer need exam For such as for detec this purpose, s, such an exam the authors contion of myomas, , they also will not need ducte evid denc a MEDLINE searc e of pelvic relax to see their gyne h of relevant ation and stres cologist annu articles addressin incontinence, ally. s g these questions signs of endometr published from iosis, chronic pelvic 1946 to 2014. inflammatory Based disease, cervical polyp s, vaginal cysts , etc. this aCP guidelin e will add yet ano ther barrier to our abil ity to provide approp riate preventative car e to our patients. can/will be provided “free” flies in the face of marketplace realities. In the asymptomatic patient, the greatest benefit we could offer would be early detection of ovarian cancer, one that is clearly not supported in the literature. And the role of ultrasound in screening for cancer is similarly rejected in current studies. This may be heresy to those of us in clinical practice, but perhaps we are not employing the “Primum non nocere” principle in our current management. Random, evidence-based studies are needed to clarify how we should proceed in the future. Dr. John P. gallagher Posted on ContemporaryoBGYN.net totAlly AgrEE WIth All your PoInts except that finding certain pathology in asymptomatic patients is unlikely, such as endometriosis. And for internists to not do annual exams may be appropriate since I have yet to meet any who are comfortable or experienced in doing pelvic exams. As to sonography, I use TVS in all symptomatic patients as well as abnormal or questionable findings, especially SEPTEMBER 2014 ES495028_obgyn0914_016.pgs 08.29.2014 02:33 ADV Letters to the editor in obese patients. I recall a study showing we are at best 50/50 in our bimanual exams, so a large study with “routine” TVS would be quite revealing, although I wonder about the consequences of incidental findings. Did someone actually pay these people to do this “research”? The emperor has no clothes on here. Dr. J. E. Mendez Posted on ContemporaryoBGYN.net thAnk you, ACP AnD AnnAls for doing what others have tried to do for decades or centuries and that is to move back in time. Eliminating the gynecologic examination is a step back into the Victorian age or worse, and picking the failure to find early ovarian carcinoma as a reason to avoid pelvic examinations will clearly lead to loss of function and lives when parallel screening for cervical cancer and As Dr. MEnDEz sAys, I, too, AgrEE with all of your points. Thank you for clarifying an issue that these internists have certainly done a great job of obfuscating. Maybe we should do a MEDLINE analysis to demonstrate that stethoscopes are useless instruments, too? Dr. stephen Waszak Posted on ContemporaryoBGYN.net STDs is discontinued. By curtailing female pelvic examinations there will be some short-term financial and time saving for which society will pay dearly when missed diseases bloom and grow. Should we stop examining the heart and lungs because there are no symptoms? Eliminating the pelvic examination will [lead to] eliminating medical care and physicians, since much of what doctors do is not clearly in response to an identified illness. Thank you, ACP and Annals, for alerting us to a new direction. What is your next target? Reading and writing? Potable water? Garbage disposal? Dr. robert Wallach Via email Do you want more information about the use of medications and vaccines during pregnancy? MotherToBaby studies conducted by the Organization of Teratology Information Specialists (OTIS) may help provide more answers. The purpose of our research studies is to prospectively evaluate the risks to the fetus from various conditions and the medications used to treat them during pregnancy, including: UÊ ÃÌ > UÊ ÕÌ ÕiÊ`Ãi>ÃiÃÊÃÕVÊ>ÃÊ À ½ÃÊ`Ãi>Ãi]Ê multiple sclerosis, psoriasis, and rheumatoid arthritis UÊ 6>VViÃÊ>`Ê>ÌÛÀ>Ê i`V>Ì Ã For more information about medication and/or vaccine use in pregnancy, or to refer a patient to one of our studies, call toll-free (877) 311-8972 or visit PregnancyStudies.org `ÕVÌi`ÊÞÊ/iÊ"À}>â>Ì Ê vÊ/iÀ>Ì }ÞÊv À >Ì Ê-«iV>ÃÌÃÊ"/-® magenta cyan yellow black ES495027_obgyn0914_017.pgs 08.29.2014 02:32 ADV ONLINE TRENDING NOW The top ob/gyn clinical and practice management resources from ContemporaryOBGYN.net Vaginal itching, discharge, and odor are among the most common complaints in gynecologic and primary care offices. Tailoring treatment to the correct disease process is paramount when managing patients with recurrent vulvovaginal symptoms. YOUR GUIDE TO WHAT’S HAPPENING ONLINE AT CONTEMPORARYOBGYN.NET on facebook See news, make your opinion known, and read what your colleagues are saying. Expert Advice for Today’s Ob/Gyn Contemporary OB/GYN August 16 Joshua A. Copel, MD, starts the 2nd annual GOHO Ultrasound Course for OB/GYN Residents with humor. Like our Facebook page and follow us on Twitter (@contempobgyn) as we provide updates on the class all weekend. (Photo courtesy of Kim Abruz.) Recurrent vulvovaginitis Tips for treating a common condition Contemporaryobgyn.net/recurrent-vulvovaginitis Twitter / KimAbruz: .@ ContempOBGYN @jacopel starts ... A few recent tweets and retweets from and about ContempOBGYN Expert Advice for Today’s Ob/Gyn CMQCC @cmqcc @ContempOBGYN Infographic: #pregnancy complications increase lifetime risk for #heartdisease #pregnancyheart http://ow.ly/zFFHR Doctor Gale @DoctorGale RT @yafshar “Disparities & inequalities in #healthcare a great #infographic @ContempOBGYN pic.twitter.com/iJS8excAQH” Mark Reid, MD @medicalaxioms @yafshar @ContempOBGYN Well done! Inspiring is what we do best. :) digital app Center for Fetal Med @Ctr4FetalMed RT @ContempOBGYN: Fabulous faculty working hard #goho @MountSinaiNYC http:// ow.ly/3opQTH. Rosemary Theroux, NP @rosenp2 Recurrent vulvovaginitis: Tips for treating a common condition http://shar.es/1nsqtb via @ContempOBGYN OB/GYN app for iPad and iPhone. Download it for free today at Part of the magenta cyan yellow black Now in our August issue, a 60-second synopsis of a new study about labor induction with commentary from Editorial Board member Dr. Haywood Brown. A conservative oxytocin labor protocol: Is less best? In a study performed at Duke University Hospital in Durham, North Carolina, a more conservative oxytocin protocol led to lower oxytocin maximal dosing and lower NICU admission rates... Follow us on Twitter Introducing the Contemporary www.ContemporaryOBGYN.net/ContemporaryOBGYNapp 18 Contemporary OB/GYN August 6 CONTEMPORARYOBGYN.NET twitter.com/ContempOB GYN Like us on Facebook facebook.com/ContempOBGYN Contemporary OB/GYN is part of the ModernMedicine Network, a Web-based portal for health professionals offering best-in-class content and tools in a rewarding and easy-to-use environment for knowledge-sharing among members of our community. ILLUSTRATION BY ALEX BAKER, DNA ILLUSTRATIONS, INC. on twitter SEPTEMBER 2014 ES495345_obgyn0914_018.pgs 08.29.2014 03:13 ADV With Proper Cephalad Pressure, the Uterosacral Ligaments Are Preserved Koh-Efficient Helps to Create a “Margin of Safety” by Displacing the Ureters during Colpotomy Incision Safeguarding the Ureters Is Vital ...During TLH, the Koh-Efficient Helps Distance Critical Anatomy from the Colpotomy Incision The Koh-Efficient system is available for the Advincula Arch handle or the articulating RUMI II handle design. Protecting the ureters can be a considerable concern when performing a total laparoscopic hysterectomy (TLH). The advanced Koh-Efficient™ is designed to fit snugly around the cervix and place the vaginal fornix on stretch under appropriate cephalad pressure. This delineation provides a visual landmark and backstop for distancing the colpotomy incision from the ureters and uterosacral ligaments, creating a “margin of safety” that helps protect vital anatomical structures. To experience Dr. Arnold P. Advincula’s approach to “margin of safety” during TLH, visit YouTube.com/CooperSurgical. To learn more, call 800.243.2974 or 203.601.5200 or visit www.coopersurgical.com. Arnold P. Advincula, MD, FACOG, FACS Professor & Vice-Chair of Women’s Health Chief of Gynecology, Sloane Hospital for Women Columbia University Medical Center New York-Presbyterian Hospital magenta cyan yellow black ©2014 CooperSurgical, Inc. 82465 Rev. 8/14 ES496834_OBGYN0914_019_FP.pgs 09.01.2014 18:10 ADV LEGALLY SPEAKING rISK management In obStetrIcS anD gynecoLogy bY anDreW I KapLan, eSQ Did this ob/gyn fail to timely diagnose uterine sarcoma? Facts on JUne 4, 2008, a 40-year-oLD WHIte g0 presented to the defen- dant ob/gyn with complaints of hair loss, weight gain, and premenstrual dysphoric disorder (PMDD). She reported that her Pap smears were always normal (her most recent one had been in March 2008), but that she had tested positive for human papillomavirus (HPV) in April 2007. More recently, she had amenorrhea for 3 months at the beginning of the year and her follicle stimulating hormone (FSH) levels were consistent with menopause. During this visit, an ultrasound (U/S) revealed a uterine fibroid measuring 6 x 8 cm, which the ob/gyn felt was possibly related to her Hashimoto’s disease. Because the patient had no symptoms related to the fibroid, the ob/gyn did not initiate estrogen therapy. The patient was directed to return to the office in 6 months. However, she called the office on June 24 and reported that she was having more hair loss and was interested in a hysterectomy and hormone therapy. The patient called the ob/gyn again on July 2 and reported that her last menstrual period was on May 31. She also reported moodiness and worsening depression. The doctor prescribed estradiol and Prometrium. The patient was seen in the ob/gyn’s office on December 17 and reported that her hair loss was still a problem. 20 magenta cyan yellow black contemporaryobgyn.net The doctor performed another U/S, which showed that the fibroid was stable and measured 6.2 x 7.6 cm. The patient was next seen by the ob/gyn on March 22, 2010. The doctor documented that she had a long conversation with the patient about feeling unhappy on low-dose estrogen therapy. An U/S performed by the doctor revealed that the fibroid measured 9.0 x 7.0 cm. The patient’s preference for not getting another U/S at an outside facility was also documented. A Pap smear showed no intraepithelial lesion or malignancy. The ob/gyn increased the estrogen dose. an ultrasound revealed a uterine fibroid measuring 6 x 8 cm. When the patient returned to the doctor on August 16, she reported firmness on her left side and frequent urination. U/S showed the fibroid was “significantly larger,” measuring 10.6 x 9.6 cm. The doctor encouraged her to have a laparoscopically assisted vaginal hysterectomy (LAVH) and removal of the cervix. She also advised her to have a bilateral salpingo-oopherectomy (BSO). The patient was to come back in 3 to 6 weeks to dis- cuss surgical options. The patient did not return to the doctor’s office until February 9, 2011. An U/S performed at that visit showed fluid in the uterus and that the fibroid was the same size as in August 2010. The doctor ordered another pelvic U/S, which showed a large central myoma of 8.2 x 6.7 x 6.8 cm and a fluid collection of 3.2 x 4.9 x 1.3 cm (~10 mL). The doctor noted that the patient needed to undergo a dilation, endometrial biopsy, and fluid drainage. The patient was now thinking of undergoing the LAVH and was directed to return to the ob/gyn’s office in ≤ 6 months. But about 3 weeks later, she presented to the hospital emergency department with complaints of right flank pain and lower back pain. A computed tomography (CT) scan of the abdomen and pelvis performed on April 1 showed “few” very large uterine masses, the largest in the left anterior uterine body measuring 15.4 x 9.7 x 10.5 cm. Another mass on the right posterior uterine body was 8.9 x 8.3 x 6.4 cm. The impression was that these masses could represent hyaline degenerating-type fibroids. It was suggested that magnetic resonance imaging (MRI) be obtained. An endovaginal U/S performed the same day showed a large posterior body fibroid of 9.8 x 10.2 x 10.3 cm. On April 20, the patient underwent an MRI out of state. It was highly September 2014 ES495971_obgyn0914_020.pgs 08.29.2014 22:23 ADV CERVICAL CANCER SCREENING Change the conversation The Aptima® HPV test makes it easier. Detecting HPV DNA identifies the presence of a high-risk HPV infection. HPV is a common transient infection and very few infections will lead to cervical cancer. Looking for the presence of high-risk HPV DNA can lead to unnecessary difficult patient conversations. The Aptima HPV test targets high-risk HPV mRNA. Studies have shown HPV mRNA identifies the presence and activity of a high-risk HPV infection.1 The Aptima HPV test has shown: • Excellent sensitivity — demonstrating equivalent sensitivity to DNA-based HPV tests in multiple clinical studies involving over 50,000 women worldwide2 • Improved specificity to DNA-based HPV tests — reducing false-positives by 24% in the clinical trial3 The combination of excellent sensitivity and improved specificity with the Aptima HPV test may help change patient conversations and may minimize the potential for over-treatment. Interested in learning more about mRNA and the Aptima HPV test difference? Contact us. Brought to you by Hologic, a leader in women’s health. ® Aptima HPV Test | ThinPrep® Pap Test | NovaSure® Endometrial Ablation System MyoSure® Tissue Removal System | Selenia® Dimensions® 3D Mammography References: 1. Liverani CA, et al. Am J Transl Res 2012; 4(4): 452-457 2. References available at www.gen-probe.com 3. Aptima® HPV Assay package insert #503789 Rev A 2013,Table 13 ADS-00869 ©2013 Hologic, Inc. All rights reserved. Hologic, Aptima, MyoSure, NovaSure, Selenia and ThinPrep and associated logos are trademarks or registered trademarks of Hologic, Inc. and/or its subsidiaries in the United States and/or other countries. For specific information on what products are available for sale in a particular country, please contact your local Hologic representative or email [email protected]. magenta cyan yellow black Specializing in extraordinary ES496831_OBGYN0914_021_FP.pgs 09.01.2014 18:10 ADV LegaLLy Speaking suggestive of malignant degeneration of a fibroid in the right uterine body/lower uterine segment. There was no direct regional invasion of pelvic ascites such as would be expected with a leiomyosarcoma. How- mal cell differentiation and lymph node metastasis. The patient underwent a positron emission tomography scan on May 11, which revealed expected postoperative physiologic