ESSENTIALS OF WOMEN'S HEALTH: - Continuing Education

The Division of General Internal Medicine, The Department of Medicine, and

The Department of Obstetrics, Gynecology & Reproductive Sciences presents

ESSENTIALS OF WOMEN’S HEALTH:

AN INTEGRATED APPROACH TO PRIMARY CARE AND OFFICE GYNECOLOGY

June 30 – July 5, 2013 Hapuna Beach Prince Hotel

Big Island, Hawaii

Course Chairs

Robert B. Baron, MD, MS Alison F. Jacoby, MD

University of California, San Francisco School of Medicine

Acknowledgement of Commercial Support

Exhibitor

Bayer

ESSENTIALS OF WOMEN’S HEALTH: An Integrated Approach to Primary Care and Office Gynecology

June 30 – July 5, 2013 Big Island, Hawaii

SUNDAY, JUNE 30, 2013 4:00 pm Course Registration 5:00 Welcome

Robert B. Baron, MD, MS Alison F. Jacoby, MD

5:10 G Current Controversies in Breast and Cervical Cancer Screening Rebecca Jackson, MD

6:00 G Ovarian Cancer Screening and Principles of Adnexal Mass Evaluation Alison F. Jacoby, MD

7:10 Adjourn

MONDAY, JULY 1, 2013 Moderator: Robert B. Baron, MD, MS 6:30 am Continental Breakfast 7:00 G Current Controversies in Lung, Colon,

and Skin Cancer Screening Jeffrey Tice, MD

7:50 G Prevention of Cardiovascular Disease in Women Robert B. Baron, MD, MS

8:40 Break 9:00 G Management of Hypertension in Women

Eliseo J. Perez‐Stable, MD

9:50 Preventing the Unintended: Update in Contraception Jody Steinauer, MD, MAS

10:40 Adjourn

TUESDAY, JULY 2, 2013 Moderator: Alison F. Jacoby, MD 6:30 am Continental Breakfast 7:00 G What Every Clinician Needs to Know

About Abortion Jody Steinauer, MD, MAS

7:50 Lumps, Bumps, and Pain: Management of Common Breast Disorders Rebecca Jackson, MD

8:40 Common Issues in Pediatric and Adolescent Gynecology Alison F. Jacoby, MD

9:30 Break 9:50 Concurrent Workshops (select one):

A: You Make the Call: Recognizing Common Gynecologic Lesions Alison F. Jacoby, MD LOCATION: Mauka Ballroom

B: Management of Obesity: A Systematic Approach Robert B. Baron, MD, MS LOCATION: Main Ballroom

11:20 Adjourn

WEDNESDAY, JULY 3, 2013 Moderator: Eliseo Perez‐Stable, MD 6:30 am Continental Breakfast 7:00 G Vaccinations for Adult and

Adolescent Women Eliseo J. Perez‐Stable, MD

7:50 G Current Issues in Diabetes Management Robert B. Baron, MD, MS

8:40 G Breast Cancer Evaluation and Treatment Jeffrey Tice, MD

9:30 Break

9:50 Concurrent Workshops (select one):

C: Contraception Challenges: Case Studies and IUD Insertion Practicum Jody Steinauer, MD, MAS LOCATION: Mauka Ballroom

G D: Common Problems in Older Women: Using Geriatric Principles in Everyday Practice Eliseo J. Perez‐Stable, MD LOCATION: Main Ballroom

11:20 Adjourn

THURSDAY, JULY 4, 2013 Moderator: Jeffrey Tice, MD 6:30 am Continental Breakfast 7:00 G Vitamins and Supplements in Women’s Health:

An Evidence‐based Approach Jeffrey Tice, MD

7:50 G New Developments in Osteoporosis Eliseo J. Perez‐Stable, MD

8:40 Abnormal Uterine Bleeding: From Menarche to Menopause Vanessa Jacoby, MD, MAS

9:30 Break 9:50 Concurrent Workshops (select one):

E: Case Studies in Cervical Dysplasia: How Would You Manage These Patients? Rebecca Jackson, MD LOCATION: Mauka Ballroom

F: Clinical Dilemmas in Genetic Testing: A Case‐based Approach Jeffrey Tice, MD LOCATION: Main Ballroom

11:20 am Adjourn

FRIDAY, JULY 5, 2013 Moderator: Rebecca Jackson, MD 6:30 am Continental Breakfast 7:00 Chronic Pelvic Pain:

Current Strategies for Evaluation and Management Rebecca Jackson, MD

7:50 Why Am I Bleeding?

Management of First Trimester Bleeding Alison F. Jacoby, MD

CLOSING ADDRESS:

8:40 G Caring for Challenging Patients in Women’s Health: Insights into Empathy and Professionalism Jody Steinauer, MD, MAS

9:30 Adjourn

G = Geriatric Credit

University of California, San Francisco School of Medicine Presents

Essentials of Women’s Health: An Integrated Approach to Primary Care and Office Gynecology

Increasing appreciation of the unique needs of women patients and women's health care providers has created a need for innovative educational programs on women’s health. This program, designed for family physicians, internists, gynecologists, nurses, nurse practitioners, physician assistants, pharmacists, and all others involved in providing quality health care for women, will provide a practical update on a full range of common but controversial issues in women’s health. The course will serve to enhance the skills of those already working in women’s health as well as help develop new skills for those expanding their work to include more primary care and office gynecology. Developed and taught by UCSF faculty in both primary care internal medicine and obstetrics and gynecology, the course will present an integrated approach to women’s health. Emphasis will be placed on new developments in preventive care and cardiovascular risk factors in women, issues in reproductive health, and clinical strategies in the diagnosis and treatment of common gynecologic complaints and common medical problems of women. Special emphasis will be placed on office skills needed for modern day practice including: enhanced skills in physical examination, common office procedures, clinical nutrition, assessment of new medical technologies, and how to better read the medical literature. The course will use interactive lectures, clinical vignettes, hands‐on workshops, small group discussions, an audience response system and questions and answers. A detailed syllabus will be provided. This course is presented by the Division of General Internal Medicine, Department of Medicine, and the Department of Obstetrics, Gynecology, and Reproductive Sciences and is sponsored by the Office of Continuing Medical Education, University of California, San Francisco.

Educational Objectives

The purpose of this course is to increase competence and improve clinician practice in women’s health. We specifically anticipate improvements in skills and strategies to:

Implement new guidelines in office‐based preventive medicine for prevention and early detection of cancer with clinical exam, pap tests, genetic testing and diagnostic imaging;

Implement new guidelines for prevention and treatment of cardiovascular risk factors in women;

Provide vaccinations to adults and adolescents;

Diagnose and treat common problems in women's health including cervical dysplasia, hypertension, high blood cholesterol, obesity, diabetes, osteoporosis, abnormal uterine bleeding, fibroids, incontinence, ectopic pregnancy, chronic pelvic pain, benign breast disorders, breast cancer, and dementia;

Facilitate counseling and informed decision‐making in contraception and abortion;

Examine patients and perform common office procedures in gynecology;

Diagnose and treat pediatric and adolescent patients with gynecologic concerns;

Provide empathic and professional communication with all patients.

Accreditation

The University of California, San Francisco School of Medicine (UCSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

UCSF designates this live activity for a maximum of 20.25 AMA PRA Category 1 CreditsTM.

This CME activity meets the requirements under California Assembly Bill 1195, continuing education and cultural and linguistic competency.

Family Physicians: This Live activity, Essentials of Women's Health: An Integrated Approach to Primary Care and Office Gynecology, with a beginning date of 06/30/2013, has been reviewed and is acceptable for up to 19.75 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Geriatric Medicine: The approved credits shown above include 11.75 geriatric credits toward meeting the requirement under California Assembly Bill 1820, Geriatric Medicine

ACOG: The American College of Obstetricians and Gynecologists has assigned 21 cognate credits to this program.

General Information

CME Certificates Please complete the sign‐in registration form located at the front desk area of the meeting. Make certain to indicate your total number of credits collected. Visit the below URL to complete the overall course evaluation and receive an electronic certificate immediately. EVALUATION – CME CERTIFICATE ACCESS: www.ucsfcme.com/evaluation Evaluation Your cooperation in completing and returning the course evaluation is an important part of future course planning. The evaluation is the blue packet you received at registration. Please return your evaluation at course completion to the UCSF Registration Desk. Phone Messages Any messages during the conference can be left by calling (808) 880‐1111 and asking for the UCSF “Women’s Health” course. Messages will be posted on the board near the registration desk.

Security We urge caution with regard to your personal belongings and syllabus books. We are unable to replace these in the event of loss. Please do not leave any personal belongings unattended in the meeting room during lunch or breaks.

Federal and State Law Regarding Linguistic Access and Services for Limited English Proficient Persons

I. Purpose. This document is intended to satisfy the requirements set forth in California Business and Professions code 2190.1. California law requires physicians to obtain training in cultural and linguistic competency as part of their continuing medical education programs. This document and the attachments are intended to provide physicians with an overview of federal and state laws regarding linguistic access and services for limited English proficient (“LEP”) persons. Other federal and state laws not reviewed below also may govern the manner in which physicians and healthcare providers render services for disabled, hearing impaired or other protected categories

II. Federal Law – Federal Civil Rights Act of 1964, Executive Order 13166, August 11, 2000,

and Department of Health and Human Services (“HHS”) Regulations and LEP Guidance. The Federal Civil Rights Act of 1964, as amended, and HHS regulations require recipients of federal financial assistance (“Recipients”) to take reasonable steps to ensure that LEP persons have meaningful access to federally funded programs and services. Failure to provide LEP individuals with access to federally funded programs and services may constitute national origin discrimination, which may be remedied by federal agency enforcement action. Recipients may include physicians, hospitals, universities and academic medical centers who receive grants, training, equipment, surplus property and other assistance from the federal government. HHS recently issued revised guidance documents for Recipients to ensure that they understand their obligations to provide language assistance services to LEP persons. A copy of HHS’s summary document entitled “Guidance for Federal Financial Assistance Recipients Regarding Title VI and the Prohibition Against National Origin Discrimination Affecting Limited English Proficient Persons – Summary” is available at HHS’s website at: http://www.hhs.gov/ocr/lep/ . As noted above, Recipients generally must provide meaningful access to their programs and services for LEP persons. The rule, however, is a flexible one and HHS recognizes that “reasonable steps” may differ depending on the Recipient’s size and scope of services. HHS advised that Recipients, in designing an LEP program, should conduct an individualized assessment balancing four factors, including: (i) the number or proportion of LEP persons eligible to be served or likely to be encountered by the Recipient; (ii) the frequency with which LEP individuals come into contact with the Recipient’s program; (iii) the nature and importance of the program, activity or service provided by the Recipient to its beneficiaries; and (iv) the resources available to the Recipient and the costs of interpreting and translation services. Based on the Recipient’s analysis, the Recipient should then design an LEP plan based on five recommended steps, including: (i) identifying LEP individuals who may need assistance; (ii) identifying language assistance measures; (iii) training staff; (iv) providing notice to LEP persons; and (v) monitoring and updating the LEP plan. A Recipient’s LEP plan likely will include translating vital documents and providing either on‐site interpreters or telephone interpreter services, or using shared interpreting services with other Recipients. Recipients may take other reasonable steps depending on the emergent or non‐emergent needs of the LEP individual, such as hiring bilingual

staff who are competent in the skills required for medical translation, hiring staff interpreters, or contracting with outside public or private agencies that provide interpreter services. HHS’s guidance provides detailed examples of the mix of services that a Recipient should consider and implement. HHS’s guidance also establishes a “safe harbor” that Recipients may elect to follow when determining whether vital documents must be translated into other languages. Compliance with the safe harbor will be strong evidence that the Recipient has satisfied its written translation obligations. In addition to reviewing HHS guidance documents, Recipients may contact HHS’s Office for Civil Rights for technical assistance in establishing a reasonable LEP plan.

III. California Law – Dymally‐Alatorre Bilingual Services Act. The California legislature enacted the California’s Dymally‐Alatorre Bilingual Services Act (Govt. Code 7290 et seq.) in order to ensure that California residents would appropriately receive services from public agencies regardless of the person’s English language skills. California Government Code section 7291 recites this legislative intent as follows:

“The Legislature hereby finds and declares that the effective maintenance and development of a free and democratic society depends on the right and ability of its citizens and residents to communicate with their government and the right and ability of the government to communicate with them. The Legislature further finds and declares that substantial numbers of persons who live, work and pay taxes in this state are unable, either because they do not speak or write English at all, or because their primary language is other than English, effectively to communicate with their government. The Legislature further finds and declares that state and local agency employees frequently are unable to communicate with persons requiring their services because of this language barrier. As a consequence, substantial numbers of persons presently are being denied rights and benefits to which they would otherwise be entitled. It is the intention of the Legislature in enacting this chapter to provide for effective communication between all levels of government in this state and the people of this state who are precluded from utilizing public services because of language barriers.”

The Act generally requires state and local public agencies to provide interpreter and written document translation services in a manner that will ensure that LEP individuals have access to important government services. Agencies may employ bilingual staff, and translate documents into additional languages representing the clientele served by the agency. Public agencies also must conduct a needs assessment survey every two years documenting the items listed in Government Code section 7299.4, and develop an implementation plan every year that documents compliance with the Act. You may access a copy of this law at the following url: http://www.spb.ca.gov/bilingual/dymallyact.htm

Faculty List

Program Chairs:

Robert B. Baron, MD, MS Professor of Medicine; Associate Dean for Graduate and Continuing Medical Education; Vice Chief, Division of General Internal Medicine Alison Jacoby, MD Professor of Obstetrics, Gynecology and Reproductive Sciences; Director, UCSF Comprehensive Fibroid Center

Faculty: (University of California, San Francisco)

Rebecca Jackson, MD Chief, SFGH Division Associate Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, and of Epidemiology & Biostatistics Vanessa Jacoby, MD, MAS Assistant Professor of Obstetrics, Gynecology and Reproductive Sciences Eliseo J. Perez‐Stable, MD Professor of Medicine; Chief, Division of General Internal Medicine; Director, Medical Effectiveness Research Center for Diverse Populations Jody Steinauer, MD, MAS Associate Professor, Department of Obstetrics, Gynecology and Reproductive Sciences; Assistant Director, Family Planning Fellowship Jeffrey Tice, MD Associate Professor of Medicine

Disclosure

The following faculty speakers, moderators and planning committee members have disclosed NO financial interest/arrangement or affiliation with any commercial companies who have provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity:

Robert B. Baron, MD, MS none

Alison F. Jacoby, MD none

Rebecca Jackson, MD none

Vanessa Jacoby, MD, MAS none

Eliseo Perez‐Stable, MD none

Jody Steinauer, MD, MAS none

Jeffrey Tice, MD none

The following faculty speakers have disclosed a financial interest/arrangement or affiliation with a commercial company who has provided products or services relating to their presentation(s) or commercial support for this continuing medical education activity. All conflicts of interest have been resolved in accordance with the ACCME Standards for Commercial Support:

N/A This UCSF CME educational activity was planned and developed to: uphold academic standards to ensure balance, independence, objectivity, and scientific rigor; adhere to requirements to protect health information under the Health Insurance Portability and Accountability Act of 1996 (HIPAA); and, include a mechanism to inform learners when unapproved or unlabeled uses of therapeutic products or agents are discussed or referenced. This activity has been reviewed and approved by members of the UCSF CME Governing Board in accordance with UCSF CME accreditation policies. Office of CME staff, planners, reviewers, and all others in control of content have disclosed no relevant financial relationships.

Registrant List

Abela Philip Pollock Pines CA

Ambrose Christa Longmont CO

Banka Raj Fresno CA

Baqai Fauzia Fayetteville NC

Batra Romilla Irvine CA

Beacom Rosalind Drayton Valley AB

Belissary Nicole Modesto CA

Berg Cecelia Herald CA

Berkeley Marsha Los Angeles CA

Brown Tamy El Cerrito CA

Burke Charlotte San Ramon CA

Chan Adrienne Melbourne

Chang Alice Rochester MN

Christman Claudia Kailua Kona HI

Cohen Janet Victoria BC

Collette Ron Burnaby BC

Cooper Michele Huntington Beach CA

Cotulbea Elena Sammamish WA

Daghestani Anas Austin TX

De Castro Jacqueline Hanford CA

Dizon Amy Aiea HI

Dobrotwir Andrew Melbourne VIC

Doney Jessica Chandler AZ

Dureg Karen Aiea HI

Elder Brenda Fort Gibson OK

Feakins Cynthia Redwood City CA

Fitz Emily Monmouth OR

Fored Leigh Stockton CA

Forman Rachel Toronto ON

Francis Rodney Lancaster CA

George Michael Napa CA

Gettel Nadine Puyallup WA

Glick John Longmont CO

Glodowski Jodi Amherst WI

Gravelle Lisa Murray UT

Greer Seldon Roseville CA

Guerra Juan Oakland CA

Harvey Kathryn Corralitos CA

Hasenauer Kevin Scotts Valley CA

Hill Laurie Gaffney SC

Hindia Keya O'Fallon MO

Hobbs June Tigard OR

Humphrey Stinson Kamuela HI

Ienna Larissa Portland OR

Jacklin Sadona Las Vegas NV

Johnson Lisa Anchorage AK

Johnson Susan Martin TN

Jones David Honolulu HI

Kassis Adrienne San Francisco CA

Khalili Tabrizi

Hessam San Diego CA

Klassen Cathlyn Redmond WA

La Saulle Brooke San Francisco CA

Lasher Lisa Paducah KY

Leifer Timothy Pasadena CA

Leung Jennifer San Diego CA

Lewis Leigh Portland OR

Liu Sai‐Ling Nome AK

Lusk James Seattle WA

Mason Danielle Mentone CA

McMillen Douglas Seattle WA

Meals Sam Fairmont MN

Mehta Sonia Northbrook IL

Messner Eric Sunnyvale CA

Miller Terina Oakland CA

Moga Christopher New Prague MN

Mohling Shanti Taos NM

Myles Angela Crossett AR

Nahar Pravin Warners Bay NSW

Nelson Yvonne Kaukauna WI

Pan Jo Costa Mesa CA

Payne Susan Lake Oswego OR

Pearson Lawrence Fallbrook CA

Pena‐Pridmore

M. Rosalie Browns Valley CA

Peyton Michael Drayton Valley AB

Ppowlen Angela Berkeley CA

Purvis Janey Bend OR

Pyant‐DanPullo

Courtney Freeport IL

Raman Srilata Fremont CA

Raymundo Michele Encinitas CA

Reddy Ravi Kaneohe HI

Rojas Joseph Las Vegas NV

Rojas Kirsten Las Vegas NV

Roybal G. Michael Pasadena CA

Saj Marta Naperville IL

San Tun Sabine Kailua Kona HI

Sheets Patrick Rensselaer IN

Shi Michael Livermore CA

Sirotin Nicole Woodside NY

Smith Dana Edmonton AB

Spangler Sherard Charlotte NC

Spencer Paula Happy Valley OR

Stone Barry Provo UT

Sturgeon Treena St. Louis MO

Swift Jean Kamuela HI

Tabas Jeffrey San Francisco CA

Taniguchi Paula Folsom CA

Tannous Rawah Austin TX

Tate Jennifer Longview WA

Tatini Usha Scottsdale AZ

Thiim Christian Irvine CA

Thompson Sharon Phoenix AZ

Ton Kiti Phoenix AZ

Van Dyke Michael Geyserville CA

Walterfang Mark Melbourne

Williams Michael Santa Rosa CA

Wong Juliana Danville CA

Yeturu Sumana Irvine CA

NOTES

Presentation slides will not be used for this session.

6/21/2013

1

Breast & Cervical Cancer Screening:

Updates and Controversies

Rebecca Jackson, MD

Professor, Ob/Gyn & Reproductive Sciences

Epidemiology & Biostatistics

University of California, San Francisco

I have no financial interests to disclose

Part I

Cervical Cancer Screening

1.Why USPSTF and other organizations changed guidelines (interval, start and stop ages)

2.HPV co-testing

3.What to do with HPV +, pap –

4.Which is better: pap or liquid-based cytology

Part II

Breast Cancer Screening

1. Why USPSTF changed guidelines for 40-49 yo women from B to C

2. Risk estimation for 40-49yo

3.Evidence on newer screening techniques: U/S, MRI, digital mammography

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Cervical Cancer in US

Pap smears are the most effective screening test ever invented….

Q1: 19 yo brought in by mom for pap. Sexually active since age 15. 4 male sexual partners. In addition to STI screening & counseling on safe sex and birth control, what else would you do?

A. Traditional Pap smear

B. Liquid-based cytology (eg thin prep)

C. HR-HPV only (without cytology)

D. HR-HPV with cytology (ie co-test)

E. Nothing more

Why does pap screening work?

• Sensitivity and specificity of pap/cytology not great

BUT

• The organ is easily accessible for screening

• Natural history is favorable : – precursor exists that is detectable and treatable;

– time course before cancer develops is long

– many opportunities to detect . Even if one test is false negative, get another chance.

• It is cost-effective because many years of life are saved because cancer is actually prevented.

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Can we do better?

• Half of cervical cancers occur in women who are not screened or inadequately screened. These women tend to be poor, uninsured, with lack of access to care– A more sensitive test (like many marketed directly

to the public eg Thin Prep), will not fix this problem!

• In poor countries, cervical cancer remains a huge problem.

Can we do better? YES!• False +: Although colposcopy is not that

morbid, false +’s still cause anxiety, labeling, and are costly. – Spacing the screening interval, starting screening

later and HPV typing used correctly in conjunction with cytology, will reduce false +’s and colposcopies

• Over-treatment: Only 30% of untreated CIN3 becomes invasive cancer (over 30 yrs). Destroying all CIN3 =over-treatment. Main harm is preterm delivery. • Smart screening, biomarkers, risk-based

approaches and less aggressive (but still evidence-based) treatment guidelines can help.

Potential adverse effects of LEEPPreterm delivery 70% Low birth weight 82% PPROM 169%

Lancet 2006 367:489-98

Caution: No randomized trials.

Potential adverse effects of cold knife cone

Perinatal mortality 187% Severe preterm delivery 178% Extreme low birthweight 186%

BMJ 2008 Sep 18;337

2012 USPSTF Cx Ca

• STRONGLY RECOMMENDS (“A”)

• Who? Women with cervix, regardless of sexual history

• Begin: Start age 21

• Interval:. 21-29: cytology q 3yr; after 30: can do q 5yr with cyto+HPV or cont’d q 3 yr cyto alone

• End: Age 65 if adequate prior screening (as per

ACS/ASCCP) and not at high risk for cx cancer (HIV, DES, immunocompromised)

• Other: Recommends against any HPV testing in <30yo (“D” grade)

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Other US Guidelines very similar

ACS/ASCCP/ASCP (2012)

• Begin: age 21

• Interval: Age 21-29: Q 3yr, HPV as a reflex test not as primary screen. After 30: preferred= cyto + HPV q 5 yrs; cyto alone q 3yrs also ok.

• End: age 65 if 3 nl paps or 2 nl HPV within 10 yrs, most recent within 5yrs. Continue to screen for 20yr after CIN 2/3. Do not resume even if new sex partner

ACOG (2009):

• Same

• 21-29: Q 2yr . After 30, Q 3 yrs if 3 consecutive, satisf normals & not immunocompromised. Co-screen with HPV q 3yr approp if >30yo.

• End: 65-70yo if 3 conseqnls and no abnormals in last 10 yrs

What’s similar• All strongly recommend against starting

before age 21

• None recommends annual screening

• All recommend against HPV alone or as a co-test in women <30 (ok as a reflex test after abnormal pap per ACS/ASCCP)

• All recommend no screening after hyst as long as no history of CIN2+

• All recommend stop at age 65

• None recommend changes in screening for those who’ve had HPV vaccine

What’s new/different?

• Co-test with HPV: – 1st time USPSTF has recommended co-

testing with HPV (ok for women who want to extend interval to 5 yrs)

– ACS/ASCCP: prefers co-test with 5 yr interval; acceptable to do cyto alone q3yr

• F/U after CIN2+: ACS/ASCCP: 20 yrs ACOG: 10 yrs, USPSTF vague

• Criteria to end at age 65: ACS/ASCCP—clearer guidance than others

Why is it ok to delay screening until age 21?

• Cervical cancer extremely rare in younger women

• HPV infection very common immediately after onset of intercourse and 90% is cleared by host within 2 yrs

• When dysplasia does occur in adolescents, it tends to be low grade and transient (90% regression at 3 yr).

– If persists, plenty of time to detect and treat because long progression time of pre-invasive lesions to invasive cancer

• Excision of dysplasia associated with preterm birth

• Labels adolescent with a sexually transmitted infection

• Bottom Line: HPV infection typically cleared without help from us. Screening in adolescents therefore leads to treatment that is largely over-treatment . Harms>>>Benefits

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Why is it ok to lengthen the screening interval?

• After several normal tests, very small likelihood of missed disease

• If newly acquired infection, high likelihood of regression and long time to invasion

• The more tests you do, the more false +’s. Mathematical reality: prevalence is low, tests not extremely specific.

21-29yo: The evidence for q 3 yr interval

• ACS/ACSSP: “Annual screening leads to a very small increment in cancers prevented at cost of large excess of unnecessary procedures and treatments.”

• 3 vs 1 yr screening (21-29 yo)– Lifetime risk of cancer death: 0.03/1000 vs

0.05/1000 (decrease of 2 per 100,000)– Lifetime colposcopy rates 2000/1000 vs

760/1000 women (increase of 1240 per 1000)

Why the difference between <30 and >30 yo?

• HR-HPV co-testing becomes clinically useful after age 30

• In <30yo: HPV often positive, often transiently. Therefore, HPV testing not clinically useful.

• > Age 30: HPV positivity more likely to represent persistent HPV which is a significant risk factor for dysplasia/cancer. Conversely, HPV negativity is a strong negative predictor.

Role of HR-HPV testing

• Greater sensitivity, lower specificity, better reproducibility than pap/cytology

• HPV tests may better forecast which women will develop CIN3+

• More sensitive for adeno-ca

• Has potential for increased detection (more sensitive) and increased interval of screening (more predictive of CIN3 risk)

• Harm=increased colpo/treatment. This can be mitigated by increasing interval to 5 yr

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ModelingFalse + Colposcopies CIN 2-3 Cancers Cancer

deaths

Cytology q3 years, ages 21-65

350 758 80 8.5 1.55

Cytology q3 years until age 30 then co-testing q5 years

281 625 85 7.1 1.29

Per 1000 women screened over a lifetime.

Modeling studies support similar benefits of co-testing every 5 years and cytology every 3 years, demonstrating small differences in expected cancer cases and cancer deaths.

Co-testing caveats

• HPV has decreased specificity so if we co-screen more often than q5 years, patients will incur greater harm without benefit – Before doing co-test, ensure patient is willing to be

screened every 5 years

• HPV-based strategies also lead to more positives – Some women will need prolonged surveillance

– Some women who would otherwise be able to stop at age 65 will require continued screening beyond age 65

• What to do with HPV+, cytology negative?

Cotesting: what to do with HPV positive/Pap normal women?

About 8-11% of women ages 30-55 in the US will have a positive HPV test (HC2) and a normal Pap test (Ann Int Med April, 2008)

At Kaiser Northern CA, about 3-7% of women ages 30-55 have a positive HPV test (HC2) and a normal Pap test (Obstet Gynecol March 2009)

HPV positive/Pap normal women

Recommendations by ASCCP and ACOG: • Repeat co-test at 12 months.

– If negative q 5yr screening– If still HPV+ or if >= LSIL AS-CUScolposcopy.

2012 ASCCP Guidelines; ObstetGynecol, Apr 2013

Alternate recommendation by ASCCP:• Perform HPV genotype-specific typing for 16 or

16/18. – if positive, perform colposcopy. – If negative, repeat co-test at 12 months.

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What’s Better: Pap or LBC?

• N=89,784, cluster RCT– No difference in detection rate (sensitivity) or

PPV, fewer unsatisfactory tests with LBC Conclusion: no difference

• 2nd RCT, different design, similar findings• Evidence based practice center & 2

reviews conclude: no difference in relative or absolute sensitivity or specificity

Siebers, 2009

Conclusions: Cervical Cancer

• Cervical cancer screening in the US is already very successful at decreasing cervical cancer incidence and morbidity

• Now the goal is to decrease harm by decreasing false + and over-treatment:– Start screening later (age 21)

– Screen less often (q 3yr)

– Use HPV co-test to extend interval to 5yr

– Return to traditional pap smear?

Part II

Breast Cancer Screening

1. Why USPSTF changed guidelines for 40-49 yo women from B to C

2. Risk estimation for 40-49yo

3.Evidence on newer screening techniques: U/S, MRI, digital mammography

Q2: 43 yo woman with normal mammo 2 yrs ago but with “extremely dense” breasts. No other breast cancer risk factors. She would like your recommendation re: screening.

A. Wait until age 50 and then get mammo

B. Regular (film) mammo

C. Digital mammo

D. Mammo plus ultrasound

E. Mammo plus MRI

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2009 USPSTF recommendations

• 50-74 yo: RECOMMENDS (“B”)• 40-49 yo: Individual decision (ie don’t

offer routinely) (“C”) (was“B” in 2003)

• What? Mammography with or without clinical breast exam

• How often? Every 2 years (was every 1-2 years in 2003)

• When stop? After age 75, evidence is insufficient to make recommendation (“I”)

USPSTF Rec’s: A=strongly recommends; B=recommends; C=no recommendation; D=Recommends against; I=insufficient evidence

2009 Meta-analysis by USPSTF

• 1 new trial specifically in women 40-49

• 1 trial with updated data

Nelson, Annals Int Med, 2009

40-49 yo womenNelson H D et al. Ann Intern Med 2009;151:727-737

2 trials designed to look at women in 40’s

Criticism: Most of these trials include benefits that may have accrued to women due to screening that occurred after the age of 50. On other side: Most were done long ago and mammo technology improved today so benefits may be underestimated. However, modeling studies using updated sensitivity/specificity show same magnitude of benefit

Ratio of Benefits vs Harms• Benefits= decreased mortality, increase in

# life years gained

• Harms (USPSTF doesn’t include financial costs in their analysis)

– screening (radiation risk, pain, inconvenience)

– diagnostic work-up for false positive (49% over 10 mammos, anxiety, 1/3 of total screening cost)

– over-diagnosis (harms assoc with overtreatment, 10-25% of invasive, 34% of DCIS)

• Benefit/Harm ratio varies significantly by patient age

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Why the change? Conceptually…

In women 40-49 c/w older women…

• Smaller number of deaths are prevented because: – Lower incidence of breast cancer

– Lower sensitivity of mammography

– Cancers often more aggressive, less treatable

• More false positives– Lower specificity and prevalence lower

positive predictive value & more false positives

Why the change? Numerically….

Tice, Prim Care Clin Office Pract 2009

Why the change from B to C for 40-49 yo’s from 2003 to 2009?

Bottom Line: USPSTF uses absolute benefit, not relative benefit and strongly considers risk of harm to healthy women (which is subjective and debatable).

The USPSTF notes that a "C" grade is a recommendation against routine screening of women aged 40 to 49 years. The Task Force encourages individualized, informed decision making about when to start...

Screening frequency 1 vs 2 yrs

• Similar reduction in mortality with screening every one or two years

• Every two years (compared to annually) maximizes benefits of screening & minimizes harms

Mandelblatt, Annals IM, 2009

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Other Guidelines

Given the lack of consensus, involve patient in the decision-making….

Tipping the balance toward benefit in 40-49yo

• Digital mammography– Increased sensitivity in 40-49yo and women

with dense breasts c/w film

– Studies conflict on specificity— likely slightly lower than film

• Risk based screening– If can limit the screened population to one

with similar prevalence of cancer as older women, ratio of benefit to harm becomes more favorable

Risk-based approach

• Modeling by CISNET to determine the elevated risk necessary in 40-50yo to achieve same risk/benefit ratio as in >50yo with biennial screening (risk=false +, benefit=life years gained)

• Elevated risk of breast cancer necessary to achieve parity:– Biennial filmRR=1.6, annual3.6

– Biennial digitalRR=2.0, annual4.3van Ravesteyn NT, Ann Intern Med, 2012

New Meta-analysis of risk factors 40-49yo

• Compared to average risk US popln

• Protective: Overwt/obese (0.80), fatty on mammo (0.46), late menarche (0.8), >3 births (0.73), menopause (0.60), ERT (no ut, 0.70)

Nelson, Ann Int Med, 2012

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New Technologies

• Digital Mammography

• Breast MRI

• Ultrasound plus Mammography

• Thermography?

Digital mammography

• Sensitivity:– Most studies show higher sensitivity in 40-49.

– One large study (DMIST) showed lower sensitivity in women >65yo

• Specificity:– Very mixed: some show no difference, most

show decreased specificity

2 largest US studies: <50yo

DMIST (research study)

• N=42,760 women, 14,335 <50yo

• All women got both digital and film mammo

• One year f/u• Sensitivity: 51% (F) vs

78% (D)• Specificity: both 90%

• Calculated PPV based on 2.8/1000 prevalence: 1.4 vs 2.1%,

BCSC (community based)

• N= 329 260 women, in <50yo: 77,392 digital, 221,696 film

• Women got either digital or film depending on site

• One year f/u• Sensitivity: 76(F) vs 82%(D)

• Specificity: 89.7 vs 88%

• Calc PPV: 2.1 vs 1.9%,

Pisano, NEJM, 2005 Kerlikowske, Ann Int Med, 2011

Bottom Line: Digital

• More sensitive for women<50, extremely dense breasts, ER negative breast cancer

• Easier access, transmission and storage of images, lower average dose of radiation

• Trade-off of slightly lower specificity

• From BCSC: in 10,000, 2 additional breast cancers for 170 additional false positive results

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Q2: 43 yo woman with normal mammo 2 yrs ago but with “extremely dense” breasts. No other breast cancer risk factors. She would like your recommendation re: screening.

A. Wait until age 50 and then get mammo

B. Regular (film) mammo

C. Digital mammo

D. Mammo plus ultrasound

E. Mammo plus MRI

Caution: comparing detection rates….

• Studies of new techniques typically compare detection rates

• Key q is : does improved detection lead to overall benefit (decreased mortality/morbidity)

• Observational studies prone to lead-time and length bias

• Earlier treatment may not be better than later– Ex: 10,000 50 yo’s followed for 20 yrs. Without

mammo, 260 will die of breast cancer. With biennial mammo: 223 will die. Screening averted 37 deaths per 10,000 over 20 years = 1 death saved/270 women for 20 years

Ultrasound + Mammo• Potentially useful in dense breasts

• No RCT’s of normal risk women or women with only risk being dense breasts

• Meta-analysis in women with dense breasts: – 6 cohort studies, only 2 included adeq f/u (nec to know

false + and -)– Studies small; few cancers detected (results unstable)– CONCLUSION—more study necessary

• In very high risk women (dense + 1 RF), U/S detected additional 3.7-5/1000, 7-10% biopsy rate

Nothacker BMC Cancer 2009

Berg, JAMA, 2012

MRI + Mammo• For high risk women (BRCA, personal h/o brst ca,

lifetime risk >20%)

• Systematic review– No RCT’s, no studies with long term f/u or mortality,

MRI more sensitive (80-100%) vs 25-59%, less specific 73-93% (3-5 fold higher recall rate)

– Mammo more sensitive for DCIS therefore need both

– Concl: more study needed, unknown if lead time/ length bias or real benefit, screening doesn’t detect nor cure 100% therefore consider risk reducing strategies

• ACS: Annual MRI + mammo for women with lifetime risk >20%

Warner, Ann Int Med, 2008

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Conclusions: Breast Cancer

• 40-49 informed decision– Risk evaluation—recommend if risk 2x greater

than general popln; Digital if decide to screen

• 50-74 screen every 2 years – Best benefit/harm ratio from 50-65yo

• Ultrasound + mammo for dense breasts… – More study needed.

• MRI + mammo for very high risk…. – May be useful, longer f/u necessary to confirm

benefit, ACS recommends if>20% lifetime risk

Perspective: Days of life gained and compliance with screening

Smoking cessation = 240 days gained

Last words

• Preventive interventions require a high burden of proof: the “do no harm” principle.

• Want to know that early detection improves outcomes. Comparing detection rates of newer technologies is insufficient b/c of lead-time and length bias.

• Guidelines are designed to maximize population screening benefits and minimize population screening harms—this is hard to explain to individual patient

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OVARIAN CANCER SCREENINGAND

MANAGEMENT OF ADNEXAL MASSES

Alison Jacoby, MD

UCSF

Learning Objectives

• Review ovarian cancer risk factors

• Discuss ovarian cancer screening alternatives

• Analyze management strategies for premenopausasl and postmenopausal adnexal masses

• Review ACOG guidelines for referring a patient with an adnexal mass to a gyn oncologist

• Compare CA 125 and OVA1 tests

Ovarian Cancer ScreeningCase One

WL is a 54 yr old P0 who presents for an annual exam. She mentions seeing a segment on the evening news last week about improvements in ovarian cancer screening and she would like to be tested.

She is without abdominal complaints and has no family history of gynecologic or gastrointestinal cancers but she would feel better knowing the test was negative.

How would you counsel her?

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Case One

Ovarian Cancer Screening options:

1. Perform a bimanual pelvic exam

2. Order a pelvic ultrasound

3. Send a serum CA 125

4. Discuss lack of efficacy of current screening tests

Case Two

SR is a 42 yr old woman who you are meeting for the first time. In the course of eliciting her medical and family history, you learn she has several relatives with breast and ovarian cancer. Her cousin and aunt had breast cancer in their 40’s and her grandmother died from ovarian cancer.

She’s been having routine screening mammograms but you wonder if you should be doing more surveillance.

What would you do?

Case Two

What would you do next?


2. Order a pelvic US

3. Recommend both tests

4. Refer to a genetic counselor

Cancer statistics, 2012

CA: A Cancer Journal for CliniciansVolume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1

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Ovarian Cancer Risk FactorsRR Lifetime Probability (%)*

Familial Ovarian Ca Synd Unknown 30-50

2-3 Relatives w/ Ovarian Ca 4.6 5.5

1 Relative w/ Ovarian Ca 3.1 3.7

No RF’s 1.0 1.8

Past OC use 0.65 0.8

Past Pregnancy 0.5 0.6

Infertility 2.8

Past Breastfeeding 0.8

Tubal Ligation 0.6

* Indicates probability of Ov Ca in a 50 yr old woman

Ovarian Cancer Risk FactorsHormonal and Reproductive Factors

• Nulligravity

• Early menarche (age < 12)

• Late menopause (age >50)

• Endometriosis

• PCOS

Genetic factors- 10-15% of cases

• BRCA mutations

• Lynch II Syndrome

Environmental

• Talc

• Smoking

• Diet ?

• Exercise ?

• Obesity (BMI >30)

Ovarian Cancer Protective Factors

Combined E/P OC’s• 45 studies from 21 countries

• Any use lowers risk compared to non-users

• Longer duration of use assoc’d w/ lower risk reduction

• Protective effect lasts 30 yrs

• No data for non-oral E/P contraceptives (patch, ring)

Hysterectomy and Tubal Ligation• Both reduce RR by 34%

Multiparity

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Ovarian Cancer Screening Rationale

75% present w/ Stage III disease

Barnholtz-Sloan JS et al. Am J Obstet Gynecol. 2003;189(4):1120

Benefit Risk

Detect Early Stage Ovarian Cancer

Decrease Mortality Rates

False Positive Results

Harm from Unnecessary Interventions

Screening test characteristics

What is an acceptable positive predictive value?1. 90%

2. 60%

3. 30%

4. 10%

Screening test characteristics

• Given the low prevalence of ovarian cancer….

• Given a test with an 80% sensitivity…..

• To achieve a PPV of ____ would require a screening test to have a specificity of …..

• 99.6%

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Potential Screening Tests

• Pelvic examination

• Pap smears

• Tumor markers- CA 125, HE4

• Imaging tests- US, CT

• Combination of modalities

CA 125

• Glycoprotein antigen on tumor cells

• FDA approved for monitoring treatment response and recurrence in women w/ Ov Ca

• Sensitivity

• Early stage disease: 50%

• Advanced stage disease: > 80%

• Specificity: ~68%

• Increased in a variety of benign and malignant conditions

• Endometriosis, fibroids, PID, other cancers, etc.

CA 125

Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial

• >78,000 healthy women, age 55-74

• Randomly assigned to screening or control groups

• Ov Ca Screening: annual serum CA 125, TVUS or both for 5 yrs

• Follow-up for 13 yrs

• At baseline, 436 women had elevated CA 125

• PPV 3.7%

Buys SS, Partridge E, Greene MH, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol. 2005;193(5):1630-9.

Pelvic Ultrasonography

• 4526 women at high risk for Ov Ca screened annually

• After ~13,000 scans, all of the ovarian, fallopian tube and peritoneal cancers identified were Stage III

• NO cases of early disease detected

Fishman DA, et al. Am J Obstet Gynecol. 2005;192(4):1214.

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Pelvic Ultrasonography

• 37,293 Asx, low risk women age >50

• Study began in 1987, average f/u 5.8 yrs

• Specificity: 98.5%

• PPV: 8.9%

• NNT: 11 operations performed per case of Ov Ca

• Early detection: 70% of 47 screen-detected Ov Ca cases Stage I or II

• Lower mortality: 5 yr survival for screen-detected vs. unscreened Ov Ca cases: 84.6% vs. 53.7%

van Nagell JR Jr et al. Obstet Gynecol. 2011;118(6):1212.

CT Colonography

• 2869 women screened

• 70 women incidental finding of adnexal abnormality

• Number found to have Ovarian Ca?

• 4 women with normal adnexae dx’d with Ov Ca within 4 yrs

NONE

Pickhardt PJ, Hanson ME Radiology. 2010;257(1):144.

CA 125 and TVUS

Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial

• >78,000 healthy women, age 55-74

• Ov Ca Screening: annual serum CA 125, TVUS or both for 5 yrs

• Follow-up for 13 yrs

• Early detection: NO

• Lower mortality: NO

• High false positive rate: 541 women underwent surgery without a cancer diagnosis

• Harm: 15% had at least 1 serious surgical complication

Case One

WL is a 54 yr old P0 who presents for an annual exam. She mentions seeing a segment on the evening news last week about improvements in ovarian cancer screening and she would like to be tested.

She is without abdominal complaints and has no family history of gynecologic or gastrointestinal cancers but she would feel better knowing the test was negative.

How would you counsel her?

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Case One

Ovarian Cancer Screening options:

1. Perform a bimanual pelvic exam

2. Order a pelvic ultrasound


4. Discuss lack of efficacy of current screening tests

Case Two

SR is a 42 yr old woman who you are meeting for the first time. In the course of eliciting her medical and family history, you learn she has several relatives with breast and ovarian cancer. Her cousin and aunt had breast cancer in their 40’s and her grandmother died from ovarian cancer.

She’s been having routine screening mammograms but you wonder if you should be doing more surveillance.

What would you do?

Case Two



2. Order a pelvic US

3. Recommend both tests

4. Refer to a genetic counselor

Management of Adnexal Masses

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Case Three

A healthy 32 y.o. P2 is referred to you for management of an asymptomatic pelvic mass discovered during a routine pelvic examination 10 wks ago. A pelvic US at that time revealed a 7 cm, anechoic right ovarian cyst without septations or mural nodularity. There is no free fluid in the pelvis. She continues to have regular cycles and takes no medications.

What are the key components of this scenario?

Right Ovarian Cyst

All of the following are in your DDx except:

1. Physiologic or functional cyst

2. Serous cystadenoma

3. Serous cystadenocarcinoma

4. Paratubal cyst

Additional information:

10 wks later, a physical examination confirms a mobile mass and a pelvic US reveals a slight increase in size of the cyst to 8.5 cm.

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What is the most likely diagnosis now?




4. Paratubal cyst

What are her options?

• Observation

• Cyst content aspiration

• Laparoscopic ovarian cystectomy

• Laparoscopic oophorectomy

• Check tumor markers and refer to a gyn oncologist

Observation vs. Intervention

• Asymptomatic

• Low likelihood of malignancy

• Risks of surgery

• Natural history suggests growth will continue

• Tissue sample to confirm benign

• Risk for ovarian torsion necessitating urgent surgery

Cyst content aspiration

Easy to accomplish but…..

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Cyst content aspiration

Easy to accomplish but…..

• Potential spillage of malignant cells

• Low diagnostic yield

• Reaccumulation of fluid/cyst

Laparoscopic cystectomy

What is the most likely diagnosis now?




4. Paratubal cyst

Case 4

• A 54 y.o. G0 post-menopausal woman is referred to you by an NP for evaluation of a left ovarian cystic mass. The patient was experiencing some non-specific abdominal bloating several weeks ago which prompted the pelvic ultrasound. A 5 cm, unilocular, anechoic cyst with an echogenic mural nodule is described. Color Doppler imaging shows normal vascular flow. There is no free fluid in the pelvis. Her grandmother died from ovarian cancer.


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Mural Nodule


1. Repeat an ultrasound in 6-12 weeks

2. Refer to a gyn oncologist

3. Order a serum CA 125

4. Order a serum OVA1®

5. Perform a L/S oophorectomy

ACOG/SGO Referral Guidelines-Preoperative consultation with a gynecologic oncologist for one or

more of following criteria:

Premenopausal women1. CA 125 greater than 200 units/mL

2. Ascites

3. Evidence of abdominal or distant metastasis

4. Family history of breast or ovarian cancer (in a first-degree relative)

The revisions to the College guidelines proposed by Dearking include:

1) eliminating the family history of one or more first-degree relatives with ovarian or breast cancer

2) lowering the CA 125 threshold in premenopausal women to 67 units/mL.

ACOG/SGO Referral Guidelines-Preoperative consultation with a gynecologic oncologist for one or

more of following criteria:

Postmenopausal women (older than 50 yrs)

1. Elevated CA 125 (> 35 units/mL)

2. Nodular or fixed pelvic mass

3. Ascites

4. Evidence of abdominal or distant metastasis

5. Family history of ovarian or breast cancer (in a first-degree relative)

The revisions to the College guidelines proposed by Dearking include: 1) eliminating the family history of one or more first-degree relatives with ovarian or breast cancer

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OVA1®

Multivariate Index Assay• Consists of 5 biomarkers

CA125Prealbumin

Apolipoprotein A1 Ovarian malignancyBeta 2 microglobulin risk index scoreTransferrin

• Cost- $600 vs. $100 for CA 125

OVA1®

Ovarian Malignancy Risk Index Score (0-10)

Premenopausal: Low prob, < 5.0

High prob, > 5.0

Postmenopausal: Low prob, < 4.4

High prob, > 4.4

OVA1® vs. CA 125

OVA1 CA 125

Sensitivity 94 77

Specificity 35 68

PPV 40 52

NPV 93 87

OVA1: When test is positive, 40% have cancer

When test is negative, 93% have a non-malignant mass

Miller et al, Obstet Gynecol, 2011

Guideline Applied,

by Menopausal

Status

Probability

of Malignancy

Before Testing

(Prevalence)

Proportion

With Positive

Test Results

Revised Probability

of Malignancy When

Test Result is Negative

Premenopausal Modified College

College-MIA 1939

63

8

5

Postmenopausal Modified College

College-MIA 4151

83

16

12

Sawaya & V Jacoby, Obstet Gynecol, 2011

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Case 4

• A 54 y.o. G0 post-menopausal woman is referred to you by an NP for evaluation of a left ovarian cystic mass. The patient was experiencing some non-specific abdominal bloating several weeks ago which prompted the pelvic ultrasound. A 5 cm, unilocular, anechoic cyst with an echogenic mural nodule is described. Color Doppler imaging shows normal vascular flow. There is no free fluid in the pelvis. Her grandmother died from ovarian cancer.



1. Repeat an ultrasound in 6-12 weeks

2. Refer to a gyn oncologist

3. Order a serum CA 125

4. Order a serum OVA1®

5. Perform a L/S oophorectomy

Recommendation

Women of average risk for ovarian cancer:

Do not offer screening

• ACOG, USPSTF, SGO, Canadian Task Force

Recommendation

Women with family history of Ov Ca but lowsuspicion for hereditary ovarian cancer

syndrome (BRCA, Lynch II):

Limited evidence for effectiveness of screening and potential for adverse effects of screening

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Recommendation

Women with high risk family history concerning for hereditary ovarian cancer syndrome:

Refer to Genetic counselor for discussion of BRCA mutation testing

SGO, National Comprehensive Cancer Network

In Conclusion…

The objectives of this presentation were to provide a….

• Reminder of Ovarian Cancer risk factors

• Evidence based review of Ovarian Cancer screening outcomes

• Clinically relevant examples of adnexal mass management

• Guidelines for referring patients to a gyn oncologist

• Balanced discussion of the new (heavily marketed) OVA1 test

Cancer Screening 2013

Current Controversies in Lung, Colon, and Skin Cancer Screening

Jeffrey A. Tice, MD

Division of General Internal MedicineUniversity of California, San Francisco I have no conflicts of interest

Selected Controversies

• Lung Cancer Screening

– Does screening work?

– Chest x-ray?

– What about low dose CT?

• Colorectal Cancer

– What test and how often?

– Are there new screening options?

• Skin Cancer

– Should we screen?

Estimated New Cancer Cases* in the US in 2013

Cancer Death Rates* Among Women, US,1930-2009

USPSTF

• Rigorous review of existing peer‐

reviewed evidence

–Ratings reflect the strength of the evidence on the harms and benefits of a preventive service• Task Force does not consider the costs of providing service or make recommendations for coverage

USPSTF Grades

Grade Evidence Recommendation

A High certainty of substantial net benefit Provide

B High certainty of moderate net benefitModerate certainty of moderate/substantial net benefit

Provide

C Moderate certainty that net benefit is small Selectively offer/provide

D No net benefit or harms outweigh benefits Do not provide

I Insufficient evidence regarding balance of benefits and harms

Lung Cancer Screening

Question?

• Ms. Nicka Teen is a 69 year old woman with a 50 pack-year history of smoking and COPD. You have previously been unsuccessful in encouraging her to quit smoking. She comes in for a check-up, is worried about developing lung cancer and wants to know what test you think she should have. What do you recommend?

– Chest X ray

– Sputum cytology

– Spiral CT

– None of these tests

Lung Cancer Screening:Systematic Review of Chest X-rays

• 7 trials of lung cancer screening

• Frequent screening with chest x-rays was associated with an increase in mortality

– RR 1.11 (95% C.I. 1.00-1.23)

• No difference in chest X-ray plus cytology versus chest X-ray alone

Manser, Thorax, 2003

PLCO: Lung Cancer Screening

• PCLO randomly assigned 154,901 adults

aged 55 through 74 to annual CXR for 4

years vs. usual care

• Followed for 13 years

• Cumulative lung cancer mortality

– 14.0/10,000 py screening group vs. 14.2/10,000 py control group

–Rate ratio: 0.99 (95% CI 0.87‐1.22)

Oken MM. JAMA 2011;306:1865

Low Dose Spiral Computed Tomography

• Scans lung in < 20 seconds (single breath)

• No IV contrast

• More radiation exposure than CXR but less than conventional CT

• Can detect much smaller lesions than chest X-ray

The National Lung Screening Trial (NLST)

53,454 participants randomized to CT or CXR

- Current or former heavy smokers: ≥ 30 pack-years

- Ages 55 to 74

- Annual CT scans x 3 years. 6.5 years follow-up

LDCT CXR∆ RR (95% CI)

Lung Cancer Deaths 356 44387 .80 (.73-.93)

Any death 1877 2000121 .93 (.86-.98)

Number needed to invite to screen

• NNI to prevent one lung cancer death in 6.5 years = 320

• NNI to prevent one death from any cause in 6.5 years = 218

Balanced by…

• 75,000 CT scans

• 18,146 positive tests

• 17,066 false positive tests

• 713 thoracotomy / mediastinoscopy

• 671 bronchoscopies

• 322 needle biopsies

• To prevent 87 deaths from lung cancer

NLST Harms

• False positives

– At least 1 positive test in 39% CT

• False positive results in 96% CT

• Possible over diagnosis

–Higher cancer incidence with CT

• 1060 vs. 941 cancers

• Rate ratio 1.13 (95% CI 1.03‐1.23)

• Radiation exposure

• Incidental findings

Concern: Control = Chest x-ray

• Screening with CXR was ineffective in 30,341

subjects in the PLCO meeting NSLT criteria

– 30+ pack year, smoked within past 15 years

–Cumulative lung cancer mortality was 36.1/10,000 py screening group vs. 38.3/10,000 py controls• Rate ratio: 0.94 (0.81‐1.10)

• Reasonable to conclude that CT screening is

more effective than usual care

Health Policy not yet established

• ~ 94 million current or former smokers in the U.S.

• ~ 7 million meet NLST criteria

• Implementation issues

–Multidisciplinary teams

–Trained radiologist

• Expensive… $ $ $

Guidelines and recommendations

• Recommend for those meeting NLST entry criteria at specialized centers

–ACCP / ASCP / ATS

–ACS

–ALA

–NCCN

–AATS

Guidelines and recommendations

• USPSTF recommendations

–Screening: “I” insufficient evidence (2004)

–Smoking cessation counseling: “A”(2009)• 85% of cancers among smokers attributed to smoking

Trends in Tobacco Use and Lung Cancer Death Rates* in the US

Trends in Cigarette Smoking, Adults 18 and Older, US, 1965-2011Trends in Cigarette Smoking* among Female High School Students,

US, 1991-2011

Primary Prevention OfLung Cancer

• Smoking cessation






• Smoking cessation!!!!!

Implications


• Strict adherence to NLST entry criteria

– 55-74 years, 30+ pack years

• Use experienced centers / demonstration projects to ensure quality and effectiveness

Colorectal Cancer

Question?

• What do you most commonly recommend for colorectal cancer screening?

– Fecal occult blood test (FOBT)

– Sigmoidoscopy

– Colonoscopy

– Air contrast barium enema

– Virtual Colonoscopy

– Fecal DNA

– Fecal immunochemical Test (FIT)

New Joint Guideline: ACS, ACR,…

• FOBT annually

• Fecal immunochemical test annually

• Flexible sigmoidoscopy every 5 years

• DCBE every 5 years

• CT colonography every 5 years

• Colonoscopy every 10 years

• Stool DNA testing (interval uncertain)

Levin, Gastroenterology, 2008

Joint Guideline Recommendation

• Clinicians should make patients aware of the full range of screening options

• Offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a test that is primarily effective at cancer detection

• CRC prevention should be the primary goal of screening

USPSTF

• USPSTF: “A” recommendation (2008)

–Routine screening from age 50 until 75• Individualized decisions from 76 to 85

• No screening after 85

USPSTF Annals IM 2008

USPSTF (continued)

• USPSTF: “A” recommendation (2008)

–Acceptable modalities • Colonoscopy

• Fecal blood test– Fecal immunochemical test, high‐sensitivity hemoccult

• Flexible sigmoidoscopy

– Insufficient evidence for CT colonography, fecal DNA

USPSTF Annals IM 2008

Colonoscopy

• American College of Gastroenterology

guidelines for colorectal cancer

screening (Rex DK. Am J Gastroenterol 2009;104:739)

–Colonoscopy… remains the preferred CRC screening strategy

Colonoscopy: RCTs in progress

• VA

– Colonoscopy versus fecal immunochemical test in reducing mortality from colorectal cancer

• Spain

– Colorectal cancer screening in average‐risk population: immunochemical fecal occult blood testing versus colonoscopy

• Netherlands

– Colonoscopy or colonography for screening

Flexible Sigmoidoscopy

• Flexible sigmoidoscopy reduces

colorectal cancer incidence by 21% and

colorectal cancer mortality by 26% (Schoen RE. NEJM 2012;366:25)


• Prostate, Lung, Colorectal, and Ovarian

Cancer Screening Trial (PLCO)

–Randomly assigned 154,890 average‐risk adults, age 50 to 74, to either screening with flexible sigmoidoscopy (baseline, 3‐5 years) or usual care

–Median follow‐up 11.9 years


• Reduced CRC incidence

–Relative risk: 0.79 (95% CI 0.72‐0.85)

–Absolute risk reduction: 3.3/10,000 person years• Number needed to invite to screening (NNI): 285 (95% CI 210‐427)


• Reduced CRC mortality

–Relative risk: 0.74 (95% CI 0.63‐0.87)

–Absolute risk reduction: 1.0/10,000 person years• NNI: 871 (95% CI 567‐1874)

–Mortality reduction limited to distal cancers


• United Kingdom study showed one‐time

flex sig reduced CRC incidence by 23%

and mortality by 31% (Atkin WS. Lancet

2010;375:1624)

• Fewer primary care physicians now

recommend flex sig (Klabunde CN. Am J Prev Med

2009;37:8)

–78% (2000) to 26% (2007)


• United Kingdom study showed one‐time

flex sig reduced CRC incidence by 23%

and mortality by 31% (Atkin WS. Lancet

2010;375:1624)

• Fewer primary care physicians now

recommend flex sig (Klabunde CN. Am J Prev Med

2009;37:8)

–78% (2000) to 26% (2007)

–Colonoscopy recommendations increased from 38% to 95%

Newer Tests

• Virtual Colonoscopy

• Stool-based molecular testing

– Fecal DNA

• Fecal immunochemical tests

Computed Tomographic Colonography (Virtual Colonoscopy)

• Non-invasive radiological technique– Radiation dose similar to barium enema

• Bowel preparation similar to colonoscopy– Prep-less technique is being evaluated

• Does not require sedation

• Colon distended with carbon dioxide or air

• Breath holding for 20-50 seconds

• Colonoscopy to remove polyps

Potential Harms

• Radiation Exposure– 1/1000 could develop solid cancer or

leukemia

• Procedure related harms– Perforation rate low

• Extra-colonic findings

Extra-colonic Findings

• Extra-colonic findings common: 27 – 69%

• “High” clinical significance require surgical or medical treatment or intervention or further investigation

– 5 - 11%

• 7-16% of individuals need additional evaluation for extra-colonic findings, but very few abnormalities ultimately required definitive treatment

Fecal DNA Testing

• PCR test for DNA mutations in the stool

• Potential advantages

– Non-invasive

– No preparation

– Detection along entire length of the colon

Fecal DNA Testing

• Screening test in multi-center study

• Fecal DNA test (23 mutations), FOBT, and colonoscopy

• 4482 average risk adults

• Fecal DNA detects more neoplasms than FOBT, but with more false positive results

• Expensive: $400 to $800 versus $3 to $40 for FOBT

Ahlquist, 2008

Fecal Immunochemical Testing (FIT)

• Uses labeled antibodies that attach to antigens of any human globin present in the stool

• Globin does not survive passage of the upper GI tract

• No dietary restrictions (easier than FOBT)

Fecal Immunochemical Testing

• FIT is more sensitive in detecting CRC and large adenomas (>1 cm) than FOBT

• FIT is a little less specific than FOBT

Colorectal Cancer Screening

Fecal immunochemical test (FIT) more acceptable than colonoscopy (Quintero E. NEJM 2012;366:697)


• Randomized screening trial in Spain of

biennial FIT vs. one‐time colonoscopy

53,302 subjects ages 50 to 69

• Primary outcome is CRC mortality after

10 years

Screening Outcomes

Quintero E. NEJM 2012;366:697


• Recommending only colonoscopy

resulted in lower adherence (Inadomi JM. Arch

Intern Med 2012;172:575)


• Randomized trial offering colonoscopy,

FOBT, or choice of colonoscopy/FOBT

• 997 subjects ages 50 to 79

• 12‐month follow up

Screening Completion

Inadomi JM. Arch Intern Med 2012;172:575

How Are We Doing?

Year FOBT in past year

or ever scope in 10?

2002 54%

2004 57%

2006 61%

2008 64%

Rim, MMWR, 2011

Colorectal Cancer Screening: Conclusions

• Any screening is better than no screening for reducing colorectal cancer mortality

• Increase awareness of the importance of colorectal cancer screening

• Virtual colonoscopy and fecal DNA testing are included as options in the new joint guidelines but not in USPSTF guidelines

Implications for Practice

Offer screening

Testing modalities Fecal immunochemical tests more

acceptable and accurate than Hemoccult II Flex sig no longer routinely performed Colonoscopy RCT ongoing CT colonography not reimbursed by

Medicare

Implications for Practice

• Recognize importance of patient

preferences

–“The best test is the one that gets done”

• Positive fecal blood tests must be

evaluated with diagnostic colonoscopy

Skin Cancer

The American Cancer Society Estimates

• > 1 million cases of basal and squamous cell cancers annually in the US

• ~ 68,720 melanomas and 8,650 deaths

• Melanoma rates are more than 10 times higher in Caucasians than in African Americans

Skin Cancer Screening

• USPSTF recommendations

–Screening: “I” insufficient evidence (2009)

–UV radiation counseling: “B” (2012)• Counsel the young (ages 10‐24 years) who have fair skin about minimizing exposure to UV radiation to reduce risk for skin cancer

• Australia Cancer Network/ NZ Guidelines

– Identical

• Inspect moles for changes

• Remove suspicious moles

• Remove actinic keratoses and other precancerous lesions

Screening and Early Detection

– A Asymmetry: one portion of the mole does not match the other

– B Border: edges are irregular, notched, or blurred

– C Color: different shades of black or brown, patchy colors

– D Diameter: spot is 6 millimeters across, or growing larger

A B

C D

ABCD rule for melanoma

• Most common (75%)

• Usually slow growing

• Rarely metastasizes

• Head and arms

• May cause functional or cosmetic impairment

Basal cell carcinoma

• Pink, pearly, translucent papules with prominent telangiectasia

• May ulcerate in center

• Uncommon subtypes

- Scar-like appearance

- Red macules

Basal cell appearance

(pictures of Basal Cell Carcinoma)

• Faster growing

• May metastasize (3 - 30%)

• May cause functional or cosmetic impairment

Squamous cell carcinoma

• Red nodule

• With or without ulceration

• On sun-exposed skin

• On traumatized skin

Squamous cell cancer: appearance

(pictures of squamous cell cancer)

Sunburn Prevalence* in the Past Year, Adults 18 and Older, US, 2010

Prevalence of Behaviors that Protect against Ultraviolet Radiation Exposure, Adults 18 and Older, US, 2010

Three Things To Remember

•Nearly all skin cancers are preventable by limiting unprotected exposure to the sun•Most skin cancers can be treated successfully if detected early – even melanoma.•“Slip! Slop! Slap! Wrap!”

–Slip on a shirt– Slop on SPF 15+ sunscreen– Slap on a hat– Wrap on sunglasses

Questions?Thank you!

PREVENTION OF CARDIOVASCULAR DISEASE IN WOMEN

1

Robert Baron MD, MS


Robert B. Baron MD MSProfessor and Associate Dean

UCSF School of Medicine

Declaration of full disclosure: No conflict of interest

Ford ES, NEJM, 2007

EXPLAINING THE DECREASE IN DEATHS FROM CHD

1980 to 2000:

• Death rate fell from:542.9 to 266.8 per 100K men 263.3 to 134.4 per 100K women

• 341,745 fewer deaths from CHD in 2000

Ford ES, NEJM, 2007

EXPLAINING THE DECREASE IN DEATHS FROM CHD

• 47% from CHD treatments, 44% from risk factor modification

• Reductions in cholesterol: 24%

Reductions in Major Coronary Events Relative to Placebo

Placebo-Controlled Statin Trials

simva 20-40 mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg


2

Robert Baron MD, MS

Remaining Major Coronary Events Relative to Placebo

Is there more we can do to identify and treat the

non-responders?

simva 20-40 mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg

Placebo-Controlled Statin Trials – Celebrating Successes but Forgetting the Majority?

Riskreduction

$$ Harm

The benefit from any given intervention is a function of: 1) The relative risk reduction conferred by the

intervention, and2) The native risk of the patient

A RISK-BASED APPROACH

Mosca, Circulation 2011

Overwhelming majority of recommendations are the same for women and for men

Aspirin use is a notable exception

But…”there may be gender differences in the magnitude of the relative and absolute potential benefits”

Prevention Of CVD in WomenA 40 year women, in good health. In for annual wellness visit. BMI, BP, diet and

exercise all at ideal. What blood tests will you order to screen her for a lipid disorder?

1. Total cholesterol

2. LDL cholesterol and HDL cholesterol

3. LDL, HDL, and hs-CRP

4. LDL, HDL, hs-CRP, and Lp(a)

5. No screening blood tests for lipids


3

Robert Baron MD, MS

USPSTF

USPSTF: Screening Recommendations

Men: age 35 and older, regardless of risk level

age 20 to 35, at increased risk

Women: age 20 and older at increased risk If not at increased risk, no recommendation (I)

Increased Risk:

tobacco use, diabetes, hypertension, obesity, and family history of premature CV disease.


ACC/AHA CVD Risk: Ideal All of These

Total cholesterol <200 mg/dL (untreated)

BP <120/<80 mm Hg (untreated)

Fasting blood glucose <100 mg/dL (untreated)

Body mass index <25 kg/m2

Abstinence from smoking

Physical activity at goal for adults >20 y of age: 150 min/wk moderate intensity, 75 min/wk vigorous intensity, or combination

Healthy (DASH-like) diet

A 40 year women, in good health. In for annual wellness visit. BMI, diet and exercise all at ideal. What blood tests will you order

to screen her for a lipid disorder?

1. Total cholesterol

2. LDL cholesterol and HDL cholesterol

3. LDL, HDL, and hs-CRP

4. LDL, HDL, hs-CRP, and LP(a)

5. No screening blood tests for lipids

A 40 year women, in good health. Which of the following is the most effective

intervention for primary prevention of CVD?

1. Aspirin

2. Folic acid

3. Estrogen

4. Vitamin E, C and beta carotene

5. Oily fish twice per week

6. All are effective

7. None are effective


4

Robert Baron MD, MS

Ineffective Interventions in WomenACC/AHA 2011

Hormone therapy should not be used for the primary orsecondary prevention of CVD (Evidence A).

Antioxidant vitamin supplements (eg, vitamin E, C, andbeta carotene) should not be used for the primary orsecondary prevention of CVD (Evidence A).

Folic Acid, with or without B6 and B12 supplementation,should not be used for the primary or secondaryprevention of CVD (Evidence A).

Routine use of aspirin in healthy women <65 years ofage is not recommended to prevent MI (Evidence B) Cochrane Library, 2009

Omega 3 Fatty Acids: Meta-analysis

• 48 RCTs of 36,913 participants; 41 cohort trials

• No significant effect of omega 3 fats on mortality, CV events, or cancer

• Analysis of diet only trials: also no benefit

• No reason to advise people to stop rich sources of omega 3 fats, but better trials needed

ORIGEN, NEJM, 2012

ORIGEN Trial

RCT, 12,537 subjects; impaired FBS, IGT, or new diabetes, and high CV risk

900 mg n-3 fatty acids vs. placebo; 6.2 years

Results: No difference in CV outcomes9.1% vs. 9.3% (p=0.72)

A 40 year women, in good health. Which of the following is the most effective

intervention for primary prevention of CVD?

1. Aspirin

2. Folic acid

3. Estrogen

4. Vitamin E, C and beta carotene

5. Oily fish twice per week

6. All are effective

7. None are effective


5

Robert Baron MD, MS

63 yo woman; s/p MI

LDL 115

HDL 45

TG 160

63 yo woman; s/p MI

LDL 3.0 SIHDL 1.2 SITG 4.1 SI

mg/dl / 38.67 = SI (mmol/l)

The best next step in lipid management is:

1. Continue current therapy

2. Begin a statin to goal LDL <100


4. Begin a statin plus ezetimibe to LDL goal <70

5. Begin niacin

LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%)

100 mg/dL

(<100mg/dL:drug optional)

100 mg/dL

<100 mg/dL

Optional : <70

LDL Level at Which to Consider Drug Therapy

LDL Level at Which to Initiate DietLDL Goal

Adult Treatment Panel III, 2004


6

Robert Baron MD, MS

BaselineFeature

LDL (mg/dL)

<100

≥100 <130

≥130

ALL PATIENTS

Statin Placebo(10,269) (10,267)

285 360

670 881

1087 1365

2042 2606(19.9%) (25.4%)

0.4 0.6 0.8 1.0 1.2 1.4

24% reduction(p<0.00001)

Heart Protection Study: VascularEvents by Baseline LDL-C

Risk Ratio and 95% Cl

Statin better Statin

worse

No. Events

Larosa NEJM, 2005

TREATING TO NEW TARGETS (TNT)

• RCT of 10,001 patients with stable CHD; 35-75 yr

• LDL <130 mg/dl

• Atorvastatin 10 vs atorvastain 80

• Followed for 4.9 years

• Research question: safety and efficacy of lowering LDL below 100 mg/dl

TREATING TO NEW TARGETS (TNT)

LDL Event % Death % LFTs %Atorv 10 101 10.9 2.5 0.2

Atorv 80 77 8.7 2.0 1.2

p value <0.001 0.09

Lancet, 2010

SEARCH TRIAL

• RCT; 7 years; 10,064 patients with MI; • Funded by Merck• Simvastatin 80mg vs. 20mg

• Outcome: major vascular events (coronary death, MI, stroke, revascularization)

• Results: No difference (RR 0.94; CI 0.88 – 1.01)


7

Robert Baron MD, MS

Lancet, 2010

SEARCH TRIAL

• Difference in myopathy risk• Muscle weakness + CK > 10x ULN)• 80 mg: 22 patients• 20 mg: 0 patients• Risk 5x higher in year 1 compared with

subsequent years

• Key drug interactions notedLancet, 2010

SEARCH TRIAL

• Simvastatin contraindicated in users of• Antifungals• Macrolide antibiotics• Antiretrovirals• Gemfibrozil

• Do not exceed 10mg simvastatin if using • Verapamil• Diltiazem

• Do not exceed 20mg simvastatin if using • Amlodipine• Ranolazine• Amiodorone

FDA Safety Announcement 6/8/2011

LDL-Lowering Effects of Simvastatin

Simvastatin % Lowered LDL-C

10 30%20 38%40 41%80 47%

CURRENT USE OF SIMVASTATIN

• Myopathy risk may be higher with simvastatin than other statins

• Don’t routinely use higher than 40 mg (OK to use 80 if tolerated for more than 1 year)

• If inadequate response on simvastatin 40, consider atorvastatin or rosuvastatin


8

Robert Baron MD, MS

Golomb, Arch Int Med 2012

STATINS AND FATIGUE

• Small RCT; 6 months; 1016 healthy patients

• Simvastatin 20mg vs pravastatin 40 vs placebo

• Outcome: self ratings of change in energy and fatigue with exertion on 5-point scale

• Results: • Statins worse than placebo• Simvastatin worse than pravastatin• Women more than men





4. Begin a statin plus ezetimibe to LDL goal <70

5. Begin niacin

63 yo woman; s/p MI. On atorvastatin 80.

LDL 95

HDL 40

TG 200



2. Switch to rosuvastatin

3. Add fenofibrate

4. Add fish oil

5. Add niacin

6. Add ezetimibe


9

Robert Baron MD, MS

Effects of Fibrates on Cardiovascular Outcomes

4 Recent meta-analyses

18 RCTs, 45,000 patients

Fibrate vs. Placebo and CVD Risk

OutcomeRelative

Risk 95% CI P Value

All-cause mortality 1.00 0.98-1.08 0.92

Cardiovascular death 0.97 0.88-1.07 0.59

Non-fatal coronary events 0.81 0.75-0.89 <0.0001

Total stroke 1.03 0.91-1.16 0.69

Jun et al. The Lancet 2010

ACCORD, NEJM 2010

Fenofibrate plus statin vs. statin alone: ACCORD

• RCT of 5518 patients with type 2 DM

Fenofibrate Placebo p

• CV events: 2.24 2.41 .32• Death 1.47 1.61 .33

• No difference in any secondary outcome

• Results do not support routine use of combination therapy in DM

Brukert, Atherosclerosis 2010

NIACIN META-ANALYSIS OF RCTS

• 11 RCTS

• Coronary Drug Project (1970s) only large RCT

• Others very small


10

Robert Baron MD, MS

Niacin Meta-Analysis: Summary of Results for Cardiovascular Events

27% lower risk of CVD events

Bruckert, Atherosclerosis 2010

37

?

Publication bias?

Brukert, Atherosclerosis 2010 NEJM, 2011

AIM-HIGH Trial

• RCT of 3,414 patients with established CVD

• Simvastatin (or simvastatin + ezetimibe) to keep LDL at 40 – 80 mg/dl (mean 71).

• HDL 35 mg/dl, TG 161 mg/dl

• Randomized to receive sustained-release niacin or placebo

NEJM, 2011

AIM-HIGH Trial

• Results: Study stopped early

– No reduction in cardiovascular events, MI and stroke

– Increase risk in ischemic stroke (28 vs 12)

Taylor NEJM, 2009

Extended-release Niacin vs. Ezetimibe

• RCT of 208 patients with CHD or CHD risk-equivalent on statin at goal LDL

• Niacin 2000 vs Ezetimibe 10• Outcome: carotid intima-media thickness

(IMT)

• Results: Niacin better– Reduction in IMT– Major cardiovascular events, 1% vs 5%


11

Robert Baron MD, MS

Summary Lipid-Lowering Drugs

• Statins are treatment of choice to decrease risk

• No evidence to support adding niacin or fibrates to statins

• If statin-intolerant, niacin may reduce CVD risk (weak evidence)

• Fibrates appear to lower MI risk, but no other CVD endpoints

• Ezetimibe: just say no



2. Switch to rosuvastatin

3. Add fenofibrate

4. Add fish oil

5. Add niacin

6. Add ezetimibe

63 yo woman, no risk factors

LDL 155HDL 55TG 160SBP 120Nonsmoker



2. Begin a statin

3. Begin fenofibrate

4. Begin a statin plus ezetimibe

5. Begin niacin


12

Robert Baron MD, MS

Truth About CVD Risk Prevention

Health professionals are not good at judging CV risk

Counting risk factors is a “blunt instrument”and often leads to misclassification

Calculate 10-year risk of hard CHD events (CHD death or non-fatal MI) using the Framingham Risk Score

Framingham Risk -Limitations

• Not accurate in patients under 30 or over 75

• Provide risk over 4-12 years only

• Relatively few patients with diabetes; no family history

BUT

• Good discrimination for future CHD events

• Validated in several populations and found to be relatively “transportable” for risk ordering but calibration varies

Examples of Proposed Novel Risk Markers

• C-reactive protein• Fibrinogen• vWf• Factor VII• Homocysteine• Lipoprotein a• LDL sub-fractions

• ST segment depression

• Heart rate variability

• Carotid Doppler

• Ankle-brachial index

• EBCT for coronary calcium

• Platelet activity

CRP AND Risk

CRP does not change overall predictive ability of Framingham

However, CRP (plus family history) may reclassify some patients (especially intermediate risk patients)


13

Robert Baron MD, MS

C-reactive protein (CRP)

Hard to directly integrate into the Framingham risk….

Rough calculations:

CRP in top third increases risk by

factor of 1.2-1.3

Average risk = x

Risk in top tertile = 1.3x

Risk in middle tertile = x

Risk in middle tertile = 0.7x Bonow RO, NEJM 2009

Coronary Calcium (CAC) and CV Prevention

Broad population-based strategy not warranted

CAC may reclassify intermediate risk patients

Unknown if findings lead to improved outcomes

63 yo woman, no risks

LDL 155HDL 55TG 160SBP 120Nonsmoker

10 yr risk: 2%… Therefore no medication recommended



2. Begin a statin

3. Begin fenofibrate

4. Begin a statin plus ezetimibe

5. Begin niacin (sustained release)


14

Robert Baron MD, MS


Prevention of CVD Risk in Women: Aspirin

Aspirin (81–325 mg/d) in women with CHD unless contraindicated (Evidence A).

Aspirin in women >65 y of age (81 mg daily) if benefit for ischemic stroke and MI prevention is likely to outweigh risk of GI bleed and hemorrhagic stroke (Class IIa; Evidence B)

Aspirin may be reasonable for women <65 y of age for ischemic stroke prevention (Class IIb; Level of Evidence B).

CONCLUSIONS

Patients with CHD or CHD equivalent:

• Treat aggressively with statin independent of LDL level (to LDL <70 in most cases)

• Treat other risk factors aggressively as well, especially easy ones (HTN, Aspirin use)

• Treat elevated non-HDL cholesterol and low HDL

• Patients at high risk are undertreated. Maximize adherence and avoid clinical inertia

CONCLUSIONS

Patients without CHD:

• Assess lifetime CV risk with risk factors and 10-year CHD risk with Framingham Risk Score

• Novel markers (hsCRP, coronary calcium score) may be useful for further discrimination among those with intermediate risk

• Do a better job with what we have: HTN, ASA, smoking, weight, exercise, diet

• Engage patient in shared decision making, especially if risk <10%

CONCLUSIONS


• Use medications at thresholds based on risk:

LDL goal LDL drug threshhold

High Risk (>20%) <100 (<70 optional) ≥100

Mod high risk (10-20%) <100 ≥130

Moderate risk (<10%) <100 ≥160

Low risk (no risk factors) <100 ≥190


15

Robert Baron MD, MS

CONCLUSIONS


• Use medications at thresholds based on risk:

ASA STATIN

High Risk (>20%) YES YES

Mod high risk (10-20%) YES YES

Moderate risk (<10%) NO Occasional YES

Low risk (no risk factors)NO Usually NO

NEW DEVELOPMENTS IN HYPERTENSION

Eliseo J. Pérez-Stable, MD

Management of Hypertension in Women

Eliseo J. Pérez-Stable MD

Professor of Medicine

DGIM, Department of Medicine

July 1, 2013Declaration of full disclosure: No conflict of interest

(I have never been funded by a for-profit company)

Main Teaching Points TodaySet goal SBP and treat with drugs at

any age for SBP >160Goal SBP level is relative, not fixed

or there is nothing magical in 140/90Use the Framingham Risk Score to

assess overall CV risk in all patientsThiazides, ACE-I, ARB, and CCB are

similar–combinations in almost allCo-morbid condition and age

considerations in selecting meds

Current Population Status of Hypertension

• Prevalence is 29%; Blacks at 33.5%

• About 72.5% are treated and 53.5% are

uncontrolled (average >140/90)

• Latinos, Blacks, age 18-44 and ≥80,

<300% poverty, < college degree have

higher rates of uncontrolled BP

• Having any insurance, ≥2 visits, and

usual source of care = better controlMMWR 2012;61: 703-709

Racial Difference of Elevated SBP

• Reasons for Geographic and Racial

Differences in Stroke: 27,748 Black and

White, followed 4.5 y to 2011

• 715 incident strokes

• SBP 10 mm Hg: 8% increase for Whites and

24% for Blacks

• HR = 2.38 for stage 1 Htn, age 45-64 y

• SBP elevations have differential effects on

stroke incidence by raceHoward G, et al, JAMA Intern Med 2013; 173: 46-51



BRFS and Self-Report Use of Antihypertensive Medications, US 2009

• Prevalence is 28%; Blacks at 39.6%

• 60% ≥65 y, 34% if < high school

• 62.6% treated with medications

• Blacks at 71.6%, Latinos 55.2%, age 18-

44 at 45.1%, age ≥65 at 94%, < high

school degree at 59.6%

• California lowest rate at 52.3%;

Tennessee 74.1%MMWR 2013;62: 237-244

Hypertension Control by Cardiovascular Disease and Risk: NHANES, 2003-04

Condition %HTN %Rx % Not Controlled

Average Risk 34 66 35

Diabetes 85 96 54

CKD 83 95 53

CHF 86 98 50

Any CV Dis 85 95 51

FRS ≥10% 77 68 59

Bertoia ML, et al. Hypertension 2011; 58:361-366

Co-morbid Conditions and Hypertension Management

• Clinicians are being “graded” for level of BP control in their patients

• Threshold of 140/90 held as standard• In primary care visit, other factors

intervene with “control”• Retrospective cohort of 15,459 patients

with uncontrolled HTN with 200 clinicians• Data obtained from 6 sites through EMR• Effect of 28 conditions on intensification

Co-morbid Conditions and Hypertension Control

• Average of 2.2 unrelated conditions• Intensification of treatment

decreased with number of conditions from OR = 0.85 for one to OR = 0.59 for 7 or more

• Findings persisted at visit, clinician and patient levels

• Quality of care measures need to consider co-morbid conditions

Ann Internal Medicine 2008; 148: 578-586



Hypertension Treatment after 80 y

• No clinical trial showing clear benefit• Meta-analysis of 7 RCT, 1670 patients,

75% women showed a 3.3% absolute reduction in stroke (NNT = 30) and 2.1% reduction in CHF (NNT = 48)

• Borderline trend to increase deaths from any cause in treated group

• Observational data showed risk of death inversely related to BP level

Hypertension in the Very Elderly Trial (HYVET)

• 3845 patients ≥ 80 y • >160 mm Hg – goal of 150/80 mm Hg• Indapamide SR 1.5 mg vs. placebo• Added perindopril if needed• Follow up of 2 years• 60% women, age 83.6 y, BP = 173/91• 12% with CV disease, 7% diabetes,

64% already treated for hypertensionBeckett NS, NEJM 2008; 358: 1887-1898

HYVET Study ResultsBeckett NS, NEJM 2008; 358: 1887-1898

End Point Meds Placebo HR (95% CI)

Stroke 12.4 17.7 0.64 (0.46 -0.95)

CVA Death 6.5 10.7 0.55 (0.33 -0.93)

CHF 5.3 14.8 0.28 (0.17 -0.48)

CV Death 23.9 30.7 0.73 (0.55 -0.97)

Any Death 47.2 59.6 0.72 (0.59-0.88)

Conclusions and ImplicationsOffer BP Treatment at any

age!• Benefits appear at 1 year of Rx

• NNT = 20 to prevent one stroke

• NNT = 10 to prevent one CHF

• Not a specific drug effect

• Never too old to treat SBP > 160

• Goal does not have to be < 140



Other Considerations in Elderly with Hypertension

• Canadian study of 301,591 newly treated older adults observed from 2000-2009

• 1463 incident hip fractures

• 43% increased risk during the first 45 days following treatment

• Evaluate co-morbidityButt D, Arch Intern Med 2012; 172: 1739-44

Gait Speed, Hypertension, and Mortality: NHANES

• 2340 persons, ≥ 65 y

• Walking speed over 6 m: faster = ≥0.8 m/s (n=1307)

• SBP ≥ 140 associated with mortality in faster gait speed (HR = 1.35, 95% CI 1.03-1.77)

• No association with slow gaitOdden MC, Arch Intern Med 2012; 172: 1162-68

Chronic Kidney Disease and Hypertension

• Continuous risk significant at SBP >120 and DBP >80. The lower the better?

• Detection with serum creatinine and urine albumin/creatinine ratio to identify CKD

• CKD identified patients should be treated with ACE/ARB and lower SBP

• Goal SBP is optimal in 130-140 mm Hg once CKD established

• BP control in 10,813 patients with CKD was only 13.2%; worse in early CKD

(Am J Med 2008; 121: 332-40)

SBP and Risk of Recurrent StrokeOvbiagele B, JAMA 2011; 306: 2137-44

• 20,330 patients ≥50 y with CVA < 120 da followed for 2.5 years, 695 centers

• Outcome: recurrent stroke any type• Predictors: SBP in mm Hg

– <120 8.0%120-<130 7.2%130 -<140 6.8% Optimal SBP

140 - <150 8.7%≥150 14.1%



Treatment Based on What Blood Pressure Measurement?

• Home BP measurement leads to less intensive drug Rx & BP control

• Identifies “white-coat” HTN• Ambulatory monitor measures –

higher correlation with CVD • Office clinician measures are

standard, used in trials, one point• Automated Office BP monitors may

lead to more standard measures

Clinic, Home and Ambulatory BP in Diagnosis of Hypertension

Hodgkinson J, et al. BMJ 2011: 342: d3621

• Systematic review comparing measures in initial diagnosis

• 20 studies with 5683 patients, compared to ambulatory monitor daytime mean ≥135/85

Measure Definition Sensitivity Specificity

Home 135/85 mean

85.7%+LR = 2.28

62.4%–LR= 0.23

Clinic 140/90 mean

74.6%+LR = 2.94

74.6%–LR = 0.34

Number of BP Measurements to Influence Decisions

• Compare Home, Clinic and research BP measurements in VAMC setting

• 444 patients, 92% men, inadequate control• Only 33% consistently categorized as

being out of control• Clinic > Home > Research measures• Within patient Variance reduced by doing

more –– plateau at 5-6 measures• Decision to initiate or change treatment

should not be based on one readingPowers BJ, et al. Ann Intern Med 2011; 154: 781-788

At What BP Level Do You Start Medication in 50 Year old man, non-smoker with Total Cholesterol=160?

a) SBP ≥ 140 and/or DBP over 90

b) SBP ≥ 160 and/or DBP ≥ 100

c) SBP ≥ 160 and/or DBP ≥ 90

d) SBP ≥ 140 and/or DBP ≥ 100

e) SBP 140-159 and DBP < 90 & > 80



JNC 7 Classification of Blood Pressure

mm Hg SBP DBP

Normal (115) <120 and <80

Pre-hypertension 120-139 or 80-89

HypertensionStage 1 140-159 or 90-99Stage 2 ≥160 or ≥100

Risk of CVD doubles with each increment of 20/10 mm Hg – SBP more important risk factor

When to Treat Hypertension

• Lifestyle advice for all • Initial lifestyle for stage 1 HTN• Drug treatment for all with SBP > 160 • Drug treatment for all with CV co-

morbidity and SBP > 140 or DBP > 90• Drug treatment for all with DBP > 100• If lifestyle fails, drugs for DBP > 90• If lifestyle fails, drugs for SBP >140

Individual Lifestyle Modifications for Hypertension Control

• Weight loss if overweight: 5-20 mm Hg/10-kg weight loss

• Limit alcohol to ≤ 1 oz/day: 2-4 mm Hg• Reduce sodium intake to ≤100 meq/d

(2.4 g Na): 2-8 mm Hg in SBP• DASH Diet: 6 mm alone; 14 mm plus Na

• Physical activity 30 min/day: 4-9 mm Hg

• Habitual caffeine consumption not associated with risk of HTN

Drugs always better than lifestyle in

head-to head clinical comparisons

Better Living through chemistry



Salt and Public Policy• Coronary Heart Disease Policy Model

to quantify benefits of 3 g salt/day reduction in US– average is 8-10 g/d

• Benefit through a reduction in SBP from 1-9 mm Hg in selected populations

• New cases of CHD decrease by 4.7 -8.3 and stroke by 2.4 to 3.9 /10,000

• Regulatory change leads to wide benefit and is cost-effective

Bibbins-Domingo K, et al. NEJM 2010

Benefits of Less Salt in Food• Compelling evidence associating

high sodium intake with higher SBP• Urine Na excretion shows J-shaped

curve with CV events• Higher urine K excretion lowers

stroke and SBP• Dispute regarding 24 hour data vs.

estimates• Ratio Na/K most important

O’Donnell MJ, et al JAMA 2011; 306: 2229-2238Yang Q, et al, Arch IM 2011; 171:1183-91

Stolarz-Skrzypek K, et al, JAMA 2011; 305: 1777-85

Initial Drug Treatment of Hypertension Based on JNC 7

Initial Drug Choices

Stage 1: Thiazides for mostStage 2: 2-drug combination for most – thiazides plus -blockers, ACE-I, ARB, CCB

Based on randomized controlled trials

60 Year Old Man, BP=160/96; lipids OK; Which treatment?

1) Thiazide diuretic 12.5 or 25 mg

2) Beta blocker of choice

3) Ace Inhibitor or ARB

4) Calcium Channel Blocker

5) Alpha-blocker/Other

6) Intensify lifestyle



60 Year Old woman, BP=160/96, with Diabetes; which drug?

1) Thiazide diuretic 12.5 or 25 mg

2) Beta blocker of choice

3) Ace Inhibitor or ARB

4) Calcium Channel Blocker

5) ACE/ARB plus Diuretic

6) ACE/ARB plus CCB

Possible JNC 8 Recommendations

• Medication choice menu: Thiazides, ACE Inhibitor or ARB, Calcium Channel Blocker

• Beta blockers restricted to <60 years • Use urinary albumin to identify

patients with diabetes and CKD for ACE/ARB Rx

• Combination of ACE + CCB preferred over ACE + Hctz in highest risk

• Coordinate with pharmacists to enhance adherence

Compelling Indications for Drug Selection in Hypertension

• Low EF Heart Failure: BB, ACE-I or ARB, and aldosterone antagonist

• Post ant MI: Beta Blocker, ACE-I• CAD Risk: BB or just lower SBP• Diabetes with proteinuria: ACE-I, ARB• Renal Disease: ACE-I, ARB• Recurrent stroke prevention:

thiazide, ACE-I

NICE Guidance: Management of Hypertension

Krause T, et al, BMJ 2011; 343:d4891

• Guideline development in the UK• If BP 140/90 in office, use ambulatory

monitor to confirm • Estimate CV risk (FRS), evaluate for target

organ effects (LVH, CKD, retinopathy)• Treat stage 1 with meds only if target

organ damage, known CVD, diabetes, 10-year CV risk ≥ 20%

• Offer meds to all at any age with stage 2 (>155/95) independent of other effects



Step 4

Summary of antihypertensive drug treatment

Aged over 55 years or black person of African or Caribbean family origin of any age

Aged under55 years

CCBA –ACE/AR

B

ACE/ARB + CCB

ACE/ARB + CCB + Thiazide

Resistant hypertension

A + C + D + consider further diuretic3, 4 or alpha‐ or

beta‐blocker5

Consider seeking expert advice

Step 1

Step 2

Step 3

Thiazide Diuretics

• Very effective for systolic BP• Do not increase sudden death• Most effective in LVH regression• Lipid effects are short lasting (1 y)• Hyperglycemia only in high doses• Still effective in early CKD• Erectile dysfunction in 20%• Adverse effects of low Na or K?

Chlorthalidone vs. HCTZPopulation-based Cohort Study

• 29,873 patients, >65 yrs, 59% women: 10 384 on chlorthalidone (CTD)

• Event rate: 3.2 /100 person-yrs CTD and 3.4/100 person-yrs on HCTZ; HR = 0.93 (95% CI 0.81-1.06)

• CTD led to more hospitalizations for low K (HR = 3.06; 95% CI 2.04-4.58) and low Na (HR = 1.68; 95% CI 1.24-2.28)

Dhalla IA, et al, Ann Intern Med 2013; 158:447-55

Chlorthalidone Treatment in Systolic Hypertension

• 2365 treated with CTD and 2371 with placebo in 4.5 y; RCT

• Outcomes determined at 22 years with national death index

• CV Death reduced by 11%, but no difference in all-cause mortality

• One month of treatment = 1 day life extension

Kostis JB, et al, JAMA 2011; 306: 2588-93



Efficacy of HCTZ by Ambulatory Monitoring

Messerli FH, et al, JACC 2011; 57: 590-600

Medication Class Decrease in mm Hg

HCTZ: 12.5 -25 mg 6.5/4.5

HCTZ: 50 mg 12.0/5.4

ACE-I 12.9/7.7

ARB 13.3/7.8

CCB 11.0/8.1

Beta Blockers 11.2/8.5

Beta Blockers• Question benefit to prevent MI or

decrease all cause CAD mortality• Adverse effects limited: Do not cause

depression or sexual dysfunction• Glucose elevation with A1C increase

by 0.2% –– less with carvedilol• No lasting effect on lipids• Compelling evidence to use in systolic

HF to decrease mortality • Less efficacy in stroke prevention

among those older than 60 years

ACE–I or ARB• 30% reduction of ESRD (dialysis)

and/or of doubling of serum creatinine; optimal with GFR 30-60, proteinuria

• Not better tolerated than other drugs• Regression of LVH not more than

other drugs – SBP reduction• Elevates K+• Do not use in women < 50 y without

guaranteed contraception• Best choice in diabetes?• Infrequent need to combine the two

Renin Angiotensin System Antagonists and Mortality

• Heart failure with preserved EF• Swedish Heart Failure registry• 16,216 patients with EF ≥40%, age 75 y,

46% women; 12 453 treated with RAS antagonists

• Propensity score of all-cause mortality: • Matched cohort showed 1-year survival

was 77% vs. 72% with HR = 0.91 (95% CI 0.85-0.98); Overall in cohort: 86% vs. 69%; Dose effect observed

Lund LH, et al, JAMA 2012; 308: 2108-17



Valsartan for Prevention of DM and CV Events in Patients with Pre-Diabetes

• 9306 patients, 50% women, with pre-DM and CV risk factors or disease

• Valsartan 160 mg or placebo plus lifestyle• Follow for 5 years, outcomes are new

diabetes and CV events• Diabetes: 33.1% vs. 36.8% (HR= 0.86; 0.80-

0.92)• No benefit on CV outcomes: 14.5% vs.

14.8%• DREAM Trial showed no benefit (ramipril)

The Navigator Study Group. NEJM 2010; 362: 1477-1490

Benazepril for CKD:Is it Ever Too Late to Try?

• 442 patients randomized to benazepril or placebo and followed for 3.4 years

• Creatinine 1.5 to 3: benazepril 20 mg (1)• Creatinine 3.1 to 5: benazepril vs. placebo• Outcomes: ESRD, 2X creatinine or death• 22% in group 1; 41% in group 2 on ACE

vs. 60% on placebo• Similar AE; not mediated by SBP

NEJM 2006; 131-140

Calcium Channel Blockers

• Effective in preventing CV events• Do not reverse atherosclerosis• No increase risk of cancer• Short acting CCB may be harmful • Effective in systolic hypertension• Better outcomes in latest trials

ACCOMPLISH Calcium Blockers combined with ACE

• Comparison of combinations: ACE-I + hctz vs. ACE-I + amlodipine for htn

• RCT, 11,506 patients, ≥ 65 y, 60% men, 83% White, 60% DM, BMI = 31

• Outcomes: CV death, MI, stroke, CAD hospitalization, resuscitation after cardiac arrest, CABG or PCI

• Follow-up 36 months• Funded by Novartis: USA and 4 N

EuropeJamerson K, NEJM 2008; 359:2417-28



ACCOMPLISH Results

Primary Outcomes

Benazepril +AmlodipineN=5744

Benazepril + HCTZN=5762

Hazard Ratio (95% CI)

All Events 552 (9.6%) 679 (11.8%) 0.80 (0.72-0.90)

CV Death 107 (1.9%) 134 (2.3%) 0.80 (0.62-1.03)

All MI 125 (2.2%) 159 (2.8%) 0.78 (0.62-0.99)

All Strokes 112 (1.9%) 133 (2.3%) 0.84 (0.65-1.08)

Revasc procedure

334 (5.8%) 386 (6.7%) 0.86 (0.74-1.00)

ACCOMPLISH Conclusions

• Combination of CCB and ACE was superior to ACE/HCTZ

• BP differences of 1 mm only• Different populations may matter• Chlorthalidone vs. HCTZ?• Recommendation to change practice

in highest risk patients – ACE and CCB may have special benefits

What About Other Drugs?

• CNS sympatholytic: Clonidine plus• No reason to use methyldopa• Alpha-1 blockers: OK but inferior as

single drug and tachyphylaxis• Labetalol good 5th or 6th choice• Direct vasodilators - hydralazine or

minoxidil - need more diuretics• Peripheral adrenergic antagonists?

Final Take Home Points

Risk of CVD is linear to SBP level120-139/80-89 is “pre-hypertension”

and merits lifestyle modifications in all and may need drug treatment with co-morbidity of DM, CAD, CKDMost patients will need two or more

drugs to achieve goal SBPControl only occurs with motivated

patients who trust their clinician

6/21/2013

1

Preventing the Unintended: Update in Contraception

Jody Steinauer, MD, MASDept. Ob/Gyn & Reproductive SciencesUniversity of California, San Francisco

Disclosure Statement

I have nothing to disclose.