changes and no She testified that the plaintiff’s clinical picture was consistent with a growing fibroid and not suspicious for cancer. ever, metastatic lymphadenopathy was visualized in the pelvis, along with cystic/hemorrhagic degeneration of a fundal intramural fibroid and blood products of varying ages in the nondilated endometrium with probable internal debris. The patient was referred to a gynecologic oncologist to discuss surgical options. The last note in the ob/ gyn’s office chart is a summary of a phone conversation with the patient. The doctor documented that the patient was seen out of state and that an MRI showed a second fibroid that was suspicious for sarcoma. The plan was for the patient to see an oncologist and possibly undergo a total abdominal hysterectomy (TAH). On May 2, the patient underwent an exploratory laparotomy, TAH with BSO and right pelvic node dissection, and right peri-aortic lymph node dissection at an outside hospital. The pathology report noted: “High-grade poorly differentiated malignant tumor associated with fibroadipose tissue in the lymph nodes; uterus with highgrade poorly differentiated malignant tumor, 15.5 cm, associated with marked lymphovascular space invasion, tumor necrosis.” The final diagnosis was high-grade poorly differentiated uterine sarcoma with mixed smooth muscle and endometrial stro22 magenta cyan yellow black contemporaryobgyn.net additional disease. She began chemotherapy and underwent radiation therapy until September 19. Chemotherapy was restarted on November 3 and ended December 20, 2011. Allegations The plaintiff alleged that the ob/gyn negligently attributed the plaintiff’s complaints to a fibroid and failed to suspect and timely diagnose cancer. It was alleged that the doctor failed to follow, monitor, and measure the size of the fibroid. It was alleged that there was a failure to make the proper referrals and consultations and a failure to order an MRI. It was also claimed that the ob/ gyn negligently interpreted the various U/S that were performed while the patient was under her care and failed to advise the plaintiff of surgical options. The alleged injuries were: Stage III C2 uterine sarcoma; tumor measuring 15.5 x 9.2 x 7.8 cm with marked lymphovascular space invasion and tumor necrosis; positive lymph nodes; lobectomy revealing metastatic highgrade sarcoma with necrosis and lymphovascular invasion in the right lung; TAH; BSO; peri-aortic and retroperitoneal lymph node dissection; chemotherapy; radiation; alopecia; anxiety; headaches; weakness; dizziness; weight loss; fatigue; bloating; nausea/ vomiting; pelvic discomfort; loss of enjoyment of life; and lost earnings. Trial At trial, the defendant ob/gyn testified that she had never considered that the plaintiff had a uterine sarcoma at any time that she was treating her up to and including the office visit of August 16, 2010. She confirmed that she never visualized (on U/S) 2 masses in the plaintiff’s uterus or suspected she had 2 masses in the uterus during that period. The plaintiff’s counsel established that the fibroid size was stable when the plaintiff began hormone therapy. He then established that the fibroid was noted to grow significantly from March 2010 to August 2010, although the patient had been on a relatively lower dose of hormone therapy. (His strategy was to establish that the growth of the fibroid could not be attributed to the hormone therapy and therefore should have been suspicious.) He also argued that the growth was “significant” enough to warrant further testing, including CT or MRI. The ob/gyn testified that the plaintiff was perimenopausal, so she was still making estrogen. Therefore, the fibroid growth was not suspicious. She testified that the plaintiff’s clinical picture was consistent with a growing fibroid and not suspicious for cancer. The plaintiff’s obstetrical expert testified that the fibroid growth was significant. He testified to a “rule” that when a mass such as this grows by 1 cm in any one direction, or more than .4 cm in 2 directions, the growth should be considered suspicious and testing is warranted. He testified that the growth was significant here in light of the fact that the patient was postmenopausal and not making any estrogen. In his opinion, the hormone September 2014 ES495969_obgyn0914_022.pgs 08.29.2014 22:23 ADV LegaLLy Speaking therapy was not responsible for the fibroid growth, because the patient had been on a higher dose previously with no corresponding growth. In his opinion, the ob/gyn departed from accepted medical practice by failing to consider that the fibroid growth was suspicious for cancer and by failing to order additional testing, including CT or MRI. On cross examination, the plaintiff’s expert agreed that uterine sarcomas are extremely rare and difficult to diagnose. Most importantly, he conceded that the fibroid growth was not caused by the uterine sarcoma, assuming that it was present in March and August 2010. The plaintiff’s radiology expert conceded during direct examination that a uterine sarcoma cannot be distinguished from a fibroid on any type of imaging study, including U/S, CT, and MRI. He testified that the only way the diagnosis can be confirmed is by pathology after a hysterectomy. On cross examination he agreed that the uterine sarcoma was suspected by the radiologist who performed the MRI at the outside hospital in April 2011 because enlarged lymph nodes were seen. The radiologist would not have been able to distinguish the fibroid from the sarcoma by merely looking at the 2 masses in the uterus. Rather, the second mass was suspicious for uterine sarcoma because of enlarged lymph nodes. The expert conceded that unless enlarged lymph nodes were present and seen on CT or MRI (had either been performed in March or August 2010) nothing on the scans would have been suspicious for sarcoma. The patient testified that when she saw the defendant on March 22, 2010, she complained that her abdomen was swollen. The plaintiff’s experts relied upon this testimony in an attempt to document that the patient’s clinical picture was consistent with an abnormally large, rapidly growing fibroid. On cross-examination, however, the plaintiff testified that she was not certain that she made the same complaint to the defendant in August 2010, and this complaint is not documented for either the March or August visit. The plaintiff admitted that she did not make any complaints to any other physicians she saw during the same period. The plaintiff’s oncology expert utilized a “doubling time” analysis to support his opinion that the uterine sarcoma was both present and detectible in March and August 2010. Using that analysis, he calculated that the tumor would have been at least 1 cm3 (the size a mass must be to be detected on CT or MRI). He also testified that had the diagnosis been made in March or August of 2010, the plaintiff’s cancer would have been Stage I with a 74% chance of 5-year survival. On cross-examination, we pointed out that the measurements of the tumor in the surgical pathology report were incorrect and much larger than the size measured on the MRI performed just 3 weeks earlier. So, if he started with a smaller mass than what he initially calculated, that meant that the tumor might have been smaller than the 1 cm3 he said would have been likely in March or August 2010, and thus may not have been detectable. He further agreed that this type of cancer often spreads in patients who are diagnosed at Stage I, therefore, patients with uterine sarcoma have a poor prognosis at any disease stage. Our radiology expert refuted the “4-mm rule,” which he stated was “ridiculous.” He testified that this particular mass could not be visualized on U/S in March or August 2010 and that imaging studies cannot distinguish a fibroid from a uterine sarcoma. He testified it was not incumbent upon the ob/gyn to investigate the fibroid growth in March and August 2010, as it was not unusual or suspicious for cancer. Our final witness, a gynecologic oncology expert, also refuted the “4 mm rule” and said that there was nothing suspicious about the fibroid growth as documented in March and August 2010. He testified that the patient’s clinical picture fit perfectly with a growing fibroid and was not suspicious for cancer. He also testified that because the patient was perimenopausal and on hormone replacement therapy, it was reasonable to conclude that the fibroid growth was related to the hormone therapy. The “doubling time” theory, he said, was flawed and not based upon accepted science. He pointed out that the plaintiff’s statistics concerning the survival rate for Stage I uterine sarcoma patients were incorrect because they included patients with low-grade sarcomas, which have a much higher cure rate than highgrade sarcomas. The verdict The verdict sheet asked whether it was a departure for the ob/gyn not to have suspected cancer and/ or order further testing on March 22 and August 16, 2010. The jury unanimously answered “no.” A verdict was rendered in favor of the defendant. ANDREW I. KAPLAN, ESQ, is a partner at aaronson, Rappaport, Feinstein & Deutsch, LLp in new york City. This case was successfully tried to verdict by his partner, neil F. Brenes, esq. September 2014 magenta cyan yellow black contemporary ob/gyn 23 ES495970_obgyn0914_023.pgs 08.29.2014 22:23 ADV GRAND ROUNDS Ultrasound triage of postmenopausal bleeding By James m. shwayder, md, Jd Dr. ShwayDer is Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson. He reports receiving royalties from Cook Medical for the Goldstein SonoBiopsy Catheter. E ndometrial cancer is the most common gynecologic cancer in the United States. In 2014, an estimated 52,630 new cases will be diagnosed, with 8590 women dying from cancer of the uterine body, with uterine sarcomas comprising approximately 2% of uterine cancers.1 Approximately 3 out of 4 cases are diagnosed in women aged 55 years and older. Ninety percent of postmenopausal patients with endometrial cancer present with vaginal bleeding.2 Conversely, up to 14% of patients who present with postmenopausal bleeding (PMB)—defined as an episode of bleeding 12 months after the last menstrual period—will have endometrial cancer.3,4 These patients require timely and efficient evaluation. endometrial evaluation Historically, the routine evaluation of PMB was by dilatation and curettage (D&C) performed in an operating environment. Evaluation then progressed to the office, first with the Vabra aspirator (1970s), then the Novak curette (1980s), and ultimately (in the 1990s) the suction-piston biopsy instrument, commonly known as a Pipelle endometrial suction curette. The Pipelle reportedly detected almost 98% of endometrial cancers.5 However, subsequent studies have 24 magenta cyan yellow black contemporaryobgyn.net found that the sensitivity of detecting endometrial cancer with Pipelle endometrial sampling ranges from 83% to 98%.6,7 Two studies highlight the limitations of a blind Pipelle endometrial sample. Rodriguez et al. compared the surface area sampled by a Vabra aspirator and a Pipelle endometrial sampler in 25 patients scheduled for hysterectomy.8 The Vabra aspirator sampled 41.6% of the endometrium, while the Pipelle device sampled only 4.2%. Guido et al. performed Pipelle endometrial sampling prior to hysterectomy in 65 patients with known endometrial cancer.6 Pipelle sampling missed the cancer in 11 of 65, or 17% of patients. The cancer involved less than 50% of the cavity surface in all patients with a missed diagnosis. In 4 patients, less than 25% of the surface area was involved, while less than 5% was involved in 3 patients. Pipelle sampling missed 5 cancers confined to polyps. Since endometrial cancer can be a focal rather than global disease, blind sampling is prone to error. In addition, sampling failure, defined as an inadequate sample or inability to perform a biopsy, can be as high as 54%.9 In patients with tissue insufficient for diagnosis (TIFD) the incidence of significant endometrial disease was 20%, with endometrial cancer found in 3% of patients.10 September 2014 ES495077_obgyn0914_024.pgs 08.29.2014 02:41 ADV ILLUSTRATION By ALEX BAKER, DNA ILLUSTRATIONS, INC. tVs and endometrial thickness Transvaginal sonography (TVS) gained popularity for evaluating PMB in the early 1990s due to its ready office availability and its value in ruling out significant endometrial disease.11,12 Initial studies indicated that an endometrial thickness >5 mm would identify 96% of endometrial cancers.3 Conversely, an endometrial thickness ≤5 mm was associated with a 4% chance of endometrial cancer.3 The negative predictive value of a thin endometrium was quite good. Initial recommendations required no additional evaluation if the endometrium was ≤5 mm in double-layer thickness.2 Subsequent studies evaluated the merit of even thinner thresholds for further evaluation. Gupta et al. determined that the probability of endometrial cancer was reduced the thinner the endometrium on initial evaluation: 5 mm = 2.3%; 4 mm = 1.2%; and 3 mm = 0.4%.13 Timmermans et al. also found that decreasing the threshold endometrial thickness improved cancer detection, with sensitivities of 90% at 5 mm, 95% at 4 mm, and 98% at 3 mm.14 They recommended decreasing the cutoff for excluding endometrial cancer to 3 mm. Clearly, decreasing the thickness that prompts further endometrial evaluation increases the sensitivity but decreases the specificity of TVS. Most studies recognize that a threshold endometrial thickness >4 mm adequately screens for >98% of endometrial cancers.15 acog recommendation In August 2009, American College of Obstetricians and Gynecologists (ACOG) Committee Opinion Number 440 elucidated the role of ultrasound (U/S) in evaluating postmenopausal bleeding.16 This opinion recommends either vaginal U/S or an endometrial biopsy in the initial evaluation of patients with PMB. The presence of a thin, distinct endometrial echo ≤4 mm is associated with a risk of malignancy of 1 in 917. Thus, further endometrial evaluation is not required. An endometrial biopsy is technically possible in 82% of patients with endometrial thickness <5 mm, but a sample adequate for diagnosis is obtained in only 27%.16 U/S is a screening tool used to identify those patients with a low risk of cancer who do not require further evaluation at the initial assessment. If an endometrial biopsy is performed initially and reveals TIFD, it cannot be relied upon to eliminate significant endometrial disease (Figure 1). Patients with TIFD require further