Are you familiar with the US Medical Eligibility Criteria for Contraception?

a. Yes

b. No

How comfortable would you be offering a nulliparous woman an IUD if she had a history of Chlamydia and no current infection?

a. Very comfortable

b. Somewhat comfortable

c. Uncomfortable

6/21/2013

2

Would you offer a 20 year‐old woman with migraine the combined oral contraceptive?

a. Yes

b. It depends

c. No

Objectives

To review contraceptive methods so that you can prioritize contraceptive counseling and provision in your practice

To be comfortable using CDC Medical Eligibility Criteria (MEC) to determine safety

Review basics, controversies, myths and new updates about contraceptive methods

Jane is a 27 year‐old woman taking combined oral contraceptive pills, who presents to your clinic for an annual examination. She reports having missed two periods. Her urine pregnancy test is positive.

6.4 Million U.S. Pregnancies Annually

52 % Intended

25 % UnintendedDespite method use

23 % UnintendedNo method used

Jones PSRH 2008 Mosher Vital Health Stat 2010

6/21/2013

3

Why did Jane get pregnant?

Jane ran out of pills last month. She tried to schedule an appointment, but because she was overdue for a pap smear the clinic staff couldn’t call in refills. Today was the first day she could get an appointment.

Provider Barriers to Contraception

• Clinical Visit

– BP check to initiate estrogen‐containing methods

– No pap smear or other examination

– Refill methods without seeing patient

• Remember birth control

– 48% using D or X rx counseled on contraception1

• Knowledge about contraindications

– US guidelines

Schwarz Ann Intern Med, 2007.

Case: US Guidelines

After Jane has completed her pregnancy she returns to you for contraceptive counseling. Jane has had migraine headaches since she was a teen. She has no aura and they have not changed with the combined pill.

Can she use the pill again?

Can my patient use this method?

1 Can use the method No restrictions

2 Can use the method Advantages generally outweigh theoretical or proven risks.

3 Should not use method unless no other method is appropriate

Theoretical or proven risks generally outweigh advantages

4 Should not use method Unacceptable health risk

US Medical Eligibility Criteria (MEC)

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4

Medical Condition

Birth Control Methods

MEC Category

Where do you find the US MEC?

U.S. Medical Eligibility Criteria forContraceptive Use (USMEC)

United States Medical Eligibility Criteria for Contraceptive Use http://www.cdc.gov/reproductivehealth/unintendedpregnancy/USMEC.htm

Migraine and Combined Hormonal Contraception (CHC)

6/21/2013

5

Migraine, COC*, and Stroke

Synergistic effect of Migraine and COC

OR 8.7 (95% CI 5.0‐15.0) 1

OR 13.9 (95% CI 5.5‐35.1) 2

Etminan BMJ, 2005. Tzourio BMJ, 1995.

*COC= combined oral contraceptive pills

WHO/US: Headaches and CHC*

Non‐migrainous 1

Migraine(i) w/o focal neurologic symptoms

Age < 35 2Age > 35 3

(ii) w/ focal neurologic symptoms 4(at any age)

Focal symptoms = AURA = vision changes, numbness, parasthesias

Non‐focal = Prodrome, photo/phonophobia, N/V

WHO/US: Headaches and CHC*

Initiate ContinueNon‐migrainous 1 2

Migraine(i) w/o focal neurologic symptoms

Age < 35 2 3Age > 35 3 4

(ii) w/ focal neurologic symptoms 4 4(at any age)

Focal symptoms = AURA = vision changes, numbness, parasthesias

Non‐focal = Prodrome, photo/phonophobia, N/V

Absolute Risk of Stroke

No COC COC

Healthy 6 per 100,000 /yr 12 per 100,000 /yr

Migraine 12 per 100,000 /yr 19 per 100,000 /yr

Migraine + aura 18 per 100,000 /yr 30 per 100,000 /yr

Stroke in pregnancy: 34 per 100,000 / year

Speroff & Darney Clinical Guide for Contraception 2005

6/21/2013

6

Case: Counseling Issues

After reviewing the US and WHO MEC you decide Jane can use the pill again.

But is it the best method for her?

Safety Efficacy

Helping patients choose the best method

Patient Preference

Perfect use efficacyFrequency of intervention

ConvenienceSide effectsEfficacy

Non‐contraceptive benefitsFuture pregnancy plans

Always balance against the risk of pregnancy

How effective is the combined oral contraceptive for prevention of pregnancy?

Typical use ≠ Perfect use

Efficacy

How effective is the combined oral contraceptive for prevention of pregnancy?

8% failure rate in 1 year

How many pills, on average, do women forget to take each month (not including placebo)?

Typical use ≠ Perfect use

Efficacy

6/21/2013

7

0

1

2

3

4

5

6

1 2 3

Diary

EMD

Oral Contraceptives 2010: Missed Pills

Hou, Ob Gynecol, 2010

Mean Pills Missed

Cycle

← 5 pills

← admit 1

Contraceptive Method Use, U.S.*

0

5

10

15

20

25

30

35

40

Method

Mosher Vital Health Statistics, 2010Alan Guttmacher Institute, Facts In Brief, 2010.

6.6%

28%

*Among the 38 million women currentlyusing birth control

Most effective

EffectiveLeast effective

10 million = 800,000 pregnancies each year

Contraception Methods

Episodic Daily Weekly Monthly 3 Mo’s 3 yrs 5 yrs 10 yrs Permanent

Barrier

OCPs

Patch

Ring

DMPA(IM or SQ)

Progestin Implant

LNG-IUS

CopperIUD

BTLHysteroscopic

Vasectomy

Combined Hormonal Progestin Only IUC Sterilization

Least effective Most effective

EC

>99%94%92%<83%

Natural Family Planning

Contraceptive MethodFailure Rate

Perfect Use Typical Use

No Method 85% 85%

Periodic Abstinence

Standard Days Method®* 5% 12%

Ovulation Method 3% 22%

Symptothermal 2% 13‐20%

Two‐Day Method® 3% 14%

* Including Cycle Beads

National Center Health Statistics; Contraceptive Technology

6/21/2013

8

Barrier Methods



Withdrawal 4 % 18 %

Condoms 2 % 17 %

Cervical Cap (parous/nullip) 26%/9% 32%/16%

Sponge (parous/nulliparous) 20%/9% 32%/16%

Female Condoms 5 % 27 %

Diaphragm 6 % 16 %


Hormonal Methods



Combined Hormonal Pills <1 % 8 %

Progestin Only Pills <1 % 8 %

Transdermal Patch <1 % 8 %

Vaginal Ring <1 % 8 %

3‐Month Injection <1 % 3 %

Implants <1 % <1 %

Copper IUD/LNG IUS <1 % <1 %


http://www.fhi.org/nr/shared/enFHI/Resources/EffectivenessChart.pdf

Frequency of Intervention

• Permanent: sterilization

• Every 10 years: IUD

• Every 5 years: IUD

• Every 3 years: implant

• Every 3 Months: injection

• Monthly: vaginal ring

• Weekly: patch

• Daily: pill, NFP

• Episodic: barrier methods, NFPIncreasing efficacy

6/21/2013

9

Daily: Natural Family Planning

• Help women identify fertile days

– Fertility window 6‐8 days

– Failure rate 12‐22%

• Two‐day method®

– Simple, accurate method – quicker to learn

– Two questions

• Did I note secretions today?

• Did I note secretions yesterday?

• If yes to either, consider fertile

Natural Family Planning: Two‐day Method®

• Study of 450 women – 3,928 cycles

• Failure rates:

– 14% typical use

– 3% perfect use (no intercourse)

– 6% semi‐perfect (barriers or withdrawal)

– Half of pregnancies in first 3 months

• Mean fertile window 12 days

• High acceptability

Arevalo, Fertil Steril, 2004.

Daily: Combined Oral Contraceptives

• Estrogen + progestin

• Traditional prescription flawed

– Daily x 3 weeks / 1 week off

• Extended cycle may ↑efficacy

Baerwald, Contraception, 2004.

Extended Cycle: Shortened hormone‐free week

• 23, 24 or 26 days hormones + 2‐5 d placebo– Decreased ovarian activity at end of placebo

– Shorter withdrawal bleeds

– Similar breakthrough bleeding

– 3 FDA‐approved products in US

Spona Contraception, 1996 Bachman Contraception, 2004 Endrikat Contraception, 2001.

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10

Extended Cycle:Fewer hormone‐free weeks

• 12 weeks hormone/1 week off

• Ethinyl estradiol and levonorgestrel

– 84 days LNG 150 µg/EE 30 µg; 7 days placebo

– Decreased breakthrough bleeding over time

Anderson Contraception, 2003

Tricycle Breakthrough Bleeding/Spotting

Anderson FD, et al., Contraception, 2003.

Extended Cycle: Continuous Use

• Continuous for one year

– Increased spotting in first six months

– Median 1.5 days spotting in last trimester

• FDA‐approved: ethinyl estradiol and levonorgestrel

– 90 mcg levonorgestrel + 20 mcg EE

Miller Obstetrics and Gynecology, 2003. Kwiecen, Contraception, 2003. Foidart, Contraception, 2006.

Choosing a COC

• Estrogen dose– Low dose = < 50 mcg

• Progestin type– 1st‐generation: norethindrone– Second‐generation: levonorgestrel– Third‐generation: desogestrel– Drospirenone: spironolactone derivative

Kemmeren BMJ 2001; Lidegaard BMJ 2009

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11

VTE & oral progestin type

• Desogestrel and drosperinone OCPs may increase risk of VTE

• BUT. . . Absolute risk remains low

Non‐pregnant, no COCs: 4.4 per 10,000 ‐ yrs

Levonorgestrel COCs: 5.0 per 10,000 ‐ yrsDesogestrel COCs: 6.5 per 10,000 ‐ yrsDrosperinone COCs: 7.8 per 10,000 ‐ yrs

PREGNANCY: 29 per 10,000 ‐ yrs

Lidegaard 2009 BMJHeinemann 2007 Contraception

Choosing a COC

• Careful with very low‐dose estrogen –↑ bleeding• Monophasic fine• No clear benefit of drospirenone

– PMDD: fewer sxs 6 months – equivalent at 2 yr– Acne: Equivalent to other pills

30 or 35 mcg EE + 2nd generation progestinShortened or erased placebo week if possibleMonophasic

VanViet Cochrane 2006LaGuardia Contraception, 2003Freeman Womens Health 2001van Vloten Cutis 2002

Jane no longer wants to take a pill every day. She asks you about other birth control methods which she doesn’t have to think about as often.

What can you offer her?

Weekly

Monthly

3 months

3 years

5‐10 years

Daily:Progestin‐only Pills (POPs)

• 35 mcg norethindrone DAILY

– No hormone free interval!!

• Primary mechanism = cervical mucus thickening

• Requires punctual dosing

– If > 3 hours late, need back up x 48 hours

6/21/2013

12

Weekly: Patch

• Norelgestromin and EE

– 20mcg EE & 150mcg norelgestromin

• One patch a week for 3 weeks, then no x 1 wk• Few side effects – comparable to pills except:

– 20% skin irritation – 2% stopped method

– More breast discomfort and spotting in first 2 cyclesthan pills

– 3% detached –RCT 46% experience at least one detachment in one cycle• Prescribe replacement patch

CreininObstet Gynecol 2008

Monthly: Ring

• Ethinyl estradiol and etonogestrel– 15 mcg EE & 120 mcg desogestrel

• One ring each month:– Ring in x 3 wks– Ring out x 1 week

• Few side effects – comparable to pills except– Spotting: only 5% (significantly less in first month)

– Discharge: 1% stop method

– Discomfort: 2.5% stop method

– Expulsion: RCT: 20% expelled at least once during 3‐week period

Dieben Obstet Gynecol, 2002 CreininObstet Gynecol, 2008

Monthly: Extended Cycle Ring

• RCT of 561: 4wk, 8 wk, 12 wk, continuous:

– All regimens well‐tolerated

– Extended: ↓ bleeding days, spotting days

• Potential for use on a monthly basis

– Serum levels for 35 days

I instruct patients to remove ring the last 3‐4 days of the month if they want withdrawal bleed.

Miller Obstet Gynecol, 2005

Non‐oral HC and VTE

2 case‐control studies

• No association‐ new users

– OR=1.1 (CI 0.6–2.1) 1

• Association‐ all users

– OR=2.4 (CI 1.1‐5.5)2

Retro cohort, 9.4 m ‐yrs3

• Attributable risk:

– +7.6/10K (vs. non)

– +3.5/10K (vs. COC)

Retro cohort, 9.4 m ‐yrs3

• Attributable risk:

– +5.7/10K (vs. non)

– +1.5/10K (vs. COC)

• NNT (switch to COC):– 2000 ring users

– 1250 patch users

• No info on BMI, smoking, famhx

1. Jick SS 2007 Contraception2. Cole JA 2007 Obstet Gynecol3. Lidegaard 2012 BMJ

6/21/2013

13

EE Exposure with combined hormonal contraception

Van den Heuvel, Contraception 2005(*30 mcg EE COC)

AUC (pg/ml):

Patch = 37.7 + 5.6

COC = 22.7 + 2.8

Ring = 11.2 + 2.7

Every 3 months:Progestin Injection

• Medroxyprogesterone acetate 150 mg IM

– One injection every 12‐13 weeks

• Very effective

– Typical use failure = 3%

• Side effects:

– Delayed return to fertility (9‐10 months)

– Irregular bleeding, amenorrhea (50% at 1 yr)

– Weight gain (5 lbs at 1 year, 16 lbs at 5 yrs)

• SQ low‐dose (104 mg) version now available

Progestin Injection & BMD

• BMD decreases by 1‐2% per year

• FDA: limit to 2 yrs. in young women

– WHO & ACOG do not agree

– Bone loss reverses by 1 year after discontinuation.

– No evidence of increased fractures.

• No indication for DEXA

• Weigh risks against risk of pregnancy

Meier, J Clin EndocrinMetab, 2010. Scholes Arch Pediatr Adolesc Med, 2005.; Scholes, Epidemiology, 2002; ACOG 2008 Com Opin 415.

Progestin Injection: Delay

• Traditionally recommend caution after > 14 weeks from last DMPA injection

• WHO recommends 4‐week grace period

– Repeat up to 16 weeks

6/21/2013

14

Missed Hormonal Contraceptives: New Recommendations

• Guidelines for CHC and DMPA• For CHC:

– The hormone free interval (HFI) not > 7 days– In the 1st week

• Back‐up should be used after >1 missed dose until 7 days of use occur. Consider EC.

– In the 2nd and 3rd week• If < 3 days are missed, eliminate the next HFI• If > 3 days are missed, back‐up contraception and consideration of EC should be added

Soc Ob GYN of Canada, JOGC 2008; 219:1050‐62

Every 3 years:Single‐Rod Implant

• Etonogestrel 60mcg/day• New version replaced old in 2011

– Identical but with radiopaque rod– Easier‐to‐use inserter– Must complete FDA‐approvedtraining

• Efficacy > 99%• 1 year continuation: 75%‐90%

– Reasons for discontinuation: Bleeding ( up to 40%)

Blumenthal Eur J Contracept Reprod Health Care, 2008

Progestin Implant: Side Effects

• Bleeding: “Irregularly irregular” (40%)– Amenorrhea: 22%– 7% frequent: > 5 B‐S episodes in 90‐day period– 18% prolonged: at least 1 B‐S episode > 14 days– 20% have B‐S for >50 days in first 90‐day period– Generally NOT heavy

• Treatment of bleeding

Blumenthal Eur J Contracept Reprod Health Care, 2008 Mansour Eur J Contracept Reprod Health Care 2008.

Implant: Bleeding Treatment

Therapy Evidence?

1. COC x 21d/7d (3 mo) or Estrogen alone (0.5 mg estradiol x 21 d) (3 mo)

Minimal

2. Cyclic progestin (MPA 10bid) x 21d/7d (3mo)

Anecdotal

3. POP daily up to 3 mo Anecdotal

4. NSAIDs, COX‐2 inhibitors x 5‐10dTranexamic acid 500 bid x 5d

MinimalAnecdotal

Adapted from Mansour et al 2010, and 2011 Contraception

6/21/2013

15

Every 5‐10 Years: Intrauterine Devices (IUD, IUC, IUD, IUS)

Levonorgestrel Intrauterine System (LNG‐IUS)

• Levonorgestrel 20 mcg/day

• 0.1% failure (1 yr) 1.1% (7 yr)

Copper T 380A IUD

0.8% failure (1 yr) 1.2% failure (7 yr)

Lockhat Fertil Steril, 2005

Comparable to BTL failure rate of 1.8% /10 yrs

10 years

5 years

IUD Review

• Current IUDs do NOT cause PID!!!– Transient increased risk at time of insertion

– STI at time of insertion increases risk

– GC/CT screening can follow CDC guidelines

– Okay to screen on insertion day – treat if +

• Beyond time of insertion• Overall decreased risk with LNG IUS • No increased risk with Copper IUD

• Okay to treat for PID with IUD in place

Svensson L, et al. JAMA. 1984; Sivin I, et al. Contraception. 1991.Farley T, et al. Lancet. 1992; Hubacher, NEJM, 2003.

Routine GC/CT screening NOT necessary!

• Retrospective cohort, n=57,728 IUDs

• Evidence‐based STI screening, treat if + test

Sufrin et al In press, Obstet Gynecol

All women: Risk of PIDNon-screening = Screening

OR= 1.05 (0.78, 1.43)

Screened Women: Risk of PIDSame day = Pre-insertion

OR=.997 (.64, 1.54)

Overall PID risk = 0.54%

Women appropriately selected for non-screening

Most accurate screening time is day of insertionSame

results < 26 yo

IUC, Nulliparity & Infertility

• Nulliparity is not a contraindication

– May have increased pain with insertion

– May have increased risk of expulsion

• IUDs do NOT cause infertility

– Tubal factor 1° infertility is not associated with prior IUD use (OR=1)

Hubacher 2003 N Engl J Med

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16

Is Jane a candidate for an IUD?

Women of any reproductive age seeking

long‐term, highly effective contraception

Post‐pregnancy Intrauterine Contraception

2010 US MEC: Postpartum IUD Insertion

Postpartum (BF or non‐BF women) including post‐caesarean section

LNG‐IUD Cu‐IUD

<10 min after delivery of placenta

2 1

10 min after delivery of placenta to <4 wks

2 2

>4 wks 1 1

Puerperal sepsis 4 4

Why 10 minutes?Postpartum IUD Insertion

Chi Contraception 1985

9.5%

31.5%

37.3%

28.8%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Ad

just

ed

Cu

mu

lati

veE

xpu

lsio

n R

ates

p<0.001 (≤10 minutes compared to all other groups)

6/21/2013

17

How do you do it?Post‐placental IUD Insertion

2

1

WHO and US Medical Eligibility Criteria: Post‐abortion

LNG‐IUC Cu‐IUC

1st trimester 1 1

2nd trimester 2 2

Immediate post‐septic abortion

4 4

Permanent: Tubal Sterilization

• Postpartum salpingectomy

• Silicone Band

(Yoon, Fallope)

• Filshie Clip

• Electrosurgical dessication – unipolar lowest failure

Failure risk 0.5‐1.8%Increases over time

Permanent:Hysteroscopic Tubal Sterilization

• Coils inserted into proximal tubes via hysteroscopy

– Induces scarring reaction in tubes

• Back‐up method x 3 mo, confirm w/ HSG

• Low failure rate (0.26% at 5 yrs)

• Non‐invasive

6/21/2013

18

Post‐exposure:Oral Emergency Contraception

Levonorgestrel 120 mg x 1, up to 5 days

Ulipristal Acetate• Selective progesterone receptor modulator

• Proposed mechanism:1

– Delay follicular rupture

• Will not harm existing pregnancy

• Dosing: 30mg, FDA‐approved up to 5 days

1. Brache 2010 Hum Reprod

Emergency Contraception: Ulipristal Acetate

Effectiveness:1,2

“non‐inferior” to LNG: 1.4% vs. 2.2%

Meta‐analysis of 3445 120 hrs: OR = .55 (.32‐.93)

24 hrs: OR = .35 (.11‐.93)

Side effects: Headache (20%), nausea (12%)

1. Glasier 2010 Lancet2. Creinin 2006 Obstet Gynecol

Alternatives to LNG EC & Ulipristal acetate?

• Copper IUD– VERY effective as EC up to 7 days!

– More effective than LNG EC

• Mifepristone (10, 25 or 50 mg)– More effective than LNG

• Yuzpe regimen– More side effects and less effective

Cheng 2008 Cochrane Database

Jane

You counsel Jane about the other options available, emphasizing those with high efficacy that require less intervention. She ends up choosing a highly effective IUD which you place that same day.

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Summary

• Unintended pregnancy remains a common problem in the US.

• We can minimize barriers to successful contraception.

• Consider including efficacy in your contraception counseling in addition to other priorities of the patient.

References

Many easily accessible resources exist to help solve contraception quandaries. . . .

www.arhp.org

www.cdc.gov

http://www.who.int/reproductivehealth/publications/family_planning

http://www.managingcontraception.com/

http://www.cochrane.org/

www.acog.org

UCSF Family Planning Consult Service(415) 443-6318

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Resources

• WHO and US Medical Eligibility Criteria for Contraceptive Use

– www.who.int

– www.cdc.gov

– www.reproductiveaccess.org

• A Pocket Guide to Managing Contraception

• UCSF Family Planning Consult Service

– (415) 443‐6318

Acknowledgments

Thanks to all who have shared slides!

– Carolyn Sufrin

– Mike Policar

– Phil Darney

– Sarah Prager

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Abortion: Patient-centered Counseling and Evidence-based Care

Jody Steinauer, MD, MAS

Dept. of Obstetrics, Gynecology & Reproductive Sciences


Disclosures

• I have no relevant financial disclosures.

Acknowledgements• Karen Meckstroth and Jen Kerns

Objectives

• Understand abortion global epidemiology• Understand abortion techniques

– Many skills transferable to non-abortion settings

• List the most common complications of uterine aspiration and medical abortion

Outline

• Abortion Epidemiology– US and international settings

• 1st-trimester Abortion– Manual vacuum aspiration– Medical abortion

• 2nd-trimester Abortion• Abortion Complications

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Case: Sara is a 24-year-old woman who had a baby 2 years ago who presents to you complaining of a missed period. Her pregnancy test is positive, and she desires an abortion.

Epidemiology of Abortion in the US

Pregnancies in the United States (6.7 Million in 2006)

51 49

0

20

40

60

80

100

UnintendedIntended

% of pregnancies

Outcomes of Unintended Pregnancies(3.2 Million in 2006)

4357

0

20

40

60

80

100

Abortions Births

% of unintended pregnancies (excluding miscarriages)

1.2 million in 2008

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Abortions by Gestational Duration

Source: Henshaw adjustments to Strauss et al., 2007 (2004 data)

Weeks

% of abortions

89%

Who Has Abortions: Age


Rate of Abortion by Age

Abortions per 1,000 women

Age-group


Who Has Abortions: Economic Status

Source: Jones et al., 2002

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Rate of Abortion by Economic Status


% of poverty level

Abortions per 1,000

Who Has Abortions: Race/Ethnicity

Source: Jones et al., 2002*Non-Hispanic

Rate of Abortion by Race/Ethnicity

Race/ethnicity



Who Has Abortions:Religious Identification


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Who Has Abortions: Prior Pregnancies


Global Epidemiology of Abortion

Abortion Worldwide

Millions of abortions

Source: Sedgh, 2007


U.S. Abortion Rate Higher Than in Many Other Industrialized Countries

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Legal Status is Not Correlated with Incidence

• The lowest abortion rates in the world - less than 10 - are in countries in Europe, where abortion is legal and available.

• In Africa and Latin America - where abortion law is most restrictive - the rates are 29 and 31.

Sedgh et al., 2007

Number of abortions (millions)

20 Million Unsafe Abortions Occur Each Year

Sedgh, 2007

20 Million Unsafe Abortions Occur Each Year Complications of Unsafe Abortion

• Five million women are hospitalized each year for treatment of abortion-related complications

• Complications account for 13% of maternal deaths, or 67,000 per year.

• Approximately 220,000 children worldwide lose their mothers every year because of abortion-related deaths.

Singh, 2006; WHO 2007; Grimes 2006

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Deaths from Abortion Declined Immediately After Legalization Conclusions: Epidemiology

• Unintended pregnancy is common.

• We should be prepared to counsel women about pregnancy options.

• Abortion should be legal and safe.

Counseling Points

• What do you think/hope the results will be?

• Validate and Normalize

• Seek understanding– Can you say more about what you are feeling?

• Reframe– Use what you have learned from her

– What I hear you saying is that you are making this decision because you care about your children’s well-being

• If needed find someone to help

• www.faithaloud.org / www.yourbackline.org

Obligations to Patient

• Study of 1200 physicians in 2007• Would it be ethical to describe why the physician

objects to the requested procedure? – 63% yes

• Does the physician have obligation to present all options to patient, including information about the requested procedure? – 86% yes

• Does the physician have an obligation to refer?– 71% yes

Curlin, NEJM, 2007.

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Conscientious Refusal

• When clinicians claim a right to refuse to provide certain services, to refer patients, or to inform patients about their existing options.

• Widespread in area of reproductive medicine –pharmacists EC and contraception, IUI, life-threatening medical conditions and abortion

• Claim that to provide services would compromise the moral integrity of a provider or institution

Ethical Responsibilities

• Criteria for assessing conscientious refusal– Potential for imposition

• on patients who do not share their beliefs

– Effect on patient health

– Scientific integrity of the claim• EC, abortion and breast cancer

– Potential for discrimination • Fertility assistance in same-sex couples

ACOG Practice Bulletin

Responsibilities

• Prioritize patient’s well-being

• Provide accurate & unbiased information

• Provide potential patients with accurate and prior notice of their moral commitments, not use their authority to argue their position

• Refer in a timely manner

• Emergency – obligation to provide medically necessary services

ACOG Practice Bulletin

Abortion Safety

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Abortion Is Safe in the U.S.

• Abortion is one of the safest medical procedures

• Successful in 98-100% cases

• Complications are rare (0.04% - 0.07%)

• Abortion is even safer if earlier in pregnancy

• Early abortion is very simple to perform

Abortion Methods

Methods of Induced Abortion

1st trimester 2nd trimester

Surgical Dilation & Curettage (D&C)

–Manual suction

–Electric suction

Dilation & Evacuation (D&E)

–Standard D&E

–Intact D&E

Medical Medication

–Mifepristone + Misoprostol

–Misoprostol

–Methotrexate +Miso

Induction

–Misoprostol +/- Mife

1st Trimester Abortion

• Vacuum Aspiration Abortion – Manual or electric

– Less than 14 weeks gestation

• Medical Abortion (25%)– Less than 9 weeks gestation

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1st Trimester Surgical Abortion

• Counseling– Pregnancy options

– Procedural

– Contraception

• Preoperative Assessment• Analgesia and Anesthesia• Cervical Dilation• Aspiration• Recovery

Manual Vacuum Aspiration

• About 50% of U.S. abortion providers use MVAs1

• Usually without sharp curettage

• Must empty syringe during procedure with gestation > 7 or 8 wks

• Women appreciate less noise2,3,4

1. O’Connell, 2008, 2. Bird et al., 2001; 3. Edelman et al., 2001; 4. Dean et al 2003

First-Trimester Aspiration Abortion Surgical Abortion < 6 weeks

• Studies in 1970’s found increased rates of continuing pregnancy & complications < 6 wks

• Now new technology: sensitive urine pregnancy tests and transvaginal sonography

• May require more careful surveillance for equal success

• % of U.S. providers offering abortion at 4 weeks rose from 7% in 1993 to 40% in 2005 1

1. Jones 2008

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Cervical Block Decreases Pain

• 20 mL 1% buffered lidocaine

• Slow, deep injection at tenac + 4 sites

• Stratified by <8 weeks (early), 8-10 weeks (late)

Pain /100 BLOCK NO BLOCK

With block 49/58 24/35 p=.001

Dilation 34/51 75/83 p<.001

Aspiration 58/67 88/88 p<.001

Renner. Ob Gyn May 2012

Cervical & Uterine Nerves

Uterine fundusSympathetic nerves via: • infundibulopelvic pelvic

ligament utero-ovarian lig• inf hypogastric nerve through

uterosacral ligaments, T10 - L1

Lower uterus/cervixParasympathetic plexus lateral to

cervix, S2 - S4

Sensory nerves also found in uterine tissue

Tingaker. Repro bio & endoc 2006

Paracervical vs. intracervical

Superficial vs. deep injection

Cervical Injections

Hybrid

Cervical Block for Uterine Aspiration

1. Deep injections better than superficial (but hurt)

2. Larger volume of injection better (20ml vs. less)

3. Slow injection helps with block pain

4. Buffering lidocaine - less pain than not or bupiv

5. Routinely waiting more than a couple minutes after administering block unlikely to be helpful

6. Adding vasopressin decreases bleeding and possibly re-aspirationand increases amount ofblock that can be used

1 Wiebe et al. Am J Ob Gyn, 19922. Stubblefielf. Int J Gynecol Obstet 19893. Wiebe et al Int J Gynecol Obstet 19954. Wiebe et al. Am J Ob Gyn, 19925. Phair et al Am J Ob Gyn, 20026. Wiebe et al, Contraception. 2003

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Medical Abortion 1st Trimester Medical Abortion

• Counseling and assessment• Take mifepristone in office• Go home with pain medications• Six hours to three days later:

– Place misoprostol pills in vagina

– Over next 4 to 24 hours+ bleeding

• Return to clinic as early as 3 days later– New evidence – follow-up regimens

Medical Abortion

Worldwide

• Over 60% of outpatient abortions in several European countries

• Over 30 million worldwide

• Abortions occur earlier where MAB widely available

FDA-Approved vs. Evidenced-Based Regimens for Medical Abortion

FDA-Approved

• 600 mg Mifeprex PO given in the clinic

• Miso given orally

• 400 mcg misoprostol

• Miso 2 days later

• Miso given in the clinic

• Follow-up day 14

• Gestational limit 7 wks

Evidenced-Based

• 200 mg Mifeprex PO given in the clinic

• Miso vaginally/ buccally

• 800 mcg misoprostol

• Miso 6 hrs-3 days* later

• Pt takes at home

• Follow-up day 3 to 14

• Gestational limit 9 wks

*3 days studied to 8 wks gestation

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Medical Abortion Efficacy

• FDA-approved regimen– 92-96% effective for gestation < 49 days

– 50% complete abortion within 4 hours

• Alternative regimen– 96-99% effective for gestation < 63 days

– 93% complete in less than 4 hours

Evidence-based Regimen

Medical Abortion Outcome

• Cardiac motion & growth = continued pregnancy

• Gestational sac, no CM or growth = incomplete

• Thick endometrial stripe consistent with success

Second Trimester Abortion Techniques

Dilation & Evacuation (D&E) 80%

• Cervical dilation to about 1.5 or 2 cm• Removal of fetus with forceps

Induction Abortion +/- D&C for placenta 20%

Intact D&E / Dilation & Extraction (D&X) <1%

• Cervical dilation large enough for fetal pelvis • Manual extraction of intact breech fetus

Hysterotomy <<1%

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Reasons for Delay in2nd-Trimester Patients

*statistically significant vs. early abortion patients, p<0.05

Difficulty in getting to our clinic 63%*Emotional factors 51%Initially referred to other clinic(s) 47%*Afraid 35%Didn’t suspect pregnancy 34%*Unsure of decision 30%*In denial about being pregnant 21%*Difficulty with Medi-Cal, money, insurance 20%*Difficulty figuring out where to go 20%*Unsupportive partner 19%

Drey E et al, Ob Gyn, 2006

Induction Abortion

• Misoprostol alone: > 90% of women abort within 48 hrs, mean interval of ~ 15 hrs

• Mifepristone + misoprostol: > 90% of women abort within 24 hrs, mean interval of ~ 6 hrs

• Osmotic dilators can shorten interval

1. Autry et al. Am J Ob Gyn, 20022. Ngai, Tang and Ho. Best Prac Res Clin Ob Gyn, 2002

Dilation & Extraction (D&X)(also “Intact D&E”)

• “Partial Birth Abortion,” named by anti-abortion groups, usually describes D&X

• Goal to minimize uterine instrumentation and/or deliver an intact fetus

• Cervical dilation usually requires 2 days

• Performed when:– Family desires autopsy or to see fetus intact

– Fetal anomaly: cystic hygroma, hydrocephalus

– Hemorrhage requires intervention with induction or Sab

Surgical Abortion: Cervical Ripening to Decrease Risk of

Cervical Laceration• SFP 2007

– Consider priming for all adolescents– All women over 12 to 14 weeks

• WHO 2003– Younger than 18 years old – Nulliparous over 9 weeks – All women over 12 weeks

• RCOG 2004– Younger than 18 years old– All women over 10 weeks

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Abortion Complications

An Abortion Is Safer the Earlier in Pregnancy It Is Performed

Sources: All births and abortions: CDC.gov; Abortion by gestation: Bartlett et al., 2004 (1988–1997 data)

Deaths per 100,000 abortions

Abortions by gestation

Causes of Abortion-Related Deaths

Source: Bartlett et al., 2004 (1988–1997 data)

% of abortion deaths (on average, 8 per year)

First-trimester Complications1st trimestermedical

1st trimestersurgical

Overall ---------------- 0.07% (major)

Hemorrhage 0.1 – 0.4% (transfusion) 0.01%

Infection 0.9% 0.1 – 0.4%

Perforation ---------------- 0.1%

Cervical laceration ----------------

Retained products 2 – 5%(~8% for 9wks)

0.3 – 2%

Peterson et al. Obstet Gynecol 1983 Hern et al. Obstet Gynecol 1984Ben-Ami et al. AJOG 2009 Autry et al. AJOG 2002Frick et al. Obstet Gynecol 2012 Paul et al. NAF Textbook 2009Hakim-Elahi et al. Obstet Gynecol 1990

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Second-trimester Complications

2nd trimester medical 2nd trimester surgical

Overall ---------------- 0.6%

Hemorrhage <1% 0.8 – 2.1%

Infection 2 – 3% 0.3 – 0.6%

Perforation ---------------- 0.4%

Cervical laceration ---------------- 0.1 – 0.8% (2.1 – 6.3%)

Retained products 2.5 – 10% 0.4 – 2.7%

Peterson et al. Obstet Gynecol 1983 Hern et al. Obstet Gynecol 1984Ben-Ami et al. AJOG 2009 Autry et al. AJOG 2002Steinauer et al. Unpublished data Paul et al. NAF Textbook 2009Hakim-Elahi et al. Obstet Gynecol 1990

Risk Factors for D&E Complications

• Poor cervical dilation

• Increased gestational age

• Abnormal placentation

• Prior cesarean delivery

• Level of training

• Black race

Peterson et al. Obstetrics and Gynecology 1983Fox and Hayes Contraception 2007Bartlett et al. Obstetrics and Gynecology 2004Diedrich and Steinauer Clinical Obstetrics and Gynecology 2009

Cervical lac

BleedingMortality PerforationFeverCervical lac

Bleeding Hysterectomy

Mortality

Cervical lac

Perforation

Hemorrhage Risk

Kerns and Steinauer Contraception 2013

Long-Term Safety of Abortion

• Abortions do not increase risk of:– Infertility– Ectopic pregnancy– Miscarriage– Preterm or low-birth-weight delivery

• There is no association between abortion and breast cancer.

• Abortion does not pose a hazard to women’s mental health.

Boonstra, 2006Steinberg 2009, 2010

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Surgical Abortion: STI Screening and Antibiotic Px

• Infection rate <1%• Screen for STI according to guidelines• Abx px post-aspiration infection

– Recommend for all aspiration (EPF too)– Meta-analysis: RR 0.58– ACOG Practice Bulletin 2006

• Doxy 100 mg 1 hr prior + 200 mg after or• Metronidazole 500 mg PO bid x 5 days

– 2 Doses Doxy – one before procedure

Sawaya GF. Obstet Gynecol 1996

Medical Abortion: STI Screening and Antibiotic Px

• Overall infection rate 0.1%

• Screen for STI according to guidelines

• Minimal evidence supporting abx px

• Rare deaths from Clostridium– 1/100,000 risk of death

– US – 6 Canada – 1 – All within 1 week of medical abortion– All Mifeprex + 800 mcg miso

Fischer M et al. NEJM, 2005Cohen, et al. Obstet Gynecol Nov 2007

C. Sordellii Toxic Shock

Symptoms • Tachycardia, hypotension, edema, profound leukocytosis

hemoconcentration, and absence of fever

Diagnosis• CBC, anerobic cx culture,

histopathology/immunohistochemical

Treatment• Hysterectomy• Anerobic antimicrobial coverage

(clinda, PCN, amp, erythromycin, rifampin, tetracycline, cefoxitin, metronidazole)

• Supportive care for pre-formed toxin

Management of Hemorrhage

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Summary

• Abortions are common, safe, and most are early in the US.

• Abortion is safest and not more common when legal.

• Refer women as soon as possible for care.

• First-trimester uterine aspiration can be safely provided in outpatient setting.

• Antibiotics decrease infection after uterine aspiration.

Summary

• Early pregnancy loss

• Brief abortion update– Cervical preparation

– Medication abortion

Resources

• www.papayaworkshop.org

• Society of Family Planning guidelines

• www.yourbackline.org

• www.faithaloud.org

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Lumps, Bumps, Leaking and PainManagement of Breast Conditions

Rebecca A. Jackson, MDProfessor Department of Obstetrics, Gynecology

and Reproductive SciencesUniversity of California, San Francisco

I HAVE NO DISCLOSURES

Plan

•Palpablebreastmass•Non‐Palpablebreastmass• Mastalgia• NippleDischarge

• Mastitis

•Palpablebreastmass•Non‐Palpablebreastmass• Mastalgia• NippleDischarge

• Mastitis

Gallup Poll: Leading Causes of Death in Women

Gallup Poll

Perceived

Actual

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Failure to diagnose breast cancer in a timely manner is a leading

cause of malpractice claims

Common reasons:

• Unimpressive

physical findings

• Failure to f/u with pt

• Palpable mass with

negative mammo

Common reasons:

• Unimpressive

physical findings

• Failure to f/u with pt

• Palpable mass with

negative mammo

Likelihood of Cancer in Dominant Breast Mass by Age

Of all discrete breast masses, about 10% are cancerous. (In contrast, 8% of abnormal mammos = cancer)

“Dominant Mass”?

• Discreteordominantmass=standsoutfromadjoiningbreasttissue,definableborders,ismeasurable,notbilateral.

• Nodularityorthickening=ill‐defined,oftenbilateral,fluctuateswithmenstrualcycle

• Inwomen<40referredformass,only1/3hadconfirmeddominantmass

Breast Mass: Diagnostic Options

• Physicalexam

• Ultrasound

• Mammogram

• Cystaspiration

• Fineneedleaspiration

• Coreneedlebiopsy

• Excisionalbiopsy

• Physicalexam

• Ultrasound

• Mammogram

• Cystaspiration

• Fineneedleaspiration

• Coreneedlebiopsy

• Excisionalbiopsy

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Question 1

A42yroldwomanwithnofamilyorpersonalhistoryofbreastcancerhasfoundabreastlump.Shedoesn’tknowhowlongithasbeenthere.Itisnotpainful.

Onexam,itisadiscretemass,2cm,relativelysmooth,mobileandnon‐tender.Shehasnoaxillarylymphadenopathy.

Whatisyournextstep?

A42yroldwomanwithnofamilyorpersonalhistoryofbreastcancerhasfoundabreastlump.Shedoesn’tknowhowlongithasbeenthere.Itisnotpainful.

Onexam,itisadiscretemass,2cm,relativelysmooth,mobileandnon‐tender.Shehasnoaxillarylymphadenopathy.

Whatisyournextstep?

Q1: Palpable mass in 42 yo

Nextstep(pickone)?

A. Nothingnow.Re‐examinein1‐2months

B. Ultrasound

C. Mammography

D. Officeaspiration

E. FNAB

F. Corebiopsy

Nextstep(pickone)?

A. Nothingnow.Re‐examinein1‐2months

B. Ultrasound

C. Mammography

D. Officeaspiration

E. FNAB

F. Corebiopsy

Q1b: Palpable mass in 42 yo

Amammographywaschosenandisnegative.Nextstep(pickone)?

A. Re‐examinein1‐2months

B. F/u1yearforannualexam

C. Ultrasound

D. Officeaspiration

E. FNAB

F. Corebiopsy




C. Ultrasound

D. Officeaspiration

E. FNAB

F. Corebiopsy

Q1c: Palpable mass in 42 yo

Anultrasoundwaschosenasthefirststep.Itshowsacysticmass.Nextstep?



C. Officeaspiration

D. FNA

E. Corebiopsy




C. Officeaspiration

D. FNA

E. Corebiopsy

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Step 1: Palpable Breast Mass

• Determineifmassiscysticorsolid

• Simplecystsarebenignanddon’trequirefurtherevaluation

• 20‐25%ofpalpablemassesaresimplecysts,mostoccurringin40‐49yo’s

• Options?:Ultrasound,officeaspiration,FNA,coreneedlebiopsy

• Determineifmassiscysticorsolid

• Simplecystsarebenignanddon’trequirefurtherevaluation

• 20‐25%ofpalpablemassesaresimplecysts,mostoccurringin40‐49yo’s

• Options?:Ultrasound,officeaspiration,FNA,coreneedlebiopsy

Breast Exam

• Nethersensitive(50‐60%)norspecific(60‐90%)(evenwhendonebyexperts)

• Cannotreliablydistinguishcystfromsolid• Nonetheless,itisimportantfordeterminingifmassisdiscrete(vsnodularityorthickening),isanecessaryadjuncttomammogramandisrequiredforfollow‐upofmasses

• Performin2positions,methodical,spiralsorstrips

• Markmasspriortobiopsysootherscanfindit

• Nethersensitive(50‐60%)norspecific(60‐90%)(evenwhendonebyexperts)

• Cannotreliablydistinguishcystfromsolid• Nonetheless,itisimportantfordeterminingifmassisdiscrete(vsnodularityorthickening),isanecessaryadjuncttomammogramandisrequiredforfollow‐upofmasses

• Performin2positions,methodical,spiralsorstrips

• Markmasspriortobiopsysootherscanfindit

Ultrasound

• PrimaryUse:Classifymassascysticor

solid

• Guidanceforcystaspirationorbiopsy

• Adjuncttoevaluatesymmetricdensitiesdetectedbymammography

• Canbethefirsttestperformed&ifcystisconfirmed—theonlytestrequired

• PrimaryUse:Classifymassascysticor

solid

• Guidanceforcystaspirationorbiopsy

• Adjuncttoevaluatesymmetricdensitiesdetectedbymammography

• Canbethefirsttestperformed&ifcystisconfirmed—theonlytestrequired

Fibroadenoma Cancer

Well-circumscribed, superficial

Irregular, deep

Cyst

Anechoic, well-circumscribed,

Ultrasound is 98-100% accurate for diagnosis of simple cysts. However, for solid masses, it cannot reliably distinguish benign from malignant.

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Cyst Aspiration

• Simpleofficeprocedure:20‐23gaugeneedleandsyringe,ultrasoundguidanceoptional,specializedtrainingnotnecessary

• PrimaryUse:Confirmmassiscystic• Secondaryuse:Relievepain/pressureduetosymptomaticcyst

• Benefits:Ifcysticfluidobtained,establishesimmediatediagnosisandprovidessymptomaticrelief

• Simpleofficeprocedure:20‐23gaugeneedleandsyringe,ultrasoundguidanceoptional,specializedtrainingnotnecessary

• PrimaryUse:Confirmmassiscystic• Secondaryuse:Relievepain/pressureduetosymptomaticcyst

• Benefits:Ifcysticfluidobtained,establishesimmediatediagnosisandprovidessymptomaticrelief

Cyst Aspiration (cont’d)

Adequate/reassuringif:1.Cystfullycollapses(noresidualmass)

2.Fluidisnotbrown/red(cloudyok)

3.Doesnotre‐accumulate(i.e.frequentf/u)

• Ifallaretrue,noneedtosendfluid.

• F/uin1‐3monthstoensurenoreaccumulationorresidualmass

• Ifnofluidorifbloodyfurtherworkup

Adequate/reassuringif:1.Cystfullycollapses(noresidualmass)

2.Fluidisnotbrown/red(cloudyok)

3.Doesnotre‐accumulate(i.e.frequentf/u)

• Ifallaretrue,noneedtosendfluid.

• F/uin1‐3monthstoensurenoreaccumulationorresidualmass

• Ifnofluidorifbloodyfurtherworkup

Fine Needle Aspiration: QUIZ

• FNABshouldbedonebyanexperiencedcytopathologistorbreastsurgeon?….TRUEORFALSE?

• AdiagnosisofFATTYTISSUEonFNAmeanswhat?

• WhenshouldyouFOLLOW‐UPawomanwithapalpablemassandnegativeFNAandmammogram?

• FNABshouldbedonebyanexperiencedcytopathologistorbreastsurgeon?….TRUEORFALSE?

• AdiagnosisofFATTYTISSUEonFNAmeanswhat?

• WhenshouldyouFOLLOW‐UPawomanwithapalpablemassandnegativeFNAandmammogram?

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Fine Needle Aspiration Biopsy

• PrimaryUse:Diagnosisofsolidmasses• Leastinvasivebiopsymethod• Sensitivityisoperatordependent:

– Forexperiencedpersonnel,92‐98%– Foruntrainedpersonnel,75%Average(aslowas65%).

• Experiencedcytopathologistnecessarytointerpret• CannotdiagnoseDCIS,atypicalhyperplasiaorinfiltratingcarcinoma

• Anon‐diagnosticresultinthesettingofadiscretemassrequiresfurtherwork‐up(possiblesamplingerror)

• PrimaryUse:Diagnosisofsolidmasses• Leastinvasivebiopsymethod• Sensitivityisoperatordependent:

– Forexperiencedpersonnel,92‐98%– Foruntrainedpersonnel,75%Average(aslowas65%).

• Experiencedcytopathologistnecessarytointerpret• CannotdiagnoseDCIS,atypicalhyperplasiaorinfiltratingcarcinoma

• Anon‐diagnosticresultinthesettingofadiscretemassrequiresfurtherwork‐up(possiblesamplingerror)

Palpable mass: Diagnostic Mammography

• Cannotaccuratelydifferentiatebenignfrommalignantmassesorcysticfromsolid

• Poorsensitivityinyoungwomenduetodensity• 15‐20%ofmammosarenormal inwomenwithpalpablemass

• PrimaryUse:Screenoppositebreast(inwomen>40yo)andidentifyothernon‐palpablesuspiciousareas

• Secondaryuse:FurtherclassificationofthepalpablemassEVENIFTHEMAMMOISNORMAL,FURTHER

WORK‐UPISREQUIRED

• Cannotaccuratelydifferentiatebenignfrommalignantmassesorcysticfromsolid

• Poorsensitivityinyoungwomenduetodensity• 15‐20%ofmammosarenormal inwomenwithpalpablemass

• PrimaryUse:Screenoppositebreast(inwomen>40yo)andidentifyothernon‐palpablesuspiciousareas

• Secondaryuse:FurtherclassificationofthepalpablemassEVENIFTHEMAMMOISNORMAL,FURTHER

WORK‐UPISREQUIRED

Breast Cyst

Cyst is anechoic on ultrasound

Can’t distinguish cyst from solid on mammogram

Breast Density

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Spiculated mass

Small Cancer

Core Needle Biopsy• PrimaryUse:Diagnosisofsolidmasses,f/uofnon‐diagnosticFNAB

• UnlikeFNAB,itcandistinguishDCISfrominvasivediseaseandbecauseitisatissuespecimen,interpretationiseasier

• FewdirectcomparisonstoFNABforpalpablelesions:Studiesmixedforsensitivity‐someshowingFNAbetterandsomewithCNBbetter.Similarspecificity.