evaluation,4 which can be done with TVS. If TVS demonstrates the endometrium is <4 mm, the initial evaluation is complete. If the endometrium is >4 mm, further endometrial evaluation is recommended with saline infusion sonohysterography (SIS) or hysteroscopy. recurrent bleeding after initial evaluation Some clinicians are reluctant to rely on U/S without having a tissue diagnosis. A 2003 report by Gull et al. offers guidance.17 This study evaluated 339 patients with TVS and endometrial sampling 10 years after an initial benign evaluation with TVS and D&C for PMB. None of the patients without bleeding during the 10-year period was found to have endometrial cancer. In contrast, 11.5% of patients with recurrent bleeding were found to have cancer.17 Thus, cancer is highly unlikely if the endometrial thickness on the initial U/S is <4 mm and the patient has no recurrent bleeding. However, recurrent bleeding requires further evaluation with endometrial sampling, at a minimum, preferably in combination with SIS or hysteroscopy. September 2014 magenta cyan yellow black continued on page 31 contemporary ob/gyn 25 ES495075_obgyn0914_025.pgs 08.29.2014 02:41 ADV Lo Loestrin® Fe The only available ultra–low-dose oral contraceptive with just 10 mcg of daily ethinyl estradiol. Its unique 24/2/2 regimen may provide women with short, lighter periods.1,2 FDA draft guidance on labeling states that women taking combined oral contraceptives should take those with the least amount of estrogen and progestin to remain effective and fit the medical needs of the patient.3 Most eligible insured patients PAY NO MORE THAN $25* for Lo Loestrin Fe prescriptions! *This offer is valid only for patients with commercial prescription drug insurance and applies to prescriptions for Lo Loestrin Fe. Most eligible insured patients will pay $25 per 28-day supply for each of up to 12 prescription fills. Other eligible insured patients should check with their pharmacist for their copay discount. Maximum reimbursement limits apply; patient out-of-pocket expense may vary. Please see full terms and conditions at actavisocsavings.com. INDICATION AND USAGE for Lo Loestrin® Fe Lo Loestrin Fe is an estrogen/progestin combination oral contraceptive (COC) indicated for use by women to prevent pregnancy. The efficacy of Lo Loestrin Fe in women with a body mass index (BMI) of >35 kg/m2 has not been evaluated. SELECTED SAFETY INFORMATION about Lo Loestrin Fe, including Boxed Warning WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, Lo Loestrin Fe should not be used by women who are over 35 years of age and smoke. Lo Loestrin Fe is contraindicated in pregnant patients, and those with a high risk of arterial or venous thrombotic diseases, liver tumors (benign or malignant) or liver disease, undiagnosed abnormal uterine bleeding, or breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past. Discontinue Lo Loestrin Fe if a thrombotic event occurs, and at least 4 weeks before and through 2 weeks after major surgery. Lo Loestrin Fe should not be started any earlier than 4 weeks after delivery, in women who are not breastfeeding. If jaundice occurs, treatment should be discontinued. Lo Loestrin Fe should not be prescribed for women with uncontrolled hypertension or hypertension with vascular disease. Women who are pre-diabetic or diabetic, should be monitored while using Lo Loestrin Fe. magenta cyan yellow black ES496806_OBGYN0914_026_FP.pgs 09.01.2014 18:08 ADV O G ! W O Alternate contraceptive methods should be considered for women with uncontrolled dyslipidemia. Patients using Lo Loestrin Fe who have a significant change in headaches or irregular bleeding or amenorrhea should be evaluated. In the clinical trial for Lo Loestrin Fe, serious adverse reactions included deep vein thrombosis, ovarian vein _ 2%) were nausea/vomiting, thrombosis, and cholecystitis. The most common adverse reactions (incidence > headache, bleeding irregularities, dysmenorrhea, weight fluctuation, breast tenderness, acne, abdominal pain, anxiety, and depression. Patients should be counseled that COCs do not protect against HIV infection (AIDS) and other sexually transmitted diseases. To report a Suspected Adverse Reaction from one of our products, please contact Actavis Drug Safety Department at 1-800-272-5525. Please see Brief Summary of Full Prescribing Information for Lo Loestrin Fe, including Boxed Warning, on adjacent pages. Please see Full Prescribing Information for Lo Loestrin Fe, including Boxed Warning, available at www.loloestrin.com. References: 1. Lo Loestrin® Fe prescribing information. Rockaway, NJ: Warner Chilcott (US), LLC; 2012. 2. Data on file. Rockaway, NJ: Warner Chilcott (US), LLC. 3. US Food and Drug Administration. Guidance for industry: labeling for combined oral contraceptives. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm075075.pdf. Published March 2004. Accessed May 21, 2014. Lo Loestrin® is a registered trademark of Warner Chilcott Company, LLC. © 2014 Actavis Pharma, Inc. Parsippany, NJ 07054 magenta cyan yellow black All rights reserved. 10858 6/14 ES496826_OBGYN0914_027_FP.pgs 09.01.2014 18:09 ADV Lo Loestrin® Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) BRIEF SUMMARY: Consult the Package Insert for Complete Prescribing Information WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications (4)]. 1 INDICATIONS AND USAGE Lo Loestrin® Fe is indicated for use by women to prevent pregnancy. The efficacy of Lo Loestrin Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated. 4 CONTRAINDICATIONS Do not prescribe Lo Loestrin Fe to women who are known to have the following conditions: • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)] • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)] • Have cerebrovascular disease [see Warnings and Precautions (5.1)] • Have coronary artery disease [see Warnings and Precautions (5.1)] • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)] • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] • Have uncontrolled hypertension [see Warnings and Precautions (5.4)] • Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)] • Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.7)] • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.2)] • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3)] • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)] • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Thrombotic and Other Vascular Events Stop Lo Loestrin Fe if an arterial or deep venous thrombotic event occurs. Although use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. If feasible, stop Lo Loestrin Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest in older (> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. black Stop Lo Loestrin Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. 5.2 Carcinoma of the Breast and Cervix Women who currently have or have had breast cancer should not use Lo Loestrin Fe because breast cancer is a hormonally-sensitive tumor. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors. 5.3 Liver Disease Discontinue Lo Loestrin Fe if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Lo Loestrin Fe if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Lo Loestrin Fe. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.7 Headache If a woman taking Lo Loestrin Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Lo Loestrin Fe if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.8 Bleeding Irregularities and Amenorrhea Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. The clinical trial that evaluated the efficacy of Lo Loestrin Fe also assessed unscheduled bleeding and/or spotting. The participants in this 12-month clinical trial (N = 1,582 who had at least one post-treatment evaluation) completed over 15,000 cycles of exposure. A total of 1,257 women (85.9 percent) experienced unscheduled bleeding and/or spotting at some time during Cycles 2 to 13 of this study. The incidence of unscheduled bleeding and/or spotting was highest during Cycle 2 (53 percent) and lowest at Cycle 13 (36 percent). Among these women, the mean number of days of unscheduled bleeding and/or spotting during a 28-day cycle ranged from 1.8 to 3.2 days. ES496809_OBGYN0914_028_FP.pgs 09.01.2014 18:08 ADV Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle. Women who are not pregnant and use Lo Loestrin Fe may experience amenorrhea (absence of scheduled and unscheduled bleeding/spotting). In the clinical trial with Lo Loestrin Fe, the incidence of amenorrhea increased from 32 percent in Cycle 1 to 49 percent by Cycle 13. If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was preexistent. 5.9 COC Use Before or During Early Pregnancy Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Lo Loestrin Fe use should be discontinued if pregnancy is confirmed. Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)]. 5.10 Depression Women with a history of depression should be carefully observed and Lo Loestrin Fe discontinued if depression recurs to a serious degree. 5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs. 5.12 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.13 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. 6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and smoking [see Boxed Warning and Warnings and Precautions (5.1)] • Vascular events [see Warnings and Precautions (5.1)] • Liver disease [see Warnings and Precautions (5.3)] Adverse reactions commonly reported by COC users are: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. A multicenter phase 3 clinical trial evaluated the safety and efficacy of Lo Loestrin Fe for pregnancy prevention. The study was a one year, openlabel, single-arm, uncontrolled study. A total of 1,660 women aged 18 to 45 were enrolled and took at least one dose of Lo Loestrin Fe. Common Adverse Reactions (≥ 2 percent of all Treated Subjects): The most common adverse reactions reported by at least 2 percent of the 1,660 women using Lo Loestrin Fe were the following in order of decreasing incidence: nausea/vomiting (7 percent), headache (7 percent), bleeding irregularities (including metrorrhagia, irregular menstruation, menorrhagia, vaginal hemorrhage and dysfunctional uterine bleeding) (5 percent), dysmenorrhea (4 percent), weight fluctuation (4 percent), breast tenderness (4 percent), acne (3 percent), abdominal pain (3 percent), anxiety (2 percent), and depression (2 percent). black Adverse Reactions Leading to Study Discontinuation: 10.7 percent of the women discontinued from the clinical trial due to an adverse reaction. Adverse reactions occurring in ≥ 1 percent of subjects leading to discontinuation of treatment were in decreasing order: menstrual irregularities (including metrorrhagia, irregular menstruation, menorrhagia and vaginal hemorrhage) (4 percent), headache/migraine (1 percent), mood disorder (including mood swings, depression, anxiety) (1 percent), and weight fluctuation (1 percent). Serious Adverse Reactions: deep vein thrombosis, ovarian vein thrombosis, cholecystitis. 7 DRUG INTERACTIONS No drug-drug interaction studies were conducted with Lo Loestrin Fe. 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: • barbiturates • bosentan • carbamazepine • felbamate • griseofulvin • oxcarbazepine • phenytoin • rifampin • St. John’s wort • topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or of non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Increase in Plasma Levels of Ethinyl Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20 percent. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. 7.3 Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (for example, ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. Women who do not breastfeed should not start COCs earlier than 4 weeks postpartum. ES496828_OBGYN0914_029_FP.pgs 09.01.2014 18:09 ADV 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing OCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 10 OVERDOSAGE There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea. 8.4 Pediatric Use Safety and efficacy of Lo Loestrin Fe have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 8.5 Geriatric Use Lo Loestrin Fe has not been studied in postmenopausal women and are not indicated in this population. Manufactured By: Warner Chilcott Company, LLC Fajardo, PR 00738 8.6 Renal Impairment The pharmacokinetics of Lo Loestrin Fe has not been studied in subjects with renal impairment. Distributed By: Actavis Pharma, Inc. Parsippany, NJ 07054 8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of Lo Loestrin Fe. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.3)]. black 8.8 Body Mass Index The safety and efficacy of Lo Loestrin Fe in women with a body mass index (BMI) > 35 kg/m2 has not been evaluated. Based on Lo Loestrin Fe Prescribing information dated 06/2012. © 2014, Actavis Pharma, Inc. All rights reserved. 05/14 ES496808_OBGYN0914_030_FP.pgs 09.01.2014 18:08 ADV GRAND ROUNDS Figure 1 Figure 3 Further evaluation of a patient with tIFd thin endometrium (arrows) surrounds a 2.4 x 1.8 cm intracavitary lesion. hysteroscopy reveals an endometrial carcinoma undetected by blind endometrial sampling. Figure 2 Visualization of eec from the endocervical canal to the fundus eec of 3.8 mm extends from the fundus to the cervix. continued from page 25 technical aspects of measuring the endometrial echo U/S can be performed at any time in postmenopausal patients who are on no hormone therapy or on continuous combined therapy. Patients on cyclical hormonal therapy should have the U/S performed shortly after their bleeding episode. The endometrial thickness, also called the endometrial echo complex (EEC), should be measured only in the sagittal or longitudinal midplane view. To be reliable, the EEC should be visualized from the endocervical canal to the fundus (Figure 2). Many clinicians feel compelled to measure any white, linear area and deem it the endometrial echo. This leads to unreliable results. If the endometrium cannot be seen in its entirety, which occurs in more than 10% of cases,18 the clinician should state that the endometrium is “not well visualized” or “indistinct” and recommend further evaluation, such as SIS or hysteroscopy. When the EEC is adequately visualized, both layers of the endometrium should be measured together to arrive at the endometrial thickness. When identifying fluid within the endometrial cavity, each layer of endometrium should be measured separately and added together for the total endometrial thickness (Figure 3). Early reports about fluid within the endometrium raised concerns for cancer of the ovary, fallopian tube, cervix, or endometrium.19 More recent reports indicate that most patients (84%) have atrophic endometrium, with the fluid collection likely due to some degree of cervical stenosis.20,21 doppler at the time of tVs Color flow and power Doppler imaging enhances the ability to diagnose endometrial polyps. The presence of a central vessel in the EEC is endometrium measuring 0.7 mm + 0.7 mm = 1.4 mm thick was found to be atrophic. highly predictive of an endometrial polyp (Figure 4). Amit et al. studied 60 women with PMB and found that power Doppler had a sensitivity of 86% and a specificity of 89% in detecting endometrial polyps.22 SIS can confirm this finding and help plan for surgical removal. advantages of U/sbased triage cost Two studies, one in the Netherlands and one in the United States, determined that U/S-based evaluation was less costly than initial evaluation with an endometrial biopsy.23,24 Dijkhuizen et al. concluded that a strategy starting with endometrial biopsy was most cost-effective when the prevalence of endometrial cancer was >15.3%.23 TVS combined with biopsy was the most cost-effective strategy in cases in which the endometrial thickness was >9 mm. Weber et al. also concluded that vaginal U/S was more cost-effective than endometrial biopsy as the initial diagnostic test.24 This was based on a $72 cost for TVS and a cost for endometrial biopsy, including processing and interpretation, of $200. Using TVS resulted in a cost savings of $14 to $20 per patient. This analysis was based September 2014 magenta cyan yellow black Fluid in the endometrial cavity due to cervical stenosis contemporary ob/gyn 31 ES495079_obgyn0914_031.pgs 08.29.2014 02:41 ADV GRAND ROUNDS Figure 4 central vessel feeding an endometrial polyp on cost, not charges. Charges could well affect this analysis and change the authors’ overall conclusion. adnexal evaluation Vaginal U/S has the added advantage over hysteroscopy of allowing evaluation of adjacent organs including the ovaries and bladder. Gupta et al. compared Pipelle and TVS performed prior to hysteroscopy and curettage in evaluating 76 patients with PMB.25 They found that TVS was more sensitive and specific than Pipelle sampling in diagnosing endometrial abnormalities (83% and 77% vs 70% and 70%, respectively). In addition, 5 ovarian masses were detected on TVS: 3 that were missed on pelvic exam and 2 that were malignant. Thus, 2.6% (2 of 76) of patients presenting with PMB were found to have ovarian cancer. The significance of this study is illustrated by the case of a 61-yearold patient presenting with spotting for 2 months. Office hysteroscopy revealed atrophic endometrium, which was confirmed on biopsy (Figure 5). She then had a TVS that revealed a 3.5-mm endometrium, consistent with the hysteroscopic findings. However, she was found to have a 4.67-cm left ovarian mass that was a papillary cystadenocarcinoma (Figure 5). 32 magenta cyan yellow black contemporaryobgyn.net bladder evaluation TVS also allows evaluation of the bladder. A representative case is that of a 70-year-old presenting with PMB. This patient was referred for a SIS. Her initial TVS revealed a 2.0-mm endometrial thickness, which was confirmed on SIS with a 1.9-mm bilayer thickness (Figure 6). Her endometrial biopsy revealed atrophic findings. However, a cystic mass was found in the base of the bladder with adjacent wall thickening (Figure 6), which proved to be a ureteral cyst with transitional cell carcinoma of the bladder. These cases illustrate the additional advantages of TVS over hysteroscopy and endometrial biopsy. The ability to assess adjacent organs separates TVS from the other technologies. type I versus II endometrial cancer Conventional understanding holds that a thin EEC does not exclude type II endometrial cancers.26 Type II cancers include endometrioid adenocarcinomas, serous adenocarcinomas, clear cell adenocarcinomas, and mixed adenocarcinomas, which all have a poor prognosis.27 A report by Hosoi et al. found that the endometrium was Figure 5 >4 mm in 89% of type I endometrial cancers and 93% of type II cancers, a difference that was not statistically significant.27 This report concluded that the “4-mm (5-mm) rule” was applicable even with type II cancers. sonohysterography Sonohysterography offers an excellent alternative to hysteroscopy in diagnosing endometrial abnormalities. It is indicated when patients are found to have an indistinct or thickened endometrium (Figure 7). SIS is readily available in any office with TVS capabilities, requiring only a suitable catheter and saline for infusion. Infusing saline distends the endometrial cavity, demonstrates intracavitary focal lesions, and delineates each layer of the endometrium. Epstein et al. evaluated 105 women with PMB with TVS, SIS, and hysteroscopy.28 They found 96% agreement between SIS and hysteroscopy in identifying endometrial polyps and submucous myomas, both with 80% sensitivity.28 Of interest, they also found a 7-fold greater risk of malignancy (odds ratio 7.3) in patients whose cavities were difficult to distend at SIS. Ultimately, two-thirds of women with a poorly distensible cavity were di- hysteroscopy of atrophic endometrium, ovarian cancer on U/s Ultrasound reveals a thin eec (3.5 mm), consistent with an atrophic endometrium. the left ovary has a 4.67 cm complex papillary cystic mass that proved to be a serous cystadenocarcinoma. September 2014 ES495080_obgyn0914_032.pgs 08.29.2014 02:42 ADV GRAND ROUNDS agnosed with endometrial cancer.28 technique A complete TVS exam should be performed prior to SIS. This allows assessment of the uterine orientation and evaluation of the adnexa and bladder. SIS is indicated in patients with an indistinct or thickened endometrium, or in those with suspected focal lesions on TVS. The cervix is visualized and prepped with a suitable antiseptic solution, eg, povidone-iodine or chlorhexidine gluconate solution, prior to insertion of the catheter. Many suitable catheters are available. If there is a small cervical opening, a Shepherd insemination catheter is helpful because it has a 5.4 F diameter with a small hollow stylet within the catheter. The stylet is rigid and allows molding of the catheter to the curve of the uterine cavity. A balloon catheter is helpful in the presence of a patulous cervix or large fibroids. The catheter enhances distension and improves SIS image quality in most cases. Finally, if an endometrial biopsy is anticipated, specifically designed catheters such as a Goldstein SonoBiopsy catheter or a Bernard catheter can be used for both saline infusion and subsequent biopsy, facilitating one-step in-office evaluation. Attach a 10-mL syringe filled with saline to the catheter and flush prior to insertion to prevent air from entering the cavity and causing image distortion. If the Goldstein SonoBiopsy catheter is being used, the pyramidal “stopper” should be adjusted to approximately .5 cm less than the measured length from the external os to the fundus. This avoids penetrating the fundus with the catheter, while the stopper retards backflow of fluid from the cervix. If using a balloon catheter, fill the balloon with Figure 6 evaluation of the bladder thin eec (1.9 mm total) consistent with atrophy. Ureteral cyst with thickening of the bladder mucosa in 2 areas, which proved to be transitional cell carcinoma. Figure 7 tVs and sIs Initial tVs with an indistinct endometrium. sIs reveals an endometrial polyp and asymmetric endometrium. saline to avoid acoustic distortion. Prep the cervix with an appropriate disinfecting solution, locate the catheter within the endometrial cavity, and remove the speculum, being careful to avoid pinching the cervix. The 10-mL syringe allows the catheter and syringe to pass through the opening of a traditional speculum, thus negating the need for an opensided speculum. Replace the transducer in the vagina and infuse saline under direct U/S visualization. Take images in the longitudinal and transverse views. If 3D is available, a sweep in the longitudinal plan is often the only image required to reconstruct and measure the endometrium and identify any focal lesions. Retained fluid should be withdrawn by drawing back on the syringe plunger. Advise the patient to anticipate a watery discharge for several days following the procedure. Patients tend to experience mild discomfort during specific maneuvers: traversing the internal cervical os, touching the fundus with the catheter, expanding the balloon (usually 1.5 mL is sufficient), rapidly distending the cavity, and performing a biopsy. Thus, advise the patient accordingly during these times, avoid touching or penetrating the fundus, and expand the balloon slowly. The discomfort experienced during sonobiopsy (an endometrial biopsy performed with the SIS catheter) is similar to or less than during a suction-piston endometrial biopsy. September 2014 magenta cyan yellow black continued on page 44 contemporary ob/gyn 33 ES495076_obgyn0914_033.pgs 08.29.2014 02:41 ADV postmenopausal hormone therapy Two experT opinions beneFItS anD rISkS oF poStmenopaUSal Hormone tHerapy new options and additional information add perspective BY HUgH S. taylor, mD J Dr. taylor is the Anita O’Keeffe Young Professor and Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut. He reports receiving consulting fees from AbbVie, Bayer, and Pfizer, and performing contracted research for AbbVie and Pfizer. 34 magenta cyan yellow black udicious use of therapies for treatment of menopausal symptoms has been a topic of debate for more than a decade. Many concerns about hormone therapy (HT) arose from interpretation of results of the Women’s Health Initiative (WHI), a large, prospective, randomized clinical trial (RCT) that evaluated use of menopausal HT and helped to define its risks and benefits. The initial findings from the WHI were concerning, but subsequent detailed analysis and long-term follow-up of women enrolled in these trials have brought perspective. Moreover, new prospective RCTs have shed more light on appropriate use and safety of HT. Finally, several novel FDA-approved therapies for treatment of menopausal symptoms address many concerns. These therapies offer exciting new options for women suffering from menopausal symptoms. The WHI results astounded the media and the public. Some of the purported benefits of HT were not seen in the population treated, while the risks were initially thought to be similar to or greater than those previously reported.1 Most prescribers treat women who are newly menopausal and rarely treat women contemporaryobgyn.net in the seventh and eighth decades of life, as was done in the WHI. While media reports typically lumped together therapies composed of estrogens or estrogens given concomitantly with progestins, we have come to learn that the risks and benefits of these therapies are distinct. The combination estrogen and progestin in the WHI studies did not decrease the risk of cardiovascular disease (CVD); in fact, the risk of CVD and stroke was increased in older women using combination HT.1 Reports on the WHI data eventually clarified that use of estrogen alone was not associated with increased risk in the 50- to 59-year-old age group.2,3 In fact, many CVD outcomes were improved in women using conjugated equine estrogens (CEE) alone.4 Further, coronary calcium, a surrogate marker of atherosclerosis, was significantly reduced in the younger women who used CEE alone. This finding suggests that the development of CVD was indeed reduced in newly menopausal women after hysterectomy who were using unopposed estrogen. Although the risks for both combination and estrogen-based therapies increased with age, current data from the WHI suggest that September 2014 ES495245_obgyn0914_034.pgs 08.29.2014 02:54 ADV these therapies can be safely administered without increased risk in women in and around the menopausal transition.5 Further, the use of CEE alone in women who have undergone hysterectomy may have some cardiovascular benefits before age 60.3,6 More recent prospective RCTs have confirmed the safety of combination HT in newly menopausal women; the Kronos Early Prevention Study showed no evidence of coronary artery calcium deposition or worsening of progression of coronary artery atherosclerosis when combination HT was used in newly menopausal women for 4 years.7,8 Taken together, these studies show that in younger patients typically treated for menopausal symptoms, CVD is not increased by menopausal HT and there may be real cardiovascular benefits with the use of unopposed estrogen. Other findings from the WHI were not surprising. HT reduced the risk of fracture and HT is known to improve vasomotor symptoms (VMS) and relieve vulvovaginal atrophy (VVA). For many women in the menopausal transition, HT will provide tremendous quality-of-life benefits. The primary concern of patients and physicians is the potential for increasing the risk of breast cancer with HT.9,10 The WHI results clearly show that combination HT increases the risk of breast cancer.11 Subsequent studies showed that not only was this risk increased, there was also an accompanying increase in breast cancer mortality. These findings overturned the misconception that only less aggressive, non-fatal tumors would be stimulated by hormones. The risk of breast cancer with traditional combination HT is low and comparable to the risk of automobile fatality that driving creates, a risk that we assume for the convenience it provides. More importantly, the WHI has shown us the clear distinction between combination HT and estrogenalone therapies in impact on risk of breast cancer. In women who have undergone hysterectomy and used estrogen alone, the long-term WHI post-treatment intervention follow-up showed a marked reduction in breast cancer among women who used CEE. Contrary to popular misconceptions, estrogens and progestins are distinct hormones with different effects on the The primary concern . . . is the potential for increasing the risk of breast cancer with HT. breast. For a well-informed woman who has had a hysterectomy and is not at risk of venous thromboembolism (VTE), the decision to use HT should be an easy one. New HT options For women who have not undergone hysterectomy and require a progestin for protection against endometrial cancer, several new alternatives to traditional combination HT are available with greater safety and minimal side effects. New products include paroxetine, an antidepressant, for reduction in VMS.12,13 