• PrimaryUse:Diagnosisofsolidmasses,f/uofnon‐diagnosticFNAB

• UnlikeFNAB,itcandistinguishDCISfrominvasivediseaseandbecauseitisatissuespecimen,interpretationiseasier

• FewdirectcomparisonstoFNABforpalpablelesions:Studiesmixedforsensitivity‐someshowingFNAbetterandsomewithCNBbetter.Similarspecificity.

Core Needle Biopsy (cont’d)

• Like FNAB, requires training to prevent false negatives due to sampling error

• Used instead of FNAB by consultant preference or where cytopathology service not skilled in interpretation

• Also preferred for evaluation of non‐palpable lesions

• Like FNAB, requires training to prevent false negatives due to sampling error

• Used instead of FNAB by consultant preference or where cytopathology service not skilled in interpretation

• Also preferred for evaluation of non‐palpable lesions

Question 1

A42yearoldwomanwithnofamilyorpersonalhistoryofbreastcancer hasfoundabreastlump.Shedoesn’tknowhowlongithasbeenthere.Itisnotpainful.

Onexam,itisadiscretemass,about2cm,relativelysmooth,mobileandnon‐tender.Shehasnoaxillarylymphadenopathy.

Whatisyournextstep?

A42yearoldwomanwithnofamilyorpersonalhistoryofbreastcancer hasfoundabreastlump.Shedoesn’tknowhowlongithasbeenthere.Itisnotpainful.

Onexam,itisadiscretemass,about2cm,relativelysmooth,mobileandnon‐tender.Shehasnoaxillarylymphadenopathy.

Whatisyournextstep?

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So, what is the best first step?• Firststep=determineifcysticorsolid.

• Howdependsonyourinstitution(availabilityandexpertiseofvariousservices)andwhetherpatientissymptomatic

• FNAB:Therapeutic,diagnosticandcost‐efficient

• U/S:SimilarincosttoFNAB,butFNABmorecosteffectiveb/c80%ofmassesareNOTcysticonU/SandwillrequireFNABtofurtherevaluate

• IfFNABnotavailable:U/Sfirstwilleliminateneedforcorebiopsyin20%thatdohavecysts

• Firststep=determineifcysticorsolid.

• Howdependsonyourinstitution(availabilityandexpertiseofvariousservices)andwhetherpatientissymptomatic

• FNAB:Therapeutic,diagnosticandcost‐efficient

• U/S:SimilarincosttoFNAB,butFNABmorecosteffectiveb/c80%ofmassesareNOTcysticonU/SandwillrequireFNABtofurtherevaluate

• IfFNABnotavailable:U/Sfirstwilleliminateneedforcorebiopsyin20%thatdohavecysts

So, what is the best first step?• Officeaspiration:Reasonable1st stepespifsymptomatic.Ifnotcystic,willrequirebiopsy

• Mammography: notbest1st stepb/ccan’treliablydistinguishbenignfrommalignantorcysticfromsolid(butisusuallypartofacompleteevaluation)

• F/U1‐2mos:Couldbeokinyoungwoman(<40)whowillreliablyfollow‐up.Discussoptions,getagreement,documentwell.Ifmasspersists,gotoU/SorFNA.

• Officeaspiration:Reasonable1st stepespifsymptomatic.Ifnotcystic,willrequirebiopsy

• Mammography: notbest1st stepb/ccan’treliablydistinguishbenignfrommalignantorcysticfromsolid(butisusuallypartofacompleteevaluation)

• F/U1‐2mos:Couldbeokinyoungwoman(<40)whowillreliablyfollow‐up.Discussoptions,getagreement,documentwell.Ifmasspersists,gotoU/SorFNA.

Triple test

• Improvedaccuracybycombining:

1.FNABorcorebiopsy2.Mammography(orultrasound)3.Physicalexam

• Whenall3resultsconcordant,99%accuracy

• However,PEaddslittleb/cnotspecific.Itsroleissimplytodocumentdominantpalpablemass

• Ifanyoneissuspicious,coreorexcisionalbiopsy

• Improvedaccuracybycombining:

1.FNABorcorebiopsy2.Mammography(orultrasound)3.Physicalexam

• Whenall3resultsconcordant,99%accuracy

• However,PEaddslittleb/cnotspecific.Itsroleissimplytodocumentdominantpalpablemass

• Ifanyoneissuspicious,coreorexcisionalbiopsy

Accuracy of triple test

Mass “benign “on Palpation

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Step 2: for a cystic mass…

• Ifsymptomatic,aspirate• Ifdiagnosedbyultrasoundandnoaspirationisdone,f/u1year.

• Ifaspiratedandfluidisnotbloody,f/u1‐3monthstoensurenoresidualmassorre‐accumulation

• Foranypatient>40,alsogetmammoforscreening(>50recommend,>40shareddecision)

• Ifsymptomatic,aspirate• Ifdiagnosedbyultrasoundandnoaspirationisdone,f/u1year.

• Ifaspiratedandfluidisnotbloody,f/u1‐3monthstoensurenoresidualmassorre‐accumulation

• Foranypatient>40,alsogetmammoforscreening(>50recommend,>40shareddecision)

Step 2: for a solid mass

Biopsy (FNAorcoreneedlebiopsy)

PLUS

Mammogram (tofurthercharacterizemassandtoscreenrestofbreasts)

• Ifbotharenegative,f/u3‐6months

• Ifeitherisequivocalorresultsarenotconcordant,refertobreastsurgeonforfurtherevaluation

Biopsy (FNAorcoreneedlebiopsy)

PLUS

Mammogram (tofurthercharacterizemassandtoscreenrestofbreasts)

• Ifbotharenegative,f/u3‐6months

• Ifeitherisequivocalorresultsarenotconcordant,refertobreastsurgeonforfurtherevaluation

Ultrasound F/u instead of biopsy for solid mass?

• 2smallretrospectivecohortstudies—largestn=312withpalpablemass&U/S=“probablybenign”

• Mostlyyoungwomensolowpretestprobabilityofcancer(avgage34yo)

• Strictcriteriaforcallinglesion“probablybenign”

• 2of312werecancer.NPV=0.6%.

• Concludeoktonotbiopsyandfollowwithq6mou/sfor2yrs(simtof/uofbirads3mammo)

• Caution:retrospective

• 2smallretrospectivecohortstudies—largestn=312withpalpablemass&U/S=“probablybenign”

• Mostlyyoungwomensolowpretestprobabilityofcancer(avgage34yo)

• Strictcriteriaforcallinglesion“probablybenign”

• 2of312werecancer.NPV=0.6%.

• Concludeoktonotbiopsyandfollowwithq6mou/sfor2yrs(simtof/uofbirads3mammo)

• Caution:retrospectivePark, Acta Radiologica, 2008

How are we doing?

• Inastudyofwomenwithapalpablemassandnegativemammo,only57%receivedany subsequentevaluation.– Latinas,obeseanduninsuredlesslikelytohaveanysubsequentevaluation

• Arecentstudyofdelayindiagnosisfoundthemostcommonreasonwasinappropriatereassuranceofwomenwithalumpandnormalmammogram

• Inastudyofwomenwithapalpablemassandnegativemammo,only57%receivedany subsequentevaluation.– Latinas,obeseanduninsuredlesslikelytohaveanysubsequentevaluation

• Arecentstudyofdelayindiagnosisfoundthemostcommonreasonwasinappropriatereassuranceofwomenwithalumpandnormalmammogram

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Summary: Palpable Breast Mass• Choiceofwork‐upoftendependsonavailabilityandexpertiseofFNA,U/Sandcoreneedlebiopsy

• Noneofthesetestsis100%accurate,maintainahighindexofsuspicion

• Tripletestisgoldstandard.Ifanyofthe3testsisdiscordant continuework‐up

• Frequentf/uevenformassesthoughttobebenigntodetectfalsenegatives

• Choiceofwork‐upoftendependsonavailabilityandexpertiseofFNA,U/Sandcoreneedlebiopsy

• Noneofthesetestsis100%accurate,maintainahighindexofsuspicion

• Tripletestisgoldstandard.Ifanyofthe3testsisdiscordant continuework‐up

• Frequentf/uevenformassesthoughttobebenigntodetectfalsenegatives

Recommended Review: Kerlikowske, Annals Int Med, 2003

Dominant Breast Mass

U/S or Aspirate*

Solid or complex cystDo FNA or core bx

Simple cyst

If aspirate and no residual lump, fluid not bloody then do CBE 4-6 wks. If u/s, no further w/u.

BenignAtypical, suspicious

Cancer Non-diagnostic

Treat

Core or excisional biopsy

Repeat FNA, core or excision biopsy

Positive Mammo

Negative Mammo

CBE 3-6 mos

More imaging, core

or excision bx

U/S or Aspirate*

* Aspirate=office aspiration or FNAB Adapted from Kerlikowske, Ann Int Med, 2003

Q1b: Palpable mass in 42 yo




C. Ultrasound

D. Officeaspiration

E. FNA

F. Corebiopsy




C. Ultrasound

D. Officeaspiration

E. FNA

F. Corebiopsy

Mammo cannot distinguish cyst from solid and is negative in 15% with palpable mass so need to proceed with work-up from Step 1 ie cyst vs solid

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Q1c: Palpable mass in 42 yo




C. Officeaspiration

D. FNA

E. Corebiopsy




C. Officeaspiration

D. FNA

E. Corebiopsy

Simple cysts are benign and no further work-up is required. If the cyst is symptomatic, may aspirate in office.

Work-up of non-palpable lesions

BI-RADS: Breast Imaging Reporting and Data System

Pre/Post Test Probability of cancer based on mammo results and age

Kerlikowske, Annals Int Med, 2003

Follow-up of abnormal screening mammogram

Kerlikowske, K. et. al. Ann Intern Med 2003;139:274-284

If normal, repeat screen 6 mos then q 1-2 yrs

Consider breast exam to see if lesion is palpable & biopsiable

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Breast Pain

• 2/3 -3/4 report it

• > 1/2 of breast visits

• Etiology unknown: not associated with prolactin,

estrogen or progesterone levels

• 2 types: cyclic & non-cyclic

• Both types chronic, relapsing especially if severe or early onset

• Severe breast pain interferes with sex (46%), activity (36%), social (13%), work (6%)

• 2/3 -3/4 report it

• > 1/2 of breast visits

• Etiology unknown: not associated with prolactin,

estrogen or progesterone levels

• 2 types: cyclic & non-cyclic

• Both types chronic, relapsing especially if severe or early onset

• Severe breast pain interferes with sex (46%), activity (36%), social (13%), work (6%)

Mastalgia: Treatment

• Work‐up:riskfactorevaluation,exam,

mammoif>40years

• DetermineeffectonQOL

• 60‐80%resolvespontaneously.

• Reassuranceoftensufficient

• Work‐up:riskfactorevaluation,exam,

mammoif>40years

• DetermineeffectonQOL

• 60‐80%resolvespontaneously.

• Reassuranceoftensufficient

Mastalgia: TreatmentProven in RCT’s:• NSAID’s (topical and oral) • Evening Primrose Oil • Iodine• Vitex agnus castus extract-

containing solution (VACS) • Gestrinone (N/A in US)• Progesterone vaginal cream• Bromocryptine• Danazol• Tamoxifen

Proven in RCT’s:• NSAID’s (topical and oral) • Evening Primrose Oil • Iodine• Vitex agnus castus extract-

containing solution (VACS) • Gestrinone (N/A in US)• Progesterone vaginal cream• Bromocryptine• Danazol• Tamoxifen

No benefit (per RCT’s, though many are small and likely underpowered)

• Caffeine restriction• Vitamin E• Vitamin B6• Diuretics• Provera • Soya protein• Isoflavones

No benefit (per RCT’s, though many are small and likely underpowered)

• Caffeine restriction• Vitamin E• Vitamin B6• Diuretics• Provera • Soya protein• Isoflavones

Other: Supportive, well fitting bra, bra at night, trigger point injections for localized pain, OCP’s—help some, make worse in others. If on OCP, try lower dose of Estradiol

Most effective but poorly tolerated

Possibly effective, 1000 mg bid-tid for 2-3 months

Topical diclofenac very effective

Topical NSAID for mastalgiaDiclofenac topical (Voltaren) q 8hr vs placebo cream. Randomized, double-blinded

Colac, Journal of the American College of Surgeons, April 2003

Very large decrease in pain score

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Mastalgia: Prescribing GuideProven in RCT’s:

• **NSAID’s (topical diclofenac q 8hr very effective in 3 RCTs; oral NSAIDs—moderately effective in some but not all RCTS )

• Evening Primrose Oil: 1000mg tid for at least 1 mo trial, >$2/day, mild nausea. Recent meta-analysis showed no benefit

• Bromocriptine: increase dose gradually to decrease side effects (nausea, dizziness, orthostatic hypotension, headache). 1.25 mg qhs, increase by 1.25 mg every week until 5 mg/day.

• Danazol: best of the endocrine agents but virulizing side effects make it less desirable, teratogenic, expensive. Start at 200mg qd. Taper down as tolerated to 100mg every other day or qd during luteal phase.

Proven in RCT’s:

• **NSAID’s (topical diclofenac q 8hr very effective in 3 RCTs; oral NSAIDs—moderately effective in some but not all RCTS )

• Evening Primrose Oil: 1000mg tid for at least 1 mo trial, >$2/day, mild nausea. Recent meta-analysis showed no benefit

• Bromocriptine: increase dose gradually to decrease side effects (nausea, dizziness, orthostatic hypotension, headache). 1.25 mg qhs, increase by 1.25 mg every week until 5 mg/day.

• Danazol: best of the endocrine agents but virulizing side effects make it less desirable, teratogenic, expensive. Start at 200mg qd. Taper down as tolerated to 100mg every other day or qd during luteal phase.

Mastalgia: Prescribing Guide

Proven in RCT’s (continued):

• Tamoxifen: 10 mg qd, hot flashes, expensive

• Torimefin: 30 mg qd, vag d/c, irreg menses

• GnRH agonists: very expensive, menopausal side effects, can only use for 6 months due to bone loss.

• Local Injections: trigger point injection of 1% lidocaine (1cc) and methyl prednisone (40mg). Half require second injection in 2-3 months.

Proven in RCT’s (continued):

• Tamoxifen: 10 mg qd, hot flashes, expensive

• Torimefin: 30 mg qd, vag d/c, irreg menses

• GnRH agonists: very expensive, menopausal side effects, can only use for 6 months due to bone loss.

• Local Injections: trigger point injection of 1% lidocaine (1cc) and methyl prednisone (40mg). Half require second injection in 2-3 months.

Nipple Discharge

• Usually benign or malignant?

• Most common cause of unilateral discharge?

• Other causes: duct ectasia, nipple eczema,

Paget disease

• If associated with mass, more likely to be

cancer (but cancer rarely presents with nipple d/c)

• Usually benign or malignant?

• Most common cause of unilateral discharge?

• Other causes: duct ectasia, nipple eczema,

Paget disease

• If associated with mass, more likely to be

cancer (but cancer rarely presents with nipple d/c)

benignintraductal papilloma

Paget’s

Nipple Discharge

Physiologic:

• Due to galactorrhea (ie

increased prolactin) or

nipple stimulation

• With compression

• Multiple ducts

• Clear, yellow, white

• No mass

Physiologic:

• Due to galactorrhea (ie

increased prolactin) or

nipple stimulation

• With compression

• Multiple ducts

• Clear, yellow, white

• No mass

Pathologic:

• Papilloma, cancer

• Spontaneous

• Single duct

• Bloody

• Mass present

Pathologic:

• Papilloma, cancer

• Spontaneous

• Single duct

• Bloody

• Mass present

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Nipple Discharge: Diagnosis

Physiologic:

• History: running,

breast stimulation

• Prolactin, TSH

• Meds:

Psychotropics

Physiologic:

• History: running,

breast stimulation

• Prolactin, TSH

• Meds:

Psychotropics

Pathologic (Spont, unilat):

• Isolate involved duct

• Hemoccult to confirm blood, cytology not useful

• Mammography with retro-alveolar views

• Galactography controversial

• Surgery referral

Pathologic (Spont, unilat):

• Isolate involved duct

• Hemoccult to confirm blood, cytology not useful

• Mammography with retro-alveolar views

• Galactography controversial

• Surgery referral

Mastitis

• 2types:lactatingvsnon‐lactating

• Primaryvssecondary(cellulitis,folliculitis,hydradinitis,sebaceouscyst)

• 2types:lactatingvsnon‐lactating

• Primaryvssecondary(cellulitis,folliculitis,hydradinitis,sebaceouscyst)

Cellulitis

Lactational Mastitis

• Suspect in any breast-feeding woman with a fever and malaise

• Often wedge shaped redness over involved duct

• Staph, Strept—(community acquired MRSA becoming more common so do culture of milk)

• Suspect in any breast-feeding woman with a fever and malaise

• Often wedge shaped redness over involved duct

• Staph, Strept—(community acquired MRSA becoming more common so do culture of milk)

Non-Lactational Mastitis

• Difficult to treat

• Often chronic, recurrent

• Peri-areolar: young (avg 32), 90% are smokers, central pain, nipple retraction and discharge, often assoc with abscess

• Difficult to treat

• Often chronic, recurrent

• Peri-areolar: young (avg 32), 90% are smokers, central pain, nipple retraction and discharge, often assoc with abscess

• Peripheral: elderly, usually associated with underlying disease (diabetes) or trauma

• Gram negatives, staph, strept, anaerobes

• Peripheral: elderly, usually associated with underlying disease (diabetes) or trauma

• Gram negatives, staph, strept, anaerobes

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Mastitis Treatment

Lactational

• Increase feeding, warm compresses

• Keflex, Dicloxicillin

• IV if not better quickly

• Septra or Clinda for community acquired MRSA

Lactational

• Increase feeding, warm compresses

• Keflex, Dicloxicillin

• IV if not better quickly

• Septra or Clinda for community acquired MRSA

Non-Lacatational

• Include anaerobic coverage

• Clindamycin or Flagyl + Ancef or Nafcillin

Non-Lacatational

• Include anaerobic coverage

• Clindamycin or Flagyl + Ancef or Nafcillin

** Biopsy if recurrent or doesn’t resolve

Cancer can mimic mastitis

Inflammatory Cancer

Breast Abscess• Suspectif“lump”onexamorifmastitisnotrespondingtoabx

• Ultrasoundtoconfirm• Getculture• AspirationnowpreferredoverI&D

• Sometimesneedrepeatedaspirations

• I&Doftenassocwithpoorcosmeticresultorfistula

• Suspectif“lump”onexamorifmastitisnotrespondingtoabx

• Ultrasoundtoconfirm• Getculture• AspirationnowpreferredoverI&D

• Sometimesneedrepeatedaspirations

• I&Doftenassocwithpoorcosmeticresultorfistula

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Topics inPediatric & Adolescent Gynecology

No financial disclosures

No discussion of off label medications

Objectives Illustrate techniques for examining

children

Review common Pedi-Gyn conditions

Discuss etiology and treatment of AUB in adolescents

Normal Anatomy: baby

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Case 1

A 4 week old infant has a mass bulging at her introitus. She has no difficulty passing urine or stool.

The family’s medical insurance expires in 2 weeks…

What would you do?

A. Schedule hymenotomy in ORB. Aspirate fluid to decompress C. Reassure parents it will resolve

spontanouslyD. Check chromosomes

Case 2

A 4 yr old presents with a 6 wk history of vulvar erythema, itching and scant yellowish discharge on her underwear. Her parents are very concerned.

Vulvovaginitis

History

•Duration, color, odor, quantity, bleeding, itching, burning, dysuria, redness

Detailed description of symptomsDetailed description of symptoms

•Nylon tights, wet bathing suits, close fitting jeans

ClothingClothing

•Front to back wiping

Hygiene habitsHygiene habits

•Recent URI or GI illness

Systemic illnessSystemic illness

•Autoimmune, atopic dermatitis, eczema

Chronic illnessChronic illness

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Vulvovaginitis

MedicationsMedications

•Laundry detergents, bubble baths

SoapsSoaps

AllergiesAllergies

BedwettingBedwetting

PetsPets

Favorite play activitiesFavorite play activities

•Potential for sexual abuse

CaretakersCaretakers

History

Case 2

She is a healthy little girl without any systemic or dermatologic problems. She has no allergies and takes no medications. She is active in ballet and swimming.

Physical ExaminationGeneral Principles: Maximize exposure for visualization Minimize stress Win her confidence Give her a sense of control Never be forceful or hurried

Pediatric Genital Exam

Supine Frog Leg Position Knee Chest Position

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Supine labial separation method Supine labial traction technique

Supine labial traction technique Knee Chest Position

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DischargeDischarge

InflammationInflammation

TraumaTraumaStool

ContaminationStool

Contamination

ForeignBody

ForeignBody

What to look for:

Vulvovaginitis

Most common gynecologic problem for pre-pubertal girls

Accounts for at least half of all visits to pediatric gynecologists

Anxiety producing for parents

Why does it happen?

Vulvovaginitis

Contributing factors Suboptimal handwashing Tight, non-absorbent or wet clothing Topical irritants- bubble baths, detergents

Vulvovaginitis

Short distance between vagina and anus

Lack of vulvar fat pads

Small labia minora

Small hymenalopening prevents outflow of secretions

Anatomic Factors

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Vulvovaginitis

Physiologic factors

Lack of estrogen atrophic mucosaneutral pH

Minimal antibodies in secretions

Auto-inoculation eg. Strep URI

Vulvovaginitis

Etiology:

Non-Specific vs. Specific

Non-Specific Vulvovaginitis

75% of vulvovaginitis cases Vaginal culture identifies normal flora No infectious etiology found Clinically, less discharge and erythema

than in cases with infectious etiology

Non-Specific Vulvovaginitis

Treatment: Remove tight-fitting clothes and wet

bathing suits immediately after use Avoid bubble baths and strong detergents Cotton underwear Desotin, A&D ointment, other emollients Short course of a mild topical steroid to

reduce itching

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Case 3

A 5 yr old girl presents with a 2 month history of vulvar irritation and a pink, malodorous vaginal discharge. She has mild perineal itching. Her history is otherwise negative.

In frog leg position, the introitus and perineum are erythematous. A pink discharge is visible in the lower vagina.

Case 3

Vaginal gram stain and cultures show moderate PMN’s, RBC’s and abundant genital flora including E. coli.

Case 3

A 10 day course of amoxicillin resulted in modest improvement in the discharge

Symptoms and discharge recurred within 2 weeks


Case 3

In addition to general measures such as good hygiene and mild soaps, What would you do next?

A. Retreat with Amoxicillin for 30 daysB. Change to a Cephalosporin C. Perform an exam under anesthesiaD. Apply topical estrogen cream

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Vulvovaginitis

Detailed history

Physical examination

CulturesExam under anesthesia

Treatment• Recurrent VV• No response to Rx• Vaginal bleeding• Suspected FB

Not indicated unless• Recurrent sxs• Distinct d/c and odor

Specific to diagnosis

Specific Vulvovaginitis

Infectious Etiologies

Respiratory Pathogens

Group A Strep, Staph aureus, H. Influenza, Strep pneumo

Enteric Bacteria

E. coli, Shigella, Yersinia

STD’s

Gonorrhea, Chlamydia,

HSV, Trich, HPV

Candida Pinworms

Gp A Strep Vulvovaginitis

Sx: Dysuria, vulvar pain, pruriitis or burning

Hx: Prior URI

PE: Bright red vulva and introitus

Tx: 1st G PCN or cephalosporin x 2-4 wk

STD’s and Vulvovaginitis

• Should alert provider to possibility of sexual abuse

• Non-sexual transmission of Chlamydia b/t mother and newborn can persist for up to 1 yr

• Cultures for GC and Chlamydia should be collected from the vagina, not the cervix, in prepubertal girls

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Candida Vulvovaginitis

Sx: Pruritis, thick white d/c

Hx: Rare in prepubertal girls unless recent Abx use, wearing diapers, diabetic or immunocompromisedCommon in pubertal girls

PE: Bright red vulva and satellite lesions

Tx: Topical antifungal

Pinworm (Enterobius vermicularis)

Sx: intense vulvar or perianal pruritis, esp at night

Hx: Siblings with similar sxs

PE: Scotch tape test in am, affix to slide, observe for eggs

Tx: Mebendazole 100 mg PO x 1

Specific Vulvovaginitis

Non-Infectious Etiologies

Foreign Body

Systemic Illness

Kawasaki disease Mononucleosis, Crohn’s disease

Vulvar Skin

Disease

Atopic dermatitis, Seborrhea,

Psoriasis, Lichen sclerosis

Trauma Misc

Draining pelvic

abscess, Ectopic ureter

Vaginal Foreign Body

Sx: Purulent, foul smelling, often bloody vaginal discharge

PE: Vulvovaginal erythema

Tx: EUA, vaginoscopy

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Vaginal Foreign Bodies

All cases of foreign body presented with bloody or brown discharge

In Summary: Pre-pubertal vulvovaginitis is common

and relatively easily managed

Familiarity with potential causes and treatments will improve outcomes

Majority will resolve with better hygiene, skin protection, emollients and reassurance

Case 4

A 2 yr old is brought in for evaluation of changes in her previously normal external genitalia.

You make the diagnosis of agglutination of the labia minora

Occurs primarily in girls age 3 m to 6 yr May be caused by poor hygiene and

vulvar irritation

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Labial Agglutination

What would you recommend?A. Await spontaneous resolutionB. Apply topical estrogen cream x 6 wkC. Perform a manual separation in the officeD. Incise the adhesion in the OR

Labial Agglutination3 month old 9 month old

Teenagers and

Abnormal Uterine Bleeding

Case 5

A 15 yr old presents for evaluation of irregular cycles and prolonged, heavy bleeding. She had menarche at age 14 and has never had reg cycles. She runs track and has a BMI of 19. She denies sexual activity.

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AUB What is it? Irregular cycles Prolonged periods (> 7d) Heavy bleeding (1-2 pads/hr)

Who does it affect? Transcends ethnic and geographic boundaries

What is the impact of AUB? Adversely affects academic, athletic and social activities

Why do teens have AUB?

A. Underlying bleeding disordersB. Anovulatory cyclesC. Endocrine abnormalitiesD. Eating disorders

The Menstrual Cycle

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Anovulatory Cycles Due to an immature H-P-O axis Malfunctioning + and – feedback loops

1 yr after menarche: 85% 4 yr after menarche: 44%

Earlier menarche assoc’d w/ faster normalization of H-P-O axis than later menarche

AUB(not pregnant)

Hormonal Anatomic

Fibroids

Polyps

Trauma

Neoplastic

Cervical Ca

Infectious Hematologic

vWD

Platelet Dysfunction

ITP

Clotting Factor Defic.

Hospitalized adolescents and risk for coagulation disorders

Claesson, 1981 Falcone, 1994

N=59 Coagulation Disorder: Total group= 20% Requiring txn= 33% Presenting at

menarche= 50%

N=61 Coagulation disorder: Total group= 3%

Hormonal = Oligo- or Anovulation

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AUB Work-up

HistoryHistory• Detailed menstrual history• Family hx of bleeding disorders

Physical examPhysical exam• Limited value in pelvic exam

ImagingImaging• If abdominal mass palpated

LaboratoryLaboratory• CBC, PT, PTT, TSH, Factor VII, VWF ristocetin cofactor and antigen• Urine for HCG, GC, Chlamydia

AUB Management

Anovulation Bleeding Disorder

Tranexamic Acid X X

DDAVP - X

NSAIDS X -

COC’s, ring, patch X X

LNG-IUS X X

Cyclic Progestins X X

TranexamicAcid

TranexamicAcid

Anti-fibrinolytic

Anti-fibrinolytic

40-50% less blood

loss

40-50% less blood

loss

FDA approved in 2009

FDA approved in 2009

1300 mg TID x 5 d1300 mg TID x 5 d

Pills, Patch &

Ring

Less Blood Loss

Less Pain

Reliable and safe

contraceptives

Cycle Regulation

No effect on future fertility

No effect on bone density

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Take home points:

Minimize emotional trauma and physical discomfort for children having a genital exam by knowing examination techniques and the appearance of normal anatomy

When necessary, examine under anesthesia

Take home points: Be familiar with common causes and

interventions for vulvovaginitis Remove vulvar irritants Improve hygiene Treat with organism-specific antimicrobials

Leave labial agglutination to resolve spontaneously Unless inability to void or recurrent UTI’s.

Take home points:

AUB in adolescents is common and almost always due to anovulatory cycles

Anticipate that parents may be reluctant to start teens on birth control pills

Remember bleeding disorders, especially in a teen who is hospitalized, transfused or presents during her first period

Thank You

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What’s That?Recognizing common gynecologic lesions

Alison F. Jacoby, MDUCSF

Objectives

Review normal features of the external genitalia, vagina and cervix

Recognize common abnormal findings such as herpes, molluscum and warts

Discuss diagnosis and management of various vulvovaginal conditions

Vulvar Bumps

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What is this?1. Condylomata

2. Hymenal tags

3. Vulvar papillomatosis

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3

What is this? 1. Condylomata

2. Vulvar papillomatosis

Pigmented Lesions

6/21/2013

4

What is this?

1. Benign

2. Malignant

6/21/2013

5

Which is concerning for melanoma?1. A2. B

A B

What is the diagnosis?1. Angiokeratomas

2. Nevi

3. Cavernous hemangioma

4. Melanoma

6/21/2013

6

Vulvar Papules & Ulcers

6/21/2013

7

6/21/2013

8

Vaginal and Vulvar Cysts

6/21/2013

9

6/21/2013

10

6/21/2013

11

6/21/2013

12

What is this?

1. Gartner’s duct cyst

2. Bartholin’s cyst

3. Inclusion cyst

4. Skene’s duct cyst

6/21/2013

13

Genital Growths

6/21/2013

14

Vulvar Skin Conditions

6/21/2013

15

6/21/2013

16

6/21/2013

17

6/21/2013

18

Other STD’s

6/21/2013

19

6/21/2013

20

Congenital Anomalies

6/21/2013

21

6/21/2013

22

Pediatric Lesions

How would you treat this?

1. Topical estrogen cream

2. Supportive care until menarche

3. Surgical separation

4. Manual separation

6/21/2013

23

Cervical Lesions

6/21/2013

24

6/21/2013

25

6/21/2013

26

What is this?1. Cervical cancer

2. Cervical ectropion

3. CIN I

Thank you and see you at the pool

Picture credits go to Mark Theisswww.UltimateChase.com

MANAGEMENT OF OBESITY: A SYSTEMATIC APPROACH

1

Robert Baron, MD, MS


Robert B. Baron MD MS


Associate Dean for GME and CME

Director, UCSF Weight Management Program

Declaration of full disclosure: No conflict of interestFlegal JAMA 2010

Prevalence of Obesity (Adults)

Obesity: 33.8%Men: 32.2% Women: 35.5%

Overweight + obesity: 68% Men: 72.3% Women: 64.1%

Severe Obesity: 6%

.

Men and Women Aged 40 to 59 Years in 1999-2000 and 2007-2008

Flegal JAMA 2010

Prevalence of Obesity (Children)

Severe obesity (97 percentile): 11.9%

Obesity (95 percentile): 16.9%

Overweight (85 percentile): 31%

No increase from 1999 to 2008 (except severe obesity in boys)


2


Copyright © 2012 American Medical Association. All rights reserved.

Prevalence of Obesity and Trends in Body Mass Index Among US Children and Adolescents, 1999-2010

JAMA. 2012;307(5):483-490

Flegal JAMA 2010

Obesity Disparities

Women, 40-59Black: 52%, Hispanic: 47%, Whites: 36%

TeensBlack: 29%, Hispanic: 17.5%, Whites: 14.5%

Mental illnessOverweight + obese: 83%

Obesity Trends* Among U.S. AdultsBRFSS, 2010

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

For a 40 yo woman, with normal BP, lipids, and FBS which BMI is

associated with the lowest all-cause mortality?

1. 18

2. 24

3. 28

4. 34

5. 38


3


CLASSIFICATION OF OVERWEIGHT AND OBESITY BY BMI

Obesity Class BMI (kg/m2)

Underweight <18.5

Normal 18.5 – 24.9

Overweight 25.0 – 29.9

Obesity I 30.0 – 34.9

II 35.0 – 39.9

Extreme Obesity III >40

Flegal, JAMA, 2005

BMI AND MORTALITY: Overall

Combined NHANES I, II, and III data set

BMI 25-59 y 60-69 y ≥70 y

<18.5 1.38 2.30 1.6918.5-<25 1.00 1.00 1.0025 to <30 0.83 0.95 0.9130 to <35 1.20 1.13 1.03≥35 1.83 1.63 1.17

Flegal, JAMA, 2013

MORTALITY AND OBESITY

Meta-analysis of 97 studies of 2.8M people, 270,000 deaths

BMI HRBelow 25 (Normal) 1.025-30 (Overweight) 0.94Above 30 (Obese) 1.18

***30-35 (Grade 1 Obesity) 0.95Above 35 (Grade 2/3 Obesity) 1.29

For a 40 yo woman, with normal BP, lipids, and FBS which BMI is

associated with the lowest all-cause mortality?

1. 18

2. 24

3. 28

4. 34

5. 38


4


Epidemic of Inactivity

60% US adults don’t exercise regularly

25% are sedentary

Shaw, Cochrane, 2006

EXERCISE FOR OBESITY Meta-analysis of 43 RCTs: 3476 participants

• Exercise plus diet vs diet alone – -1.1 kg

• Increased intensity of exercise – -1.5 kg

• Exercise without weight loss– Reduced: BP, triglycerides, blood

sugar

Wei, JAMA 1999

FITNESS AND MORTALITYAerobics Center Longitudinal Study

CV death (RR)normal overweight obese

Fit 1.0 1.5 1.6Not fit 3.1 4.5 5.0

Total death (RR)normal overweight obese

Fit 1.0 1.1 1.1Not fit 2.2 2.5 3.1

25,714 men, 44 years old, 14 year observational study

Relative Risk* of Death According to Body Mass and Physical Activity

Body mass index (BMI)

25 – 29.9< 25 > 30

> 3.5 hours/week

1 – 3.4 hours/week

< 1 hour/week

Physical activity level

* RR’s adjusted for age, smoking status, family history, menopausal status, hormone use, and other factors

** Reference group = women with 3.5 or > hours/week of physical activity and BMI of 25 or less

Hu FB, et al. N Engl J Med 2004;351:2694

2.42

1.91

1.64

1.331.28

1.55

1.181.00

**


5


Estimating Calorie Needs

To estimate calories for weight maintenance: If you are moderately active, multiply current

weight (pounds) x 15.

To estimate calories for weight loss: Subtract 500 calories to lose approximately 1.0

pound per week A pound of fat is about 3500 kcals

Dansinger, JAMA 2005

COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE

Intention to treat at 1 yearAtkins Ornish WW Zone

Wt Loss (kg) 2.1 3.3 3.0 3.2Completers (%) 53 50 65 65

Completers at 1 yearAtkins Ornish WW Zone

Wt Loss (kg) 3.9 6.6 4.6 4.9

160 patients, randomly assigned

Dansinger, JAMA, 2005

COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE

Weight loss associated with adherence, but not diet type

Each group: 25% lost 5%, 10% lost 10% of initial weight

Each diet reduced LDL/HDL by 10%

No significant effects on BP or glucose


6


Sacks, NEJM, 2009

COMPARISON OF WEIGHT LOSS DIETS WITH DIFFERENT MACRONUTRIENTS

RCT of 811 patients, 4 diets: fat/protein/carbs20/15/65; 20/25/55; 40/15/45; 40/25/35

6 months: 6kg, 7% weight; at 2 years: completers lost 4kg; 15% lost 10% of weight

Results similar for: 15% pro v. 25% pro 20% fat v. 40% fat 35% carbs v. 65% carbs

Attendance highly correlated with weight loss; satiety, hunger, lipids, insulin all equal

Heterogeneity of Response to Weight Loss Diets: Insulin Resistance

Insulin sensitive: low carb and high carb both effective for weight loss

Insulin resistant: low carb more effective

Tsai and Wadden, Obesity, 2006

Very Low Calorie Diets (VLCD) vs Low Calorie Diets (LCD): Meta-analysis of 6 RCTs

• Trials with direct comparisons• Short-term: mean 12.7 weeks • Long-term: mean 1.9 years

Weight loss (as % of initial weight):short-term long-term

LCDs 9.7 5.0VLCDs 16.1 6.3

(p) (0.001) (0.2)

WEIGHT LOSS DIET BOTTOM LINE

• The type of diet does not really matter for weight loss.

• Sticking to the diet does matter

• Calories “trump” macronutrients

• But, select healthy, nutrient rich foods


7


Weight Loss Diet Tips

• Ready to lose weight?

• Set realistic expectations.

• Choose diet that is easy to follow and compatible with lifestyle.

• Control portion size (plate method, etc).

• Vegetables, fruit and whole grains

• Maintaining the weight you lose is key.

BEHAVIORAL ASPECTS OF WEIGHT LOSS

Goal setting

Self-monitoring

Stimulus control

Cognitive skills

40 yo woman, BMI 36. Much to your surprise (and satisfaction),

she has lost 35 pounds. In order to maintain her new weight, her

lifelong daily calorie intake should be:

1. 2000 kcals

2 1800 kcals

3 1600 kcals

4. 1400 kcals

5. 1200 kcals


8


Wing, Am J Clin Nutr, 2005

SUCCESSFUL WEIGHT LOSS MAINTENANCE

3000 subjects in National Weight Control Registry: 30-lb weight loss for 1-year

Average weight loss 33 kg (10 BMI units less), average weight maintenance 5.5 years

45 years old, 80% women, 97% Caucasian

46% overweight as child, 46% one parent obese, 27% both parents

SUCCESSFUL WEIGHT LOSS MAINTENANCE

• High levels of physical activity• Women 2545 kcal/week, men 3293 kcal/week • (1-hour moderate intensity per day• Only 9% report no physical activity

• Diet low in calories• 1381 kcal day• 4.87 meals or snacks/day• Fast food 0.74/week

• Regular self-monitoring of weight• 44% weigh once per day; 31% once per week

40 yo woman, BMI 36. Much to your surprise, she has lost 35

pounds. In order to maintain her new weight, her lifelong daily

calorie intake should be:

1. 2000 kcals

2 1800 kcals

3 1600 kcals

4. 1400 kcals

5. 1200 kcals


9


In the last year, I have prescribed a medication for weight loss.

1. Yes

2 No

The medication I most commonly prescribe for weight loss is:

1. Phentermine2. Orlistat (Xenical™, Alli™)3. Buproprion (Wellbutrin™)4. Exenatide (Byetta™, Bydureon™)5. Phentermine/topiramate (Qsymia™)6. Other

The Neuroendocrinology of Energy Balance“LONG TERM” PHARMACOTHERAPY OF

OBESITYReview of all RCT’s more than 36 weeks published since 1960

Weight loss in excess of placebo:

% of initial kg’s

Phen-fen 11.0% 9.6 kg

Phentermine 8.1% 7.9 kg

Sibutramine 5.0% 4.3 kg

Orlistat 3.4% 3.4 kg

Dexfenfluramine 3.0% 2.5 Kg

Fluoxetine -0.4% -0.4 kg

Diethyproprion -1.5% -1.5 kg


10


James, NEJM 2010

SIBUTRAMINE AND CARDIOVASCULAR OUTCOMES (SCOUT)

9804 patients, over 55, with CV disease or diabetes

Sibutramine vs. placebo, 3.4 year f/u

Outcomes MI, stroke, cardiac arrest, CV death

ResultsWeight: -1.7 kg BP: 1.2 vs 1.4 mm Hg Combined outcome: 11.4% vs. 10.0% (HR 1.16, p = 0.02) Nonfatal MI: 4.1% vs. 3.1% (HR 1.28; p = 0.02) Nonfatal Stroke: 2.6% vs 1.9% (HR 1.36; p = 0.03) Death: No differences

LORCASERIN

Selective serotonin 2C receptor agonist

RCT of 3,182 adults, 52 week study

45% vs. 55% drop-out (lorcaserin vs. placeb)

5.8±0.2 kg vs. 2.2±0.1 kg wt. loss

Frequent adverse events: headache, dizziness, and nausea

No increase in valvulopathy

Smith, NEJM, 2010

Weight Loss Medications: October, 2010

• Sibutramine (Meridia™): withdrawn by Abbott• Increased risk of stroke and MI

• Lorcaserin (selective serotonin receptor agonist, more specific than fenfluramine): not approved by FDA• Animals with increased mammary adenocarcinoma

• Phentermine/topiramate (Qnexa™): not approved by FDA• Psychiatric adverse events: sleep, anxiety depression:

21% vs 10% with placebo• Increased heart rate• Teratogenicity

Lorcaserin Update: May-June 2012

• FDA panel approved after new round of studies

• Industry sponsored study: 604 patients with type 2 diabetes• After 1 year, 3.1% more weight loss (criteria >5%)• 38% lost >5% weight vs. 16% on placebo

• Lingering uncertainty re breast tumors, valvular heart disease, psychiatric issues

• Approved June 2012. Trade name Belviq™


11


Lorcaserin Update (Belviq™): June 2013

• Classified as Schedule IV controlled substance

• Available as of June 7, 2013

Phentermine/Topiramate Update: February-July 2012

• FDA panel approved 20:2

• Industry sponsored study: 4323 subjects• 9.3% weight loss• Increased heart rate, increased cleft lip

• Recommend post-market monitoring for CV risk and recommendation against use in pregnancy

• Company plans larger trial (16,000 subjects)

• Approved July 2012. Trade name Qsymia™

Phentermine/Topiramate (Qsymia™) Side Effects

• Paraesthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth

• Fetal harm: cleft lip, cleft palate• Mood disorders: anxiety and depression• Suicidal thoughts or behavior• Acute angle glaucoma• Cognitive dysfunction: concentration memory,

language• Metabolic acidosis and renal failure• Hypoglycemia (in association with diabeyes meds)• Interactions with alcohol and sedatives

Prescribing Phentermine/Topiramate (Qysmia™)

• Two prescriptions: • 14 days on 3.75/23 and • 30 days on 7.5/46

• Need DEA #• Fax to certified pharmacy• Pharmacy will call patient• Drug delivered to patient’s home

• Local pharmacy availability soon


12


OTHER INVESTIGATIONAL DRUGS

• Buproprion/naltrexone (Contrave™): Approved by FDA panel 12/10; rejected by FDA 2/11 (concern re heart attacks and CV risk.)

• Buproprion/zonisamide (Empatic™): Phase 3

• Exenatide (Byetta™), Liraglutide (Victoza™: Phase 2/3

• Pramlintide/metreleptin: Phase 2/3

• Cetilistat: Phase 3 in Japan

PRINCIPLES OF DRUG THERAPY

• NIH: BMI > 30 kg/m2 or 27 kg/m2 with co-morbidity (but in practice almost never)

• Motivated to begin structured exercise and low calorie diet

• Begin medications at completion of one month successful diet and exercise

• Continue medications only if additional weight loss achieved in first month with meds

Wouldn’t It Be Easier Just To Have Surgery ?

Definition BMINormal < 25Overweight 25-29.9Obese, class 1 30-34.9

Obese, class 2 35-39.9Obese, class 3 40+“Superobese” 60+

SURGERY

with co-morbidity

INDICATIONS FOR BARIATRIC SURGERY


13


Types of Surgery

Restrictive• Horizontal Gastroplasties• Vertical Banded Gastroplasty (VGB)• Silastic Ring Vertical Gastroplasty (SRVG)• Adjustable Gastric Banding• Sleeve Gastrectomy

Malabsorptive• Jejunoileal Bypass (JIB)• Biliopancreatic Diversion (BPD)• Duodenal Switch• Long Limb Gastric Bypass

Restrictive with Malabsorptive Component• Roux-en-Y Gastric Bypass (RYGPB)

Restrictive and Mixed Procedures

VBG Adjustable Gastric Banding Roux-en-Y GB

Sleeve Gastrectomy

Years

Bariatric Surgery: Weight Change


14


LABS Consortium, NEJM, 2009

LONG-TERM OUTCOMES OF LAP BAND

• 151 patients, single center, 12 year f/u; 54.3% included

(82/151)

• Operative mortality: 0

• Mean weight loss: 20.75 kg (BMI decreased from 41.6 to

33.8)

• 60% of patients satisfied; overall quality of life unchanged

• 39% major complications; 60% required re-operation

Conclusion: Lap band results in poor long-term

outcomes

Sleeve Gastrectomy Indications

Very high risk of co-morbidities

BMI >60

Possible non-compliance with meds (less risk of micronutrient deficiencies)

IBD, IBS, abdominal pain, SBO, adhesions, other GI morbidities

Sjostrom, NEJM, 2007

Bariatric Surgery and MortalitySwedish Obese Subjects Study

4047 subjects, surgery vs. matched control. 10.9 years f/u

Max weight loss % Final weight loss %Control 2

Gastric bypass 32 25

Vertical banded Gastroplasty 25 16

Banding 20 14

Resolution of Comorbidities


15


35 yo woman, BMI 42 in good health, asks about bariatric surgery. Her surgeon suggests a laporoscopic

roux-n-y. Her risk of mortality, DVT, reintervention, or prolonged hospital

stay is:

1. 1 in 200 2. 1 in 1003. 1 in 504. 1 in 255. 1 in 10

LABS Consortium, NEJM, 2009

BARIATRIC SURGERY OUTCOMES

• Ten sites, 4776 patients. 3/4 roux-en-y (87% lap); 1/4 lap band

• 30 Day overall mortality: 0.3%

-lap band 0.0%

-roux-en-y (lap) 0.2%

-roux-en-y (open) 2.1%

• Composite (death, DVT, reintervention, 30 + days in hosp): 4.1%

-lap band 1.0%

-roux-en-y (lap) 4.8%

-roux-en-y (open) 7.8%

35 yo woman, BMI 42 in good health, asks about bariatric surgery. Her surgeon suggests a laporoscopic

roux-n-y. Her risk of mortality, DVT, reintervention, or prolonged hospital

stay is:

1. 1 in 200 2. 1 in 1003. 1 in 504. 1 in 255. 1 in 10

57 yo woman, BMI 42 with diabetes, hypertension, and

creatinine 1.4 asks about bariatric surgery. Her risk of mortality 30

days post-op is

1. 1 in 200 2. 1 in 1003. 1 in 504. 1 in 255. 1 in 10


16


Mortality After SurgeryCommunity Medicare Data: 55-64 year old

30 days 90 days 1 Year

2.0% 2.7% 5.2%

Sjostrom, NEJM, 2007

Bariatric Surgery and MortalitySwedish Obese Subjects Study

Deaths HR Rate MI deaths Cancer deaths

Control 129 0.063 25 47

Surgery 101 0.76 0.050 13 29(p = 0.04)

NNT 77 over 11 years (approx 850 per year)

Benotti, Arch Surg, 2009

Weight Loss Before Bariatric Surgery

881 patients with gastric bypass; 6 month program to achieve

10% weight loss; 2/3 lost 5%; 1/2 lost 10%

Weight Change Complications %

Gain 5% 28.4

Gain 0-5% 27.9

Loss 0-5% 23.5

Loss 6-10% 14.2

Loss 10% 18.0

(p for trend = 0.004)

Nutrition after Bariatric Surgery

Gastric Bypass Lap Band

Mulitvitamin 2 daily Mulitvitamin 1 daily

(400 mcg folate)

Omeprazole 20 mg daily Omeprazole 20 mg daily

Calcium (500mg TID) Calcium (500mg TID)

Vitamin D (200 IU TID) Vitamin D (500 IU TID)

Iron sulfate 325mg daily

(women)

Vitamin B12 500mcg SL daily


17


BARON’S FACTS ABOUT OBESITY

Environmental changes work: YES

Diets work, but not for long in most people: YES, BUT THEY DO FOR SOME

Exercise improves health independent of weight change and aid in weight maintenance: YES

Continuation of conditions that promote weight loss promotes weight maintenance: YES

BARON’S FACTS ABOUT OBESITY

For children, programs that involve parents and home promote greater weight loss: MAYBE

Provision of meals and meal replacement products promote greater weight loss: IN THE SHORT TERM

Medications can help achieve meaningful weight loss for as long as agents can be used: BUT WHAT ABOUT LONGER TERM CLINICAL OUTCOMES?