It does not have the same level of efficacy as traditional menopausal HT, but paroxetine provides relief for women who want a nonhormone-based alternative. Selective estrogen receptor modulators (SERMs), which have tissue-specific selective targeting through the estrogen receptor (ER), also have potential in treatment of menopausal symptoms. Raloxifene, a SERM approved for pre- vention and treatment of osteoporosis, effectively targets ERs in bone while not stimulating those in breasts.14,15 Like many SERMs, it has an antagonistic hormone effect on breasts, reducing the risk of breast cancer.16 Because raloxifene does not effectively provide an estrogen-like effect in the central nervous system and may increase the incidence and severity of VMS. However, other SERMs that may offer benefits have been introduced. Ospemifene, an oral SERM that targets the vagina, provides relief from vaginal atrophy without stimulating the endometrium.17 VVA can be targeted through the oral or vaginal route. This decision includes balancing the risks of systemic therapy (eg, VTE) with the convenience of oral administration. Perhaps the most innovative and novel therapy to be approved in the United States is the first tissue-selective estrogen complex—a combination of CEE and the SERM bazedoxifene (BZA).18,19 BZA’s unique properties allow it to be specifically coupled with estrogens without the need for a progestin. Its tissue-specific selectivity antagonizes estrogen action on the breast and uterus, but does not effectively counteract the benefits of estrogen on the brain or bone. Replacing a progestin with a SERM is expected to result in a much more favorable risk profile than combination HT.20 Clinical trials of CEE/BZA have shown effective relief of VMS and improved bone density.21-24 Remarkably, the combination of CEE and BZA produced bleeding rates comparable to placebo, far less than traditionally noted with any estrogen and progestin combination HT.25 Further, it does not increase breast tenderness as was seen with estrogen and progestin. Mammograms obtained in women using CEE/BZA in clinical trials September 2014 magenta cyan yellow black contemporary ob/gyn 35 ES495246_obgyn0914_035.pgs 08.29.2014 02:55 ADV postmenopausal hormone therapy showed no increase in mammographic density, which is in contrast to the increase seen with combination HT.26 Summary More than a decade after the first WHI results, detailed follow-up analysis has revealed a clearer picture of the actual benefits and risks of menopausal HT. Many of the risks that led women to reject therapies for VMS have finally been put into perspective. The distinctive risks of CEE alone versus combination therapy are now unambiguous. The important effect of age has also become apparent. Newly menopausal women can feel confident that they have a full and accurate assessment of the risks and benefits of HT. The reduction in breast cancer risks with use of CEE alone is still underappreciated, but important to our patients to relieve their fears and enable them to make more informed decisions. Finally, several new products have become available, offering more options and potentially greater safety. Nonhormonal and tissue-specific hormonal therapies have been added to our armamentarium. Perhaps the most promising therapy for women with a uterus is CEE/BZA. A renaissance in treatment of menopausal symptoms has begun. We are better informed than ever about the side effects and risks of HT and armed with new options. It is time to reengage and inform our patients; we can help them to make knowledgeable decisions. RefeRences 1. Manson JE, Hsia J, Johnson KC, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523–534. 2. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in 36 magenta cyan yellow black contemporaryobgyn.net postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–1712. 3. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465–1477. 4. Manson JE, Allison MA, Rossouw JE, et al; WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591–2602. 5. Taylor HS, Manson JE. Update in hormone therapy use in menopause. J Clin Endocrinol Metab. 2011;96(2):255-264. 6. Harman SM, Vittinghoff E, Brinton EA, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med. 2011;124(3):199–205. 7. Miller VM, Black DM, Brinton EA, et al. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J Cardiovasc Transl Res. 2009;2(3):228–239. 8. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014 [Epub ahead of print] 9. Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Women’s Health Initiative clinical trial and observational study. Am J Epidemiol. 2008;167(12):1407–1415. 10. Stefanick ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647–1657. 11. Chlebowski RT, Kuller LH, Prentice RL, et al; WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573–587. 12. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289(21):2827–2834. JAMA. 1999;282(7):637–645. 16. Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727–2741. 17. Bachmann GA, Komi JO; Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480–486. 18. Komm BS. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci. 2008;15(10):984–992. 19 . Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology 2008;149(12):6084–6091. 20. Taylor HS, Ohleth K. Using bazedoxifene plus conjugated estrogens for treating postmenopausal women: a comprehensive review. Menopause. 2012;19(4):479–485. 21. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/ conjugated estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):E189–98. 22. Pinkerton JV, Abraham L, Bushmakin AG, et al. Evaluation of the efficacy and safety of bazedoxifene/conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective estrogens, Menopause and Response to Therapy (SMART) trials. J Womens Health. 2014;23(1):18–28. 23. Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92(3):1045–1052. 13. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013; 20(10):1027–1035. 24. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause. 2009;16(6):1116–1124. 14. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997;337(23):1641–1647. 25. Archer DF, Lewis V, Carr BR, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92(3):1039–1044. 15. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. 26. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20(2):138–145. September 2014 ES495241_obgyn0914_036.pgs 08.29.2014 02:54 ADV The World’s Only Complete Portfolio of Products to Perform LESS* Hysterectomy Autoclavable 5 mm HD Deflectable-Tip Video Laparoscope Fully-Integrated Ultrasonic and Advanced Bipolar Technology Triport+ and Triport15 Up to Four 5 mm Instruments Through a 15 mm Incision Discover Where Innovation Can Take You For more information, call 800-848-9024 to speak to your local Olympus sales representative *Laparo-Endoscopic Single-Site Surgery medical.olympusamerica.com/less © 2014 Olympus America Inc. Trademark or Registered Trademark of Olympus or its affiliated entities in the U.S. and/or other countries of the world. All patents apply. AD624-0913 magenta cyan yellow black ES496833_OBGYN0914_037_FP.pgs 09.01.2014 18:10 ADV postmenopausal hormone therapy Two experT opinions Ht is safe and beneficial when used appropriately BY Holly m. tHacker, mD, Facp, ccD, ncmp T Dr. tHacker is Professor and Chair, Center for Specialized Women’s Health, OB-GYN and Women’s Health Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio. She reports receiving salary/honoraria from Pfizer, Shionogi, and Amgen. 38 magenta cyan yellow black his is an ideal time to review the benefits and risks of hormone therapy (HT) in menopause, in light of the recent publication of the Women’s Health Initiative (WHI) outcomes, ACOG’s Practice Bulletin update on the management of menopausal symptoms, and recent research documenting that ob/gyn residents have inadequate experience and exposure to menopausal medicine.1-3 In the last year, the FDA has approved 2 nonhormonal therapies for treatment of menopausal symptoms: an oral therapy (a selective estrogen receptor modulator [SERM] also called an oral estrogen agonist/antagonist with tissue-selective effects) for moderate to severe dyspareunia caused by menopausal vulvovaginal atrophy (VVA) and a low-dose oral selective serotonin reuptake inhibitor (SSRI) for the treatment of moderate to severe vasomotor symptoms (VMS) that comes without the psychiatric labeling of other SSRIs. Systemic HT—with just estrogen (in women without a uterus) or estrogen plus progestin (in women with a uterus)—remains the most effective therapy for treating menopausal VMS.2 Clinicians should individualize care and use the lowest effective dose consistent with the indication for therapy, which does not necessarily imply a limit to therapy. The most important data point in the WHI long-term health outcomes is reduced all-cause mortality with both estrogen alone (in women without a uterus) and combination HT (in women with a uterus) compared to placebo in women within 10 years of menopause who used therapy for more than 5 years. The benefit of estrogen was mathematically and strikingly demonstrated in a recent analysis that suggested up to 90,000 deaths contemporaryobgyn.net may have occurred due to post-WHI withholding of estrogen therapy.4 For some time, Dr. Wulf Utian (the founder of both the International Menopause Society and the North American Menopause Society) has called for an independent commission to re-evaluate the WHI investigators’ reports.5 It is up to all women’s health practitioners and educators to educate our patients and our trainees about menopause and menopausal HT. The Study of Women Across the Nation revealed that the productivity of menopausal women suffers if their symptoms are not treated.6 Economic stability is an important component of health and wellness. In my opinion, the long-term outcomes of the WHI as well as the Danish Osteoporosis Prevention Study7 swing the pendulum back from using menopausal HT as limited treatment in women severely affected by menopausal hormone deficiency only to using it for primary prevention based on mortality reduction, including bone protection and reduction of cardiovascular disease (CVD). Hodis and Mack compare the risks of HT with other commonly used medicines.8 They note that data from randomized clinical trials are very reassuring in that risks associated with HT are rare (fewer than 1 event per 1000 women treated) and even rarer in women who initiate HT within 10 years of menopause. Strikingly, HT reduces CVD and total mortality (while aspirin and statins in women treated for primary cardiovascular prevention do not).9 The major risk with the use of HT is venous thromboembolism (VTE). Some have postulated that the use of transdermal estracontinued on page 40 September 2014 ES495242_obgyn0914_038.pgs 08.29.2014 02:55 ADV magenta cyan yellow black ES496810_OBGYN0914_039_FP.pgs 09.01.2014 18:08 ADV postmenopausal hormone therapy continued from page 38 diol and oral micronized progesterone may reduce the risk of VTE and breast cancer, respectively.10 With respect to breast cancer, oral conjugated equine estrogen (CEE) used for 11 years in the estrogen-only arm of the WHI was not associated with any increase in breast cancer diagnosis, and in adherent women, was associated with a decrease in breast cancer diagnosis. Because of miscommunication of the results of the WHI, many women turned to unregulated compounded so-called bio-identical hormone therapy (BHT). BHT in the compounded form typically is used in transdermal progesterone cream, which does not achieve high-enough serum levels to reliably protect the endometrium.11 Assessing for relief of menopausal symptoms, visually inspecting for resolution of VVA, and assessing bone density are indirect tissue-level assays of estrogen adequacy.11 Women requesting BHT can be prescribed regulated oral progesterone and oral or transdermal or vaginal estradiol. These products are FDA-approved, commercially available, and do not have to be compounded for most women. The table on page 42 describes options for delivering HT. In general, estrogen alone is used in cases of hysterectomy and progestin is used either continuously with the goal of amenorrhea within 6 months or cycled for 12 days each month. Testosterone is not FDA-approved and therefore not standard of care in the United States. However, for women with androgen deficiency, one generic oral esterified estrogen with oral methyltestosterone combination is available. It can also be considered, along with off-label compounded topical testosterone, for women who have undergone hysterectomy with oophorectomy and have persistent VMS on estrogen 40 magenta cyan yellow black contemporaryobgyn.net alone, but that should be done carefully to avoid supra-physiologic levels.12 Pellets of estrogen, progesterone, and testosterone are not FDA-approved and are not recommended. Data do not support the use of progestin alone, testosterone alone, compounded BHT, phytoestrogens, herbal supplements, and/or lifestyle modifications to treat menopausal VMS.2 Half of all women have vasomotor symptoms, and for some they last for decades. Benefits of HT include relief of VMS (which can include hot flashes, night sweats, and rarely formication, which is a sense of something crawling on the body) and treatment of VVA. If VVA is the only menopausal symptom, local estrogen or the new nonhormonal ospemifene should be considered.13 The major risk with this systemic SERM is the risk of VTE. Local estrogens are available in 2 creams, 1 vaginal ring and 1 vaginal tablet. Some women prefer oral therapy to local vaginal therapy and may be candidates for systemic HT or oral ospemifene alone. The only nonhormonal agent approved to treat VMS is low-dose paroxetine, which has shown statistical significance at week 4 and week 12 with persistence of benefit of treating VMS at week 24.14 Coadministration of paroxetine can alter concentrations of other drugs such as tamoxifen. The lower doses of paroxetine do not appear to be associated with weight gain and sexual dysfunction. Many other SSRI and norepinephrine serotonin reuptake inhibitors (NSRI) have been studied, although only low-dose paroxetine is FDA-ap- proved. Choosing an appropriate therapy requires careful assessment of the risk-benefit as well patient preference and comorbid medical conditions.15 Other benefits associated with HT use include reduction in type 2 diabetes, colon cancer, and fracture and improvement in minor mood and neurocognitive symptoms associated with sleep deprivation from VMS. Estrogen also may benefit skin and hair among women who are estrogen-deficient but who have endogenous levels of androgens promoting hair thinning and acne, and in some women, even a deepening of the upper register of the voice. Risks besides VTE and invasive breast cancer (with long-term combination HT) include a higher incidence of all cardiovascular events, gall bladder disease, and probable dementia.1 Among the nuisance side effects are breast tenderness and uterine bleeding. Endometrial hyperplasia and endometrial cancer are associated with unopposed estrogen use. Oral estrogen can be associated with increase in blood pressure in some women and elevated triglyceride levels and gallstones. Fluctuating hormone levels can affect migraine headaches. Women with seizure disorders need adequate progestin therapy as estrogen can lower the seizure threshold. Several societies, including the international Menopause Society and the Endocrine Society, have issued helpful guidelines.2,16,17 The North American Menopause Society’s most recent position admits that the data support the initiation of HT around the time of menopause to treat symptoms and to prevent osteoporosis in women at high risk of fracture.18 Risks of stroke, dementia, and myocardial infarction are highest in women initiating therapy several decades from menopause. continued on page 42 September 2014 ES495243_obgyn0914_040.pgs 08.29.2014 02:54 ADV DO I FOCUS ON FINANCIAL PLANNING? I’m a gynecologist, not a financial expert. How do doctors’ lives differ from other professions? We start our careers nearly 10 years later. Many of us leave med school with more than $150K in debt. There is simply less time to save for the kids’ tuition and our retirement. Disability? Life insurance? Financial planning? I need someone to do the legwork for me; help me calculate what I need to build a safety net, so that my family can maintain their lifestyle. I want a resource that gets it—a doctor’s financial life is different. 1 • 800 • 458 • 5736 www.amainsure.com magenta cyan yellow black ES496800_OBGYN0914_041_FP.pgs 09.01.2014 18:07 ADV postmenopausal hormone therapy TABLe options for postmenopausal hormone therapy estrogen only Dosages oral Formulations premarin (conjugated estrogen) 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg, 2.5 mg daily menest (esterified estrogen) 0.3 mg, 0.45 mg, 0.625 mg daily transdermal Formulations Divigel (gel) 0.025 mg, 0.05 mg, 0.10 mg daily elestrin (spray) 1 to 2 squirts daily evamist (spray) 1 to 3 squirts daily Climara (transdermal patch) Generic estradiol (transdermal patch) 0.025 mg, 0.0375 mg, 0.05 mg, 0.060 mg, 0.075 mg, 0.100 mg weekly Vivelle-dot (transdermal patch) 0.025 mg, 0.0375 mg, 0.050 mg, 0.075 mg, 0.010 mg twice weekly minivelle (transdermal patch) 0.0375 mg, 0.050 mg, 0.075 mg, 0.010 mg twice weekly Vaginal ring estring 0.05 mg, 0.10 mg once every 3 months Femring estrogen + progestin Dosages oral Formulations prempro (estradiol/progesterone) 0.625 mg/2.5 mg, 0.4 mg/1.5 mg, 0.3 mg/1.5 mg daily Activella (estradiol/norethindrone acetate) 0.5 mg, 0.1 mg, 1 mg/0.5 mg daily femHrt (estradiol/norethindrone) 5 mcg/1 mg daily Angeliq (estradiol/drospirenone) 0.5 mg/0.25 mg, 2.5 mg/0.5 mg daily transdermal Formulations Climara-pro (estradiol/levonorgestrel) 0.045 mg/0.015 mg weekly Combipatch (estradiol/norethindrone acetate) 0.05 mg/0.14 mg, 0.05 mg/0.25 mg twice weekly progestin only Dosages oral Formulations* prometrium (micronized progesterone) 100 mg nightly, 200-mg cycled *Should be taken with food for better absorption and taken at night for its potential sedative hypnotic effect. prometrium should not be used by women who are allergic to peanuts. 42 magenta cyan yellow black contemporaryobgyn.net continued from page 40 Menopause is a potential endocrinopathy. If a patient has premature menopause or early menopause, pressing long-term consequences of hormone deficiency include premature death, CV disease, osteoporosis, sexual dysfunction, and neuropsychiatric problems.19 Many women produce enough steroid hormones to be free of symptoms or to experience only asymptomatic bone loss and later-onset VVA. Some women will never experience VMS even with castration. However, half of all women have VMS, and for some they last for decades. Half of all women experience an osteoporotic fracture in their lifetime, which is generally related to estrogen deficiency. A vast majority experience VVA, which may not be symptomatic, but if it progresses and/ or is not treated, can lead to structural changes in the vagina, vulva, trigone of the bladder, and urethra, and elevation in vaginal pH. Women who have had menopausalonset neuropsychiatric problems and/ or sleep disorders such as insomnia should continue on long-term HT even after their condition has stabilized. The newest HT approved by the FDA is oral conjugated estrogen plus bazedoxifene (BZA), a SERM. It is approved for treatment of VMS and prevention of osteoporosis.20 BZA replaces the progestin medroxyprogesterone acetate (MPA) in Prempro. BZA has estrogen antagonistic endometrial effects and independent agonistic effects on bone. Many menopausal women have osteopenia, not osteoporosis, and thus are not candidates for other osteoporosis therapies. Therefore, systemic HT or systemic estrogen plus a SERM like CEE/BVA (or if no VMS and osteopenia or osteoporosis and increased risk of breast cancer then oral daily raloxifene) should be considered. Ral- September 2014 ES495244_obgyn0914_042.pgs 08.29.2014 02:54 ADV postmenopausal hormone therapy oxifene is FDA-approved to prevent and treat osteoporosis and to reduce risk of diagnosis of estrogen receptor (ER)-positive breast cancer. All systemic estrogens and all SERMS can increase the risk of VTE 2 fold. Work-up for menopause When evaluating a woman for menopause, first ascertain whether she is menopausal. Not all amenorrhea is menopause and not all midlife symptoms are menopause. Next, does she have a uterus? If she has had a hysterectomy, is she a candidate for estrogen alone? If she has had a provoked VTE in the past, it is best to consider transdermal HT.17 If she has active ERpositive breast cancer, unstable CVD, or uterine cancer, then non-estrogen alternatives should be considered. Fear of breast cancer is not a reason to avoid oral estrogen. If she has a uterus/endometrium, then the decision to use progestin cyclically or continuously needs to be made. If she is not a candidate or declines HT, then FDA-approved non-hormonal therapies should be considered. Finally, any woman who was on systemic HT for menopausal symptoms who has stopped and has not had recurrence of VMS needs to be assessed for bone loss and VVA. There are several lower-dose HT options.21 I am not a fan of ultra-lowdose systemic HT in otherwise healthy recently menopausal women particularly if it leads to incompletely treated VMS requiring SSRIs or sleep agents, incompletely treated VVA requiring additional local estrogen therapy, and/ or bone loss requiring addition of a bone-sparing agent. However, women over age 60–65 who are stable should be evaluated for a reduction in HT dose. The lowest dose of estrogen that is FDA-approved for women ages 60–80 with T scores between -1.0 and -2.0 is the estradiol transdermal 0.014 weekly patch to prevent osteoporosis. Based on this ultra-low dose of estrogen, a progestin is needed for 12 days only once or twice a year in women with a uterus and has been FDA-approved for the last decade.22 Summary When evaluating menopausal women for menopausal HT, it is important to look at the totality of the data, review recent position papers by national societies, and individually evaluate your patients. The pendulum is swinging back to primary prevention with HT. It is up to you to communicate this to your patients and offer the newer FDA-approved non-hormonal options to those for whom they are appropriate. RefeRences 1. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative Randomized Trials. JAMA. 2013;310:1353–1368. 2. American College of Obstetricians and Gynecologists. Practice Bulletin No. 141. Management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202–216. 3. Christianson MS, Ducie JA, Altman J, et al. Menopause education: needs assessment of American obstetrics and gynecology residents. Menopause. 2013;20:1120–1125. and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks. J Am Geriatr Soc. 2013;61:1011–1018. 9. Hodis H, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 1: comparison of therapeutic efficacy. J Am Geriatric Soc. 2013;61:1005–1010. 10. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause. 2014;21:1–15. 11. Pattimakiel L. Thacker HL Bioidentical hormone therapy: Clarifying the misconceptions. CCJM. 2011;78(12):829–836. 12. Thacker HL. The Cleveland Clinic Guide to Menopause. 2009 Kaplan. Chapter 11 Customizing Hormone Therapy pgs 181–200. 13. Portman DJ, Bachman GA, Simon JA, and the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20:623–630. 14. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013;20(10):1027–1035. 15. Thacker HL. Assessing risks and benefits of nonhormonal treatments for vasomotor symptoms in perimenopausal and postmenopausal women. J WH. 2011;20:1007–1016. 16. Sturdee DW, Pines A. International Menopause Society Writing Group, et al. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2011;14:302–320. 17. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95:s1–s66. 18. The 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 2012;19:257–271. 4. Sarrel PM, et al. The mortality toll of estrogen avoidance: An analysis of excess deaths among hysterectomized women age 50 to 59. Am J Pub Health. 2013;109(9):1583–1588. 19. Shuster LT, Rhodes J, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010;65(2):161. 5. Utian WH. A decade post WHI, menopausal HT comes full circle—need for an independent commission. Climacteric. 2012;15:320. 20. Tella SH, Gallagher JC. Bazedoxifene + conjugated estrogens in HT for the prevention of osteoporosis and treatment of vasomotor symptoms associated with the menopause. Expert Opin Pharmacother. 2013;14:2407–2420. 6. Tseng LA, El Khoudary SR, Young EA, et al. The association of menopausal status with physical function. The SWAN. Menopause. 2012;19:1186–1192. 7. Shierbeck LL, Renjnmark L, Tofteng CL, et al Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ. 2012;345:e6409. 8. Hodis, H, Mack WJ. The timing hypothesis 21. Sivandandy MS, Masimasi N, Thacker HL. Newer hormonal therapies: Lower doses: oral, transdermal, and vaginal formulations. CCJM. 2007;74:369–374. 22. Ettinger B, Ensrud KE, Wallace R, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol. 2004;104:443–451. September 2014 magenta cyan yellow black contemporary ob/gyn 43 ES495247_obgyn0914_043.pgs 08.29.2014 02:55 ADV GRAND ROUNDS continued from page 33 endometrial cancer and other endometrial abnormalities. JAMA. 1998;280(17):1510–1517. summary 4. Goldstein SR. Modern evaluation of the endometrium. Obstet Gynecol. 2010;116(1):168– 176. TVS for initial triage of PMB identifies patients who do not need further endometrial evaluation at the initial visit, ie, those whose EEC is wellvisualized and <4 mm thick. The risk of underlying cancer in these patients is quite low (1/917). TVS offers the additional advantage of evaluating the adnexa and the bladder. If the endometrium is >4 mm thick, proceed to SIS or tissue sampling. SIS allows reliable detection of focal intracavitary lesions, such as endometrial polyps or submucous myomas. Patients with thickened, asymmetric, or irregular EEC should undergo endometrial sampling following SIS. Patients with focal intracavitary lesions should be triaged to surgical removal. Management of the remaining patients is based on endometrial biopsy results. If endometrial biopsy is not performed initially and a patient has recurrent bleeding, SIS and endometrial biopsy should be performed, with surgical treatment as indicated. TVS, followed by SIS when indicated, allows prompt in-office evaluation of patients with PMB, offering a reliable assessment of endometrial pathology, while minimizing cost and inconvenience to the patient. RefeRences 1. American Cancer Society. What are the key statistics about endometrial cancer? www.cancer.org/cancer/endometrialcancer/ detailedguide/endometrial-uterine-cancer-keystatistics. Accessed April 30, 2014. 2. Goldstein RB, Bree RL, Benacerraf BR, et al. Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in UltrasoundSponsored Consensus Conference Statement. J Ultrasound Med. 2001;20(10)1025–1036. 3. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude 44 magenta cyan yellow black contemporaryobgyn.net 5. Goldstein SR. The role of transvaginal ultrasound or endometrial biopsy in the evaluation of the menopausal endometrium. Am J Obstet Gynecol. 2009;201(1):5–11. 6. Guido RS, Kanbour-Shakir A, Rulin MC, Christopherson WA. Pipelle endometrial sampling. Sensitivity in the detection of endometrial cancer. J Reprod Med. 1995;40(8):553–555. 7. Stovall TG, Photopulos GJ, Poston WM, Ling FW, Sandles LG. Pipelle endometrial sampling in patients with known endometrial carcinoma. Obstet Gynecol. 1991;77(6):954–956. 8. Rodriguez GC, yaqub N, King ME. A comparison of the Pipelle device and the Vabra aspirator as measured by endometrial denudation in hysterectomy specimens: the Pipelle device samples significantly less of the endometrial surface than the Vabra aspirator. Am J Obstet Gynecol. 1993;168(1 Pt 1):55–59. 9. Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia. Cancer. 2000;89(8):1765– 1772. 10. Farrell T, Jones N, Owen P, Baird A. The significance of an “insufficient” Pipelle sample in the investigation of post-menopausal bleeding. Acta Obstet Gynecol Scand 1999;78(9):810– 812. 11. Goldstein SR, Nachtigall M, Snyder JR, Nachtigall L. Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding. Am J Obstet Gynecol. 1990(1 Pt 1);163:119–123. 12. Granberg S, Wikland M, Karlsson B, Norström A, Friberg LG. Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality. Am J Obstet Gynecol. 1991(1 Pt 1);164:47–52. 13. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand. 2002;81(9):799–816. 14. Timmermans A, Opmeer BC, Khan KS, et al. Endometrial thickness measurement for detecting endometrial cancer in women with postmenopausal bleeding: A systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):160–167. 15. Chandavarkar U, Kuperman JM, Muderspach LI, Opper N, Felix JC, Roman L. Endometrial echo complex thickness in postmenopausal endometrial cancer. Gynecol Oncol. 