Surgery results in long term weight loss and reductions of diabetes and mortality: WITH COMPLICATIONS IN SOME/MANY AND A HIGH NNT Casazza, NEJM 2013

GOALS OF MANAGEMENT

Be as fit as possible at current weight

Prevent further weight gain

If successful at 1 and 2, begin weight loss

The Magic Formula

Vaccinations for Adult and Adolescent Women

Eliseo J. Pérez-Stable, MDProfessor of MedicineDGIM, Department of Medicine



Vaccines Available in the US

Tetanus, Diptheria, Pertussis, Measles, Mumps, Rubella,

Varicella, HPV, Polio Meningococcus, Pneumococcus,

Influenza, Hepatitis B, Hepatitis A, H influenza, Rabies, Typhoid, Yellow Fever, Japanese

encephalitis, Typhoid

Effect of Full Use of Adult Immunizations

Deaths/yr. Efficacy Use Prev Deaths/yr

Influenza 36,000 70% 65% 18,000

Pneumonia 40,000 60% 60% 20,000

HBV 6,000 90% 30% 4,000

Tetanus-D < 25 99% 64% < 15

MMR < 30 95% varies < 30

Trends in Vaccine-Preventable Diseases Post Vaccine

• Measles and Rubella: 99.9% reduction (66 cases total and 1 case CRS in 2006)

• Tetanus: 93% reduction• Pertussis: 92% reduction (recent increase)• Hepatitis A: 87% reduction• Acute HBV: 80% reduction• Invasive pneumococcal disease: 34%

cases and 25% mortality reduction• Varicella: 85% reduction

Roush SW, et al. JAMA 2007; 298: 2155-63

Vaccination Coverage in US Adults by Age Groups, 2011

• HPV: 29.5% women 19-26 y• Td or TDaP past 10 years: 64.5% (19-49 y),

63.9% (50-64 y), 54.4% (≥65 y)

• Hepatitis A: 12.5% (19-49 y) and 20.1% for those who travel outside US

• HBV: 35.9% (19-49 y)

• Pneumococcal: 20.1% (19-64 y), 62.3% (≥65 y)

• Varicella: 15.8% ≥60 y• Health Care Staff: TDaP 26.8% and HBV

63.8%CDC, MMWR 2013; 62: 66-72

26 year old woman, immigrant from Guatemala with no records; says she got “usual shots”. What would you do?

10

1. Order tests for rubella, measles, and varicella antibodies before immunizing

2. Obtain detailed clinical history of possible childhood infections

3. Offer vaccines without tests given that immunization rate is low

4. Obtain medical record documentation or immunization card

5. Ask about possible social contacts before giving live viral vaccines

45 year old woman traveling to South Africa in May for 3 months and asks about need for vaccines. Besides advising her to check the CDC web site, are any of the following NOT needed?

10

1. Tetanus booster if more than 10 years from last dose

2. Influenza vaccine

3. Hepatitis A vaccine in two doses if not previously given or one dose if > 10 years

4. Hepatitis B series

5. Meningococcal C vaccine

70 year old man with diabetes and hypertension for routine visit. Which of the following do you recommend?

10

1. Tetanus booster with acellular pertussis – last Td was 3 years ago

2. Intra-nasal Influenza vaccine

3. Pneumococcal vaccine booster originally given at age 65

4. Zoster vaccine without checking antibodies

5. Zoster vaccine only if no prior shingles and with documented positive varicella Ab

Summary of Presentation

• Pertussis vaccine revisited

• Varicella Zoster Vaccine

• Influenza & Pneumonia vaccines

• Hepatitis A and B

• Measles, Mumps, Rubella

• Human Papilloma Virus vaccine

New Information from Today

• Pertussis vaccine for 65 y +• Varicella Zoster Vaccine at 50?• Pneumonia vaccine for asthma• Pneumococcal conjugate vaccine for

selected adults• Hepatitis B vaccine for persons with

diabetes• Human Papilloma Virus vaccine 2

doses may be good enough

PertussisTdap for Adults

Pertussis…not just for children anymore

Pertussis Vaccine•Original - whole cell vaccine

consisting of killed organisms•Acellular vaccine contains purified,

detoxified antigens•Childhood DTaP: diptheria toxoid,

tetanus toxoid, and acellular pertussis•Adult/adolescent Td and Tdap:

tetanus + reduced dose diptheria +/-reduced dose pertussis antigens

Tetanus and Diphtheria Toxoid +Acellular Pertussis Vaccine (Tdap)

• Available as of June 2005• Replace Td with Tdap in adolescents at

age 11 - 12 or give as single dose by 18 y • Tdap should replace Td in adults 18-64 y

as a one-time dose as part of primary series or as routine booster

• Administer to adults caring for children <1 year and all staff with direct patient contact at any age

• May be done at any timeCDC, Updated recommendations MMWR 2011; 60:13

Pertussis Vaccine – What’s the Evidence?

2781 subjects aged 15-65 randomized to reduced dose of acellular pertussis vaccine or hepatitis A “placebo”

Followed for 2.5 years

Based on primary pertussis definition (cough and positive culture/PCR), vaccine 92% effective

Ward JL et al. NEJM, 2005;353(13)

Varicella Zoster Virus VaccinePrevention of Chicken Pox

Disease and MortalityVaccine to Prevent Shingles

and Neuralgia

Varicella Mortality – 1990-2001

• Incidence decreased by 70% to 80% between 1995 and 2001

• Mortality decreased by 66%: 0.41 to 0.14 per million persons

• Benefit clear in persons < 50 yrs

• Benefit in all racial and ethnic groups

• Immunization program against varicella led to fewer deaths

Nguyen, NEJM 2005; 352: 450-458

A Vaccine for ZosterPathogenesis- Varicella>90% in U.S. serologic +

Sensory nerves to Dorsal Root GangliaCell Mediated ImmunityReactivationIncidence >75yrs:

2-3/1000 yrsLifetime risk 10-20%PHN – pain > 30 days

Zoster––Adult ImmunizationLive attenuated Oka/Merck Zoster Vaccine

20-60K cfu (1350 cfu in varicella vaccine)RCT n=38,546 healthy >60 years old, VZI +

(placebo)(Zoster shot)

315 (1.6%) cases 642 cases (3.3%) 61.1 RRR

27 (8.6%) cases PHN

80 (12.5%) cases PHN

66.5 RRR

No zoster cases had vaccine virus detectable in lesions

No serious difference in group side effects

NEJM 352;22 June 2, 2005

Varicella Zoster Vaccine•Frozen for storage, administered

immediately after reconstitution•Cost of vaccine is $150-$200•Decrease in pain burden by 61%•Vaccinate 17 people to prevent 1 case

of zoster – $3,330•Vaccinate 31 to prevent 1 case of

post-herpetic neuralgia – $6,405 • Adverse events sub-study: local––16% vs.

48%; no hospitalization or death differences at 3.4 years

Kimberlin DW. NEJM, 2007;356Simberkoff S, Ann Intern Med 2010; 152: 545

Barriers to Use of Zoster Vaccine

• National survey of primary care MDs

• 72% response: 301 GIM and 297 FM

• 49% stock and deliver in their office

• 36% refer to purchase and bring back

• 33% refer to a pharmacy for shot

• 88% recommend HZV; 41% strongly

• 45% aware Medicare part D covers

• Reimbursement issues–12% stoppedHurley L, et al. Ann Intern Med 2010; 152:555-560

Varicella Zoster Vaccine• Vaccinate once at age 60 • No need to check for evidence of

varicella immunity• FDA approved VZV for adults at age 50,

but CDC is not recommending• If high coverage with childhood

varicella vaccine, what happens to Zoster?

• Patients with previous shingles

Influenza and Pneumonia

Seasonal FluH1N1

Pneumococcal Vaccine

Adult Vaccines Did Not Precipitate Acute Cardiac Events or Strokes

• British study of 20,486 patients with MI and 19,063 cases of stroke

• No increase in risk of MI or stroke after vaccination against the flu, pneumococcal disease and tetanus

• There was an increased risk in the 3 days after a systemic respiratory infection–RR = 4.95 (4.43 a 5.53)

Smeeth, NEJM, 2004; 351: 2611-2618

Seasonal Influenza Vaccine:The Evidence to Support Use

RCT of 1952 healthy adults age 18-49 during 2007-2008 of Inactivated vs. live attenuated vaccine

•Absolute efficacy of inactivated vaccine was 73%

•Absolute efficacy of the live vaccine was 51%

Monto AS, et al. NEJM, 2009;361.

Influenza Vaccine Priority Recommendations

•Persons 50 years of age and older

•Residents of chronic care facilities

•Chronic cardiopulmonary disorders

•Chronic metabolic diseases, renal dysfunction, hemoglobinopathies, or immunosuppression requiring regular medical follow up

• Women who will be in 2nd or 3rd trimester of pregnancy

Universal Immunization Recommended

Seasonal Flu Vaccine for All Persons

Effectiveness of Influenza Vaccine(Nichol KL, et al. NEJM 2007; 357:1373-81)

• Pooled data, 18 cohorts from 1990-91 to 1999-2000

• 713,872 person-seasons of observations• 58% vaccinated; mean age 73; 43% men• High-risk conditions more prevalent by

among vaccinated (56% vs 46%)•27% (OR= 0.73; 0.68-0.77) reduction in

hospitalizations (all but 1 season)• 48% (OR=0.52; 0.50-0.55) reduction in risk

of death present in all seasons• 1 death prevented for every 302 flu shots!

Influenza Vaccine Points

• Flu vaccine for Health Care Workers helps patients: 17% vs. 10% mortality in study of SNF in Scotland

• Survey in 2011-12 of 2348 health care workers: 66.9% vaccinated (86% MDs)

• Decline in GBS cases from 0.17 to 0.04 per 100,000 coincided with stepped up food safety interventions and 28% decline in campylobacter infections

• 65% adults >65 vaccinated, 50% for Latinos and Blacks, more if MD contact

• Automatic orders work

Influenza A H1N1April 21, 2009: CDC

confirms 2 in CASegments from

previous swine influenza viruses

June 11, 2009: 30,000 cases across 74 countries

WHO issues phase 6 alert = official pandemic is now over!

Pneumococcus - BackgroundRisk factors for invasive disease

Age >65 or <2 yearsPeople with chronic illnessCrowding Chronic use of Proton Pump InhibitorsAntecedent respiratory infection and

recent antibioticSmokersAfrican Americans and American

Indians

Pneumococcal Vaccine Indications･ All persons older than 65 y –– 50 y?

･ Chronic cardiovascular disease

･ Chronic pulmonary disease + asthma

･ Diabetes mellitus, smokers

･ Cirrhosis, Alcoholism, CSF leaks

･ Functional or anatomic asplenia

･ HIV infection

･ Immunocompromised persons

MMWR1997; 46:1-24 (RR-8)

Pneumococcal vaccine Re-Vaccination: CDC

• Only one-time re-vaccination at 5 years recommended for:–no spleen - functional or anatomical–chronic kidney disease–immune suppressed conditions –chemotherapy with cancer drugs

• Persons at age 65 years if first dose was given ≥ 5 years before

• Otherwise--Re-vaccination not needed!

Efficacy of Pneumococcal Vaccine

• Randomized trials showed no decrease in death or bacteremia; 50% decrease in pneumonia

• Case control studies--60% to 70% protective efficacy for bacteremia

• CDC cohort analysis: 57% (95% CI= 45%-66%) protection, sustained over time

• Vaccine cost effective: saves money and lives even after including future costs

Pneumococcal Conjugate Vaccine

• Used for infants in the US since 2000• Cases of drug resistant Strep Pneumo

invasive disease decreased (cases /100,000)1999 2004

Penicillin resistant 6.3 2.7Muliple Abx resistant 4.1 1.7

• Decline of 50% among adults 65 years and older

NEJM 2006;354:1455-63

Recommendation of Pneumococcal Conjugate (PCV13) Vaccine in Adults

• More immunogenic, 3X more expensive• PCV13 first, followed by PPSV23 ≥ 8 weeks later• If already received PPSV23, give PCV13 ≥ 1 yr

later; boost once at 5 years if given < 65 y• Conditions: CSF leak, cochlear implant• Sickle cell disease, asplenia• HIVn infection, chronic renal failure, nephrotic

syndrome, leukemia, lymphoma, Hodgkin disease, myeloma, solid organ transplant, iatrogenic immunosuppression

CDC, MMWR 2012; 61: 8116-19

Hepatitis Vaccines

Prevention of Acute and Chronic Hepatitis and

Cancer!

Global Burden of Illness of Hepatitis B

• 2 billion persons with hepatitis B• 350 million chronic carriers• 1 million deaths per year• HBV vaccination programs have been

implemented in > 100 countries• Reduction of chronic infections and liver

cancer • Most of chronic infections are acquired

as children

Hepatitis B Vaccination• 2006: 13,200 acute cases, 1460 hospitalized,

47 deaths; 2007: 1815 deaths from chronic HBV

• Adults–target sexually active, health care workers, injection drug users, ESRD, diabetes < 60 y

• Needle exchange programs are effective

• Immunity = >10 U/ml anti-HBs

• Check post-vaccination serology 1-2 m after series in selected patients

• Universal vaccination is the goal

HBV Vaccination Protection• Antibody (HBsAb) levels decline to

undetectable by 6 yrs. in up to 50%

• Initial non-responders re-vaccinated with one more dose 15% to 25% respond three more doses 50% to 75% respond

• No documented case of symptomatic hepatitis in vaccine recipient with initial antibody response

• Long incubation of HBV allows triggering T cell memory

• Boosters are not routinely recommended

Hepatitis A Vaccination• Only 19.7% of adults 19 to 49 years with

chronic liver conditions have received 2 doses of hepatitis A vaccine

• Target: Injection drug usersPatients with chronic liver diseaseTravelers to high/intermediate risk areas in LMICHousehold contacts adoptees

Measles, Mumps, Rubella

Have you ever seen a case?

Status of MMR Diseases in 2006

Measles55 cases; no deathsGlobal: 242,000 deaths; 68% reduction from 2000

Mumps6584 cases; no deaths

Rubella11 cases; no deaths; 1 CRS

Measles, Mumps, Rubella Vaccine

•Use combined MMR vaccine in most people

•Born after 1957––limited exposure

•Documentation of vaccine receipt; Clinical diagnosis of disease––documented or Serologic evidence of immunity

•Health care workers a priority

•Non-infectious clinical syndromes

•No evidence for autism association

Human Papilloma Virus Vaccine

Cancer Prevention at its Best?

Human Papilloma Virus• HPV causes cervical cancer (90%+)• 50% of adults are infected with HPV• 13,000 cases of cervical cancer per year

in the US; 3700 deaths• High burden of disease in low and

middle income countries•HPV is not curable or treatable• $2 billion dollars to prevent up to 7000

cases of cervical cancer if vaccine is 100% effective

HPV Vaccine Efficacy

• Prevention of warts, persistent HPV infection, and HGSIL lesions

• Lag time to detect efficacy in prevention of cervical cancer will be 10 to 20 years

• CIN 2 or CIN 3: about 40% progress to cervical cancer

• Near 100% effective at decreasing HGSIL of cervix in published trials

• HPV 16/18 include about 70% of oncogenic HPV types but varies by country

HPV Vaccine Recommendations by CDC/ACIP and the ACS

• All girls at age 9 to 11 years or as adolescents (CDC)

• All Women 18 to 26 years (not ACS)• Give before onset of sexual activity• Not to be administered during

pregnancy• Boys at age 11-12; 13-26 if not done• Adverse effects: minor local

reactions, low-grade fever, fainting

• Cost is about $360 –– it is covered

HPV Vaccine Phase 3 Trials:Futures I and II

• HPV 16/18 + 6/11 vaccine• 12,167 and 5455 women age 15-26 y; 3

years follow up• Per-protocol analysis = no viral evidence of

infection by month 7• CIN grade 2 or 3 or cancer––Efficacy = 98%

(86 to 100)• Intention to treat efficacy = 44% (26–58) or

34% (15 to 49)• Efficacy for all CIN 2/3 or cancer was only

17% (1 to 31) or 20% (8 to 31)

HPV Vaccine Questions

• Duration of immunity unknown• Acceptability by parents?• Reassurance regarding safe sex?• Cover more oncogenic types?• Alter routine Pap screening?• Global Application?• 21% of women age 18-26 had

received HPV in 2010

HPV Vaccine In “Older” Women•Women aged 24-45 yrs, randomized,

placebo-controlled, double-blind study with no h/o genital warts or cervical disease

•3817 women received quadrivalent HPV vaccine vs. placebo – 3 doses

Outcome=disease/infection related to HPV 6, 11, 16, 18

Efficacy 90.5%, but ITT efficacy: 30.9%Munoz N, et al. Lancet, 2009;373

Immunogenicity of 2 Doses of HPV Vaccine in Adolescents

•Mean Ab levels to HPV-16 and 18• 830 women randomized; girls 9-13

y to either 2 or 3 doses; women 16-26 y received 3 doses

• Outcome = geometric mean titer of Ab; non-inferiority up to 36 months

• No significant difference in GMT

• Dobson S, et al. JAMA 2013; 309: 1793-1802

Patient Reminders for Immunizations

• Are effective: 5% to 20% absolute increase in 33 of 41 RCT

• Immunization rate: 42% vs. 27%

• Influenza, pneumococcal, tetanus

• All ages--children do better

• Academic > private or public clinic

• Telephone is most effective, costly

• Mailed postcards and auto-dials OK

Immunization Information Resources

CDC Travel Advisoryhttp://www.cdc.gov/travel/diseases.htm

National Immunization Programhttp://www.cdc.gov/nip/

National Vaccine Program Officehttp://www.cdc.gov/od/nvpo/

Immunization Action Coalitionhttp://www.immunize.org/

CURRENT ISSUES IN DIABETES MANAGEMENT

1



Robert B. Baron MD MS

Professor and Associate Dean

UCSF School of Medicine

Declaration of full disclosure: No conflict of

interestADA Diabetes Care, 2013

Screening for Diabetes 2013

BMI ≥25 plus other risk factorsInactivity Low HDL or high TG

First degree relative PCOS

High-risk ethnicity Acanthosis nigricans

Gestational DM Hx CVD

HTN

Age 45

ADA Diabetes Care, 2013

Diagnosis of Diabetes 2013

A1C ≥ 6.5% (New, 2010)

FPG ≥ 126 mg/dl (7.0 mmol/L)

2-h plasma glucose ≥ 200 during OGTT

Symptoms and random plasma glucose ≥200 mg/dl (11.1 mmol/L)

Need two separate measurements

Advantages of HbA1c as a Diagnostic Test

Non fasting

Lower intra-individual variation

HbA1c: 2%

FPG: 6.5%

2 hour plasma glucose: 16-17%


2



Diagnosis of Pre-Diabetes 2013

A1C 5.7 – 6.4% (New, 2010)

FPG 100 - 125 mg/dl (5.6mmol/L - 6.9 mmol/L)

2-h plasma glucose 140 mg/dl – 199 mg/dl during OGTT (7.8mmol/L – 11.0 mmol/L)


Risk of Pre-Diabetes 2013

Increased risk of progression to diabetes

44,203 individuals; 16 studies, 5.6 years

A1C 5.5 – 6.0: risk of DM 9 - 25%

A1C 6.0 – 6.5: risk of DM 25 – 50%


Treatment of Pre-Diabetes 2013

Weight loss 7%; physical activity 150 min/week

Metformin (but only metformin) may be considered, especially for those with BMI >35, age <60, and women with history of gestational DM


2013 Practice Guidelines: ASA

ASA: only in those at increased CV risk (10 year risk >10%. (Typically men over 50, women over 60 with other risk factors)

2009:

ASA: over age 40 and for those with other CHD risk factors


3



2013 Practice Guidelines: HTN and Lipids and Tobacco

BP: Goal less than 130 and less than 80

LDL: Goal less than 70 (with CVD); less than 100 (without CVD)

Don’t forget tobaccoACCORD, NEJM 2010

Intensive BP Control in Type 2 DM: ACCORD

• RCT of 4733 patients with type 2 DM • Compare BP less than 120 mm Hg vs 140

120 140 p• BP 119 133• CV events plus death 1.87% 2.09% .20 • Mortality 1.28% 1.19% .55• Stroke 0.32% 0.53% .01• Adverse events 3.3% 1.3% .001

In type 2 DM: treating to 120 mm Hg did not reduce therate of composite fatal and non-fatal CV events

Case 1

70 yo woman with type 2 diabetes, hypertension, and coronary heart disease (s/p MI in 2003).

Meds: Metformin, glipizide, aspirin, lisinopril, metoprolol, and simvastatin

Exam: BP 130/80, BMI 29 kg/m2

Normal exam

Case 1 Her glycemic goal should be:

1. HbA1c <6.0%

2. HbA1c <6.5%

3. HbA1c <7.0%

4. HbA1c <7.5%

5. HbA1c <8.0%


4


Glycemic Control Update

3 newer trials

ADVANCE

ACCORD

VA Diabetes Trial

ACCORD, NEJM, 2008

ACCORD Trial

NIH RCT in DM 2, 10,251 patients, known CVD or risk factors, mean A1c 8.1%

Intensive vs. standard BP (120 v. 140)Lipid control (statins v. statins + fibratesNormalization v. standard BS control (A1c 6 v. 7-7.9)Outcomes: CV events. Also microvascular

events, quality of life, others

ACCORD trial

Intensive

n=5,128

Standard

n=5,123 HR (95% CI)

A1c achieved: 6.5% 7.5% -

1° outcome: 352 371 0.90 (0.78-1.04)

Total mortality 5.0% 3.1% 1.22 (1.01-1.46)

CVD mortality 2.6% 1.8% 1.35 (1.04-1.76)

Hypoglycemia 10.5% 3.5% -

Wt. gain>10 kg 27.8% 14.1% -

ACCORD Trial

Standard Intensive

Deaths 203 25711/1000/y 14/1000/y

Number Needed to Harm: 333

February 2008 (after 3.5 years): NIH stops this arm of study


5


ACCORD, NEJM, 2011

ACCORD Trial5-Year Outcomes

Additional follow-up of 1.5 years

All subjects treated to HbA1c of 7-7.9% during this period

Results: Mortality still higher in intensive

group (7.6% vs 6.4%; HR 1.19)Boussageon, BMJ 2011

Outcome of Intensive Glucose Lowering in Type 2 DM

Meta-analysis of 13 RCTs in DM 2; 34,533 pts

RRAll cause mortality 1.04 (0.91 – 1.19CV death 1.11 (0.86 – 1.43)Non-fatal MI 0.85 (0.74 – 0.96)*Microalbuminuria 0.90 (0.85 – 0.96)*Severe hypoglycemia 2.33 (21.62 -3.36)*

* P <0.001

Boussageon, BMJ 2011

Outcome of Intensive Glucose Lowering in Type 2 DM

Over five year period:NNT to prevent one MI 117-150

NNT to prevent onemicroalbuminuria 32- 142

NNT to cause one episode of severe hypoglycemia 15-52

ORIGEN, NEJM, 2012

ORIGEN Trial

RCT, 12,537 subjects; impaired FBS, IGT, or new diabetes, and high CV risk

Mean FBS 131 mg/dl

Glargine to FBS <95 mg/dl; 6.2 years

Results: No difference in CV outcomes


6


Glycemic Control Summary No consistent evidence that tight glycemic

control reduces risk of CVD in DM 2

Possible subgroups with benefit:

shorter diabetes duration, no CVD

Strong evidence to support decrease in microvascular disease outcomes with more intensive glucose control

More hypoglycemia and weight gain with more intensive regimens


2013 Practice Guidelines: Glucose Control

Goal A1C ≤7 for most

Goal A1C <6.5 for some: short duration, long life expectancy, and no CVD

Goal less stringent (≤8) for history of hypoglycemia, limited life expectancy, mico or macrovascular complications, comorbid conditions, and those in whom the goal is difficult to attain

Critically Ill patients?Meta-analysis of 29 RCTs (n=8,432 patients)

Mortality Rates

Tight Usual RR (95% CI)

Overall 21.6% 23.3% 0.93 (0.85-1.03)

Very tight, ≤110 mg/dl 23.0% 25.2% 0.90 (0.77-10.4)

Moderate, <150 mg/dl 17.3% 18.0% 0.99 (0.83-1.18)

Medical ICU 26.9% 29.7% 0.92 (0.82-1.04)

Surgical ICU 8.8% 10.8% 0.88 (0.63-1.22)

Med-Surg ICU 26.1% 27.0% 0.95 (0.80-1.13)

Glycemic Control Summary

No consistent evidence that tight glucose control improves mortality in hospitalized patients.


7



2013 Practice Guidelines: Glucose Control in Hospital

Critically ill: Goal 140 - 180.

IV protocol

Non-critically ill: premeal <140 if can be done safely; random < 180. Less stringent if severe comorbidities

Scheduled subcu insulin with basal, nutritional, and correction components

Case 1 Her glycemic goal should be:

1. HbA1c <6.0%

2. HbA1c <6.5%

3. HbA1c <7.0%

4. HbA1c <7.5%

5. HbA1c <8.0%

In my practice, I have initiated:

1. Exenatide (Byetta™) or Liraglutide (Victoza™)

2. Sitagliptin (Januvia™) or Saxagliptin (Onglyza™)

3. Both exenatide and sitagliptin

4. Pramlintide (Symlin™)

5. All three of the above

6. None of the above


8


Case 2: 48 yo woman with DM, BMI 33, on diet and exercise and max dose metformin. HbA1C is now 8.5. Your next best step is:

1.

2. Begin a sulfonylurea

3. Begin pioglitizone

4. Begin NPH insulin or long-acting insulin analogue

5. Begin exenatide (Byetta™), liraglutide(Victoza™), sitagliptin (Januvia™) or saxagliptin (Onglyza™)

Generic Oral Hypoglycemic Slide

HgA1c

Time

Change from Drug A to B, C, or D

Add Drug A to B, or B to A

Add Drug C

Add Drug D

Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease?

“There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared with other oral hypoglycaemic treatments.”

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes. Cochrane Database Syst Rev 2010;4: CD002967.

Graham et al, JAMA 2010

Rosiglitazone vs Pioglitazone

Observational study, FDA, 227,571 Medicare patients, over 3 years.

Rosi/Pio HRMI 1.06Stroke 1.27CHF 1.25Death 1.14Composite 1.18

Number Needed to Harm with Rosiglitazone = 60 per year


9


Oral Agent “Failure”Why does this occur?

Changing HbA1c goals

Compliance, side effects

Wrong diagnosis (LADA--latent autoimmune diabetes in adults 10%)

Stress, diabetogenic medications

Postprandial hyperglycemia

Natural progression of the disease

Relative Contributions of Fasting and Postprandial Plasma Glucose to Total Glycemic Excursions as a Function of A1C

Monnier L et al. Diabetes Care. 2003;26:881-885.

0

20

60

80

2(7.3–8.4)

3(8.5–9.2)

4(9.3–10.2)

5(>10.2)

1(<7.3)

40

Co

ntr

ibu

tio

n (

%)

A1C (%) Quintiles

Postprandial hyperglycemia

Fasting hyperglycemia

Natural History of Type 2 Diabetes

050

100150200250

-10 -5 0 5 10 15 20 25 30

Years of Diabetes

Glucose(mg/dL)

Relative Function

(%)

Insulin Resistance

Insulin Level`Beta-cell failure

*IFG = impaired fasting glucose

50100150200250300350

Fasting Glucose

Post-meal Glucose

Obesity IFG* Diabetes Uncontrolled hyperglycemia


050

100150200250

50100150200250300350

-10 -5 0 5 10 15 20 25 30Years of Diabetes

Glucose(mg/dL)

Relative Function

(%)

Lifestyle SU

Insulin Resistance

Insulin Level

Fasting Glucose

Beta-cell failure

Post-meal Glucose

Insulin

Biguanide


10


Insulin Plus Oral Agents

Introduction of insulin

– Bedtime

– Intermediate/Long-acting insulins

• NPH, glargine, levemir

• 10 units

– Self-monitoring of blood glucose (hypoglycemia education)

Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)

When to go to > 1 shot per day HgA1c >7

Glucose in AM at goal but glucose before dinner >140

Options

Add premeal lispro/aspart

Add bid premixed insulin – 70/30, 75/25

Questions

Continue metformin

? Sulfonylurea, ? Thiazolidinedione (mostly not)

Function of Insulin in Regimens

Meal coverage (carbohydrates)

Basal insulin

Correction of high blood sugar

INCRETINS

Gut factors that promote insulin secretion in response to nutrients

Major incretins: GLP-1, CCK, GIP


11


Oral Glucose Promotes More Insulin Release than IV

Glucose - Indicating a Role for Incretins

Incretin Drugs

GLP Agonists

– Exenatide

– Liraglutide

– Exenatide Lar

– Semaglutide

– Aliglutide

– Taspoglutide

– Lixsenatide

DPP IV Inhibitors

– Sitagliptin

– Saxagliptin

– Vildagliptin

– Alogliptin

– Linagliptin

– Dutogliptin

– Metogliptin

A1C (%) Effect (change from baseline)

Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID

MET 0.1 -0.4 -0.8

SFU 0.1 -0.5 -0.9

MET+SFU 0.2 -0.6 -0.8

Changes in A1C from baseline vs placebo statistically significant


12


Weight (change from baseline) & Hypoglycemia

Placebo BID

5 mcg exenatide BID 10 mcg exenatide BID

Weight (kg) -1.4 -3.1 -4.2

Hypoglycemia (%)

MET

SFU

MET + SFU

5.3

3.3

1.26

4.5

14.4

19.2

5.3

35.7

27.8

Open-label extension study to 90 weeks: persistence in weight loss and A1C

Side Effects

GI– Nausea (44% vs 18% with placebo); incidence

lessens over time; 3% dropout rate due to nausea

– Vomiting (13% vs 4%)– Diarrhea (13% vs 6%)

Headache (9% vs 6%)Hypoglycemia (see previous slide)

Improvements in HbA1C With Initial Co-administration of Sitagliptin and Metformin

Placebo

Sita 100 mg QD

Sita 50 mg BID + Met 500 mg BID

Sita 50 mg BID + Met 1000 mg BID

Met 1000 mg BID

Met 500 mg BID

* Placebo-subtracted LS mean change form baseline at Week 24.Sita=sitagliptin; Met=metformin.

-2.5

-2.0

-1.5

-1.0

-0.5

Hb

A1C

(%)* -0.8

-1.0

-1.3

-1.6

-2.1

Mean Baseline HbA1C = 8.8%

N=1091

Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.

Number of patients (%)

Sitagliptin Placebo

Monotherapy n = 443 n = 363

Nasopharyngitis 23 (5.2) 12 (3.3)

+ pioglitazone n = 175 n = 178

Upper resp. infection

11 (6.3) 6 (3.4)

Small increase in WBC – neutrophil count higher by 200 on Sitagliptin

No nausea or vomiting

No weight loss

Sitagliptin – adverse reactions


13


Increased Incidence of Pancreatitis and Cancer Among Patients

Given Glucagon Like Peptide-1 Based Therapy

Sitagliptin or exenatide increased the odds ratio for pancreatitis 6-fold ( P <2 x 10 -16).

Pancreatic cancer was more commonly reported among patients that took sitagliptin or exenatide,

( P <0.033, P <2x10 -4)

All other cancers occurred more frequently among patients that took sitagliptin, ( P <1x10 -4)

Gastroenterology (2011)

SGLT2 InhibitorsSodium-glucose cotransporter 2 Inhibitors

Inhibit glucose reabsorption in renal proximal tubule

Potential advantagesWeight loss, low risk of hypoglycemia, reduced

BP

Potential disadvantagesPolyuria, electrolyte disorders, UTI, fungal

genital infections, ?


050

100150200250

50100150200250300350

-10 -5 0 5 10 15 20 25 30Years of Diabetes

Glucose(mg/dL)

Relative Function

(%)

Lifestyle SU

Insulin Resistance

Insulin Level

Fasting Glucose

Beta-cell failure

Post-meal Glucose

Insulin

Thiazolidinedione ? - Biguanide Incretins/Others ?

Drug Cost Comparison

Drug and Dose Cost/month

Glucose strips (2 per day) $66Sulfonylurea

Generic $4-14Brand $50

Rapaglinide 2 mg tid $193Acarbose 100 mg tid $88Metformin 1000 bid

Generic $4-32 Brand $161

Rosiglitazone 8 mg qd $266Pioglitazone 45 mg/d $245Sitagliptin/Saxagliptin $207/190Exenatide 10 mcg/Liraglutide 1.2mg $271/280Glargine, 45 U/d $150

24 hour fitness Center $35YMCA $65


14


Case 2: 48 yo woman with DM, BMI 33, on diet and exercise and max dose metformin. HbA1C is now 8.5. Your next best step is:

1.

2. Begin a sulfonylurea

3. Begin pioglitizone

4. Begin NPH insulin or long-acting insulin analogue

5. Begin exenatide (Byetta™), liraglutide(Victoza™), sitagliptin (Januvia™) or saxagliptin (Onglyza™)

Conclusions Tight glycemic control not effective in lowering

total mortality or CV mortality.

Many newer diabetes agents available, all with some side effects and higher costs…few with hard outcome data.

Glucose control may be more important early in diabetes

Good BP and lipid control is important throughout the diabetes life course

6/21/2013

1

Department of Medicine

Breast Cancer: Key issues for the non-oncologist

Essentials of Women’s HealthJeffrey A. Tice, MDAssociate Professor

July 2013


• I have no financial disclosures

• I developed and validated one of the models that will be discussed. I hold no patents and derive no financial benefit from the model.

2


OUTLINE• Risk Assessment

• Risk Reduction

• Screening

• Tests at Diagnosis

3


Case: Maria

• 35 yo white woman, has 2 children ages 1 and 4. She started menstruating at age 11 and took birth control pills from age 19 to 26.

• She recently had a biopsy for a breast lump which was benign (cyst)

• Her mother diagnosed BC at age 69

• She is an advertising executive and drinks 2-3 glasses of wine/night.

6/21/2013

2


Maria’s questions

• What is my risk for developing breast cancer?

• What can I do to lower my risk?


6

Risk Assessment


Why risk assessment?

• Breast cancer is most commonly diagnosed cancer in U.S. women

– 1 in 8-9 women will be diagnosed in her lifetime

• 2nd most common cause of cancer death in women

– >39,000 deaths in 2011

• Risk assessment tools are available

• Risk reduction is possible


Risk factors for breast cancer

• Strong– Age

– Breast density

– Atypical hyperplasia

– LCIS

– BRCA mutation

• Moderate– Family history

– Breast biopsy

– Race / ethnicity

– Hormone therapy

– Hormone levels (E2, T, IGF-1)

– Benign breast disease

• Weak– Age at first birth

– Menarche age

– Height, weight, BMI

– Bone mineral density

– NAF/Lavage

– SNPs

– Age of diagnosis for family history

– 2nd degree relatives

– Alcohol intake

– Diabetes

– Physical activity

– Breast feeding

– Menopause age

6/21/2013

3


Factors Considered inThe Gail Risk Model

• Current age• Race / Ethnicity • Age at menarche• Age at first live birth• Number of 1° relatives with BC • Number of breast biopsies• Presence of ADH

Gail et al. J Natl Cancer Inst 81:1879; 1989.


Gail Model on NCI website

• 5 year and lifetime estimates by race

Validated for populations; but modest discriminatory value for the individual.

Rockhill et al. J Natl Cancer Inst 93:358, 2001.

http://www.cancer.gov/bcrisktool/


Case: Maria

• 35 yo white woman, has 2 children ages 1 and 4. She started menstruating at age 11 and took birth control pills from age 19 to 26.

• She recently had a biopsy for a breast lump which was benign (cyst)

• Her mother diagnosed BC at age 69

• She is an advertising executive and drinks 2-3 glasses of wine/night.


What is Maria’s 5-year risk for BC?

1. < 0.5%

2. 0.5 to 1.49%

3. 1.5 to 2.49%

4. ≥ 2.5%

6/21/2013

4


Maria’s risk using the Gail model

• 5 years: 1.0%

• Lifetime (to age 90): 25.8%

Average 35 year old woman

• 5 years: 0.3%

• Lifetime (to age 90): 12.6%


Risk factors not in Gail model

• Strong– Age

– Atypical hyperplasia

– LCIS

• Moderate– Family history

– Breast biopsy

– Race / ethnicity

– Hormone levels (E2, T, IGF-1)

– Benign breast disease

• Weak– Age at first birth

– Menarche age

– Height, weight,

– Bone mineral density

– NAF/Lavage

– SNPs

– Age of diagnosis for family history

– 2nd degree relatives

– Diabetes

– Breast feeding

– Menopause age


Mammographic Breast Density

• BI-RADS RR

1 Almost entirely fat 1.0

2 Scattered densities 2.0

3 Heterogeneously dense 2.8

4 Extremely dense 4.1

• Prevalence: 45% for BIRADS 3 and 4 density

• About 10% for BIRADS 1 and 10% for BIRADS 4

Kerlikowske JNCI 2007


SB 1538: California’s New Breast Density Law

• For women with BIRADS 3 and 4 BD, radiologists must inform women

– that they have dense breasts

– that dense breasts make it harder to detect breast cancer

– That dense breasts are associated with a higher risk of breast cancer

16

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BCSC breast density model

• Age, race, BD, family history, breast biopsy

Tice, Annals IM, 2008.

https://tools.bcsc-scc.org/BC5yearRisk/


Maria’s 5-year risk comparing models

Gail Model 1.0%

BCSC Model

• Almost entirely fat .24%

• Scattered densities .50%

• Heterogeneously dense .77%

• Extremely dense 1.0%

(Average 35 yo woman’s 5 year risk is 0.3%)


19

Risk Reduction


Which of these will NOT decrease Maria’s risk for breast cancer?

1. Eating more fruits and vegetables

2. Brisk walking 30 minutes/day

3. Losing 10 kg (to BMI of 24 kg/m2)

4. Cutting back on alcohol

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Which of these will NOT decrease Maria’s risk for breast cancer?

1. Eating more fruits and vegetables

2. Brisk walking 30 minutes/day

3. Losing 10 kg (to BMI of 24 kg/m2)

4. Cutting back on alcohol


LIFESTYLE

22


No association with breast cancer

• Fruits & vegetables

– Smith-Warner, JAMA, 2001

– Pooled prospective studies

– 7377 cases in 351,825 women

• Carotenoids; Vitamins A, C, E

• Selenium

Mixed results on dietary fat intake – the jury is still out

Obesity

• Premenopausal – small decreased risk

• Postmenopausal – increased risk

Alcohol and breast cancer risk:Meta-analysis

0 10 20 30 40 50 60Total Alcohol Intake g/d

Mu

ltiv

aria

te R

elat

ive

Ris

k 2.52.0

1.5

1.0

0

Smith-Warner, 1998

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Exercise and risk of breast cancer

• Overall 25-30% decreased risk

• Greatest in thinner women

• Lifetime exercise matters

• Modest amounts: 1-3 hours brisk walking/week

0

0.2

0.4

0.6

0.8

1

1.2

0 ≤5 5 to10

>40

RR

MET-h/week

WHI Observational Cohort(n=74,171; 1780 cancers)

McTiernan, JAMA, 2003.


Hormone Therapy

Women’s Health Initiative

• E + P 1.24 (1.01-1.54) ITT

1.49 (as treated)

• E 0.77 (0.59-1.01)

• Survival curves do not separate until 3 years on treatment

• Risk is lower if started at least 5 years after menopause

• Risk dropped to baseline within 2 years of stopping therapy

Chlebowski, JAMA, 2003/2004; NEJM 2009


CHEMOPREVENTION

27


SERMs Reduce the Risk of Breast Cancer

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Adverse Events From Prevention Trials of Tamoxifen & Raloxifene

• DVT/PE: 1.9 (1.4-2.6)

• Endometrial cancer 2.4 (1.5-4.0)

• risk fatal stroke

• risk cataracts

• risk hot flashes

** Majority of adverse events in women ≥ 50 years

Fisher JNCI,1998; Cuzick Lancet, 2003; Barrett-Conner, NEJM, 2006.


• SERMS

– BCPT 1998:

• 5-yrs tamoxifen reduced risk of invasive breast ca 49% -- increased endometrial CA, VTE, cataracts

– STAR trial 2006:

• raloxifene equal to tamoxifen in reducing risk of invasive breast cancer –significantly less thromboembolism and cataracts

30


USPSTF Draft Recommendation

• “…clinicians engage in shared decision-making with women at increased risk of breast cancer regarding medications to reduce their risk. For women who are at increased risk for breast cancer and at low risk for adverse medication effects, clinicians should offer to prescribe risk-reducing medications such as tamoxifen or raloxifene.”

• “In general, women with an estimated 5-year breast cancer risk of 3% or greater are more likely to benefit from tamoxifen or raloxifene”

http://www.uspreventiveservicestaskforce.org/

31


SERM Risk Benefit Ratio LikelyTo Be Favorable For …

5 yr Gail

Age <50 >1.5 – >1.67%

Age >50no uterus >2.5%uterus intact >5.0%

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Raloxifene vs. Tamoxifen

• Pro raloxifene

– Equivalent reduction in IBC

– Less thromboembolism, uterine cancer, and cataracts

– Primary care comfort with therapy

• Con raloxifene

– No reduction in DCIS/LCIS: long-term follow-up concerns

– Post-menopausal women only

– Generic tamoxifen less $$$


Case: Ana

• 34 year old woman born in Mexico

• My mother’s fine and I don’t have a sister.

• But my dad had 4 sisters, 2 of whom developed breast cancer and my paternal grandmother also had breast cancer

• 5-year Gail risk = .31%

The Gail Model Can Underestimate Hereditary Risk of Breast Cancer

This woman’s breast cancer risk greatly underestimated by Gail model

Breast, 44

Breast, 38 Breast, 29Ovary, 42

Ana, 34


Features that indicate increased likelihood of BRCA mutations

• Multiple cases of early onset breast cancer

• Ovarian cancer

• Breast and ovarian cancer in the same woman

• Bilateral breast cancer

• Ashkenazi Jewish heritage

• Male breast cancer

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BRCA1/2 Mutations Increase the Risk of Early-Onset Breast Cancer

Population Risk

Hereditary Risk

By age 50

2%

33%-50%

By age 70

7%

56%-87%

By age 40

10%-20%

0.5%

38


Surgical strategies for women with BRCA mutations

• Risk-reducing oophorectomy (RRSO)

– 50% reduction in breast cancer

• Risk-reducing mastectomy (RRM)

– 90% - 95% risk reduction

Rebbeck , NEJM 2002Kauf, NEJM 2002Rebbeck, JNCI 1999Rebbeck, JCO, 2004


40

Screening

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Screening controversies

• Covered by Dr. Rebecca Jackson Sunday evening


42

Tests at Diagnosis


Abnormal Mammogram

• Cumulative risk of false positive result: 49% after ten mammograms

Elmore et al NEJM 1998

• False positive rates highest for women in their 40’s and 50’s

Nelson et al Annals Int Med 2009


Case

• Your patient AH, a 56 yo woman, goes for her screening mammogram. A few days later, you get a call from the radiologist. The mammogram shows increased density and possibly a calcification on the right. The radiologist says they are reading it as a BIRADS 0 and the patient should get follow-up, could you please let her know?

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What kind of follow-up does this patient need next?

1. A repeat mammogram in 3-6 months

2. A mammogram at the usual screening interval

3. A diagnostic mammogram with spot-compression views

4. A referral to the breast surgeon/clinic for a biopsy


American College of Radiology BIRADS category (breast imaging reporting and data system)

Normal

1: negative routine follow-up

2: benign finding routine follow-up

Abnormal

0: indeterminate immediate follow-up

(spot-compression views +- u/s)

3: low chance malignancy (~2%) short interval follow-up

(3-6 months repeat mammo)

4: >2-95% chance malignancy (a: low; b: intermediate;

c: moderate) biopsy

5: ≥95% chance invasive malignancy biopsy


MQSA: Mammography Quality Standards Act

• Passed by U.S. Congress in 1992

• Mammography facility must send patient written report of her mammogram within 30 days of exam

• Report must be in words she can easily understand

• For BIRADS 4 or 5 results, facility expected to contact patient as soon as possible –‘expectation’ within 5 days

• If verbal contact, still need to send letter

47

www.fda.gov/Radiation-EmittingProducts/MammographyQualityStandardsActandProgram/ConsumerInformation/ucm113968.htm


Communication Matters• Adequate communication of abnormal

results improves receipt of appropriate follow-up

Poon et al, JGIM 2004

• Minority women report lower rates of adequate communication, and are less likely to know their abnormal mammogram results

Zapka et al, Prev Med 2004

• Women who received their results verbally (in person or over the telephone) more likely to know that their mammogram was abnormal

Karliner et al, JGIM 2005

48

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Delays in Diagnosis• 20-40% women undergoing breast ca

diagnosis experience delays to diagnosis or treatment

• Delay of ≥ 3 months (symptoms to treatment)associated with 12% lower 5-year survival

– Most of this attributable to later stage diseaseRichards et al, Lancet 1999

• African-American women are more likely to suffer delays than White women

Elmore et al, Med Care 2005

• Hospitals disproportionately serving non-English speaking and minority women have longer delays

Karliner et al, Med Care 2011


Causes of Delay• Mammogram Facility

– Resource issues

– Tracking systems

– Appointment access

• Communication

– Physician inaction (not contacting patient; not ordering follow-up tests)

– Inadequate communication of abnormal results and need for follow-up

– Language barriers

• Patient

– Patient inaction (lack of knowledge / understanding, fear, anxiety)


Case: Gwen

• You are seeing Gwen, a 50-year-old Chinese-American woman, for her routine annual exam. She tells you about a new lump she found in her breast, which you feel and find to be firm with regular borders.

• You send her for a diagnostic mammogram which shows an area of calcification BIRADS 4 and next she undergoes a core biopsy.


What Pathologic Staining Findings are Indicative of the Poorest Prognosis Tumor?

1. ER/PR positive staining

2. ER/PR and HER2Neu positive staining

3. ER/PR/Her2Neu negative staining

52

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Hormone Receptors and HER2Assay for estrogen, progesterone receptors and HER2

– Perform on core biopsy specimen

– If negative on core specimen, should be repeated at definitive surgery:

• up to 15% of cases with negative markers on biopsy specimen will be positive on larger surgical specimen

• ER/PR + cancers responsive to anti-estrogen therapy

• Over-expression of HER2/neu oncogene

– worse prognosis

– responsive to trastuzumab (Herceptin)


Poor Prognosis Tumors• Triple negative tumors

– ER- / PR- / HER2-

– Unresponsive to anti-estrogen therapy and trastuzumab

– Neo-adjuvant chemotherapy

– Clinical trials investigating immune modulators and receptor-blockers for growth factors

• African Americans, Latinas and BRCA1 carriers more at risk for triple negative tumors


Sentinel Lymph Node Biopsy• Initial standard axillary staging procedure for

invasive breast cancer without palpable nodes

• SLN: any node receiving drainage directly from the primary tumor (can be >1)

• Technetium-labeled sulfur colloid or vital blue dye injection around tumor / biopsy cavity / subareolar

• Identifies SLN in 92-98% of patients

• 97.5-100% concordance with complete axillary lymph node dissection (ALND)

55


SLN biopsy and survival

• RCT of 5,611 women with invasive breast CA, 8-years of follow-up

ALND in +SLN only ALND in all

Overall Survival 90.3% 91.8% p=0.12

Disease Free Survival 81.5% 82.4% p=0.54

If SLN negative then can avoid axillary dissection

56

Krag et al, Lancet Oncology 2010

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SLN and Survival

• If SLN positive – medical necessity of ALND is at question –

– RCT of no further axillary treatment vs. ALND– T1-T2 invasive breast cancer, no palpable adenopathy,

– 1-2 SLN with mets

– No difference in 5-year overall or disease free survival

– Only able to enroll half target (891/1900 women)

Giuliano et al, JAMA 2011

• When ALND required, standard: removal of at least 6-10 nodes (level I and II dissection, not radical dissection)

57


Gene Expression Profiling

• Goal: improve risk stratification in early stage breast cancer to better tailor use of chemotherapy

• Used to classify tumor according to recurrence risk and to predict response to chemotherapy

• Oncotype Dx best studied

– HR+, LN- <5cm tumors

– Recurrence risk low (<18) no benefit from chemo

– Recurrence risk high (>30) + benefit from chemo

• Ongoing RCTs using Oncotype Dx (TAILORx) and Mammaprint (MINDACT)

58


Metastatic Work-up**Mets are rare without symptoms**

• Physical exam: breasts, skin, lymph nodes, abdomen

• Diagnostic bilateral mammography; possible breast MRI

• CBC, LFTs

• Chest x-ray; possibly CT pre-radiation

• Staging CT – liver, pelvis, chest – and bone scan in stage III disease and above


Post-Treatment Survival

• 2,838 women Stage I-III treated w/ adjuvant or neo-adjuvant systemic therapy

• 1985-2001; disease free x 5 years

• Residual disease-free recurrence rate

– 10 years post-diagnosis 89%

– 15 years post-diagnosis 80%

• By stage residual risk of recurrence at 10 years

– Stage I 7%

– Stage II 11%

– Stage III 13%

Brewster et al JNCI, 2008

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Summary

Risk Reduction

• Lifestyle

– Exercise, weight loss or maintenance

– Minimize alcohol

– Avoid/stop HT

– Low fat diet?

• Consider tamoxifen or raloxifene for high risk women - risk/benefit

• Assess familial risk

– Refer to genetic counseling / high risk breast clinic


Summary

Tests at Diagnosis

• Delays in diagnosis are common after an abnormal mammogram

• Improved communication of abnormal results improves receipt of appropriate follow-up

• SLN biopsy can help avoid axillary dissection and results can help determine need for chemo

• Metastases are rare without symptoms

The good news:

If a woman survives 5-years, her 10-year survival is very good (Stage I-III)

NOTES

Presentation slides will not be used for this session.



Common Problems in Older WomenUsing Geriatric Principles in Every Day Practice

Eliseo J. Pérez-Stable MD


DGIM, Department of Medicine


Summary of TopicsShift of paradigm in caring for older

or frail patients: Geriatrics Principles

Medications overuse and avoidance

Recognition and management of Cognitive Impairment

Urinary Incontinence

Falls: Risk and prevention

Osteoarthritis

Main Teaching Points Today Geriatric Principles and Topics

• Focus on quality of life and not on quantity or prolongation

• Comorbidity: Multiple chronic diseases and symptoms

• Functional Status should be a vital sign• Cognitive Status affects all• Care across settings (Home/hospital/SNF)

and and Long term care options• Palliative Care and symptom management



Comorbidity• Older persons with a major diagnosis

(such as heart failure) have other diseases as well

• Other diseases can have profound impact on clinical presentation, prognosis, optimal treatment, outcomes and management

• Dementia or Cognitive impairment is the big ticket item affecting all

Geriatrics Principles

Functional and Cognitive Status

• The holy grail of Geriatrics: The end outcome of all diseases.

• Diseases matter to the extent they impact functional status

• How do functional and cognitive status impact natural history and outcomes of the condition

• What is the impact of the condition on ADL, IADL, cognitive function?

ADL and IADL Status in All

• Activities of Daily Living: dress, transfer, toilet needs, bathing, feeding

•Patients in long-term care institutions almost always have ≥2 ADL limitations

• Instrumental Activities of Daily Living: manage own finances, transportation within community, shopping for food/clothing, preparation, use of phone or computer, housework, handle own meds



Physical and Cognitive Function• Use of functional status measures in

clinical practice as routine practice

• Measurement of gait speed predicts falls risk and morbidity/mortality

• Get up and Go Test

• Evaluate cognitive status

• Establish decision-maker for goals of care and teach communication about issues

• Use functional status as a target of therapy: prevent ADL disability or delirium

Care Across Settings and Options for Long Term Care

•Care transitions often disastrous for elders

•Hospital-home; hospital-SNF; SNF-hospital

•Interventions to improve care transitions

•Long term care not just nursing homes

•Family caregivers

•Other informal care

•Assisted living

•Evaluate personal finances

Palliative Care and Symptom Management

• End of life care and hospice are underused for virtually any clinical problem

• Palliative Care is focused on improving symptoms, well being, and quality of life

• Should be present throughout the course of serious illness

• Focus on major sources of distress including patient perspective

How these Principles Apply to Patient with COPD as an Example

• Comorbidity

– How do conditions such as diabetes, dementia, depression impact outcomes of steroid treatment for exacerbations

• Function/Cognitive impairment

– As COPD progresses, what happens to ADL and IADL function. Does COPD increase risk for dementia?



How these Principles Apply to Patient with COPD as an Example

• Transitions/Long Term Care

– How can we prevent readmission in persons with COPD and cognitive impairment

– Treatment of COPD in nursing homes• Palliative Care

– What are the most important sources of distress in older persons with COPD?

Medication Management

Appropriate Medication Management in Geriatrics Medicine

• 90% take medications every day and 46% take 5 or more

• 54% have more than one clinician prescribing and 35% use >1 pharmacy

• Over 50% of all prescribed drugs• Half do not take all medications as

prescribed• Up to 60% of outpatients have

medications considered suboptimal

Adverse Drug Effects are Common

• 25% of outpatient practices report• Abiut 10% to 17% of hospital

admissions are due to ADE• Increase in ADE is disproportionately

affecting elderly: 20% of all ADEs• Greatest predictor of ADE is the total

number of prescribed meds



Beers Criteria 2012+www.americangeriatrics.org

• Goal to reduce inappropriate medications Beers meds linked to ADE, hospitalization, delirium, falls, GI bleed

• 53 classes of medications listed in 3 categories:

– Avoid regardless

– Inappropriate with certain diseases or syndromes

– Use with caution

New Beers Listed Meds to Avoid regardless or in some

• Megestrol: minimal benefit on appetite, weight but increase in embolic events

• Glyburide: Prolonged hypoglycemia• Spironolactone >25 mg: High K• Sliding scale insulin• Pioglitazone/rosiglitazone in heart failure• Acetyl cholinesterase inhibitors in

patients with syncope• SSRIs with falls or fractures• Histamine blockers in delirium/dementia

Cognitive Impairment

Cognitive Impairment Clinical Case

EM is a 67 year-old woman with a h/o high blood pressure. Brought in by husband who is reporting that patient’s personality has changed over the last year. She is becoming more suspicious, and at times talks and “doesn’t make sense”. She is paranoid about the neighbors.



Prevalence Cognitive Impairment

• AD estimated prevalence 24.3 million world-wide in 2001

• Predicted rise to 42.3 million in 2020

• 81.1 million by 2040• Lifetime risk of

dementia after age 65 is 17-20%

• Costs $150 billion/yr

Ferri CP, et al. Lancet 2005; Simmons BB et al. AAFP 2011

Risk Factors for Cognitive Impairment

• Age• Down’s syndrome• Head trauma• Fewer years of formal education• Female sex• Family history of Alzheimer• Vascular Disease risk factors • Cerebrovascular events

Clinical Presentation of Dementia

• Cognitive changes• Personality changes• Changes in day-to-day functioning• Activities that require calculation or

planning first to be impaired• Psychiatric symptoms• Problem Behaviors• Dementia is under-diagnosed• Have a High index of suspicion• Ask caregivers, family and friends

Rapid Screening for Cognitive Impairment

• Routine screening not recommended• Use as indicated as diagnostic screen • Verbal Fluency Test: Sensitivity 88%;

specificity 96%; takes One minute• Ask patient to name as many animals as

possible in one minute

– 1 point/animal

– Score <15 suggestive of dementia

• Score <12 if 1-7 years of school

• Score <9 if no education

Simmons BB, et al. AAFP, 2011



Mini-Cog: Three Item Recall and Clock Draw

• Ask the standard orientation questions

• Give three items to learn and repeat right away and then ask for recall after one minute

• Draw a clock

• Validated in multiple languages

• Sensitivity is 76%

• Specificity is 89%

Borson, JAGS, 2003

Definitions of Dementia

Clinical (DSM4) diagnostic criteria Memory impairment AND one or more:

Aphasia: language problems Apraxia: motor problems Agnosia: sensory problems Disturbance in executive functioning

Deficits impair social/occupational function, represent a decline from baseline, not due to delirium

Mild cognitive impairment: impairment does not affect function

Mini-Mental State Exam• Maximum score 30

Score <24 suggests cognitive impairment Decline of 4 points over 1-4 y significant

Scores inversely correlated with age; median score = 25 if age >80

Not as sensitive in people with higher levels of education; median score = 22 if 0-4 yr of educationhttp://www.angelfire.com/retro/michaelpoon168/mini_mental_state_examination_normative%20data.htm

MMSE is proprietaryCrum RM et al. JAMA, 1993;269(18); Holsinger T, et al. JAMA, 2007;297.

Montreal Cognitive Assessment

Maximum score is 30 points

>26 is normal

May be better at diagnosing mild cognitive impairment

Includes executive function testing

Better for use with patients with limited formal education

www.mocatest.org

Not proprietary



Symptomatic Treatment of Memory Disturbance

Cholinesterase Inhibitors delay degradation of acetylcholine at the synaptic cleft

Indicated for mild-moderate Alzheimer’s

Donepezil (Aricept)--5-10mg/day Rivastigmine (Exelon)--6-12mg/day

Galantamine (Razadyne)--24-32mg/day or patch 4.6-9.5mg

May cause weight loss, nausea, vomiting, diarrhea, vivid dreams, AV Block, bradycardia

Clinical Significance of Long-term Donepezil Treatment

565 patients with mild-mod AD randomly assigned to donepezil 5mg or placebo for 12-week run-in; Followed up to 3 years

End points: Institutionalization or progression of disability (loss of ADLs): No difference in rates by treatment No difference in care costs, unpaid

caregiver time, behavioral/psychological symptoms AD2000 Collaborative Group, Lancet 2004;363.

Exercise and Dementia Prevention

• Meta-analysis: 33,816 non-demented patients followed prospectively

• Participants with high-level physical activity protected against cognitive decline (HR=0.62; 95% CI 0.54-0.7)

• Low-moderate exercise was also protective (HR 0.65; CI 0.57-0.75)

Sofi F et al. J Intern Med, 2011

β-Amyloid 42/40, Cognitive Reserve and Cognitive Decline

Yaffe K, et al. JAMA, 2011;305(3)



Evaluation of Driving Risk in Dementia – Practice Parameter

• Patient at increased risk for unsafe driving:

– Caregiver rates patient’s driving ability as marginal or unsafe

– Pt has previous accidents or citations

– Pt has reduced driving mileage or self-reported situational avoidance

– MMSE score < 24

– Pt with aggressive/impulsive personality

– Report to DMV Iverson DJ, et al. Neurology, 2010;74.

Urinary Incontinence

70 year-old African American woman, for follow-up of hypertension, obesity, and pre-diabetes. Her weight has remained the same since her last visit 2 months ago. Her current medications are amlodipine and atorvastatin, although she’s been somewhat inconsistent in taking them in the past year. During your initial review of systems, she denies any complaints, but as you prepare to wrap up, she pulls out an authorization form for adult diapers for you to sign. On further questioning, she admits to experiencing involuntary urine leakage at least once or twice a week, for more than 5 years. When you ask her why she never brought this up before, she says, “I did not think there was anything you could do– I just had too many kids, and now I’m getting old.”

Which of the following statements about risk factors for UI in women are true?

(Choose ALL that apply)

A. Although UI can occur in young women, the prevalence of UI increases linearly with age

B. Both vaginal and C-section delivery increase the risk of UI in women

C. Obesity is a risk factor for UI, but weight loss does not usually improve UI

D. Diabetes is associated with an increased risk of UI in women, independent of obesity



Prevalence of urinary incontinence in women across the age spectrum

Hannestad et al. J Clin Epidemiol, 2000; 53: 1150-1157.

The EPINCONT Study (N=27,000)

Changes in Lower Urinary Tract Function with Aging involuntary bladder muscle

contractions total capacity of the bladder bladder contractility and

urinary flow atrophy of urethral mucosal

epithelium

Over-activity of thedetrusor muscle

Sphincter deficiency &/orpelvic floor weakness

Urge incontinence(leakage from a sudden or

strong urge to urinate)

Stress incontinence(leakage associated with in abdominal pressure)

Pathophysiology of incontinence

Bladder outlet obstruction or detrusor weakness

Overflow incontinence(frequent or constant small-volume urine leakage)

Major mobility or cognitive impairment

Functional incontinence(inability to get to the toilet or recognize the need to void)

Distribution of stress, urge, and mixed UI in women across the age spectrum

Adapted from Hannestad et al. J Clin Epidemiol, 2000

The EPINCONT Study (N=27,000)



Rortveit G, et al. NEJM. 2003;348:900-907.

Comparison Any UI Moderate or severe UI

C-section vs no delivery

1.7 (1.3-2.1) 1.6 (1.1-2.3)

Vaginal delivery vs no delivery

2.8 (2.5-3.2) 3.3 (2.7-4.0)

Vaginal delivery vs C-section

1.7 (1.2-2.1) 2.2 (1.5-3.1)

Adjusted odds ratios for UI by mode of delivery*

Vaginal and C-section delivery both increase risk of incontinence

*Adjusted for age, parity, years since last delivery, & BMI

Dose-response between body mass index and incontinence risk

Subak L, et al. Journal of Urology 2009; 182: S2-S7.

Any incontinence Severe

The impact of diabetes on urinary incontinence risk in women

• Diabetic women with 28% risk of any UI and 40% risk of severe UI in Nurses Health Study

• Risk of incident UI increased with increasing duration of diabetes

• Adjustment for age, parity, BMI, and medication use did not explain increased risk

• Possible mechanisms– damage to innervation of bladder & urethra, volume of urine

Behavioral treatment for Urgency Incontinence

• Pelvic floor muscle exercises

• Bladder training techniques

• Urge suppression techniques



Pelvic floor muscle exercises

• Encourage patients to work up to holding contractions for 3+ seconds at a time

• Teach patients to distinguish between pelvic vsabdominal or buttock muscles

• Recommend repetitions on a set schedule (e.g., set of 10, 5 times/day)

Bladder training techniques

• Instruct patients to starting void every hour regardless of need to urinate

• Progressively increase the interval by 30 minute increments to reach 3-4 hours

• Recommend pelvic muscle contractions for urgency between voiding

Urge suppression techniques

When you feel the urge to urinate. . . .

- Stop, sit down, and take deep breaths- Imagine the urge peaking, then subsiding- Practice pelvic floor muscle exercises

Once you feel the urge is under control- Walk slowly to the bathroom and void

The traditional extended evaluation for incontinence in women

Clinical history

Urinalysis test

Voiding diary

Neurologic exam

Pelvic exam

Post void residual

Cough stress test



Relationship of PVR to urinary symptoms in 1017 older women

Urinary symptom PVR <50

(N = 780)

PVR 50-99

(N = 95)

PVR 100-199

(N = 67)

PVR ≥200

(N = 45)

Urgency UI (weekly)

(N=312)

32% 30%) 25% 47%

Stress UI (weekly)

(N=351)

37% 32% 21% 44%

Daytime frequency

(N=299)

29% 38% 33% 27%

Nocturnal frequency

(N=305)

30% 36% 36% 38%

None of the above

(N=322)

34% 30% 30% 27%

Huang AJ, et al. Journal of the American Geriatrics Society, 2010

The 3 Incontinence Questions (3IQ)1.During the last 3 months, have you leaked urine, even a small amount? a. Yes; No → no further questions.2. During the last 3 months, have you leaked urine: a. When you were performing some physical activity such as coughing, sneezing, lifting or exercise? b. When you had the urge or the feeling that you needed to empty your bladder but you could not get to the toilet fast enough? c. Without any physical activity or a sense of urgency3. During the last 3 months, have you leaked urine most often:a. When you were performing some physical activity such as coughing, sneezing, lifting, or exercise? b. When you had the urge or the feeling that you needed to empty your bladder but you could not get to the toilet fast enough? c. Without any physical activity or without a sense of urgency? d. About equally as often with a physical activity and with urgency?

Diagnostic Aspects of Incontinence Study (DAISy)

Multi-center study of ambulatory women with weekly incontinence (N=301)

Exclusions: self-reported stroke or major neurologic condition, prolapse, urologic surgery

Compared diagnosis by 3IQ+urinalysis versus traditional extended evaluation

3IQ had sensitivity & specificity of 0.75 and 0.77 for urge UI, 0.86 and 0.60 for stress UI

BRIDGES clinical trial

Goal: evaluate efficacy and safety of pharmacologic therapy for urgency UI in women diagnosed by 3IQ

645 ambulatory women identified by the 3IQ randomized to pharmacologic therapy vs placebo

Moderate decrease in incontinence frequency over 12 weeks (average reduction of 1 episode per day)

No serious adverse events associated with pharmacologic therapy in this setting

Huang AJ, et al. American Journal of Obstetrics & Gynecology 2012



Name Available forms

Instructions for use Cost

Immediate-release

Oxybutynin (Ditropan)

2.5 or 5 mg Start at 2.5 mg (1/2 pill) BIDAdjust to maximum of 5 mg QID

$

Tolterodine (Detrol)

1 or 2 mg Start at 2 mg BID, lower to 1 mg BID if poorly tolerated

$$$

Trospium (Santura)

20 mg Take 20 mg BID, lower to 20 mg QHS if poorly tolerated

$$$

Extended-release

Oxybutynin ER (Ditropan XL)

5, 10, or 15 mg

Start at 5 or 10 mg QD, increase to max of 30 mg QD

$

Tolterodine LA (Detrol LA)

2 or 4 mg Start at 4 mg QD, lower to 2 mg QD if poorly tolerated

$$$

Darifenacin (Enablex)

7.5 or15 mg Start at 7.5 mg QD, wait ≥2 weeks before increasing dose to 15 mg

$$$

Trospium XL (Santura)

60 mg Take 60 mg QD $$$

Solifenacin (Vesicare)

5 or 10 mg Start at 5 mg QD, increase to max of 10 mg QD as tolerated

$$$

Fesoterodine (Toviaz)

4 or 8 mg Start at 4 mg QD, increase to max of 8 mg as tolerated

$$$$

Tips on starting an anti-muscarinic medication for urge incontinence

• Avoid in patients with gastric retention, severely-decreased GI motility

• Contraindicated in narrow-angle glaucoma (consider possibility in elderly, farsighted, Asian)

• Start with a low dose (e.g., ½ pill of oxybutynin 5 mg twice daily), then increase as tolerated

• Discuss strategies for preventing or decreasing side effects (e.g., lozenges)

Risk and Prevention of Falls

Falls Burden in Older Adults

• 15,000 deaths, 475,000 hospitalizations, 1,360,000 ED Visits; Latinos have highest rate of falls

• Serious Falls-related Injuries:

– Hip fractures (55%): 20% mortality at 1 year

– Non-Hip fractures (21%)

– Traumatic Brain Hemorrhage (10%)

– Chest Injury (7%)



Functional Consequences of Falls

• 60% report moderate activity restriction

• 33% require help with ADLs

• Increases risk of nursing home placement

• One-third develop fear of falling:

– Decreases physical and social activity

– Decreases self-reported health status

– Increased depression

LR of Risk Factors for Future Falls

• Fall in last year: 2.8 - 3.8

• Orthostatic hypotension –

• Visual acuity –2

• Gait and Balance 2

• Medications 1.7

• Assess Cognition 4 - 17

• Limitation in ADLs or IDLs: 2 - 4

Gait and Falls

• Gait abnormalities in 20% to 40% of persons >65 and over 50% if ≥ 85 y

• Gait speed predicts 10-year mortality• Assess normal, safe speed• In office tests: Gait balance test• Learn with physical therapy evaluation• Risk of multiple falls among >64 y from

California Health Interview Survey: Latinos 17%, Blacks 11%, Asians 8%, Whites 12%

Falls Recommendations USPSTF

• Exercise and physical therapy significantly reduces falls; the more the better: RR = 0.85 (0.78-0.92)

• Vitamin D supplementaion without calcium: RR = 0.83 (0.77-0.89)

• Vision correction shows no reduction• Multifactorial intervention seems to

reduce falls but not statistically significant



Osteoarthritis

Radiographs: Two keys to ordering knee X-rays

• Minimum 2 views of every joint (AP and lateral)

• Knee has 2 articulations: want 2 views of each: 1. Patella – femur 2. Femur- tibia

• Weight-bearing views to evaluate for arthritis

• Arthritis is not painful if it’s not weight-bearing. Reproduce the painful situation to see the degree of cartilage loss.

Radiographic findings in osteoarthritis

1. Joint space narrowing

2. Sub-chondral sclerosis

3. Osteophytosis

4 components of non-operative treatment for knee osteoarthritis

• Patient education• Modules on exercise, healthy eating,

medications, surgical treatment• Identify goals and action plans Moderate

effect size on pain relief• Exercise: low-impact aerobic ––

significant pain relief• Weight loss: 5% body weight significant

functional improvement, unclear effect on pain



Acupuncture in Treatment of Neck and Knee Pain

Mechanical Neck Pain• RCT in UK, 135 pts

age 18 to 80• Outcome: Pain 1 week

after treatment (visual analog)

• 8 sessions• 12% (3%-21%) better• 1 practitioner• Clinical significance?

AIM 2004; 141:911-919

• OA Knee• RCT, 570 pts age 65• 23 sessions; 26 wks• Pain and function

scores, SF-36, 6’-walk• Pain: –2.5 (–4.7 - –0.4)

at 26 wks• drop out in controls• Benefit shown–useful

adjunctive therapyAIM 2004; 141: 901-910

Medications for OA Pain control

• Glucosamine• APAP (≤ 3 g/day) or NSAID unless

contraindication • Significant reduction in pain compared to placebo• NSAIDs more effective than APAP but higher GI

risk –– Consider topical NSAIDs• Steroid injection: Significant short-term pain

relief for at least 3 weeks; No effect on function Max 4/year due to concern about cartilage

• Visco-supplementation: Evidence limited by publication bias; May provide longer term pain relief (5-13 weeks)

Vitamins and Supplementsin Women’s Health

An Evidence-Based Approach

Jeffrey A. Tice, MD

Division of General Internal MedicineUniversity of California, San Francisco I HAVE NO CONFLICTS OF INTEREST

Nutrition in a Bottle?

?

Vitamins / supplements to be covered

• Antioxidants

– Beta-carotene / Vitamin A

– Vitamin E

– Vitamin C

• Folic acid / B-vitamins and homocysteine lowering

• Vitamin D / Calcium

• Omega – 3 polyunsaturated fatty acids

What percentage of Americans regularly use vitamin supplements?

• 0 to 20%

• 21 to 40%

• 41 to 60%

• 61 to 80%

• 81 to 100%

Vitamin Use in the U.S.A.

• 52% of Americans and increasing

– More than doubled since 1970s

• $9.4 billion in 2009

• Reports from observational studies of diet are very popular with patients and are always in the news

Why are they so popular?

• Diseases of deficiency

– Vitamin C: Scurvy

– Vitamin D: Rickets

– Thiamine (B1): Beriberi

• More is better philosophy in America

– Super-size me!

• Self-efficacy / prevention / wellness

Guiding Principle: Primum non nocere

When recommending a therapy to an otherwise healthy person (i.e. for disease prevention / wellness), you should have the highest level of evidence guiding your recommendation: randomized trials with patient-centered outcomes.

Why antioxidants?

• Laboratory and animal research show that antioxidants prevent the free radical damage that is associated with cancer, heart disease, and aging

• Antioxidants are provided by a healthy diet that includes a variety of fruits and vegetables

• Vitamins A, C, E, beta-carotene

ß Carotene and RetinolEfficacy Trial (CARET)

• Subjects

–18,314 smokers, former smokers, asbestos

–Age 45 - 74, mean 58. 34% women

–Enrolled 1985, Seattle

• Follow-up 4 years

• RCT ß-carotene 30 mg, Vit A 25000 IU

• Outcome: Lung CA, Death, CVD death

CARET Randomized Trial Results

> 18,000 participants followed for 4+ years on beta-carotene or placebo

Omenn, NEJM, 1996

Vitamin E

• Factor X: a group of fat soluble compounds, the tocopherols

• Deficiency: Rare

• They are the primary fat soluble anti-oxidants

• US RDA 22 IU in men and women

Nurses’ Health Study (NHS)

• Subjects

–87,245 US Female Nurses

–No CHD, Stroke or Cancer

• Follow-up 8 years

• Outcome: Non fatal MI, CHD Death

Stampfer, NEJM, 1993

NHS Results for MI or CHD Death

Quintiles of Vitamin E Intake

1st 2nd 3rd 4th 5th

IU/d 2.8 4.2 5.9 17 208

RR 1.0 1.0 1.1 .74 .66

More is better: p-value for trend = 0.001

Stampfer, NEJM, 1993

Women’s Health Study

• 40,000 healthy women at least 45 years old

• 10+ years of follow-up

• Vitamin E 600 IU every other day

– No effect on cancer (RR 1.01)

– No significant benefit for major CVD events

Lee, JAMA, 2005.

The answer!

• Meta-analysis of 47 high quality randomized trials of antioxidants

• 181,000 individuals

• 25,000 deaths

Bjelakovic, JAMA, 2007.

Death from any cause

• Vitamin A 16% increase

• Beta-carotene 7% increase

• Vitamin E 4% increase

• Vitamin C Trend towards increase (6%)

All p << 0.05 except vitamin C

Bottom line: actively discourage anti-oxidant useBjelakovic, JAMA, 2007.

Why?

• Postulated benefits of controlled oxidative damage (free radicals)

– Kill bacteria

– Eliminate damaged cells

Vitamin C…Brrrrr

• Marathon runners, skiers, soldiers on sub-arctic exercises

– 50% reduction in the incidence of colds

• General public

– No reduction in incidence

– 10% reduction in duration

Hemila, Chalker. Cochrane review, 2012.

Vitamins, Homocysteine, and Heart Disease

Homocystinuria

• In-born error of metabolism (1962)

• Homocysteine levels in the blood: 100-400 µmol/L

• Normal homocysteine 8 to 12 µmol/L

• 1 in 150,000 live births

Homocystinuria: Clinical Features

• Premature cardiovascular disease

– 50% experience major event by age 30 years

• Connective tissue defects

– Osteoporosis

– Lens dislocation

• Cognitive deficits

Homocysteine and Risk of Death

Homocysteine RR

< 9 1.0

9-14.9 3.3

15-19.9 6.3

≥ 20 9.9 p<0.001

Nygard, NEJM, 1997

Vitamins To Lower Homocysteine

• > 40 Randomized Clinical Trials

• Folic acid lowers homocysteine 25%

• Vitamin B12 lowers it an additional 7%

The Answer!

• Pooled meta-analysis of 8 large, high quality randomized trials

• 37,485 individuals

• 5,125 deaths

• 9,326 major vascular events

• 3,010 cancers

Clarke, Archives IM, 2010.

Folate / Homocysteine RCTs

• Homocysteine 25% decrease

• Death No effect: 1.02 (.97-1.08)

• CVD events No effect: 1.01 (.97-1.05)

• Cancer No effect: 1.05 (.98-1.13)

Folate does not prevent cancer or heart disease

Clarke, Archives IM, 2010.

Folate And Neural Tube Defects (NTD)

• 70% reduction in 2nd occurences

– 4 mg of folate

• 63% reduction in 1st occurrence

– 0.4 mg of folate

• Since flour fortification

– 46% reduction in NTD Meta-analysis, Blencowe, IJE, 2010.

MULTIVITAMINSIn the news

Multivitamins…kill?

• Iowa Women’s Study

–38,772 women ages 55-69 followed 19 years

–MVI: RR death 1.06 (1.02-1.10)

–2.4% absolute increase in mortality• NNH = 42

–Observational!

Mursu, Archives IM, 2011

TO D OR NOT TO D...?That is the question!

Nutrient of the year!The sun is rising on Vitamin D

Sales increased 82% from 2008 to 2009

Vitamin D

• Vitamin: prevents rickets in children

• Hormone: 1,25 dihydroxy-vitamin D

– Intestinal and renal absorption of calcium, phosphate

– Lowers PTH, prevents secondary hyperPTH

– Neuromuscular function

– Regulation of up to 10% of the human genome

Institute of Medicine Report

Panel reviewed 1000 studies on 25 health outcomes to updateprevious 1997 recommendations

Vitamin D:Adult Dietary Reference Intake* (U.S.)

• Age

• 1-70 years 600 IU / day

• > 70 years 800 IU / day

*Institute of Medicine, 2010: Sufficient to meet the needs of virtually all people.

Vitamin D Status: Levels of 25(OH)D

ng/mL nmol/L

Deficient < 12 < 30

Insufficient 12 – 20 30 - 50

Sufficient ≥ 20 ≥ 50

Potentially harmful ≥ 50 ≥ 125

(hypercalcemia, hyperphosphatemia)

1 ng/mL = 2.5 nmol/L

Vitamin D levels in Americans

Prevalence of inadequate 25(OH) vitamin D among American women ≥14 years old by IOM definitions

< 12 ng/ml 10 to 12% At risk of deficiency

< 20 ng/ml 34 to 39% At risk of inadequacy

< 30 ng/ml ~80%

NHANES 2003-2006

Why so little D?

Vitamin D and Sunlight

• Most of the world relies on natural exposure to sunlight to maintain adequate levels

• Sunscreens of > 8 SPF can prevent synthesis

• Smog, smoke, window glass, even window screens can reduce synthesis

Sources of Vitamin D

400 IU/ tsp 100 IU/ 8 fl oz 20 IU/ egg yolk

400 IU/3oz 90 IU/ 8 fl oz 2700 IU/ serving

Treatment Of Low Vitamin D

• At risk for Deficiency (< 12 ng/ml)

– 50,000 IU of Vitamin D2 or D3 per week for 6-8 weeks and then 800-1000 IU per day

• Nutritional Insufficiency (< 20 ng/ml)

– 800-1000 IU per day

– Goal will be reached in 3 months

• Monitor at 3 months

• Tolerable upper limit for Vitamin D is 4000 units per day per IOM.

Vitamin D supplements: Two forms

• Vitamin D2: ergocalciferol

• (milk fortification, U.S. supplements, plants)

• Vitamin D3: cholecalciferol

• (“natural”: sunlight, fatty fish)

Should we be recommending supplementsfor prevention?

Systematic Review for fracture prevention: Conflicting Results

• 25 RCTs of vitamin D with fracture outcomes

• Heterogeneity: Population

– Average age 53 to 85 years

– Nursing homes versus community

– Prior hip fracture versus no prior fractures

• Heterogeneity: Treatment

– 300 to 500,000 IU D2 or D3

– Daily to annually

– With or without calcium

Best Early Trial: Benefit!

• Chapuy NEJM 2002

– 3270 women in 180 nursing homes in France

– Daily 800 IU D3 + 1200 mg calcium versus placebo

– Hip fractures

• 5% versus 7%, p = 0.004

– Non-vertebral fracture

• 10% versus 13%, p < 0.001

Most Recent Trial: Harm!

• Sanders JAMA 2010: The VITAL D trial

– 2256 women ≥ 70 years in Australia with risk factors for hip fracture

– Annual 500,000 IU D3 without calcium. (~1400 IU/d)

– Falls: 15% increase with vitamin D (p = 0.03)

– Fractures: 26% increase (p = 0.047)

Why The Variation?

• Significant contributors

– Calcium supplementation with vitamin D

• Not significant

– Age, sex, baseline vitamin D level

– Vitamin D type, dose, frequency

– Calcium for control group

** Note: All of the studies that included calcium

used daily dosing of vitamin D

Vitamin D and Fractures

• Daily vitamin D plus calcium reduces fracture risk

– 18% for hip fractures

– 14% for all fractures

• Greater absolute benefit in high risk groups

– Age > 70 years

– Prior fracture

– Low baseline intake

• Harms are uncommon, though recent concerns about calcium supplementation and heart disease

Harms of Vitamin D ± Calcium

• Slight excess of hypercalcemia, constipation

– Approximately 1% more in vitamin D group

• Significant increase in kidney stones over 7 years

– 2.5% versus 2.1% (HR 1.17, 95% CI 1.02 to 1.34) in WHI

• Non-significant trend towards fewer deaths

– In WHI: 63 fewer deaths, 68 more kidney stones

Vitamin D: The New Panacea

• Reduces the following diseases...

– Cancer (Colon, Breast, Prostate, Pancreatic, ...)

– Cardiovascular disease

– Multiple sclerosis, Type 1 DM, RA

– Influenza and URIs

– Chronic pain

– Total Mortality!

Melamed, M. L. et al. Arch Intern Med 2008;168:1629-1637.

Serum 25-hydroxyvitamin D and all-cause mortality in13,331 NHANES 3 participants

Meta-analysis of D and Total Mortality

• 24 randomized trials, n = 88,097

– 87% female

– Median age 70

• Vitamin D alone did not affect mortality

• Vitamin D + calcium reduced total mortality 9% (95% CI 2% to 16%)

• NNT = 151 over 3 yearsRejnmark, JCEM, August 2012

Copyright restrictions may apply.

Ginde, A. A. et al. Arch Intern Med 2009;169:384-390.

Upper Respiratory Tract Infection By Serum 25-hydroxyvitamin D Level And Season

RCT: VIDARIS Trial, JAMA, October 2012

• 322 healthy adults in New Zealand

• 100,000 IU D3 monthly

• 18 months follow-up

25(OH) D URI incidence

Vitamin D 48 ng/mL 3.7 infections/person

Placebo 25 ng/mL 3.7 infections/person

What About Calcium?

Calcium Does a Lot!

• Ion transport across cell membranes

–Nerve transmission

–Muscle contraction (including the heart)

• Blood pressure regulation

• Blood clotting

• Secretion of hormones, digestive enzymes, neurotransmitters

• Activation of many cellular enzymes

IOM Report Calcium Recommendations

DRI – Adequate Intake

Adolescents: 1300 mg/day

Women and men (19-50 years): 1000 mg/day

Women and men (>50 years): 1200 mg/day

Current intake levels:

Women: ~1/3 of their recommended intake

Men: ~3/4 of their recommended intake

Tolerable Upper Intake Level: 2500 mg/day

Yet Another Caveat

• 1000 mg calcium supplement may be too much: 24% increase MI (p=.004), 15% increase MI or Stroke (p=.009)

Vitamin D and Calcium Take Home Points

• Vitamin D insufficiency is common

• 25 OH vitamin D is a predictor of bone health in terms of fracture risk and risk of falls

• Target frail, older patients

• 800 IU of vitamin D3 per day is sufficient

– Ensure adequate calcium intake

• Testing is expensive and unnecessary

• Evidence is weak for other diseases

OMEGA 3 FATTY ACIDSA fishy story…

Epidemiology

• Sinclair 1944: CHD rare in Greenland Eskimos despite a high fat diet with few vegetables, fruits, or complex carbohydrates

Omega-3 Fatty Acids: Observations

• Oily, cold water fish = best sources of Ω-3 fatty acids–EPA = eicosapentanoic acid–DHA = docosahexanoic acid

• People who consume fish rich in EPA and DHA have fewer fatal and non fatal CV events

• 1-2 servings/week fish associated with 36% less risk of CV death and 17% less total mortality

How Much Should I Consume?

American Heart Association 2003 Guidelines

• Healthy people:

–At least 2 servings of fish/week AND plant-based sources of Ω-3’s

• People with CAD:

–1 gram of EPA + DHA/day

Randomized trials of Ω-3s in heart disease

• GISSI-Prevention: Lancet 1999

– 11,323 patients within 3 months of MI

– 1 gram EPA + DHA

– 21% reduction total mortality

– 45% reduction in sudden death

• 2010: 5 studies. NEJM, Circ, JAMA, BMJ

– Not even a trend towards benefit for post-MI, CVD or atrial fibrillation

• Intubated with acute lung injury: JAMA 2011

– Harm: 3 extra days in ICU, trend - more death (p=0.054)

2012 Meta-analysis of RCTs

• 14 RCTs: 20,485 patients with CVD

• 0.4 to 4.8 g/day omega-3 fatty acids

• 1-5 years of follow-up, mean 2 years

• No significant reduction in

– All-cause mortality

– Sudden cardiac death

– Major cardiovascular events

Kwak, Archives IM, 2012

Since meta-analysis

• ORIGIN trial: RCT in NEJM 6/11/12

– 12,536 patients with DM or high sugar

– 1 g daily of omega-3 x 6.2 years

– NO reduction in death, CVD events

• Risk and Prevention Trial: NEJM May 2013

– 12,513 patients at high risk for CVD

– 1 g daily of omega-3 x 5 years

– NO reduction in death, CVD events

Summary Omega-3 FA / Fish oil

• No benefit in modern era of medical therapy for vascular disease

• No significant harms: trend towards fewer deaths in most trials

We Evolved to Eat REAL Food

• When nutrients are isolated from whole foods, they don’t always act the same

≠

Dietary studies: Randomized

• RCT Mediterranean diet vs. low fat

– Spain, 7500 people, 5 years FU

– Enriched for olive oil or nuts

– 30% reduction in CVD events

• Recommend: fruits, vegetables, legumes, tomato sauce, fish, wine

• Discourage: sodas, sweets, pastries, red and processed meats.

Estruch, NEJM, 2013

Dietary studies: Observational

• Adventist Health Study 2

–73,000 participants; 2570 deaths

–5.8 years follow-up

• Compare: vegans, pesco-; lacto-ovo-; and semi-vegetarians to non-vegetariants

• Outcome: lowest mortality in pesco-vegetarians and vegans (15-20%).

Orlich, JAMA IM, 2013

Summary

• Beta-carotene Discourage - harmful

• Vitamin E Discourage - harmful

• Folate For child-bearing age to prevent neural tube defects

• Vit D + calcium Older, frail patients to prevent fractures & falls

• Omega-3s No benefit

Michael Pollan’s Recommendations

• Eat real food

• Not too much

• Mostly plants

• Some fish

QUESTIONS?Thank you!

If I Decide to Take a Supplement,How Can I Find a Quality Product?

Use Information from Independent Testing Laboratories

• ConsumerLab.com

Look for a “Seal of Approval” Learn As Much As You Can

• Office of Dietary Supplements http://ods.od.nih.gov

• Medline: CAM on PubMed

• Natural Standard database ($)

www.naturalstandard.com

The final word

“Vitamins taken in excess of the dose required to prevent deficiency states have not improved our patients’ health and may harm them. We should recommend therapies to prevent disease in healthy patients only when randomized trials unequivocally demonstrate that net benefits outweigh net harms, and we should continue to emphasize the importance of a nutritious diet, regular physical activity, and no smoking as the best ways to optimize health.”

Tice, JA. Archives IM, 2010.

Observational studies: Healthy user effect

• Vitamin supplement users have healthier lifestyles:

– More educated

– More physically active

– More likely to eat a healthy diet

– Thinner

– Less likely to smoke

– Less likely to have diabetes

– Have lower blood pressure

New Developments in Osteoporosis

Eliseo J. Pérez-Stable MDProfessor of Medicine

Division of General Internal MedicineDepartment of Medicine

July 4, 2013

Declaration of full disclosure: No conflict of interest

What’s New in Osteoporosis

• Absolute risk

• Under-recognition

• Poor medication adherence

• When to stop bisphosphonates

• New treatments

55 year old woman for routine visit, what do you ask and do about bone health?

A) Screening DxA of hip and spine

B) Screening DxA of hip only

C) Recommend calcium and vitamin D supplements

D) Ask about family history, alcohol, smoking, get BMI and check Vitamin D

E) Defer until age 60 or 65

What Would You Do? Mrs. C…

• 66 WF recently moved to Switzerland. No previous fracture. Sister had breast cancer, 3 drinks/d, healthy. No meds. Exam normal.

• About 5’7” and weighs 130

• Hip BMD T-score -2.2

• No contraindication to treatment

• What tests would you order? How would you manage her?

Osteoporosis in a Nutshell

• What is it?

• Risk factors

• Evaluation

• Treatments–Efficacy of available agents–New side effects and clinical

implications

What is Osteoporosis?

• In adults, bone is constantly removed and replaced

• Osteoporosis is loss of mineral and structural integrity with resulting fragility

• Fractures common in older individuals

What About Trauma?

• Even non-osteoporotic bone will fracture with extreme trauma

• There is no threshold for skeletal fragility

• The weaker the bone the less trauma required to fracture…

Traditional Risk Factors for Fracture

• The Big Three: Older age, Postmenopausal woman, and Caucasian/East Asian race

• Other important risk factors- Family history of fracture- Low body weight (<127 lbs. in women) - Smoker, >3 drinks/d- Certain drugs (steroids, PPIs) and diseases- Previous fracture (especially hip or spine)

• Measurement of bone mineral density (BMD) strongly predicts fracture

Bone Mineral Density (DXA)Interpretation of DXA Scans: Really Confusing

• Absolute mineral (calcium) content using x-rays

• Relative to young adult reference population

• T-score is the number of standard deviations above or below average 30 year old–T greater than -1.0 = “normal”–T between -1.0 and -2.5 = “osteopenia” (now

called “low bone mass”)–T less than -2.5 = “osteoporosis”

• Large studies show low BMD increases fractures risk in both women and men

BMD Tertile and Risk Factors

Cummings et al., NEJM 332(12):767-773, 1995

Who Should Have a DXA?

• Guidelines for general population*

–All women > 65 y or older

–Postmenopausal with fracture, family history, smoker, weight <127 lbs, certain medications

–Women <65 y with fracture risk equal to 65 y old White woman

• Usually covered by insurance (Medicare: pays $128)

Revised 2013 National Osteoporosis Foundation Guidelines

Hip BMD and Fracture Risk at Age 50

Hip fracture risk

T-score 5 year Lifetime

> -1 <1% 10%

-1 to -2 1% 16%

-2 to -3 1% 27%

< -3 2% 41%

Hip BMD and Fracture Risk at Age 70

Hip fracture risk

T-score 5 year Lifetime

> -1 1% 4%

-1 to -2 1% 8%

-2 to -3 4% 16%

< -3 9% 29%

http://www.shef.ac.uk/FRAX/tool.jsp

Calculating Absolute Fracture Risk: FRAXTreatment Threshold Concept

80

AGE

70

60

50

Current treatment threshold based on T-score

Treatment threshold concept based on WHO Absolute Fracture Risk

Adapted from JA Kanis et al, Osteoporos Int. 2001;12:989-995

What About Interval Screening?

• Recommendations of q 2 y as interval to measure change

• No evidence based guidelines

• 4597 women in Study of Osteoporosis Fractures: BMD baseline, 2, 6, 10, 16 y

• Estimated interval to transition from normal to low bone mass, to osteoporosis

Risk of Osteoporosis in 15 years by BMD Result at Age 65 (NEJM 2012; 366: 225-33)

BMD ResultFemoral Neck

Risk of Osteoporosis

Time to 10% BMD <–2.5

Normal > –1.0

0.8% 16.8 y

Mild OsteopeniaT = –1.01 to –1.49

4.6% 17.3 y

Moderate OsteopeniaT = –1.50 to –1.99

20.9% 4.7 y

Advanced OsteopeniaT = –2.00 to –2.49

62.3% 1.1 y

Implications for Screening

• BMD results of more than –1.49 at age 65 can defer repeat screening to age 80

• BMD results of–1.50 to –1.99 at age 65 can merits repeat screening BMD at 5 years

• BMD results –2.00 to –2.49 may need rescreening at 2 years

• Caution: 49% original SOF sample had osteoporosis

Gourlay ML, et al. NEJM 2012; 366: 225-33

Under Recognition of Osteoporosis

• Among women with fracture or BMD T < –2.5 only 20-30% are evaluated and treated!

• 12 months after hip fracture at the VA: 2% had DXA, 15% treated with appropriate drug

• Implications for providers: Ask about fracture history, note vertebral fractures, use chart reminders for DXA

Soloman, Mayo Clin Proc, 2005Shibli-Rahhal, Osteo Internat, 2011

Medical Work-up: Opinion, Little Data

A reasonable start:–Vitamin D (25-OH, not 1,25-OH) –Serum calcium, kidney, TSH

• Additional tests to consider:–Sprue serology, SPEP, UEP

• Unlikely to help: PTH, urine calcium

Jamal et al, Osteo Inter, 2005

Summary: Osteoporosis Risk Factors and Evaluation

• Osteoporosis is silent until something bad happens: Under recognized

• Routine assessment of risk factors and screening DXA. Extensive lab testing wasteful.

• Everyone should receive lifestyle and nutritional counseling

• Calculation of absolute risk (FRAX) at www.NOF.org helps clinicians/ patients

Who Should Be Treated*?• Preventive measures for everyone:

adequate calcium and vitamin D in diet, exercise, no tobacco, limit alcohol

• When to offer pharmacologic therapy:

–Anyone with hip or vertebral fracture

–T-score ≤–2.5 in femoral neck, hip, or spine

–“Low bone mass” and 10-year fracture risk ≥ 20% or hip fracture risk ≥ 3%

*Revised 2013 National Osteoporosis Foundation Guidelines

Mrs. C

What Can Be Done To Prevent Osteoporosis?Non-pharmacologic Interventions

• Smoking cessation, avoid alcohol abuse

• Physical activity: modest transient effect on BMD but reduces fracture risk

• Conflicting data on hip protector pads (adherence is big problem)

• Calcium and vitamin D

Calcium and Vitamin D

• Chapuy, 1992– Elderly women in long-

term care– 30% decrease in hip

fracture

• Porthouse, 2005:

– Independent women >70 with 1+ risk factor

– No benefit on hip or other fractures

Chapuy, NEJM, 1992

• Pooled studies: 12% fewer fractures together, little benefit alone

News Flash: Calcium Kills!!!

• Pooled 15 calcium trials: cardiovascular events up 30% – Not 1° endpoint; trials with vitamin D excluded– Calcium + vitamin D in WHI did not increase risk

• Pool calcium + D trials? Similar but only after excluding those taking personal calcium supplements in WHI

• Little supporting scientific data – No effect on other surrogates (coronary calcium on CT)– Dietary calcium not implicated in German study

• The weight of the evidence is insufficient to conclude that calcium supplements cause adverse CV events

Bolland, BMJ, 2010, 2011Bockman, ASBMR, 2010

How Much Is Enough for Skeletal Health? The Institute of Medicine

• Calcium– 1200 mg/d for women >50, men >70

• Vitamin D–Recommends daily intake 600-800 IU/d,

no more than 4,000/d–Recommends serum levels 20-50 ng/ml–Non-skeletal benefits not established,

harms minimized

IOM Report, 2010

US Preventive Task Force Recommendations

• Insufficient evidence to assess risks/benefits for daily supplementation with calcium >1000 mg/d and vitamin D3 400 IU

• Recommends against daily supplements of Vitamin D 400 IU or less and calcium 1000 mg or less to prevent fractures

• Vitamin D supplements effective in preventing fractures in ≥65 y at risk of falls

Moyer VA, USPTF, Ann Intern Med 2013; 691-6

Bisphosphonates• Bind to bone and prevent absorption and remodeling

–Resides in bone for decades

• Four approved agents: alendronate, risedronate, ibandronate, and zoledronic acid– No head-to-head fracture studies

• What we know: fracture risk reduced 30-50% if – Existing vertebral fracture OR– Low BMD (T-score < -2.5)

• May not be as useful if higher BMD (“osteopenia”)

Effect of Alendronate on Non-spine Fracture Depends on Baseline BMD

Baseline hip BMD

Overall

T < -2.5

T -2.0 – -2.5

T -1.5 – -2.0

0.1 1 10Relative Hazard (± 95% CI)

0.86 (0.73, 1.01)

0.69 (0.53, 0.88)

0.97 (0.72, 1.29)

1.06 (0.77, 1.46)

Cummings, Jama, 1998

Risedronate HIP Study: Two Groups

Group 1

• 5445 age <80; hip BMD T-score < -3.0

• 39% decreased hip fracture risk

Group 2

• 3886 age >80; risk factors for hip fx

• No significant effect on hip fracture riskMcClung, NEJM, 2001

Adherence with Bisphosphonates is Poor

• Burdensome oral administration (fasting, remain upright for 30 minutes)

• Upset stomach and heartburn can occur

• 50-60% persistence after one year with daily dosing–Similar to other preventative tx–Multiple practice settings

• Likely better with weekly, monthly and yearly (intravenous) administration

Bisphosponates Once-a-week

• Identical effects on BMD

• Possibly fewer effects on esophagus

• No fracture trials

Schnitzer, Aging, 20

Alendronate: Daily vs. WeeklyAlendronate: Daily vs. Weekly

Does Dosing Interval Matter?