2013;131(1):109–112. 16. American College of Obstetricians and Gynecologists. Committee Opinion No. 426: The role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. Obstet Gynecol. 2009;113(2 Pt 1):462–464. 17. Gull B, Karlsson B, Milsom I, Granberg S. Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol. 2003;188(2):401–408. 18. Goldstein SR. Use of ultrasonohysterography for triage of perimenopausal patients with unexplained uterine bleeding. Am J Obstet Gynecol. 1994;170(2):565–570. 19. Carlson JA Jr, Arger P, Thompson S, Carlson EJ. Clinical and pathological correlation of endometrial cavity fluid detected by ultrasound in the postmenopausal patient. Obstet Gynecol. 1991;77(1):119–123. 20. Debby A, Malinger G, Glezerman M, Golan A. Intra-uterine fluid collection in postmenopausal women with cervical stenosis. Maturitas. 2006;55(4):334–337. 21. Goldstein SR. Postmenopausal endometrial fluid collections revised: Look at the doughnut rather than the hole. Obstet Gynecol. 1994;83(5 Pt 1):738–740. 22. Amit A, Weiner Z, Ganem N, et al. The diagnostic value of power Doppler measurements in the endometrium of women with postmenopausal bleeding. Gynecol Oncol. 2000;77(2):243–247. 23. Dijkhuizen FP, Mol BW, Brölmann HAM, Heintz AP. Cost-effectiveness of the use of transvaginal sonography in the evaluation of postmenopausal bleeding. Maturitas. 2003;45(4):275–282. 24. Weber AM, Belinson JL, Bradley LD, Piedmonte MR. Vaginal ultrasonography versus endometrial biopsy in women with postmenopausal bleeding. Am J Obstet Gynecol. 1997;177(4):924–929. 25. Gupta JK, Wilson S, Desai P, Hau C. How should we investigate women with postmenopausal bleeding? Acta Obstet Gynecol Scand. 1996;75(5):475–479. 26. Wang J, Wieslander C, Hansen G, Cass I, Vasilev S, Holschneider CH. Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers. Gynecol Oncol. 2006;101(1):120–125. 27. Hosoi A, Ueda y, Shindo M, et al. Endometrial thickness measured by ultrasonography in postmenopausal patients with endometrial carcinoma has significance, irrespective of histological subtype. Int J Gynecol Cancer. 2013;23(7):1266–1269. 28. Epstein E, Ramirez A, Skoog L, Valentin L. Transvaginal sonography, saline contrast sonohysterography and hysteroscopy for the investigation of women with postmenopausal bleeding and endometrium > 5 mm. Ultrasound Obstet Gynecol. 2001;18(2):157–162. September 2014 ES495078_obgyn0914_044.pgs 08.29.2014 02:42 ADV Coming in October Surgical Technology: From Promise to Practice Look for a special section in next month’s edition of Contemporary OB/GYN on gynecologic surgery advances and innovations. Edited by Jon I. Einarsson, MD, PhD, MPH, it features authoritative, peer reviewed information on procedures, techniques, tools, and controversies including: • An up-to-the-minute review of commercially available in-bag morcellation devices • A “how I do it” article from a top expert on identification of the ureter in hysterectomy • Point/Counterpoint debates on the future of robotics in gynecologic surgery and use of mesh for prolapse Only Contemporary OB/GYN brings you so much practical advice on gynecologic surgery in a single focus issue. Expert Advice for Today’s Ob/Gyn magenta cyan yellow black ES496829_OBGYN0914_045_FP.pgs 09.01.2014 18:09 ADV CLINICIAN TECH TOOLS TO CLINICIAN bY brIan a. LeVIne, mD, mS, AND Dan goLDScHLag, mD, Facog Noninvasive prenatal testing: A new standard of care T he presence of fetal DNA in maternal plasma and serum was first reported nearly 20 years ago.1 Fetal DNA is believed to be primarily placenta-derived and comprises 3% to 13% of total cell-free maternal DNA. Studies of women who have conceived by in vitro fertilization have demonstrated that fetal DNA can be detected in maternal serum as early as the seventh week of gestation and there is an increase in cellfree fetal DNA (cfDNA) concentration as pregnancy progresses, although cfDNA is cleared from the maternal blood within hours of childbirth.2 Although recent data suggest that invasive tests such as amniocentesis and chorionic villus sampling (CVS) are much safer than initially surmised (with risks of miscarriage 0.11% and 0.22%, respectively), obtaining information about a conceptus at an early stage is still the holy grail of prenatal diagnosis.3 One of the first reproducible applications of cfDNA analysis was detecting fetal RhD sequences in maternal serum of Rh-negative (sensitized) women.4 That study helped advance 46 magenta cyan yellow black contemporaryobgyn.net prenatal diagnosis technology by demonstrating that fetal single-gene disorders could be detected prenatally using DNA isolated solely from maternal serum. noninvasive prenatal testing has the ability to capitalize on robust tools for genetic evaluation. Part of the motivation for developing maternal blood-based or noninvasive prenatal testing (NIPT) is rooted in the ability to achieve an early diagnosis; even nuchal translucency and analyte-based aneuploidy testing followed by CVS for positive tests generates significant delay between testing and ultimate diagnosis (anywhere between 12 and 14 weeks). However, because genetic technologies appear to be experi- encing the same kind of exponential growth as computing technology, NIPT has the ability to capitalize on robust tools for genetic evaluation, allowing for more accurate early diagnoses beyond aneuploidy and single-gene defects. Many studies have validated NIPT to accurately detect trisomy 13, trisomy 18, and trisomy 21 using shotgun sequencing and massively parallel genomic sequencing (MPGS) while other researchers have capitalized on the power of other next-generation sequencing (NGS) modalities to detect fetal autosomal trisomies, sex chromosome aneuploidies, and triploidy.5-7 In the first part of this 2-part genetic-technology review, we will discuss the current NIPT landscape and compare/contrast NIPT technologies. Table 1 gives information about cost and turnaround times for the 4 commerically available NIPT technologies.8 opTion 1 maternit21 The first NIPT to come to the commercial market was MaterniT21, September 2014 ES496172_obgyn0914_046.pgs 08.30.2014 02:07 ADV Tech Tools TABLE 1 cost and turnaround times for commercial nIpt technologies cost turnaround Sequenom maternit21 plus Verinata Health Verifi ariosa Diagnostics Harmony prenatal test natera panorama prenatal test $1700 out-of-pocket $295 out-of-pocket $795 out-of-pocket $235 co-pay with insurance coverage $200 co-pay with insurance coverage $95 co-pay with insurance coverage Unknown out-of-pocket $1495 directly billed to insurers $2900 directly billed to insurers $1200 directly billed to insurers 8 to 10 days 8 to 10 days 8 to 10 days 15 days Adapted from: Agarwal A, Sayres LC, Cho mK, Cook-Deegan r, Chandrasekharan S. Commercial landscape of noninvasive prenatal testing in the United States. Prenat Diagn. 2013;33(6):521–531. which was developed by Sequenom and designed for trisomy 21 detection. It was released in 2011, followed in 2012 by MaterniT21 PLUS, which has the ability to diagnose not only trisomy 21, but also trisomy 13 and 18. Sequenom is also utilizing MPGS for their test. In theory, NGS allows for multiple studies of multiple pieces/ regions of DNA to be analyzed in parallel (at the same time), which allows for efficient evaluation of the whole genome rather than just specific targets that are representative of a discrete chromosome, as is done with fluorescence in situ hybridization (FISH). In Sequenom’s initial clinical validation studies of nearly 2000 specimens for each trisomy, they were able to achieve almost 100% sensitivity and specificity; trisomy 21: 99.1%/99.9%, trisomy 18: >99.9%/99.6%, trisomy 13: 91.7%/99.7%, Down syndrome and other trisomies: >99.9% detection.9-11 opTion 2 Verifi The next test to come to market was Verinata Health’s Verifi, which similarly capitalizes on the power of MPGS but also utilizes a propriety algorithm called SAFeR. According to the Verinata Health website, the SAFeR method calculates a normalized chromosome value (NCV) for each chromosome, thereby reducing data variation. They state that in a large-scale study population (no reference is provided on their website), “approximately 0.2% to 0.6% of results were classified as ‘Aneuploidy Suspected’ for each particular chromosome.” Because both aneuploid and euploid samples can be categorized as “Aneuploidy Suspected,” the chances of a false positive are higher without the SAFeR method.12 Interestingly, screening for fetal aneuploidy in twin gestations is challenging because of the lower levels of DNA available for analysis from each fetus as a result of the smaller uteroplacental junctional areas seen in monozygotic twins.13 By expanding the sensitivity and overall capability to detect aneuploidies, Verinata Health openly states that their test can be used for twins. However, it would not be possible to distinguish which twin has an abnormal result without further invasive testing. opTion 3 Harmony prenatal test At approximately the same time that Verifi was released, Ariosa Diagnostics launched the Harmony Prenatal Test. That technique addresses one of the main concerns about MPGS, which is that it requires a large amount of DNA for sequencing because of the requirement to analyze the entire genome. The Harmony Prenatal Test utilizes a proprietary technology known as digital analysis of selected regions (DANSR), which sequences loci from only the chromosomes under investigation. As such, the assay requires approximately 10 times less DNA sequencing than MPGS approaches. To further enrich their platform, Ariosa Diagnostics also integrated their own statistical algorithm, fetal-fraction optimized risk of trisomy evaluation (FORTE). Essentially, the algorithm integrates age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy. In what some view as one of the landmark studies demonstrating the utility of NIPT, researchers at the University of London screened subjects who were at risk of aneuploidies and had undergone CVS. The DANSR/ September 2014 magenta cyan yellow black contemporary ob/gyn 47 ES496174_obgyn0914_047.pgs 08.30.2014 02:07 ADV Tech Tools TABLE 2 cell-free fetal Dna testing limitations cfDNA testing: 1 is not a diagnostic test although it has high sensitivity and specificity 2 should be an informed patient choice after obtaining a family history and performing pretest counseling 3 should not be part of routine prenatal laboratory assessment 4 should be offered to those women with an increased risk of aneuploidy 5 should not be offered to low-risk women or women with multiple gestations 6 should not be offered to those women in whom a fetal structural anomaly is identified on ultrasound examination 7 does not replace the accuracy and diagnostic precision of prenatal diagnosis with CVS or amniocentesis Adapted from ACOG Committee Opinion on noninvasive prenatal testing for fetal aneuploidy18 FORTE combined analysis distinguished all cases of trisomy 21 and 98% of trisomy 18 cases from euploid pregnancies.14 In an online commentary about the study, the senior author noted that plasma samples were obtained from high-risk pregnancies with some evidence of impaired placental function. (As previously discussed, cfDNA is believed to originate in the placenta.) “As such, the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population.”15 That issue was highlighted in a recent report about a study in which aneuploid samples were significantly more likely to not return a result; the number of aneuploidy samples was especially increased among samples with low fetal fraction.16 opTion 4 panorama prenatal test In 2012, California-based Natera released the Panorama Prenatal Test, which is the only test to analyze single 48 magenta cyan yellow black contemporaryobgyn.net nucleotide polymorphisms (SNP). The advantage of using a SNP-based technology is that it requires less cfDNA and, unlike other noninvasive methods, can detect genetic abnormalities such as short insertions/deletions/ aberrations that cause Mendelian disorders. noninvasive prenatal testing is widely available and likely will soon become the standard of care. At the time of this article, Panorama is able to detect trisomies 21, 18, and 13 as well as 45,X (Turner syndrome). Studies have shown that the test has high sensitivity and specificity in high-risk and low-risk cohorts (>99% detection rate for trisomies 21, 18, and 13 and a >90% detection rate for 45,X).17,18 It is important to note, however, that while SNP-based analyses are powerful tools, they have discrete limitations. Because SNP-based sequencing utilizes a reference sample of the maternal blood to distinguish maternal from fetal DNA, although such cases are rare, Panorama cannot be used for pregnancies conceived with an egg donor or those that used a gestational carrier, and cannot be performed on women who have received a bone marrow transplant. Summary Taking all of these advances together, the field of NIPT is incredibly exciting. In less than 2 years, 4 distinct robust technological tools have been added to the obstetrical armamentarium. Each tool has its strength and weakness, and it is important to know which tool to use for which clinical scenario (twins, singleton, donor egg, etc.). We also need to recognize that while NIPT is widely available and likely will soon become the standard of care, as obstetricians and gynecologists, we still have to practice within the guidelines and recommendations of the American College of Obstetricians and Gynecologists. The 2012 ACOG Committee Opinion on Noninvasive Prenatal Testing for Fetal Aneuploidy cautioned that the use of cfDNA testing should be an active, informed choice and not part of routine prenatal laboratory testing (Table 2). Lastly, we will all have to learn how to best utilize the new information that this testing generates. For many of us, NIPT will forever change how we practice medicine. Many of us have become facile in using technology such as ultrasound to help identify potential pregnancy complications. But in the recently September 2014 ES496173_obgyn0914_048.pgs 08.30.2014 02:07 ADV Tech Tools AcoG cautions that cfDnA testing should be an active, informed choice, not part of routine prenatal laboratory testing. released International Society of Ultrasound in Obstetrics and Gynecology consensus statement on the impact of NIPT on prenatal ultrasound practice, the authors caution that “so-called ‘genetic sonogram,’” which includes looking for soft markers of trisomy 21, should not be performed in women with a normal NIPT result due to ultrasound’s high false-positive rate and poor positive predictive value.19 Therefore, as uptake of NIPT increases, we will not only have to learn how and when to use NIPT, but we will also have to unlearn to use many older technologies. DR. LEVINE is clinical Fellow, Reproductive endocrinology & infertility, Ronald o. perelman and claudia cohen center for Reproductive Medicine, Weill cornell Medical college, new York. DR. GOLDSCHLAG is Assistant professor of clinical obstetrics and Gynecology and Assistant professor of clinical Reproductive Medicine, Ronald o. perelman and claudia cohen center for Reproductive Medicine, Weill cornell Medical college, new York. neither author has a conflict of interest to report with respect to the content of this article. REFERENCES 1. lo YM, corbetta n, chamberlain pF, et al. presence of fetal DnA in maternal plasma and serum. Lancet. 