• Poor quality data:– Daily to weekly may improve compliance– Weekly to monthly may not

• Yearly dosing now available: zolendronate–Extremely potent bisphosphonate–3 year, multicenter controlled trial–7741 women 55-89, T-score <-2.5 or < -1

+ vertebral fracture–Zolendronate 5mg IV once/yr vs. placebo

Black et al, NEJM, 2007

A New Side Effect of Potent Bisphosphonates? Osteonecrosis of the Jaw

• Associated with potent bisphosphonate use:

–94% treated with IV bisphosphonates

–4% of cases have OP, most have cancer

–60% caused by tooth extraction. Other risk factors unknown. Infection?

• Key points: extremely rare, early identification, conservative treatment

• Dental exam recommended before Rx, but no need to stop for dental procedures

Atypical Subtrochanteric Fractures?

• Rare case reports in long-term bisphosphonate users (and others)

• Transverse not spiral, cortical thickening, minimal trauma

• Often bilateral, preceding pain, abnormal x-ray or bone scan

• ASBMR Task Force (2011)

“Causation not established”“Risk factors uncertain”“Mechanism unknown”

How Long to Use Bisphosphonates?

• Prolonged use (decades) common

• Long half-life suggests that life-long treatment is not always necessary

• What happens when you stop?

• FIT Long-term Extension (FLEX) study– Women given ALN in FIT for 5 yr.– Randomized to ALN or PBO for 5 yr.

Black; Jama, 2006

FLEX Change in Hip BMD: % Change from FIT Baseline

= Placebo= ALN (Pooled 5 mg and 10 mg groups)

0

1

2

3

4

5

6

F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5

Mea

n P

erc

ent

Ch

ang

e

Year

2%

Start of FLEX

P<0.001 ALN vs PBO

FIT FLEX

New Fractures During FLEX

ALN (N = 662) RR (95% CI)

3%

19%

2%

1.1 (0.5, 2.3)

1.0 (0.8, 1.4)

0.5 (0.2, 0.8)

3%Hip

20%Any

5%

PBO (N = 437)

10% 0.9 (0.6, 1.2)11%Any

Vertebral

Non-spine

Painful

FDA View of Long-term Bisphosphonate Use (Sept. 2011)

• Independent review of epidemiologic studies to date and all bisphosphonate trial data…

• After 5 years of treatment, fracture benefit less certain

• Regarding side effects

–Atypical fractures: “conflicting results…causality uncertain” “no agreement on effects of duration or cumulative dose”

–ONJ: “some evidence that risk increases after 4 yr.” “causality not established”

Discontinuation of Bisphosphonates After 3-5 Years?

• NOF recommendation for clinical reassessment after 3-5 years of use

• Driven by lack of non-spine fracture benefit after 5 yr and accumulating evidence of harm even if small risk

• No pharmacologic therapy should be considered indefinite

• Decisions need to be individualized

Implications of Bisphosphonate Trials

• Bisphosphonates reduce risk of spine, hip and non-spine fracture in women with existing spine fracture or low BMD (T-score < -2.5)

• May not reduce risk of non-spine fracture in women without spine fracture or BMD < -2.5, even if at high risk.

• Intermittent dosing, even yearly, effective

• Best data of any approved treatment

• After 5 years of treatment, some may stop–BMD >-2.5 and no hip or vertebral fractures

Other Anti-resorptive Agents

• Less effective than bisphosphonates

–Calcitonin (poor quality studies)

–Raloxifene (prevents vertebral fractures only; use for breast cancer prevention)

• Hormone replacement: WHI benefits

• Denosumab (antibody to RANKL)

Women’s Health Initiative• RCT of ERT, PERT or PBO among women age

50-79, 10,739 with hysterectomy. Primary prevention

• PERT, ERT arms stopped after 5-7 years

– Follow-up 93% complete

• Fracture Endpoints: ERT vs. PBO

– Hip RR = 0.61 (0.41, 0.91)

– Non-spine RR = 0.70 (0.63, 0.79)

– CVD RR = 1.12 (1.01, 1.24 WHI Writing Group, Jama, 200

The Future: Anabolic AgentsNeer, NEJM, 2001

• Most treatments for osteoporosis inhibit bone resorption (and formation)

• Anabolic agents (anabolic steroids, fluoride, intermittent parathyroid hormone) stimulate formation

• Daily injections of PTH for 18 mo. reduces vertebral and non-spine fracture. No hip fracture data.

• Should be followed by bisphosphonate therapy

• Very expensive, daily self-administered injections...– Use with severe OP, when other agents have failed?

Summary of Treatment

• Bisphosphonates: treatment of choice in selected individuals: Spine/hip fracture or T<-2.5. Benefit for others less clear.

• Duration of therapy? 3-5 years then off?

• Other agents available but expensive and unclear when to use

• New diagnostic tests and better treatments on the way…

Take Home Points• Absolute risk estimates help with decisions

• Aggressive screening and treatment = fewer fractures; start for all women by 65 yrs

• Interval screening defined by baseline BMD

• Identify those who have already have the disease!

• Bisphosphonates: treatment of choice– Use for spine/hip fracture or T< – 2.5– Adherence counseling. Intermittent dosing.– Duration of therapy? 5 years then off?

1

Abnormal Uterine Bleeding:Evaluation of Premenopausal Women

Vanessa Jacoby, MD, MASAssistant Professor

Ob, Gyn, & Reproductive SciencesUCSF

Objectives

• Define normal and abnormal menstrual bleeding

• Review differential diagnosis and evaluation for abnormal bleeding in premenopausal women

• Recommend guidelines for the use of endometrial biopsy

Normal Uterine Bleeding

Classically…

• Cycle length 21 to 35 days

• Menses 2-7 days

• Less than 80 cc per cycle

The Menstrual Cycle

2

Case 1

A 24 year old G0 presents with heavy irregular bleeding for 6 months. Her bleeding is every 15-35 days, lasts 4-15 days.

She has…

A. Menorrhagia

B. Dysfunctional uterine bleeding (DUB)

C. Menometrorrhagia

Classic Definitions

Excess Bleeding• Menorrhagia: heavy, regular timing• Metrorrhagia: light, frequent intervals• Menometrorrhagia: heavy, frequent, irregular• Polymenorrhea: regular, <24 days apart• Intermenstrual spotting: bleeding between menses

Decreased bleeding• Oligomenorrhea: bleeding >35 days apart

Dysfunctional Uterine Bleeding

• Excessive noncyclic bleeding not caused by anatomic lesion, medications, pregnancy or systemic disease

• Primarily due to anovulation

Challenges with Classic Definitions

• Data is from women in Minnesota, 1930s

• Lack of uniformity across clinical settings

Treloar EA, Boynton, Int J Fertil 1967

Hallberg L, Hogdahl AM et al, Acta Obstet Gynecol Scand 1966

3

Challenges with Classic Definitions

• International meeting of experts 2007 (Menstrual Agreement Process)

• Recommendations:– Discontinue use of classic terms– Use descriptive terms that patients

understand– Create uniformity for research

Fraser I, Critchley H, et al Fertil Steril 2007

New Descriptive Terms for AUB

Clinical Dimensions Descriptive Terms Normal limits (5th to 95th percentiles)

FREQUENCY (days)Frequent

Normal

Infrequent

<24

24-38

>38

REGULARITY Cycle to cycle variation over

1 year

Absent

Regular

Irregular

-

Variation +2-20 days

Variation >20 days

DURATION (days)Prolonged

Normal

Shortened

>8

4.5-8

<4.5

VOLUME (monthly mL)Heavy

Normal

Light

>80

5-80

<5

Fraser I, Critchley H, et al Fertil Steril 2007

Case 2

A 33 yo G1P1 with regular, normal periods but three months of light spotting in between periods. Spotting is 5-9 days a month, randomly distributed between cycles. She uses a copper IUD for contraception.

What is the differential diagnosis?

Evaluation: premenopausal women

Four steps:

1) Is it uterine?

2) Is she pregnant?

3) Describe the bleeding.

4) Is it ovulatory?

4

FIGO Classification: PALM-COEIN

– Fraser I, Hilary OD, et al Fertil Steril 2007

Munro et al, Fertil Steril 2011;95:2204–8


Four steps:

1) Is it uterine?• Detailed history to r/o GI/GU sources

• Exam to r/o obvious vulvar, vaginal, cervical lesions

• Up to date Pap smear

Case 2

During the pelvic exam, the patient is noted to have a 2cm cervical polyp which is removed in the office. She has full resolution of her bleeding at 6 week follow-up.


Four steps:

1) Is it uterine?

2) Is she pregnant?Check pregnancy test in at-risk women

5

Case 3

A 41 yo G3P2 with 4 months of abnormal bleeding. Regular cycle length every 29-32 days, lasts 7 days, but bleeding is heavy. She changes a tampon every hour for the first 3 days and has to get up at night to change tampons/pads.


Four steps:

1) Is it uterine?

2) Is she pregnant?

3) Describe the bleeding.• Detailed history will guide w/u and treatment

• Consider menstrual calendar X 2-3 cycles

Tips to assess bleeding history

Factors associated with heavy bleeding:

1. Bleeding history (but only 34% with “heavy bleeding” had EBL >80cc)

2 Change pads/tampons <3 hour intervals

3. High number of pads/tampons per cycle (>21)

4. Require change of tampon/pad during night

5. Have clots >1 inch

Warner, Critchley et al, Am Jo Obstet Gynecol, 2004

Case 3


Bleeding is REGULAR in timing and duration but HEAVY volume (menorrhagia).

6


Four steps:

1) Is it uterine?

2) Is she pregnant?

3) Describe the bleeding.

4) Is it ovulatory?– Regular intervals

• Moliminal symptoms

Classic Definitions

Ovulatory• Menorrhagia: heavy, regular timing• Polymenorrhea: regular, <24 days apart• Intermenstrual spotting: bleeding between regular

mensesAnovulatory• Metrorrhagia: light, frequent intervals • Menometrorrhagia: heavy, frequent, irregular • Oligomenorrhea: bleeding >35 days apart• Intermenstrual spotting: bleeding between menses

Ovulatory AUB

Hypothalamic-pituitary-ovarian axis intact

GnRH

Ovulatory AUB: Differential Diagnosis

OVULATORYAUB

AnatomicBleeding disorder/

MedicationIdiopathic

FibroidsAdenomyosis

Polyps

VonWillibrandsITP

Coumadin

7

Ovulatory AUB: History

• Medical comorbidities

• Medications

• Thyroid symptoms (see Thyroid slides)

• Disorder of hemostasis

– Heavy menses since menarche OR

– History of postpartum hemorrhage, bleeding with surgery/dental work OR

– 2 or more of the following---bruising >5cm or epistaxis 1-2/month, frequent gum bleeding, family history of bleeding

Kouides P, Conrad J, et al, Fertil Steril 2005

Ovulatory AUB: Physical exam

Fibroids Adenomyosis

Ovulatory AUB: Blood tests

• CBC, TSH

• Screen for disorders of hemostasis according to history or if pt plans major surgery

– PT, APTT

– VWF antigen, ristocetin cofactor, factor VIII

Kouides P, Conrad J, et al, Fertil Steril 2005

Ovulatory AUB: Imaging Options

• Pelvic ultrasound vs. MRI

• In 108 premenopausal women with ovulatory AUB scheduled for hysterectomy: *both performed well for fibroid detection

*MRI better for exact fibroid location

DETECTION OF FIBROIDS

Pelvic Ultrasound Pelvic MRI

Sensitivity (%) 99 99

Specificity (%) 91 86

Positive predictive value (%) 96 92

Negative predictive value (%)

97 97

Dueholm, et al, Am J Obstet Gynecol:2002

8

Ovulatory AUB: Imaging Options

Overall evaluation of endometrial cavity:MRI, Hysterosalpingogram (HSG), hysteroscopy superior to US

Endomterial polyps: HSG and hysteroscopy superior to MRI and US

Submucosal fibroids: MRI superior to all

EVALUATION OF UTERINE CAVITY MORPHOLOGY

Pelvic Ultrasound

Pelvic MRI HSG Hysteroscopy

Sensitivity (%) 69 76 83 84

Specificity (%) 83 92 90 88

PPV(%) 71 86 85 80

NPV (%) 82 86 89 91

Dueholm, et al, Fert Sterility, August 2001

Case 3


Bleeding is REGULAR in timing and duration but HEAVY volume (menorrhagia).

• No PMH

• No medications

• Exam: nl size uterus

• Hct 29

Submucosal Fibroid: Ultrasound vs. MRI

Ovulatory AUB: Treatment

SURGICAL MEDICAL

Endometrial Ablation NSAID

Hysterectomy Tranexamic Acid

FibroidsMyomectomyUterine Artery Embolization

Hormonal contraceptionCyclic progestinLNG-IUD (more effective than other hormonal treatment or NSAIDs)

GnRH agonistsMifepristone (fibroids)

Proven benefit in randomized trials:

No randomized trials to date: SURGICAL MEDICAL

MR Guided Focused Ultrasound

Myolysis

9

Ovulatory AUB: Medicine vs. Surgery

In meta-analysis of 12 randomized trials (n=1,049 women):

-- 58% of “medical management” group had undergone surgery

within 2 years.

– Surgery (hysterectomy or endometrial ablation) decreased

bleeding more than oral medication.

– LNG-IUD comparable to surgery for improvement in quality of life.

Marjoribanks J, et al, Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2006.

Case 4: Ovulatory bleeding

49 yo G2P2 with 5 months of heavy bleeding. Regular cycle length and duration, but heavy bleeding resulting in significant anemia with hct of 25%.

Does she need an endometrial biopsy?

1) Yes

2) No

Case 5: Anovulatory bleeding

38 yo G2P2 with 5 months of irregular bleeding. Bleeding is every 2-3 weeks, lasts 5-12 days, and heavy. Has to change tampon every 1-2 hours for the first few days.

Does she need an endometrial biopsy?1) Yes2) No

Endometrial Biopsy

Endometrial Cancer Facts

• 4th most common cancer in

women (2.5% lifetime risk)

• Average age 61 but 25%

occur pre-menopausally

• Rare to have cancer without abnormal bleeding

• Risk factors: unopposed estrogen (anovulation),

obesity, nulliparity, diabetes, hypertension

10

ACOG guideline

“…based on age alone, endometrial

assessment to exclude cancer is

indicated in any woman older than 35

years who is suspected of having

anovulatory uterine bleeding.”

ACOG guideline July 2012

“Endometrial sampling should be

performed in patients with AUB who are

>45 years as a first-line test.....and <45

years with a history of unopposed

estrogen exposure, failed medical

management, and persistent AUB”

ACOG Practice Bulletin, Number 128, July 2012

Normal Perimenopause

•12% suddenly stop menstruating

•18% have longer, heavier menses

•70% have short, irregular menses

Should we perform EMB on 88% of

perimenopausal women?

Treloar EA, Boynton, Int J Fertil 1967Hallberg L, Hogdahl AM et al, Acta Obstet Gynecol Scand 1966

Suggested guidelines for performingendometrial biopsy

Premenopausal, age >45 years:

– Heavy, irregular bleeding:

– Risk factors for cancer:

– Perimenopausal infrequent/scant bleeding:

– Regular bleeding pattern:

YES

YES

NO

NO

ACOG guideline: Level C evidence (not studies, consensus and expert opinion)

11

AUB: Thyroid disorders

HYPERthyroid HYPOthyroid

Frequency of abnormal cycles

21% 23%

Oligo/amenorrhea 63% 55%

Heavy bleeding 37% 30%

•Consider checking TSH in women with any type of AUB

•Check TSH/Free T4 if suspect hypothalmic/pituitary lesion to detect central hypothyroidism

Krassas, G, Fertil Steril 2000


A 24 yo G0 with 8 months abnormal bleeding. Bleeding is every 10-45 days, lasts 5-20 days, heavy for most days of bleeding. BMI 33.


Four steps:1) Is it uterine? YES.2) Is she pregnant?

Upreg neg.3) Describe the bleeding.

Heavy, frequent, irregular, prolonged(menometrorragia)

3) Is it ovulatory? NO.

Anovulatory AUB: Differential Diagnosis

ANOVULATORYAUB

Estrogenic(excess bleeding)

Hypoestrogenic(decreased bleeding)

12


ANOVULATORYAUB

Estrogenic

Physiologic Hyperandrogenic

AdolescencePerimenopause

PCOS, CAH, Cushings

Systemic disease/Medications

Renal or liver diseaseChronic steroids


ANOVULATORYAUB

Hypoestrogenic

Hypothalamic(stress, anorexia,

mass lesion)Hyperprolactinemia

Ovarian Failure(Premature: POF)

Miscellaneous

Ovulatory, but irregular

• Infection

Usually light/frequent bleeding

• Endometrial hyperplasia/cancer

Usually heavy/frequent

Anovulatory, iatrogenic

– Use of hormonal contraception

Anovulatory AUB: History

History (Estrogenic)• Hirsutism, other androgen excess• Medications• Chronic diseaseHistory (Hypoestrogenic)• Galactorrhea• Hot flashes, other menopausal symptoms

Physical• BMI• Hirsutism• Acanthosis nigracans

13

Anovulatory AUB: Tests and Imaging

Labs• CBC• TSH• Prolactin

– for oligomenorrhea only

• FSH – For oligomenorrhea in <40 years with menopausal symptoms

and/or no other explanation of hypoestrogenism

Androgens for PCOS if no clinical manifestations (Be aware of accuracy of free testosterone assay in your clinic)

Consider EMBImaging• Not necessary unless abnormal exam or

does not respond to treatment


A 24 yo G0 with 8 months abnormal bleeding. Bleeding is every 10-4 days,

lasts 5-20 days, heavy for most days of bleeding. BMI 33.

• No PMH. No meds.

• Removes hair from upper lip and chin every 2 weeks.

• Exam: obese, coarse dark hair upper lip, uterus/adnexa not palpable.

• Labs: Hct 30. TSH wnl.


A 24 yo G0 with 8 months abnormal bleeding. Bleeding is every 10-14

days, lasts 5-20 days, heavy for most days of bleeding. BMI 33.

• No PMH. No meds.

• Removes hair from upper lip and chin every 2 weeks.

• Exam: obese, coarse dark hair upper lip, uterus/adnexa not palpable.

• Labs: Hct 30. TSH wnl.

Diagnosis: Polycystic ovarian syndrome

Treatment: Oral contraceptives to

*decrease bleeding

*prevent hyperplasia

*decrease hirsuitism

Anovulatory AUB: Treatment

SURGICAL MEDICAL

Endometrial AblationHysterectomy

Hormonal contraceptionCyclic progestinLNG-IUD (more effective than other hormonal treatment or NSAIDs)

For estrogenic anovulatory bleeding:

For hypoestrogenic anovulatory bleeding:

SURGICAL MEDICAL

Dopamine agonists for high prolactin

Estrogen/progestinreplacement or hormonal contraception for POI

14

Summary

• Distinguish ovulatory (regular) vs. anovulatory (irregular) bleeding

• If ovulatory, likely anatomic cause– Order pelvic imaging (ultrasound vs. MRI)

– Consider surgery for long term treatment

• If anovulatory, most likely estrogenic:– Consider endometrial biopsy

– Prevent endometrial hyperplasia with progestin

1

Workshop: Case Management of Abnormal Pap Smears and Colposcopies

Rebecca Jackson, MDProfessor

Obstetrics, Gynecology & Reproductive Sciences and Epidemiology & Biostatistics

I have no financial interests to disclose.

Case Based Problems

Emphasis on 2012 guidelines by ASCCP (American Society of Colposcopy and Cervical Pathology) and how they differ from last

Changes for <25yos Who needs colposcopy vs who can be

managed expectantly? Next steps after colposcopy Treatment options: cryotherapy, laser,

LEEP and cone biopsy Post-treatment surveillance

Recommended Guidelines

ASCCP guidelines 2012– For work-up of abnormal cytology and treatment of

CIN: (or just search ASCCP guidelines)http://www.asccp.org/Portals/9/docs/Updated%20ASCCP%20

Algorithms%204%2011%2013%20-%20PDF.pdf

Rationale behind guidelines: – ObstetGynecol: 2013; 121(4); 829–846

SFGH 2010 guidelines in your syllabus (developed by Dr. George Sawaya, very similar to ASCCP but not yet updated with the new 2013 recommendations)

2

$7.00

$9.99 $9.99

Laminated cards with tabs at top so can find the algorithm you need

Either enter pt info and it gives you the recommendation and assoc algorithm OR you can simply view the algorithms

Good news: most prior guidelines reaffirmed, easier to read, guidance for no ECC’s on pap & discordant co-test results

Bad news: even more complex than prior guidelines

What’s New (2012 ASCCP)

**Extend adolescent (age <21) management guidelines to women < age 25: there are now 2 pathways for most algorithms—One for<25 and one for >25

Less aggressive w/u of ASC-US How to manage discordant cotest results: (HPV+/PapNl;

HPV-/Pap ≥ ASC-US), unsatisfactory cytology and missing endocervical or t- zone cells

Post-colpo management now includes co-testing, even in <25 yo

Treat CIN1 on ECC as CIN1 (not as +ECC)

Histology Primer

Cervical intraepithelial neoplasia (CIN)Graded based on proportion of epithelium involved

CIN 1: indicates active HPV infection; treatment discouraged since spontaneous resolution is high

CIN 2: most are treated, but about 40% resolve over 6 month period; treatment may be deferred in young women

CIN 3: the most proximal cancer precursor, also known as carcinoma in situ always treat

Adenocarcinoma in situ (AIS): widely considered a cancer precursor always treat

3

CIN 1 CIN 3

Case List

0. Pap normal, HPV positive1. ASC-US, not young2. 19yo ASC-H; CIN2 on colpo3. 78yo ASC-USx2, CIN1 on colpo4. AGC5. 22yo ASC-US/HPV+, colpo neg6. 24yo CIN3 on colpo7. 58yo CIN3, can’t r/o invasion8. 27yo positive endocervical LEEP margins CIN39. 16yo pregnant, HSIL

Case 0

A 35 yo woman has co-test result: HR-HPV positive, cytology normal.

What are next steps?

4

Pap normal, HPV positive

Remember: Use co-test only in women >30yo (b/c HPV often + in younger women and is transient)

2 options:1. Repeat co-test at 12 months.

If both negative 3yr co-test If still HPV+ or if >=AS-CUScolposcopy.

2. HPV genotype-specific typing for 16 & 18 If positive for either colposcopy. If negative repeat co-test at 12 months.

Case 1A 32 year old woman’s Pap smear comes back “AS-CUS”

What are your management options?

Repeat cyto at 1 yr (not 6 mos)OR HPV test. If Neg—cotest at 3 yrs

Case 1: AS-CUS, not adolescent3 equivalent 2 options (HPV preferred):1. Repeat cytology at 6, 12 months

Colpo if >ASC; (if negcyto in 3 yrs)

2. Immediate colpo3. Reflex HPV test (preferred)

– If negrescreen in 12 months with cytology. Cotest at 3 yrs

– If poscolposcopy * 2012 guidelines: Less aggressive w/u of AS-CUS

5

Case 2A 19 year old Go woman, sexually active since the age of 15, has a Pap smear read as “ASC-H.”

What are your management options? Although you wish she hadn’t had the pap given <21, you can’t ignore it…• ASC-H requires colpo in adults and adolescents. • HPV not helpful for triage—all get colpo.• Management after colpo differs greatly for <25yo

Case 2--continuedColposcopy is satisfactory and biopsy-proven CIN 2 is diagnosed in a single quadrant.


• Be sure to read the fine print—lots of info there• Work-up and treatment differs for <25 yo (longer surveillance

prior to treatment, less aggressive treatment options)

• Regression is common in younger women and usually occurs within 2 yrs

• Note now recommend co-test for f/u (even though it breaks the rule of no HPV co-test in <30yo)

6

Case 2: CIN 2/3 in adolescents

• Treatment (excision or ablation) OR observation

• For CIN2—observation is preferred (as long as colpo is satisfactory*) and patient is reliable (If CIN3excision/ablation)

• Colposcopy plus cytology q 6 months for 1 yr• If normal cytology x2 co-test 1 yr later, if nl, co-test

q 3yr• If colpo worsens or high grade cytology or colpo lesion

persists x 1yr repeat biopsy

• Treat only if CIN2 persists for >2 yrs

* If colpo unsatisfactory, diagnostic excisional procedure preferred

Case 3A 78 year old woman who has never had any abnormal Pap smears now has a Pap smear read as ASC-US. She has not been sexually active for over 15 years. A repeat pap in 12 months is also ASC-US.

Options?

Again, you wish she hadn’t had a pap (stop age= 65 in women with prior normals). However, can’t ignore…..

Two consecutive paps with ASC-US colpo

No difference in management of ASCUS for post-menopausal women. However, reflex HPV testing is more efficient than in younger women b/c fewer women will be referred to colposcopy

Case 3: continued

Colposcopy reveals an attenuated, flush cervix. Unsatisfactory. ECC shows CIN 1.

Management options?

7

Observation ok for CIN1 preceded by ASC-US, LSIL, HPV +.

Only treat if persists for 2 years.

HPV testing may help to avoid colpo if negative.

Case 4A 43 year old woman has a Pap smear read as AGC (atypical glandular cells)-not otherwise specified (NOS).

What is the differential diagnosis of AGC?What are your management options?

Differential diagnosis of AGC

Atypical endocervical cells Adenocarcinoma-in-situ Adenocarcinoma Squamous CIN Endometrial hyperplasia Endometrial adenocarcinoma Ovarian carcinoma

AGC needs more thorough work-up than ASC-US because underlying abnormalities are more serious and more common (40% have SIL, AIS, endometrial hyperplasia)

Colpo plus ECC plus EMB (in many)

8

Note that if initial cytology had been AGC-favor neoplasia and colpo had been negative, cone recommended as next step

Case 4 continuedPt reports occasionally irregular periods. Colposcopy is satisfactory without lesions. ECC is normal. EMB is normal.

Given it it AGC-NOS, you follow as per guidelines with co-test at 12 and 24 months

24 month pap is AGC again. Now what?

Repeat AGC: pelvic ultrasound to evaluate ovaries/tubes. If ultrasound negative, cone biopsy

Case 5An 22year old transfers care to your practice. 8 months ago, she had “ASC-US with HPV DNA test positive for a high-risk type.” She then had colposcopy at other practice, 6 mos ago, which was noted to be satisfactory with no lesions seen.

Next steps?

9

Cytology preferred for f/u AS-CUS in young women (reflex HPV testing ok)

If HPV posrepeat cytology only at 12 mos (ie shouldn’t have had colpo)

What to do when pts receive testing that was not recommended per guidelines or who are lost to f/u after abn pap and then have repeat pap nl?

In general, act on most severe abnormality. EG, If 30yo had LSIL pap then lost to f/u and has repeat nl pap, still needs colpo

In this case, can follow per guidelines after nl colpo b/c f/u is essentially the same as if she hadn’t had colpo

Case 6A 24 yo G0 woman has biopsy-proven CIN 3, a satisfactory colposcopy and a negative endocervical curettage.

What are your management options? What if the ECC were positive?

Potential adverse effects of LEEP

Preterm delivery 70% Low birth weight 82% PPROM 169%

Lancet 2006 367:489-98

No randomized trials.

Perinatal mortality 187% Severe preterm delivery 178% Extreme low birthweight 186%

BMJ 2008 Sep 18;337

Potential adverse effects of cone biopsy

10

Given ablative and excisional methods are equally efficacious, choose ablation for women desiring fertility (as long as colpo satisfactory, ECC negative and lesion <2cm and completely visible)

Case 7A 58 year old widow has a Pap smear read as ASC-US and you send a test for HPV. It is positive.

Colposcopy is unsatisfactory.ECC shows severe dysplasia (CIN 3) cannot rule out invasion.


Case 7: CIN3, can’t r/o invasion

Typically, CIN3 is treated with LEEP However, if can’t r/o invasion, cone

biopsy is indicated in order to get a pathologic specimen from which depth of invasion can be assessed

Case 8

A 29 yo with biopsy proven CIN3 had a LEEP showing CIN3 with positive endocervical margins.

What are the management options?

11

†If CIN2,3 is identified at the margins of an excisional procedure or post-procedure ECC, cytology and ECCat 4-6mo is preferred, but repeat excision is acceptable and hysterectomy is acceptable if re-excision is not feasible.

Positive LEEP margins

5 fold higher rate of recurrence compared to complete excision

High grade dz post-treatment in 18% (82% didn’t develop it) vs 3% with complete excision

Endocervical vs Ectocervical margins:– ASCCP doesn’t differentiate. – In our practice, we do ECC plus colpo in 6 mos for

positive endocervical margins, colpo only for + ectocervical margins

Repeat Excision “acceptable” ? Given 82% do not have persistent high grade dz, we advise f/u

Ghaem-Maghami, Lancet-Oncol, 2007

Case 9A 16 year old is pregnant within six months of becoming sexually active. She was late to care at 22 weeks at which time she had a Pap smear that was read as HSIL.


Case 9: pregnant, hsil

Although you wish she’d never gotten the pap, now you must act on the HSIL

In pregnancy, colpo should be done by experienced colposcopist b/c biopsy will only be done if lesion appears to be invasive cancer.

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General rules

Less is better for adolescents/<25yo (start screening later, space out surveillence, less aggressive treatment)

Don’t use HPV test in <30yo unless it is to follow colpo (possibly can decrease need for repeat colpo, if negative)

AGC is worse than ASC-US. Requires extensive work-up

Typically don’t need to treat CIN1 unless persists

Consider getting pap/path results re-read if discordant

Pearls

Make sure women have adequate education about HPV if HPV DNA testing is used

Involve women in decisions when uncertainty exists in guidelines

Stress smoking cessation Consider HIV testing for women with biopsy proven

dysplasia

Final Thoughts

Cervical cancer screening will never completely eliminate cervical cancer: must balance benefits (which occur rarely) and harms (which affect a large number of women)

Goal: optimal strategies aim to identify HPV-related abnormalities that are likely to progress to invasive cancers while avoiding treating lesions not destined to become cancerous

Additional summary from 2012 ASCCP guidelines

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Unsatisfactory or Absent endocervical cells

Unsatisfactory cytology:– No HPV done or Neg HPV: repeat cytology 2-4 mos– Pos HPV: either repeat cyto 2-4 mos or colpo– 2 conseq unsats: colpo

Cytology Neg but absent/insuff EC/TZ:– <30yo: Routine screening (don’t’ do HPV)– >30yo, no HPV: Do HPV (pap 3 yr also ok)– >30, HPV neg: routine screening– > 30 HPV pos: co-test in one year

Excision vs ablation

Excision: – CIN2+ AND unsatisfactory colpo– ECC showing CIN2+– Recurrent cin2+– Negative colpo preceded by AIS, AGC-favor

neoplasia, HSIL papx2

Ablation:– Preferred in younger women (possibly less

chance of preterm delivery)– Lesion < 2 cm and completely visible

1- Sawaya & Smith-McCune, August 2010

Guidelines for Screening for Cervical Cancer and its Precursors, 2010 San Francisco General Hospital

These are guidelines for use of cervical cytology in asymptomatic women as a screening tool for cervical cancer and its precursors. Tests performed in symptomatic women should be evaluated in clinical context. Screening guidelines do not apply to women with prior treatment of high-grade cervical dysplasia (CIN 2 or CIN 3) or cervical cancer; see other aspects of this guideline for surveillance after treatment. Age to begin screening Age 21 years; avoid screening within 3 years of

becoming sexually active and in known virgins. Interval of screening Screen every 2 years with cytology. At or after age

30 years, women with 3+ prior consecutive, normal tests may be screened every 3 years.

Age to end screening Screening may end at or after age 65 years if 3+ consecutive, normal cytology tests have been documented within the prior 10 years and there is no history of treated CIN 2, CIN 3, AIS or cervical cancer.

Special populations Pregnant women Screen as above; do not screen within 3 years of

becoming sexually active. Women with HIV infection or

immunocompromised Annual screening after 2 normal cytology tests 6 months apart in the year following initial HIV diagnosis or immunocompromised state.

After total hysterectomy in women with no prior history of CIN 2 or CIN 3

Screening should not be performed.

After total hysterectomy in women with a prior history of CIN 2 or CIN 3

Annual cytology. After 3 consecutive, normal tests, screening may be performed every 3 years.

After diagnosis and treatment of cervical cancer

Surveillance as per gynecologic oncology protocols

CIN indicates cervical intraepithelial lesion.


Guidelines for Initial Management of Abnormal Cervical Cytology, 2010 San Francisco General Hospital

Cytology Interpretation Action Common Benign Findings

Unsatisfactory Repeat cytology next available Satisfactory, but no endocervical cells Repeat cytology in 12 months Benign-appearing endometrial cells Pre-menopausal: No action. Post-menopausal: Endometrial biopsy.

Epithelial Cell Abnormalities Atypical squamous cells of

undetermined significance (ASC-US) Three different strategies may be adopted, but colposcopy is the least preferred: 1. Repeat cytology at 6 and 12 months. If ASC-US+, colposcopy. After 2 normal cytology tests, resume routine screening. 2. HPV testing for high-risk types. If positive, colposcopy. If negative, repeat cytology in one year; do not do HPV testing in women age 20 or less. 3. Colposcopy† If age 20 or less, repeat cytology at 12 months (colposcopy if ASC-H or HSIL+) and at 24 months (colposcopy if ASC-US+). If normal, resume routine screening. For pregnant women age 21+, repeat cytology at 6 months; if ASC-US+, colposcopy 6 weeks post-partum.

ASC, cannot exclude HSIL (ASC-H) Colposcopy† Low-grade SIL (LSIL) Colposcopy†

If age 20 or less, repeat cytology at 12 months (colposcopy if ASC-H or HSIL+) and at 24 months (colposcopy if ASC-US+). If normal, resume routine screening. For pregnant women age 21+, colposcopy may be deferred to 6 weeks post-partum. For post-menopausal women, LSIL may be managed identically to ASC-US.

High-grade SIL (HSIL) Colposcopy† Squamous cell carcinoma Colposcopy†

Glandular Cell Abnormalities Atypical glandular cells (AGC) • endocervical Colposcopy† with endocervical curettage (ECC) • endometrial Colposcopy† with ECC and EMB • not otherwise specified Colposcopy† with ECC; add EMB if abnormal bleeding, chronic

anovulation or age 35+ Adenocarcinoma in situ (AIS) Colposcopy† with ECC and EMB

Common Infections • shift in flora suggestive of bacterial

vaginosis (BV) Consider evaluation of and treatment for BV if symptomatic. Repeat cytology at appropriate screening interval.

• fungal organisms consistent with Candida.

Consider evaluation of and treatment for yeast vaginitis if symptomatic. Repeat cytology at appropriate screening interval.

• cellular changes consistent with herpes simplex virus (HSV)

Diagnostic of HSV. Finding may indicate other STIs. Repeat cytology at appropriate screening interval.

• Trichomonas vaginalis (TV) Consider evaluation of and treatment for TV if symptomatic. Finding may indicate other STIs. Repeat cytology at appropriate screening interval.

DEP indicates diagnostic excisional procedure (e.g., cone biopsy, loop excision). HSIL+ indicates HSIL, AGC, AIS and/or cancer. ASC-US + indicates ASC-US, ASC-H, LSIL and/or HSIL+. ECC indicates endocervical curettage. †ECC should be performed in all non-pregnant women with unsatisfactory colposcopy and in those with cytology interpreted as AGC, AIS and cancer. Vaginal colposcopy with Lugol’s solution should be performed in all women with no obvious lesion seen and cytology interpreted as HSIL, AGC, AIS or cancer. In pregnant women, ECC is contraindicated.


Guidelines for Follow-up after Initial Colposcopy, 2010 San Francisco General Hospital

These are guidelines for the most common clinical scenarios. Patients may be managed individually based on clinical judgment. Referral Cytology (pre-colposcopy)

Findings at initial colposcopy

No visible lesion Visible lesion, biopsy-proven CIN 1

Biopsy-proven CIN 2 or 3

ASC-US once Cytology in 12 months. If normal, resume routine screening; if ASC+, repeat colposcopy at the next available appointment.

ASC-US twice (unknown HPV status)

ASC-US, positive high-risk HPV Atypical squamous cells, cannot exclude HSIL (ASC-H)

Low- grade SIL (LSIL)

Cytology in 6 and 12 months. The 6-month cytology result should be managed as follows:

• If ASC or LSIL, repeat colposcopy at the next scheduled appointment (6 months). • If ASC-H or HSIL+, repeat colposcopy at the next available appointment. • If normal, repeat cytology at the next scheduled appointment (6 months); if cytology is normal at that time (i.e., at the 12-month visit), resume routine screening; if ASC+, repeat colposcopy at the next available appointment.

If colposcopy is satisfactory, ECC is normal and the vagina has no lesions, colposcopy and cytology every 6 months for 1 year is acceptable. DEP may also be performed (non-pregnant women only); review of outside cytology suggested prior to DEP.

Treatment is preferred.

High-grade SIL (HSIL)

If colposcopy is unsatisfactory, DEP is preferred (non-pregnant women only). Atypical glandular cells (AGC) Cytology in 6, 12, 18 and 24 months. Repeat colposcopy if ASC-US+. After 4 normal cytology

tests, resume routine screening. If AGC recurs, perform cone biopsy. Pelvic sonogram to rule out adnexal malignancy is recommended in women with persistent AGC.

See “Guidelines for Treatment of biopsy-proven cervical intraepithelial neoplasia (CIN) 2 (moderate dysplasia) and CIN 3 (CIS, severe dysplasia)”

Adenocarcinoma in situ, cancer Cone biopsy CIN indicates cervical intraepithelial neoplasia. SIL indicates squamous intraepithelial lesion. HSIL+ indicates HSIL, AGC, adenocarcinoma in situ and/or cancer. ASC-US + indicates ASC-US, ASC-H, LSIL and/or HSIL+. DEP indicates diagnostic excisional procedure (e.g., cone biopsy, loop excision).

Smoking cessation is advised in all patients. HIV testing should be offered in all women with biopsy-proven CIN 3.

Additional information on colposcopy by UCSF authors can be found by typing “GLOWM” and “colposcopy” into your search engine.


Guidelines for treatment of biopsy-proven cervical intraepithelial neoplasia (CIN) 2 (moderate dysplasia) and CIN 3 (CIS, severe dysplasia), 2010

San Francisco General Hospital • CIN 2 and 3 can be treated by either an ablative or an excisional procedure in non-pregnant women. • Ablative methods include laser and cryotherapy; excisional methods include loop excision and cone biopsy. • In adolescents and young women with satisfactory colposcopy, CIN 2 may be managed with colposcopy and cytology surveillance every 6 months; routine screening may resume after 2 normal cytology tests and colposcopic exams. If surveillance is chosen, CIN 2 may be followed for up to 24 months without treatment. Alternatively, ablative therapy (e.g., cryotherapy) is the preferred treatment.

Treatment Factors affecting choice Cryotherapy

Appropriate for CIN 2 or CIN 3 if following general criteria met: • Satisfactory colposcopy • No prior cervical treatment • Lesion(s) completely visible and <2 cm in diameter • Lesion(s) can be covered entirely with the cryoprobe

Laser ablation Often used for large lesions (>2 cm) with or without vaginal extension. Candidacy same as for cryotherapy.

Loop excision (aka LEEP) Choose for CIN 2 or CIN 3 lesions in which cryotherapy is inappropriate (e.g., unsatisfactory colposcopy, endocervical curettage with dysplasia).

Cone biopsy Choose instead of loop excision if suspicion for malignancy or recurrent atypical glandular cells (AGC) on cytology and/or cervical architecture disrupted.

Guidelines for follow-up after treatment of CIN 2 and CIN 3

Treatment Follow-up Cryotherapy or laser ablation Cytology in 6 and 12 months; colposcopy for ASC-US+.

After 2 normal tests, annual cytology. Loop excision (LEEP) or cone biopsy

Dysplasia in specimen, negative endocervical margin

No dysplasia in specimen

Cytology in 6 and 12 months; colposcopy for ASC-US+. After 2 normal tests, annual cytology.

Dysplasia in specimen, positive endocervical margin

Cytology and ECC in 6 months; colposcopy for ASC-US+. Then, cytology alone in 12 months; colposcopy for ASC-US+. Repeat excision if HSIL+ at any time. After 2 normal tests, annual cytology.

Hysterectomy Annual cytology. After 3 consecutive, normal tests, screening may be performed every 3 years.

ECC indicates endocervical curettage. ASC-US indicates atypical squamous cell of undetermined significance. HSIL indicates high-grade squamous intraepithelial lesion. HSIL+ indicates HSIL, AGC, adenocarcinoma in situ and/or cancer. ASC-US + indicates ASC-US, ASC-H, LSIL and/or HSIL+.

Guidelines for treatment and follow-up of adenocarcinoma in situ Treatment Follow-up

Hysterectomy (treatment of choice) Annual cytology. After 3 consecutive, normal tests, screening may be performed every 3 years.

Cone biopsy Cytology and ECC every 4 months for 2 years, then every 6 months until hysterectomy.

Smoking cessation is advised in all patients.

HIV testing should be offered in all women with biopsy-proven CIN 3.

Clinical Dilemmas in Genetic Testing

A Case-based Approach

Jeffrey A. Tice, MD

Division of General Internal MedicineUniversity of California, San Francisco I have no conflicts of interest

Definitions

• “Genetic Testing”

–Many types (full sequencing, single site, common mutations, chromosome analysis, etc.)

–Many tissues (tumors, blood, buccal mucosa)

–Not just a test, a process

–Specialty labs

• “Disease Predisposition”

–Risk is a complex issue, not “all or nothing”

–What to do with results?

4 possible cases

• Ivana Test: 24 year old, mother just diagnosed; aunt died of breast cancer “I just want the test”

• Cy Fibrosis: 28 year old with male infertility. His genetic testing for cystic fibrosis is prompting his wife to consider testing.

• Ima Clotter: Healthy 30 year old whose sister was found to carry “blood clotting genes” after several miscarriages. Not sure she wants to test, “How would it change things for me?”

• Dina Child: Healthy 36 year old woman who is pregnant and wants that new DNA test using her blood to tell her the sex of the fetus.

Ivana Test’s Family History

• Mother diagnosed last month with breast cancer

• Aunt with breast cancer was paternal, died at 45

• Eastern European

• Not close with paternal side

– Only one cousin

– Paternal grandmother died young

Three Generation Pedigree

85MI

45

22

47Breastca 65

2824

66

Breast ca 40, d45

d. 50 or so?StomachDiabetes

Breast cancer UCSF

Cancer Risk Program

d.71d.62

Three Generation Pedigree, Next Visit

85MI

45

22

47Breastca 65

2824

Prostate ca 55, Now 66

Breast ca 40, d45

d. 40OvarianDiabetes

Breast cancer

Prostate cancer UCSF

Cancer Risk Program

d.71d.82

Breast 33

Ovarian cancer

• “Cancer on the father’s side of the family doesn’t count.”

• “Ovarian cancer in the family history is not a factor in breast cancer risk.”

• “The most important thing in the family history is the number of women with breast cancer.”

Misconceptions About Family History

•Half of all women with hereditary risk inherited it from their father.•Ovarian cancer is an important indicator of hereditary risk, although it is not always present.•Age of onset of breast cancer is more important than the number of women with the disease.

© 2001 Myriad Genetic Laboratories

Genetic Counselor’s Family History

• Extensive pedigree, including cousins

• Verify cause of death, age of diagnosis and death

• Ovarian and “female” cancers often not discussed

• Ask about Jewish ancestry

• Next step is to test individual already affected with cancer

–“Genetics is a family business” ASCO

How Much Breast Cancer Is Hereditary?

Sporadic

Family clusters

Hereditary

Breast Cancer5%–10%

15%20%

Lifetime Risk of Breast Cancer by AgeBRCA1-2 Mutations Increase the Risk of

Cancer More Than Other Factors

Relative risk of breast cancer

Family history

BRCA1-2mutation

Early menarche

Late age at birth of 1st child

Benign breast

disease

Hormone replacement

therapy

Alcohol use

Cells have Two Copies of BRCA1

and BRCA2

BRCA2 BRCA1

Adapted from Tools for Understanding GeneticsNational Human Genome Research Institute

Office of Science Education and Outreachwww.nhgri.nih.gov/DIR/VIP

Each child has a 50% chance of inheriting an autosomal dominant disorder

Father withmutation on one chromosome

Autosomal Dominant Inheritance

BRCA 1 / 2 Associated Cancers:Lifetime Risk

Breast Cancer 12% 60-85%

Second Primary Breast <1% 40-50%

Ovarian Cancer 1.5%

BRCA1 - 20-40%

BRCA2 - 10-20%

General BRCA Population Population

Other cancers associated with BRCA2 mutations

Relative Risk*

• Melanoma 2.6

• Stomach 2.6

• Pancreatic 3.5

• Prostate 4.7

• Biliary tree 5.0

* Br Ca Linkage Consortium, JNCI 1999

ASCO

Features Indicating Increased Probability of BRCA Mutations

• Multiple cases of early onset breast cancer

• Ovarian cancer (with family history of breast or ovarian cancer)

• Breast and ovarian cancer in the same woman

• Bilateral breast cancer

• Male breast cancer

• Ashkenazi Jewish ancestry

Founder Mutations

General population

~ 1/500 carry BRCA mutations

Hundreds of different mutations identified

Ashkenazi Jewish population

1/40 carry one of 3 specific mutations

2 in BRCA 1 and 1 in BRCA 2

Other “founder” populations

French Canadians, Icelanders, Polish,…

Three Possible BRCA results

• Positive: Known deleterious mutation found

• Negative:

–True negative: Known mutation in family and patient doesn’t have it

–Uninformative negative: No mutation found, but family history is not explained

• Variant of Undetermined Significance: Change in DNA, but unsure whether it’s deleterious or benign

How many “uninformative negatives” are really positive?

• 300 very high risk families with “uninformative negative”results AND 4 family members with breast or ovarian cancer

• 12% had duplications (repeated words), deletions (missing word), or rearrangements (misplaced word) in BRCA1 or BRCA2

• Unclear how common these “false negatives” are in the larger population receiving BRCA testing

Walsh, JAMA 2006

What are the Options for Carriers of Mutations?

Breast Cancer

Increased and earlier surveillance

Chemoprevention

Prophylactic Mastectomy-- 90% risk reduction

Ovarian Cancer

Trans-vaginal ultrasound and CA-125 q 6 mos

Birth control pills—50% risk reduction in 5 yrs

Risk Reducing Salpingo Oophrectomy (RRSO)

Insurance Questions • Will health insurance cover testing?

– Most cover if medically indicated: Pre-authorization

• Can health insurance plans increase premiums with a positive test?

– It is illegal to change or drop coverage based on a test result; not a pre-existing condition (HIPAA)

• Are there any protections against life insurance discrimination?

– Currently, no federal laws include life insurance

Ivana Test, Conclusion

• Ivana’s father tested positive for a mutation common in the Jewish population

– Men can carry mutations in BRCA1/2

– Start with an affected individual if possible

• Ivana then tested using the Jewish panel and was negative

– A negative result is only a “true negative” when there is a positive result in the family

Cy Fibrosis’s History

• Infertility work-up showed azoospermia

• Congenital absence of vas defrens (1-2% of infertile men)

• Standard CF testing showed patient is a carrier of Delta F508

• He wants to use ICSI (intracytoplasmic sperm injection)

CF is Autosomal Recessive

Cystic Fibrosis Genetics

• CF is caused by mutations in a single large gene on chromosome 7 (codes CFTR protein)

• 250 kilobases, 1480 amino acid protein

• Wide phenotypic variation of disease

• 1998 consensus statement for screening– Family history of CF or partner’s family hx of CF

– Whites of European or AJ descent planning pregnancy or seeking prenatal care

Screen Cy’s wife? If so, how?