1997;350(9076):485–487. 2. lo YM, Tein Ms, lau TK, et al. Quantitative analysis of fetal DnA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998;62(4):768– 775. 3. Akolekar R, Beta J, picciarelli G, ogilvie c, D’Antonio F. procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2014. doi: 10.1002/uog.14636. 4. Bischoff FZ, nguyen DD, Marquéz-Do D, Moise KJ Jr, simpson Jl, elias s. noninvasive determination of fetal RhD status using fetal DnA in maternal serum and pcR. J Soc Gynecol Investig. 1999;6(2):64–69. 5. Fan hc, Blumenfeld YJ, chitkara U, hudgins l, Quake sR. noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DnA from maternal blood. Proc Natl Acad Sci USA. 2008;105(42):16266–16271. 6. chiu RW, Akolekar R, Zheng YW, et al. noninvasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DnA sequencing: large scale validity study. BMJ. 2011;342:c7401. 7. nicolaides Kh, syngelaki A, Gil M, Atanasova V, Markova D. Validation of targeted sequencing of single-nucleotide polymorphisms for noninvasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn. 2013;33(6):575–579. 8. Agarwal A, sayres lc, cho MK, cook-Deegan R, chandrasekharan s. commercial landscape of noninvasive prenatal testing in the United states. Prenat Diagn. 2013;33(6):521–531. 9. palomaki Ge, Kloza eM, lambert-Messerlian GM, haddow Je, neveux lM, ehrich M, van den Boom D, Bombard AT, Deciu c, Grody WW, nelson sF, canick JA. DnA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011 nov;13(11):913–920. of twinning. iii. placentation, calcium reduction and modified compaction. J Reprod Med. 2001;46(11):995–1002. 14. Ashoor G, syngelaki A, Wagner M, Birdir c, nicolaides Kh. chromosome-selective sequencing of maternal plasma cell-free DnA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012;206(4):322.e1–5. 15. science Daily. noninvasive method accurately and efficiently detects risk of Down syndrome, researchers say. http://www.sciencedaily.com/ releases/2012/02/120221125151.htm. Accessed August 14, 2014. 16. pergament e, cuckle h, Zimmermann B, et al. single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol. 2014;124(2 pt 1):210–218. 17. Zimmermann B, hill M, Gemelos G, et al. noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn. 2012;32(13):1233–1241. 18. American college of obstetricians and Gynecologists committee on Genetics. committee opinion no. 545: noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012;120(6):1532–1534. 19. salomon lJ, Alfirevic Z, Audibert F, Kagan Ko, Yeo G, Raine-Fenning n; isUoG clinical standards committee. isUoG consensus statement on the impact of non-invasive prenatal testing (nipT) on prenatal ultrasound practice. Ultrasound Obstet Gynecol. 2014;44(1):122–123. 10. palomaki Ge, Deciu c, Kloza eM, et al. DnA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2014;14(3):296–305. 11. canick JA, Kloza eM, lambert-Messerlian GM, et al. DnA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 2012;32(8):730–734. 12. Verifi prenatal Test. http://www.verifitest. com/verifi-advantage/. Accessed August 14, 2014. 13. steinman G, Valderrama e. Mechanisms September 2014 magenta cyan yellow black Look for the second part of this 2-part series on noninvasive prenatal testing in the November 2014 issue of Contemporary OB/GYN VISIT US ON FACEBOOK AT FACEBOOK.COM/CONTEMPOBGYN contemporary ob/gyn 49 ES496175_obgyn0914_049.pgs 08.30.2014 02:07 ADV Products & Services ShowcaSe Go to: products.modernmedicine.com Feminine Hygiene OMG! 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Our full-service Department includes specialists in REI, MFM, MIGS, SPU, Urogynecology, Menopause, and Vulvovaginal disorders. Excellent call schedules. Onsite and remote access to electronic medical records. Strong clinical and administrative practice management support to include nurse practitioners and certified nurse midwives. Competitive compensation with comprehensive benefits including a 401(k) employer-match contribution. Boston is home to top ranking academic schools, international airport, four-season living, fine arts, multicultural activities, and winning sports teams! All interested candidates, please send your confidential CV to Lin Fong, Harvard Vanguard Medical Associates Email: [email protected] | Fax: 617-559-8255 Mail: 275 Grove Street, Suite 3-300, Newton, MA 02466 Phone: 800-222-4606 | EOE/AA | www.harvardvanguard.org No third party agency. 54 magenta cyan yellow black ContemporaryObgyn.net Intermountain Healthcare is widely recognized as a leader in transforming healthcare through high quality and sustainable costs. We are seeking BC/BE OB/GYN physicians to practice with our medical group in Mount Pleasant, Utah. Contact Intermountain Healthcare, Physician Recruiting, 800-888-3134. [email protected], http://physicianjobsintermountain.org CONNECT with qualifed leads and career professionals Post a job today www.modernmedicine.com/physician-careers Joanna Shippoli RECRUITMENT MARKETING ADVISOR (800) 225-4569, ext. 2615 [email protected] SePtember 2014 ES496938_obgyn0914_054_CL.pgs 09.02.2014 19:03 ADV Calendar october November Obstetricians and Gynecologists Albuquerque, New mexico http://www.caog.org/future_meetings. cfm Annual Meeting, Advances in Prenatal Molecular Diagnostics boston, massachusetts http://www.healthtech.com/ prenatal-diagnostics 8–11: Central Association of 15–18: North American Menopause Society Annual Meeting Washington, DC http://www.menopause.org/ annual-meetings/future-meetings https://www.smfm.org/ the-pregnancy-meeting 5–7: Cambridge Health Institute 2nd march 4–7: Council on Resident Education in Obstetrics and Gynecology and Association of Professors of Gynecology and Obstetrics San Antonio, texas https://www.apgo.org/meetings/creoga-apgo-annual-meeting.html 7–12: Association of American Medical Colleges Annual Meeting Chicago, Illinois https://www.aamc.org/meetings/annual/ am2014/ 22–25: Society of Gynecologic Reproductive Medicine Annual Meeting Honolulu, Hawaii http://www.asrm.org/ASRM2014/ Minimally Invasive Gynecology Vancouver, british Columbia https://www.aagl.org/globalcongress/ Surgeons 41st Annual Scientific Meeting Orlando, Florida http://www.sgsonline.org/ scientific-meeting 21–26: Pacific Coast Obstetrical and Gynecological Society marana, Arizona http://www.pcogs.org/meetings.cfm 20–22: World Symposium of Perinatal Medicine San Diego, California http://www.worldsymposium.net 25–28: Society for Reproductive Investigation Annual Meeting San Francisco, California http://www.sgionline.org/sri-meetings 24–26: Transforming the Future of Women’s Health & Fetal Medicine Houston, texas https://www.smfm.org/events/6transforming-the-future-of-womenshealth-fetal-medicine 21–22: Council of Medical Specialty 28–31: Society of Gynecologic Oncology Annual Meeting on Women’s Cancer Chicago, Illinois https://www.sgo.org/education/ annual-meeting-on-womens-cancer/ 26–29: International Society for the February 2015 18–22: American Society for Study of Hypertension in Pregnancy New Orleans, Louisiana http://isshp2014.com/ 17–21: 43rd AAGL Global Congress on Societies Washington, DC http://www.cmss.org/ DefaultTwoColumn.aspx?id=70 2–7: The Society for Maternal-Fetal Medicine 35th Annual Pregnancy Meeting San Diego, California ❯ have an event? E-MAIL your event to: [email protected] Please type “Event” in the subject line. advErtisEr indEX | Companies featured in this issue to obtain additional information about products and services advertised in this issue, use the contact information below. This index is provided as an additional service. The publisher does not assume any liability for errors or omissions. ACTAVIS US LABCORP QUEST DIAGNOSTICS ACtAVIS CONtrACeptION ..........26-30 INFOrmASeQ ........................................CV4 QUeSt/NIpt.................................................. 7 www.actavis.com www.Labcorp.com www.questdiagnostics.com AMA INSURANCE AGENCY INC LACLEDE INC /MED PRODUCTS DIV THERAPEUTICS INC SUbSIDIArY OF tHe AmA ...................41 LUVeNA .............................................. CV2-01 VItApeArL ...................................................39 www.amainsure.com www.luvenacare.com www.vitamedmdrx.com COOPER SURGICAL MERCK AND CO INC UCSD OTIS STUDIES UterINe mANIpULAtOrS....................19 mIrALAX ............................................... CVtIp OtIS StUDIeS ............................................17 www.coopersurgical.com www.miralaxmd.com www.otispregnancy.org CYNOSURE INC OLYMPUS AMERICA INC VEIN CLINICS OF AMERICA LASerS........................................................... 3 tHUNDerbeAt & LeSS .........................37 HeALtHCAre SerVICe .....................CV3 www.Cynosure.com www.olympusamerica.com/less www.veinclinics.com HOLOGIC/CYTYC PFIZER INC AptImA ..........................................................21 DUAVee ..................................................12-15 www.hologic.com www.duaveehcp.com September 2014 magenta cyan yellow black contemporary ob/gyn 55 ES495269_obgyn0914_055.pgs 08.29.2014 02:55 ADV OB/GYN STAT BITE PAULA J. ADAMS HILLARD, MD SECTION EDITOR PERSONAL HEALTH TRACKING Nearly two-thirds of US adults keep track of at least one personal health indicator, such as weight, diet, exercise, or a symptom, according to a national telephone survey of 3,014 adults by Pew Research Center’s Internet & American Life Project. Most (49%) monitor progress “in their heads” but 34% track health data on paper and 21% use an electronic method. Only about one-third of trackers share their data with anyone and of them, only half do so with a clinician. 60 33 40% 19% 2+ chronic conditions 1 chronic condition No chronic conditions TRACK personal weight, diet, or exercise routine Sharing of data 34 % of trackers share records or notes with another person or group, online or offline magenta cyan yellow black CONTEMPORARYOBGYN.NET TRACK % other health indicators track for loved onea (eg, blood pressure, sleep, headaches) 53 Informing health decisions 52 % of the 34% share with clinicians Source: Pew Internet/CHCF Health Survey, August 7–September 6, 2012. N=3014 adults ages 18+. Interviews were conducted in English and Spanish and on landline and cell phones. Margin of error is +/- 2.4 percentage points for results based on all adults. 56 12 ZZZ % 33 of trackers living with 2+ conditions say tracking has led them to ask a doctor new questions or seek a second opinion vs % of trackers living with no chronic conditions GETTY IMAGES/ISTOCK 360/USSR (TOP); THINKSTOCK/ISTOCK/JOHAVEL (ICONS) US adults who track 62% % % Chronic conditions SEPTEMBER 2014 ES495295_obgyn0914_056.pgs 08.29.2014 02:56 ADV For your patients with varicose and spider veins… SM They’d say: You have been dedicated to her health throughout the most important nine months of her life— So don’t forget to talk to her about treating varicose veins after pregnancy. Don’t let vein disease stand in her way. Our phlebologists will treat your patients with the same care and expertise you have provided them to ensure healthy, strong legs after pregnancy. Refer your patients to the largest network of highly trained vein specialists who have been helping patients since 1981. Our physicians provide free consultations* for your patients. To speak to a representative, please call (855) 953-VEIN (8346) or visit veinclinics.com/foryourpatients *Due to legal constraints, this offer cannot be extended to licensed healthcare providers, Medicare or Medicaid benefciaries, or other recipients of federal or state healthcare beneft programs. Offer expires December 31, 2014. Consultation must occur on or before December 31, 2014. This offer valid at all participating VCA network locations. New patients only. One free consultation per person during promotional period. Not redeemable for cash. © 2014 Vein Clinics of America, Inc. All rights reserved. VCA-0306 magenta cyan yellow black ES496801_OBGYN0914_CV3_FP.pgs 09.01.2014 18:07 ADV Introducing Integrated Genetics now offers informaSeqSM Prenatal Test – an advanced, non-invasive, next generation prenatal screening for T21, T18, and T13 chromosomal aneuploidies that can be administered as early as 10 weeks gestation. A test your patients can trust. A company you know and trust. You have the opportunity to select the test that best meets the needs of your patients. informaSeq Appropriate for high-risk patients. Provides only risk assessment for the most common autosomal trisomies. informaSeq with Y analysis Appropriate for high-risk patients. Provides risk assessment for the most common autosomal trisomies and fetal gender, but not sex chromosome aneuploidies. informaSeq with XY analysis Appropriate for high-risk patients with singleton pregnancies. Provides risk assessment for the most common autosomal trisomies, sex chromosome aneuploidies, and fetal gender. Integrated Genetics is committed to providing comprehensive care to you and your patients. We offer: The largest commercial genetic counseling team with unparalleled services Extensive managed care contracts helping patients maximize their benefits A network of more than 1,700 patient service centers To learn more about our informaSeq test offerings, please visit www.integratedgenetics.com or call 800-848-4436. informaSeq SM Prenatal Test is Powered by Illumina ® sequencing technology. magenta cyan yellow black informaSeq SM is a service mark of Laboratory Corporation of America ® Holdings. Powered by Illumina ® is a trademark of Illumina, Inc. in the U.S. and/or other countries. ©2014 Laboratory Corporation of America ® Holdings. All rights reserved. rep-901-v1-0814 ES496811_OBGYN0914_CV4_FP.pgs 09.01.2014 18:08 ADV