Ethnicity Incidence Carrier Frequency F508

White 1/3300 1/25 70%

Hispanic 1/8500 1/46 46%

AJ 1/29 30%

Black 1/15,300 1/65 48%

Native American

Zuni 1/3970 0%

Pueblo 1/1500 0%

Asian 1/32,100 1/90 30%

Cy’s wife has a “variant”

• “Variants of Undetermined Significance” (VUS) occur in over 5% of whites receiving full sequence testing, 20-40% of non-whites

• Fetus: 1/4 chance of

–Carrying VUS

–Carrying Delta F508 mutation

–No mutation/no VUS

–Mutation + VUS

Cy Fibrosis’s Messages

• In any testing process, plan for “next step”

• Use genetic counselors to counsel and provide “informed consent”

• VUS are becoming more common

–Full sequence testing becoming more common

–Testing is becoming more accepted and available in non-white populations

Ima Clotter’s Family History

• Ima is G1P1, on birth control pills, and healthy.

• After 3 miscarriages, Ima’s older sister was found to have a “double defect”

• A third sister is currently pregnant.

• Feels it’s “opened Pandora’s Box” and wonders “How will it change my care if I test?”

What is a “double defect?”

Two inherited thrombophilias

Factor V Leiden , nucleotide 1691 transition from guanine to adenine results in Arg506Gln protein

Prothrombin 20210, guanine to adenine, untranslated

MTHFR variant (C677T)

Protein C deficiency

Protein S deficiency

Risks of first venous thrombosis

Condition Relative Risk Annual Incidence

Normal 1.0 0.008

Hyperhomocysteinemia 2.5 0.02

(MTHFR C677T) 1.0

PT 20210 2.8 0.02

OCP’s 4.0 0.03

Factor V Leiden hetero 7.0 0.06

Plus OCPs 35 0.29

Factor V Leiden homo 80 0.5-1.0

Thromboembolism in Pregnant Women with Inherited Thrombophilias

Condition Probability per pregnancy

None 0.03%

Factor V Leiden 0.25%

PT 20210 0.5%

Factor V and PT 20210 4.6%

Anti-thrombin deficiency 0.4%

Gerhardt, NEJM 2000

Would testing change management?

• Indefinite anticoagulation recommended if

–2 or more spontaneous thromboses

–1 spontaneous thrombosis and-Antithrombin deficiency or antiphospholipid Ab -Life threatening or unusual site-”Double” or more defects

• Anticoagulate during pregnancy if

–Antithrombin deficiency or “double defect”

–Consider if personal or FH of thrombosis

Ima Clotter, Conclusion

• Ima is heterozygous for Factor V Leiden

– She stops OCPs

• Ima’s pregnant sister carries a “double defect”

– She is discussing anticoagulation with her OB

• Both defects are autosomal dominant

• Testing was fairly straightforward, as there were 2 genes with known mutations

Fetal Aneuploidy Detection by Maternal Plasma DNA Sampling

Cell-free fetal DNA testing

Background

Trisomy 21(Down’s)

Trisomy 18(Edwards)

Trisomy 13(Patau)

• Most common chromosome abnormality

• Prevalence increases with maternal advancing age

• 5-10% survive to 1 year

• Severe intellectual disability

• 80% die in the first year

• Severe intellectual disability in survivors

Prenatal Testing is widely used to test for chromosomal abnormalities

Prenatal Diagnostic Testing

Noninvasive tests (screening)

• Maternal serum markers interpreted in the context of maternal age

• Nuchal translucency• Tests often used in

combination

Invasive tests (diagnostic)

• Chorionic Villus Sampling (CVS)

• Amniocentesis

ACOG recommends that pregnant women be offered screening and that all should have the option of diagnostic testing

Prenatal Diagnostic Testing

• Noninvasive tests are “screen positive” or “screen negative”

- Screen negative: risk of a baby with Down syndrome is less than a predetermined level (eg <1/500)

Individualized risk scores provided

- Screen positive: Patient is offered option of CVS or amniocentesis

• Invasive tests are diagnostic

- Fetal karyotyping

- CVS performed earlier than amniocentesis

• Fetal blood found in the maternal circulation• Cell free nucleic acids more plentiful in maternal

circulation- Fetal DNA can be detected by 5th postmenstrual week- % increases with increasing gestational age

Cell-free Fetal DNA (cfDNA)

Massive Parallel Signature Sequencing (MPSS)

Directed Analysis(DANSR)

• Massive parallel sequencing random analysis of millions of cell free DNA fragments and assigns all free DNA fragments to specific chromosomes

• Number of chromosome counts compared to control values

• Directed DNA analysis selectively sequences relevant chromosomes

• Digital analysis of selected regions (DANSR)

• Uses fewer genetic fragments than MPSS

cfDNA: Potential Roles

Primary screening to replace current noninvasive tests

“Advanced”screening test

Potentially could reduce number of invasive tests and resulting loss of normal fetuses

Cannot replace diagnostic tests

Screening Test

Currently available cfDNA tests

Company LDT nameTrisomy identified Testing approach

T21(Down

Syndrome)

T18(Edwards

Syndrome)

T13(Patau

Syndrome)DANSR MPSS

AriosaDiagnostics

Harmony Prenatal Test

X X X X

Sequenom MaterniT21 X X X X

VerinataHealth

verifi prenataltest

X X X X

cfDNA: Evidence

• Eight studies evaluated cfDNa as screening for fetal aneuploidy

- 5 used MPSS

- 3 used DANSR

• Most studies were in high risk women

• Trisomies- All studies evaluated T21

- 6 studies evaluated T18

- 2 studies evaluated T13

• In all studies, true chromosome status was known

cfDNA: Evidence

Palomaki, 2011; Palomaki, 2012;

Number of fetuses with abnormal karyotypes ranged from 39 to 283 in the largest study

Bianchi Study Palomaki Study

Aneuploid fetuses 221 283

Trisomy 21 89 212

Trisomy 18 36 59

Trisomy 13 14 12Other aneuploidies 82 None

MELISSA: cfDNA Multicenter Study

• 2,882 high risk women undergoing prenatal diagnostic procedures at 60 sites

• Nested case-control- All singleton pregnancies with any abnormal karyotype- Balanced number of randomly selected euploid

pregnancies

Bianchi, 2012

522 samples (221 abnormal karyotypes*)# cases Sensitivity Specificity

Trisomy 21 89 100%

100%Trisomy 18 36 97.2%

Trisomy 13 14 78.6%

*139 other aneuploidies

cfDNA Multicenter Validation Study

• Nested case control study in cohort of 4,664 high risk pregnancies

• 212 Down Syndrome and 1,484 matched euploidpregnancies

• 98.6% sensitivity for Down Syndrome

• 0.2% false positive rate

• Testing failed in 0.8% of pregnancies

Palomaki, 2011

NICE: Prospective Cohort Study

Multi-center cohort study: 3,228 participants all undergoing prenatal diagnostic procedure for any

reason

Norton, 2012

N=3,228Number of aneuploidy

casesSensitivity Specificity

Trisomy 21 81 100% 99.97%

Trisomy 18 38 97.4% 99.93%

cfDNA: Comparative Studies

How does use of cfDNA compare with the established alternatives?

• Currently no direct evidence comparing cfDNA with established screening strategies for primary screening

• No studies have evaluated the potential role of cfDNAas a primary screening strategy

• To date studies have only evaluated high risk women using cfDNA as an advanced screening test

cfDNA: Clinical and Economic Model

• Used clinical data from MELISSA study

• Evaluated the impact of incorporating cfDNA into routine clinical care

- High risk women

- Advanced screening test

• 66% reduction in diagnostic induced miscarriages

• 38% more women receiving T21 diagnosis

• 1% overall reduction in prenatal screening and diagnostic costs

Garfield, 2012

Average risk women

• 2,049 women undergoing routine screening at 11-13 weeks gestation

• Fetal karyotyping in 86 cases

- Remainder considered phenotypically normal

• For all 8 cases of T21, the T21 Risk Score was >99%

• For 2 of the 3 cases of T18, the risk score was >99%

• cfDNA testing could not be performed on 4.9% of cases

cfDNA: Conclusions

• Promising new technology with high sensitivity and specificity for fetal aneuploidy when evaluated in high risk women

• To date, cfDNA has not been compared with current screening methods as an alternative to primary screening

• Currently no evidence to support use in average risk women

To summarize…

Why consider testing for predisposition genes?

• To identify patients not at risk despite family history - reassurance

• To identify patients at very high risk of disease

• To allow high risk patients to consider increased screening and prevention

• To assist with prenatal counseling

• To allow patient to enter screening/ prevention trials

• To provide important health info to extended family

ASCO

A Multi-Step Process: Pretest Genetic Counseling

AssessPersonal and family medical historyRisk perception and motivation for testing

EducateBasic genetics and inheritanceGenotype/phenotype disparities and risk

DiscussRisks, benefits, and limitations of testing Test procedure Alternatives to testingManagement options

ASCO

A Multi-Step Process: Post-test Genetic Counseling

ReviewEducational concepts and family historyRisk and prior probabilities

DiscloseTest results Interpretation of results

DiscussPlans for prevention and treatmentSharing results with family membersPotentially testing other family members

6/24/2013

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Chronic Pelvic Pain…..Relief for clinicians, and for patientsRebecca Jackson, MDProfessorObstetrics & GynecologyUniversity of California, San Francisco

DisclosuresI have no affiliation with any pharmaceutical companies, etc.

I will discuss off-label use of drugs.

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The Challenge of CPPFrustrated (or desperate) patients want a definitive diagnosis and treatment right nowLack of clear national guidelinesLack of understanding of CPP among GYNs (and PCP’s)Lack of understanding among pain MDs of the pelvisHigh utilization of services often without improvement in patient pain or functioning

Goals of this lectureGive you hope (and skills necessary) that you can help many women with CPPConcentrate on interconnected, multi-factorial nature of CPPHow to create a therapeutic relationshipStepwise algorithm for diagnosis AND treatmentTreatment focus: trigger points, pelvic floor dysfunction, vulvodynia, neuropathic pain

6/24/2013

2

Syllabus NoteSyllabus includes slides that will not be addressed in lecture but are included for reference

These slides are marked with “REF”

Overview of CPP

Affects physical and sexual function, and emotional well-being Severely impacts quality of life

Multiple systems interact and contribute to the pathophysiology of CPP

In many cases a direct cause of CPP cannot be identified

Increased risk of a history of abuse, depression, and anxiety, which exacerbate painful symptoms

6

What CPP patients want1. Personalized care

2. To feel understood and taken seriously

3. Explanation of the cause

4. Reassurance

Set clear expectations Ask for her goals/concerns (and acknowledge them)

Set realistic expectations: 1. Improvement in pain/function; not pain free2. You will look for conditions that can be treated, but

even if can’t make clear diagnosis, you have options to help with pain

3. This will take awhile. Multiple visits. Multiple treatment modalities

4. If she wants relief, she will have to work at it. (PT, exercises etc)

5. Visits scheduled, not during flares6. Outline next steps, but don’t be pushed into an

immediate diagnosis7. You will partner with her throughout to help her

improve8. Pain contract for opiates (if necessary)

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Differential Diagnosis!

Gynecologic Urinary tract Mental health issues(cause increased pain)

Endometriosis* Interstitial cystitis* SomatizationAdenomyosis* Recurrent UTI Substance abusePost-PID syndrome Urethral diverticulum Physical and sexual abuse, PTSDVulvodynia, vulvar vestibulitis Chronic urethral syndrome Depression, Anxiety

Pelvic adhesions (maybe?) Neoplasia Musculoskeletal Pelvic congestion (maybe?) Radiation cystitis Pelvic floor myalgia*

Ovarian remnant syndrome Gastrointestinal tract Myofascial pain (trigger point neuralgia)*

Leiomyoma (pressure) Irritable bowel syndrome* HerniaEndosalpingiosis Chronic constipation Abnormal postureNeoplasia Inflammatory bowel disease Fibromyalgia

Fallopian tubal prolapse (post-hyst) Diverticular colitis Chronic abdominal wall pain

Tuberculous salpingitis Chronic intermittent bowel obstruction Neurologic

Benign cystic mesothelioma NeoplasiaNeuralgia of pelvic/pudendal nerves* (post-surgical or ob)

Postoperative peritoneal cysts Celiac disease Herniated discNeuropathic pain (diabetes)

* Most common

Mental Health Issues

GUGIGyn Musculoskeletal

Depression, anxiety, PTSD, IPV, h/o abuse: Exacerbate painful symptoms

Primary etiology of pain can be Gyn, GI, GU or M-S

Initial insult can cause musculoskeletal dysfunction that can persist after initial insult resolves, or can feedback and make primary visceral symptoms worse

It’s all connected

Musculoskeletal

Stepwise approach to Eval & Treatment

Step 1: Address Mental HealthTreat depression if present

Counseling if h/o abuse

Step 2: Eval and treat musculo-skel issues

Step 3: Choose possible diagnosis and treat empirically

Step 4: If not improved: Consider another diagnosis/trtment

Add other meds (TCA, gabapentin)

Re-address M-S issues: physical therapy if not yet tried Order of steps not important: Do in

whatever order makes sense for given patient

The CPP History & PENot just for getting to diagnosis but also….

Powerful therapeutic toolCareful history, close listening, thorough (but sensitive) PE build rapport, trustTherapeutic benefit from the telling of one’s story (therefore, use written history forms only as adjunct)Reflect back what you have heardDiscuss concerns, fears

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2

Chronic Pelvic Pain.Howard, Fred; MS, MD

Obstetrics & Gynecology. 101(3):594‐611, March 2003.

Particularly Important Questions to Ask of Women With Chronic Pelvic Pain

Point to it

Did anything happen that may have brought it on?

If intermitt: how long is each episode?

Relation to BM, voiding?

CPP: History Clues

Timing relative to menses, urination, BMMost endometriosis initially includes dysmenorrhea (may progress to continuous, non-cyclic pain)Quality of painSqueezing, cramps: visceralSharp, shooting, lancinating: somaticCyclic pain is usually gynecologic but both IBS and interstitial cystitis can be worsened with menses

What do you think is the cause?

CPP: HistoryUrinary symptoms

Dysuria, frequency, nocturia, incomplete voiding

Pain worse with full bladder?

GI symptoms

Dyschezia, nausea, diarrhea, constipation, mucus stools, hematochezia, melena

Pain relieved by bowel movements?

Musculoskeletal symptoms

LBP, joint pain, sciatica

Effect of movement on pain

CPP Physical Exam GoalsIdentify underlying pathologyReproduce painEstablish trust, minimize fearNot just a pelvic exam! Observe gait/posture, thorough exam of abdwall, pelvic floor muscles, vaginal introitus

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CPP: Before Leaving…Get More Information!!

Pain diary with menstrual calendar

Voiding diary

Bladder questionnaires

Medical record review

Back to the Stepwise approach

Step 1: Address Mental HealthTreat depression if present

Counseling if h/o abuse

Step 2: Eval and treat musculo-skel issues

Step 3: Choose possible diagnosis and treat empirically

Step 4: If not improved: Consider another diagnosis/trtment


Re-address M-S issues: physical therapy if not yet tried Order of steps not important: Do in

whatever order makes sense for given patient

1. Address mental health issues

Pain has impact on quality of life and functional capacityWomen become isolated and have difficulty communicating needsRelationships become strainedPre-existing psych issues such as PTSDexacerbated by painAnxiety, depression, IPV, h/o of abuse are common act to exacerbate pain

Assess quality of life (REF) In the past month, how much has your pelvic pain kept

you from doing your usual activities such as self-care, work or recreation? (scale 1-5)

How much has your pelvic pain interfered with your quality of life?

How much have the treatments you have received for your pelvic pain improved your quality of life?

How do you cope with your pain?

How does your partner, family etc. respond when you are in pain?

20

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“Sensitive History”

IPV, h/o abuse, sexual functioning, depressionFrame it: remember, these pts may distrust medical system, think you are trying to say their pain is in their heads“I would like to ask you questions about the rest

of your life to help me understand how the pain is affecting you. This will help me know how best to treat you.”“I ask these questions of all my patients”

Emotional Health (REF)Screen for current or prior physical or sexual violence,

including events in childhood "At any time, has a partner hit, kicked, or otherwise hurt or threatened

you?" “Has your partner or a former partner every hit or hurt you? Has he or

she ever threatened to hurt you?” “Do you ever feel afraid of your partner?” Have you ever been forced to have sex when you didn’t want to?

Depression (12-35%) During the past month, have you been bothered by little interest or

pleasure in doing things?

During the past month, have you been bothered by feeling down or hopeless?”

Assess sexual functioning (68% have dysfunction) Desire, frequency, satisfaction, orgasm and discomfort

22

Treating Sexual Pain (REF)

Learn about your body Explore your pleasure spotsEducate your partnerConnect with your partner in sexual and non-sexual waysPrepare for sex: relax the PF muscles, use lubricants, take time for arousalReinvent your sex lifeAvoid painful activities

23

Heather Howard, PhD Sexual Rehab.org

1. Address mental health issues

SSRI for depression

Counseling (especially cognitive-behavioral therapy) for h/o abuse, difficulty coping with pain

Address sexual pain

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2. Evaluate and treat musculoskeletal issues

Myofascial Pelvic Pain Syndrome

28 muscles have direct attachments to the pelvis!

Inciting event: injury/trauma, visceral condition (IBS, EM, EC), referred pain from viscera, poor posture

Leads to: Short, tight, tender pelvic floor muscles and pain in pelvis, vagina, vulva, rectum, or bladder, or referred to thighs, buttocks, or lower abdomen.

Many experts believe that many, if not most, women with chronic pelvic pain have some degree of MPPS

Trigger points are the hallmark of myofascial pain

Even without classic trigger points, muscular pain prominent in many women with CPP (regardless of etiology)

Pelvic Floor Myalgia

FindingsPain is aching, throbbing, or heavinessLow back, sacral pain; can radiate to hip, thighOften worse with prolonged standingLevators are tense, tender on vaginal examManagementPelvic physical therapy and biofeedbackNeuropathic pain medications (gabapentin, TCAs)Vaginal or abdominal wall trigger point injectionsRelaxation therapy (breathing, visualization)Ice, heat (to the vagina!)

Carnett’s SignDifferentiates pain originating from the abdominal wall versus peritoneal cavity (Suleiman et al., 2001)

The patient raises her head and shoulders from the examination table while the provider palpates the tender area on the abdomen.

Positive Carnett’s sign: pain remains unchanged or increases when the abdominal muscles are tensed.

28

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Examining Pelvic Floor Muscles29

12-point Unimanual UnidigitVaginal Exam

Palpate in 4 quadrants x 3 depths Single fingerNO abdominal palpationJust beyond hymen12:00 urethra, 6:00 rectum3:00/9:00 obturator internusMid-vagina12:00 bladder base, 6:00 rectum3:00/9:00 puborectalisJust before cervix12:00 bladder, 6:00 rectum/cul-de-sac3:00/9:00 pubo/iliococcygeus

30

“Does this reproduce your pain?”

A couple patients1. 21 yo with CPP x 1.5 yr, band across her

lower abd, thinks it started with IUD placement. IUD removed 3 mos ago, no change. Of note, had leg injury and walks with cane

2. 51 yo with CPP many yrs, now w 10/10 flare. RLQ. s/p hyst (no relief), s/p l/s 1 yr ago—adhesions but o/w nl. Percoset with some relief. Thinks its due to ovarian cysts b/c had some on earlier u/s.

Both had….

Myofascial Trigger Points32

Trigger points are hyperirritable palpable nodules that are taut bands of muscle fibers (Tough et al., 2007)

When palpated the pain usually radiates to another location

Found in abdominal wall, perineum and pelvic floor locations

Abdominal wall and vagina share T10-12 dermatomes with pelvic organs: Pain from trigger points referred to pelvic organs

See also: Lavelle, E., Lavelle, W., & Smith, H. (2007). Myofascial trigger points. Anesthesiology Clinics, 25, 841-51.

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Trigger Point Injection Therapy Local anesthetic injection(s) directly into

trigger point (TP). Thought to interrupt pain pathway 93% success by 5th injection in abdomen (Kuan,

2006) Agent: Lidocaine 1%, Bupivicaine 0.25%, Plus /minus

triamcinolone 10mg (caution corticosteroids) Volume: 2 to 10 cc. (use 2 cc if multiple trigger point,

larger volume if only one. Beware lido toxicity—limit to <15-20 cc)

22 or 25 gauge needle, long enough to reach the TP. Find the TP with the needle: TP=maximal burning pain Weekly injections, stop if no relief at all. Continue if

any relief.

Best if combined with physical therapy

33

Intravaginaltrigger points can be accessed with trumpet pudendalneedle guide

Langford, Neurourology and UrodynamicsVolume 26, Issue 1, pages 59–62, January 2007

Botulinum toxinA few small studies of injections into levator ani show benefit

Consider it experimental

Risk of major side effects: urinary or fecal incontinence or retention

Another patient….25 yo with CPP and known endometriosis (l/s proven), much improved with continuous OCP but still w significant dysparunea and pain that affects her QOL.

She had….

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Myofascial pain treatment

Anti-inflammatories, ice to vagina, vulvaRefer patients to physical therapists specializing in pelvic floor muscle work (advanced training)Myofascial releaseBiofeedbackHome exercise programAbdominal breathing, rescue poses, stretching

exercises

37

See American Physical Therapy website for referrals

3. Choose possible diagnosis & treat empirically

These 5 diagnoses account for most known causes of CPP:1. IBS2. Interstitial Cystitis3. Endometriosis4. Adenomyosis5. Vulvodynia/vulvar vestibulitis

Pain or discomfort for 3 days/month in the prior 3 months with 2 or more of: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in appearance of stool

Symptoms lending support to diagnosis

>3 bm per day or <3 bm per week

Lumpy/hard or loose/watery stool, mucus passage

Urgency or incomplete emptying

Bloating or distension

Symptoms may be precipitated by meals or certain foods

Caveats: Can be worse with menses so don’t r/o if pain is cyclic

Irritable Bowel Syndrome(IBS)

Rome III Diagnostic Criteria

Treatment for IBS (REF) Dietary recommendations: Elimination diet

Fiber—Mainstay of treatment Eat at regular times

Watch dairy products

Drink plenty of fluids

Pain/gas/bloating: antispasmodic (dicyclomine, hyoscyamine)

Constipation: increased fiber and psyllium

Diarrhea: loperamide

Stress reduction

Exercise regularly

Antidepressants

Alosetron (diarrhea) or lubiprostone (constipation)

CAM: acupuncture, herbs, probiotics, hypnosis, peppermint oil

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Interstitial Cystitis (IC)Symptoms/Signs Urgency, frequency, nocturia, bladder painPain worse on filling bladder; better on voidingMay also have dyspareunia, urge incontinence Bladder tenderness + pelvic floor tenderness Absence of objective evidence of another disease that

could cause the symptoms

Diagnosis of IC: PUF Questionnaire (pain/urgency/freq)

Max score = 35 PPV 91% (vs. KCL sensitivity) if score > 20 Lowest threshold for diagnosis is score >12

Parsons CL et al. Urology 2002;59:329‐33 and 60:573‐8.PUF questionnaire avail online: search: “PUF Interstitial cysitis

Treatments for IC Start with:

Oral sodium pentosan polysulfate (PPS) 100mg TID (Elmiron)

Eliminate bladder irritants: acidic foods, artificial sweeteners, caffeine, tea, chocolate

Stop Smoking

Bladder training

Physical therapy, stretching

Refer to urogyn if not effective: Intravesical treatments Hydrodistension under general anesthesia: “mainstay of treatment”

Dimethylsulfoxide Q1-2wks x 4-8 times: remission not cure

BCG (Bacillus Calmette-Guerin) 6 weekly treatments TENS

Endometriosis (EM): Presentation

Classical EM occurs in a minority of patients

Dysmenorrhea

Dyspareunia

Perimenstrual tenesmus, diarrhea, dysuria, hematuria, sacral backache

Commonly, continuous CPP is the sole complaint (although

many will give h/o of significant dysmenorrhea)

Bimanual exam may show:

Uterosacral ligament nodularity, fixed uterine retroflexion

Stenotic cervical os, deviated cervix

Corpus and adnexal tenderness

Tender pelvic floor

Endometriosis (EM): Role of L/S

Conventional wisdom

EM requires a surgical diagnosis

Recent trend

Empirical diagnosis of women likely to have EM is safer and more cost-effective than laparoscopy

If history consistent and pain improved with either continuous hormonal methods or with GnRHagonist, assume endometriosis

Reserve laparoscopy to treat endometriosis in setting of infertility, desiring pregnancy (improved fertility rates after surgical trtment) and for endometriomas

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Endometriosis, empiric therapy

No

NSAID + Continuous OC x2‐3 mo

Improved?

Yes

Continue OC* GnRHa x2 mo

Pain Improved?#

YesComplete* 6‐9 mo No

Consider L/S, other diagnoses, Musc‐skeleval/trt

# Both pain score and functionality improve

*Or transition to DMPA, ?Implanon, LNG-IUS, (or OC)

Adenomyosis Presentation

Endometrial glands, stroma within myometriumSymptomsOnset usually in late 30s-40sNew onset dysmenorrhea; constant CPP possibleSometimes: dyspareuniaIrregular vaginal bleedingNo bowel or bladder symptoms unless EM’osisSignsUterus enlarged, “boggy” and tenderNo adnexal tenderness

Adenomyosis: Diagnosis/Treatment

DiagnosisPathologic diagnosis.

More recently, MRI being used. However, unclear clinical utility, can simply start empiric therapy.

Treatment: Ovarian suppression: OCs, Patch, DMPA, Implanon

Levonorgestrel IUD

If fail hysterectomy

Medical management often ineffective for controlling pain of adenomyosis. (works for bleeding)Unlike for other pelvic pain syndromes, hysterectomy for

adenomyosis is often curative b/c symptoms confined to uterus

VulvodyniaIncidence: 3-5% of reproductive age women

Risk Factors:Vulvovaginal infectionOC usePhysical, emotional or sexual traumaComorbid disorders:ICIBSFibromyalgia/Chronic Fatigue SyndromePsychosocial and sexual impairment

48

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Vulvodynia: Q Tip Test

Purpose: identify and map changes in sensation including allodyniaGently touch with a q-tipStart at the thigh and work down to perineum bilaterallyInclude clitoris and perianal areasProceed from labia majora to labia minora then the vestibule

49 Diagnosis of Vulvodynia & Vestibulodynia

Chronic Vulvar Pain

PENo visible findings

Erythema

Hyperalgesia

Allodynia

VulvodyniaGeneralized pain

Burning, stabbing, stinging, etc.

VestibulodyniaPain at vestibule only

Provoked

Burning

R/OInfectious,

inflammatory, neoplastic and

neurologic cause

Treat accordingly

50

Vulvar Vestibule51 Treatments: Vulvodynia & Vestibulodynia 52

• Behavioral: Avoidance of vulvar irritants, constipation, sitzbath bid followed by vaseline, Ice/cool for burning, after sex

• Meds: No meds clearly superior, may need to try several, Start with topical lidocaine or topical gabapentin 6%. 3 mos trial; Other meds: Oral TCA’s, Anticonvulsants, SSNRI’s, Opioids; Topical: estradiol cream (if atrophic), compounded antidepressants, anticonvulasants

• Pelvic floor therapy, biofeedback very important• Psychotherapy, CBT, Sex therapy• Nerve blocks, Nuerostimulation• Surgery? For generalized vulvodynia, surgery

contraindicated. For localized vestibulitis, vestibulectomyhas been shown effective

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4. If no improvementConsider another diagnosis/trtment


Re-address M-S issues: physical therapy if not yet tried

When pain is a disease and not a symptomAfter 4-6 months, pain can become an illness, not just a symptom“Central Sensitization”= Maladaptation: “an

amplification of neural signaling within the central nervous system that elicits pain hypersensitivity”

Inciting event might have been treated, pain persistsTreatment focuses not on cure but on managing the pain

Treating Pain: Medications

Analgesics:NSAIDS (try at least 3)

Opioids (short course)

Topical anesthetics*

AntidepressantsTricyclics*

SSRI’s/SNRI’s*

Anticonvulsants gabapentin

pregabalin

Muscle relaxants

Vaginal preparations (valium, anti-depressant, anti-convulsant)

Refer to pain management

nerve blocks

neurotoxin: OnabotulinumtoxinA*

medication consult

55

*Off label use

Treatment of Neuropathic Pain

Mainly helpful in women with daily painClinical depression is presentSSRI (e.g., fluoxetine) or SNRI (e.g., venlafaxine)Advance to “primary care” dosing limitsClinical depression not prominentGabapentin 100-300 mg QHS, adv to 900 mg TIDTCA: nortriptyline 10 mg QHS, adv weekly to 50 mg

Sleep problemsHerbals, antihistaminesShort acting sleeping meds: e.g., zolpidem

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Integrative ApproachMind/body interventions: breathing exercises, imagery, MBSR, laughter yoga, etc.Movement therapies: yoga, Tai Chi, Feldenkrais, etc.Nutrition: anti-inflammatory diet/herbs, multivitamins, B complex, fish oil, calcium/magnesium, herbal tonicsAlternative providers: TCM, craniosacral, chiropractic, energy medicine, strain/counter strain, etc.

57

Take It HomeSpend time to establish trust

Set realistic goals with your patient: improved function vs. complete remission

Think beyond “making a diagnosis”

Manage the reactive depression that can make the perception of pain much worse

Pelvic floor dysfunction is common and perpetuates the pain cycle. Treat with pelvic PT plus/minus trigger point injections

If your first empiric therapy is ineffective, don’t give up. Revisit other diagnoses, depression and musculo-skeletal issues.

Build a community: physical therapist, pain consultant

What CPP patients want1. Personalized care

2. To feel understood and taken seriously

3. Explanation of the cause

4. Reassurance

Although we often can’t give them #3, we can explain the interconnectedness of pelvic organs, muscles and pain pathways.

Patients don’t really come to us because they are in pain, they come to us because they are suffering.Ling, APS Conference 2010

60

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Resources

International Pelvic Pain Society

National Vulvodynia Association

Endometriosis.org

Sexuality Information and Education Council of US

Interstitial Cystitis Association

Irritable Bowel Syndrome: see NIDDK/NIH

American Physical Therapy Association

American Chronic Pain Association

UCSF Chronic Pelvic Pain Clinic

61 ReferencesReferencesACOG Committee on Practice Bulletins--Gynecology

ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol. 2004 Mar;103(3):589-605

Jarrell F, et al. Consensus guidelines for the management of chronic pelvic pain J Obstet GynaecolCan. 2005;27(8):781-826.

Howard FM. Chronic pelvic pain. Ob Gynecol. 2003;101:594-611.

Abercrombie PD, Learman LA. Providing Holistic Care for Women with Chronic Pelvic Pain. J Obstet GynecolNeonatal Nurs. 2012 Aug 3. (Entire issue devoted to chronic pelvic pain)

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Why am I Bleeding?Management of 1st Trimester Bleeding

Alison Jacoby, MD

Dept. of Obstetrics, Gynecology & Reproductive Sciences


Disclosures

• I have no relevant financial disclosures.

• I will discuss off-label use of misoprostol.

Acknowledgements• Robin Wallace, Carolyn Sufrin, Jody

Steinauer and Meg Autry

Julie is a 23 year-old G1P0 at 6+5 by LMP with spotting x 1 day, no pain, β-HCG = 2672.

MSD = 25mm, no fetal pole

Objectives

1. Review early pregnancy loss

2. Review clinical, serum, and ultrasonographic diagnostic features

3. Compare management options– Discuss role of patient preferences

– Expectant, medical, surgical (office vs. OR)

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Early Pregnancy Loss (EPL)

• 15-20% of clinically-recognized pregnancies

• 1 in 4 women experience EPL

Spontaneous abortionVaginal bleeding + IUP, <20 wks

threatened, inevitable, incomplete,complete

Embryonic demise>7 mm embryo

with no cardiac activity

Anembryonic gestationTrophoblast development without

development of an embryo

Clinical diagnosis: Ultrasound diagnosis:

Stages of SAB:VB, + IUP, <20 wks

Threatened

Inevitable

Incomplete

Complete

ClosedNo tissue passed

IUP on U/S

OpenNo tissue passed

IUP on U/S

Tissue passed

+/- IUP on U/S

Tissue passed

No IUP on U/S

Open

Closed

STAGE: Os: Tissue & U/S:

Normal ImplantationImplantation:•5-7 days after fertilization•Takes ~72 hours•Invasion of trophoblast into decidua production of HCG

Embryonic disk: 1 wk after implantation

Diagnosis of EPL

1. Clinical presentation

2. β-HCG

3. Ultrasound

Bleeding, pain, LMP, examination

Isolated value, trend

Sac, pole, pseudosac

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Beta Curves, Redefined

• Rate of increase depends on gestational age1

• 49 normal intrauterine pregnancies• Doubling time varies by gestational age

<5 wks: 1.5 d5-6 wks: 2 d>7 wks: 3d

1. Pittaway 1985 Fertil Steril & Am J Ob Gyn

Letting go of the “double in 48 hours” rule

Beta Curves, Redefined

• Early studies used 85% CI as lower limit1

– Retrospective study of 20 women

– Mean doubling time 2 days

– 66% increase in 48 hrs• Poor sensitivity and specificity in cohort:

– Of 12 ectopics – 17% normal rise

– Of 16 normal pregnancies - 18% abnormal rise

• Newer data - different median and mean 2

2. Barnhart 2004 Obstet Gynecol

1. Kadar 1981 Obstet Gynecol

Letting go of the “double in 48 hours” rule

• 287 women with pain or bleeding and +UPT– No IUP on U/S but eventually had normal IUP

– Initial β-HCG < 5000

• Ave GA by LMP = 38 days (range, 0-107)

• At least 2 β-HCG’s within 7 days

Barnhart 2004 Obstet Gynecol

Beta Curves, RedefinedLetting go of the “double in 48 hours” rule

β HCG Trends in Normal IUP

Barnhart 2004 Obstet Gynecol

99% of nl IUPs1 day rise ≥ 24%2 day rise ≥ 53%

Median rise:1 day= 50%

2 day =124%

Slowest expected increase for normal pregnancy = 53%

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Ultrasound & Early Pregnancy:Key Findings

Gestational sac

Yolk Sac

Embryonic Pole

Cardiac Activity

Double decidual signGrows ~ 1mm/day

Early circulatory system

Grows ~ 1mm/day

100bpm140 bpm

Ultrasound MilestonesWhen should you see it?

Abnormality

Gestational Sac Discriminatory Level

β = 1500-2000

Ectopic v. abnl IUP

Multiple gestation

Complete SAB

Yolk sac MSD>13-16mm (wait for fetal pole)

Fetal pole MSD >20mm Anembryonicgestation

Cardiac activity Fetal pole ≥ 5.3mm Embryonic demise

5mm cut off = 8.3% false +5.3mm cut off = 0 false +

(Abdallah et al 2011 [Oct] Ultrasound Obstet Gynecol)

Ultrasound Diagnosis of EPL:Anembryonic Gestation

Mean sac diameter >=21mm(20 mm = 0.5% false positive)AND no fetal pole

Growth?Cut off 0.6mm/day 90% specCut off 0.2mm/day 99% spec

1.4mm/week

Abdallah et al 2011 (Aug) Ultrasound Obstet Gynecol

ACR Appropriateness Criteria for First Trimester Bleeding

Failed pregnancy can be diagnosed by:

Mean sac diameter >= 25mm AND no embryo

Absence of cardiac activity in an embryo > 7mm in CRL

Barton et al 2013 (Jun) Ultrasound Quarterly

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Ultrasound: Poor Prognostic Signs• Yolk sac > 7 mm

• Abnl Sac size / Embryo size– Sac too small (MSD-CRL < 6mm)

– Sac too big

• Slow embryonic heart rate (<80)

• Subchorionic hematoma

• Thin decidual reaction (<3 mm)

• Irregular sac contour

• Low position in uterus

Not diagnostic, but may help with counseling

Summary: Diagnosis of EPL

• Be cautious of only one point of information(Lab and ultrasound errors occur)

• Clinical history varies

• HCG rise in 48 hours: Minimum 53%Average 124%

• Ultrasound:– No growth of small sac (IUP not confirmed)

– No cardiac motion of embryo > 7 mm CRL– Anembryonic MSD > 25 mm

Julie is a 23 year-old G1P0 at 6+5 by LMP with spotting x 1 day, no pain.

β-HCG = 2672

MSD = 25mm, no fetal pole

Anembryonic Gestation

EPL Management

Medical SurgicalExpectant

Depends on:1. Hemodynamic stability

2. Patient preference and follow-up

3. Stage in miscarriage process

4. Local resources

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Women’s Preferences

There is no “one best way.”

Expectant management is preferred over aspiration by 70% of women.

When uterine aspiration is indicated or preferred, the majority of women will choose an office-based procedure over one in the OR.

Smith 2006; Wieringa-de Waard 2002; Dalton 2006

Women’s Preferences• Patients report higher quality-of-life and

satisfaction when treated according to preference• Surgery

– Quick resolution – Want and value support from hospital staff1

• Expectant – Desire a natural solution1

– Fear of operation1

– More preferred with higher level information & support2– 71% with success would opt for same in future3

• Misoprostol– Faster resolution– More natural solution without surgery

1. Ogden & Marker Brit J ObGyn 2004; 2. Molnar J Am Board of Fam Pract;3. Wieringa-DeWaard et al. J of Clin Epi, 2004

Women’s Preferences

• Up to 89% express a preference– Challenges in recruitment for RCTs

– Expectant mgt. increasingly preferred (38% in 1997 to 70% in 2002), increased if good counseling and support

– Increasing interest in medical

• Physician recommendation is influential

1. Molnar et al. Am Brd of Fam Pract 2000; O’Connor Health Aff 2007; Dalton ObGyn 2006; Petrou Value Health 2008; Smith BJGP 2006; Wieringa-de Waard Hum Reprod 2002

Patient Priorities

Pain Time Complications

Safety Bleeding Privacy

Anesthesia Past experience Finality

Adapted from Wallace et al 2010 Patient Educ Couns©Robin Wallace, 2011

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Personal Priorities

o Treatment by your own provider

o Recommendation of treatment from friend

or family member

o Provider recommendation of treatment

o Experience symptoms of bleeding and

cramping in private

o Family responsibilities/needs

Physical Priorities

o Least amount of pain possible

o Fewest days of bleeding after treatment

o Lowest risk of complications

o Lowest risk of need for other steps

o Avoid invasive procedure

o Avoid medications with side effects

o Avoid seeing blood

o Avoid going to sleep in case of a surgical

procedure

o Want to be asleep in case of a surgical

procedureEmotional Priorities

o Most natural process

o Avoid seeing the pregnancy tissue

Time and Cost Priorities

o Shortest time before miscarriage is complete

o Shortest time in the clinic or hospital

o Fastest return to fertility or normalcy

o Fewest number of clinic visits

o Lowest cost of treatment to you

Previous Miscarriage or Abortion

(if applicable)

o Different treatment from previous

o Similar treatment to previous

Adapted from Wallace et al 2010 Patient Educ Couns©Robin Wallace, 2011

EPL Management Practices in the U.S.

Adapted from Dalton AJOG 2010

n=976 ob-gyn, family medicine, CNMs

Provider Issues

Training Safety Concerns

Efficacy System Resources

Time Assumptions of patients

Expectant (14 days)

OverallAnembryonicEmbryonic DemiseIncomplete

60%-70%50%35%-60%75% - 85%

Misoprostol(7 days)

800 mcg PVAnembryonicEmbryonic DemiseIncomplete

70% - 96%81%88%93%

Aspiration 97% - 100%

Overall success rates

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Expectant Management: Completion Rates

Day 7

(%)

Day 14

(%)

Day 46

(%)

Incomplete Ab (n=221) 53 71*-84 91

Anembryonic gestation (n=92)

25 53*/52 66

Embryonic demise (n=138) 30 35*-59 76

Total (n=451) 40 61*-70 81

Luise 2002 BMJ*Casikar 2010 Ultrasound Obstet Gynecol

* n=203 - Casikar

Expectant Management:MIST Trial

• MIST – RCT of 1200 women– Expectant, medical, surgical

• Infection:– No difference - expectant, medical, surgical

(3%, 2%, 3%, p=NS)

• Unscheduled D&C– 44% (expectant)– Higher efficacy with incomplete

• Transfusion:– Expectant > surgical (2% vs. 0% of embryonic

demise)Trinder 2006 BMJ

Expectant Management: Contraindications

• Uncertain diagnosis

• Severe hemorrhage or pain

• Infection

• Suspected gestational trophoplastic disease

• Indicated karyotyping

Same contraindications for medical management

Expectant Limitations

• Size: Studies generally include gestations up to 9 weeks

• Time: Safety established up to 6 weeks of observation

• Maternal conditions: inappropriate for bleeding at home

• Social: inability to obtain prompt emergency care, understand precautions

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Medical Management of EPL

Advantages:• Avoidance of

anesthesia and surgery

• Faster completion of miscarriage compared to expectant

• Reduced emergency visits and D&C’S

Disadvantages• Pain and increased

analgesic requirements

• Increased duration of bleeding vs. surgical

• Gastrointestinal and systemic side effects

• Surgical management may still be necessary

Misoprostol• PGE1 analogue

• Tabs 100 mcg unscored, 200 mcg scored

• Inexpensive

• Rapidly absorbed PO, PV, PR, SL, buccal

• Common obstetrical uses: labor induction, medical abortion, PPH, cervical ripening

Misoprostol: Off-label Use

• FDA approved for prevention/txof gastric ulcers

• Once licensed, FDA doesnot regulate how used1

• Commonly practiced, often standard of care1

• Not experimental if based on sound scientific evidence2

1. Friedman, FDA Deputy Commissioner speech to U.S. House of Representatives 19962. Rayburn, Obstet Gynecol 1993

Physiologic Effects of Misoprostol

Uterine:

Cervical:

Gastrointestinal:

Systemic:

• Stimulates contractions

• Softens and primes cervix

• Prevents/treats ulcers • Nausea & vomiting • Diarrhea

• Fever, chills

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Medical Management: Misoprostol for EPL

• Small studies with wide range of doses, follow-up and definition of success– 800 mcg vaginally, repeated in 24h PRN1,2

– ↑ Side effects with PO, buccal, SL– 400-600 mcg buccal or sublingual3

• Success (avoid surgical intervention) 70-96%4

– Incomplete: higher success

• More acceptable than surgical5,6

• 90% would choose again4. Sur et al. Best Pract ObG 20095. Wood et al, Ob Gyn 20026. Demetroulis et al, Hum Reprod 2001

1. .Zhang et al, NEJM, 20052. Weeks et al, Obstet Gynecol 20053. Gemzell-Danielsson, Int J Obstet Gynecol 2007

Misoprostol vs. Surgical: MEPF Study

• 652 w/ EPL or incomplete Ab Miso or D&C • D1: Miso 800 mcg PV

– D3: Repeat miso if not complete– D8: Uterine aspiration if still not complete– D15: follow-up (all)

• Success (no need for additional D&C) by D 8– Miso: 84% (CI, 81-87) vs. D&C: 97% (CI, 94-100)– Lowest for embryonic demise (81%)– 70% success after 1 dose; 60% after 2nd dose

• Complications: No difference • Satisfaction: No difference (78% vs. 83%)

Zhang et al 2005 NEJM

Example of Misoprostol Algorithm

Miso 800 mcg PV

Cramping w/ clot/tissue in 24-48 hrs

2nd Dose Miso on D37 Days

Clinical f/uU/S if indicated

Clinical signs of passage

DONE!

Sac present or(Endometrium >30 mm)

No Sac & (endometrium<=30mm)

DONE!

If still sac (or endo>30mm) after 2 doses:Recommend suction

If wants expectant mgmt, f/u 2-4 wksSuction if signs of infection or HD instability

Follow up precautionsBleeding should stop in 2-3 wks

Menses should resume in 6-8 weeks

No clinical passage in 24-48 hrs

(Rhogam for Rh- women)

Adapted from Goldberg 2009 in Mgmt of unintended & abnl pregnancy

Medical Management: Mifepristone and Misoprostol

• Does not appear to increase efficacy– Mife 600 + Miso 400 PV vs. Miso alone1

• 74% vs. 71% success at 1 week

– Mife 200 + Miso 800 PV• 84%2-90%3 success at 3 days or 1 week2,3

1. Gronlund 2002 Acta Obstet Gynecol Scand2. Wagaarachchi 2001 Human Reproduction3. Schreiber 2006 Contraception

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Surgical Management:Suction Curettage

• Safe, high efficacy (>95%)

• No need to do in Operating Room– Outpatient or ED setting – cost-effective

– Manual Uterine Aspiration / Manual Vacuum Aspiration

Used with 5-12 mm cannulaeCapacity 60 cc

Surgical Management:MUA/MVA

• Manual v. electric: no difference - complication (2.5% vs. 2.1%)1, pain, provider or pt. satisfaction2,3

• MUA in ER compared to EVA in OR:4

EVA in OR MUA in ER

Wait time (↓52%) 7.14 hrs 3.45 hrs

Procedure time 33 min 19 min

Total cost (↓ 41%) $1404 $827

1.Goldberg 2004 Ob Gyn; 2.Dean, Contraception 2003; 3. Edelman A. Ob Gyn 2001;184:1564; 4. Blumenthal 1992 IJOG; 5. Raush Fertil Steril 2012.

2012 study supports cost-effectiveness of outpatient MUA to OR-based UA5

Moving MUA out of OR

• Process described by U Michigan– Medical evidence review

– Review of hospital policy for office procedures

– Trained physicians, nurses, and MAs• Hands-on workshops

– Institution of privileging program

– Review experience of patients

– Review cost – gyn reimbursement same, lower institutional cost - $1965 v. $968

90% uterine aspirations are done in OR

Harris, AJOG, 2007.

Overall Success Rates

D&C: 97%-100%

Misoprostol (800 mcg pv) up to 81-96% success in 1 week

Expectant up to 70-85% in 2 wks

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Follow-up for Miscarriage

Confirm pregnancy passed:

• Surgical: done at time of aspiration

• Expectant & Medical– Symptoms, ultrasound or pregnancy test

– Phone call is an option

Other benefits of an office visit:– Emotional support

– Preconception counseling or contraception

– Recurrence risk – 2% after first SAB

The Patient – provider Interaction

•Affects patient choice and satisfaction

•One half of women would change their decision based on our recommendation

Molnar 2000

Support women in identifying their values in and priorities for management.

Be prepared to offer all options, including misoprostol and office-based uterine aspiration.

• Threatened Abortion– Keep the patient informed

• Provide reassurance, but avoid guarantees that “everything will be all right”

• Provide support through process

• What does the bleeding mean?– 50% ongoing pregnancy with closed os

– 85% ongoing pregnancy with viable IUP on u/s

– Up to 30% of normal pregnancies have VB

The Patient – provider Interaction• Remain silent after initial results or information

• Follow-up with open-ended questions & active listening

• Use neutral responses

• Determine how the woman feels about the pregnancy

• Normalize emotions

• Validate feelings rather than trying to change them

• Avoid opinions about what patient ‘‘should’’ do

• Encourage seeking emotional support from others

• Assure that you will be available to her through the process, and answer questions as they arise

Wallace, Patient Educ Couns, 2010.

The Patient – provider Interaction

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Key Points: Management

• Offer all 3 management options if stable– Know success rates when counseling patients– Patient preference plays a major role– Minimal difference in risk

• Need for surgical intervention should be based on clinical judgment

• Outpatient MUA is acceptable to women and cost-effective

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Caring for Challenging Patients in Women’s Health: Insights into Empathy and Professionalism



Statement of Disclosure

I do not have any relevant financial relationships with any commercial interests.


Obstetrics Service

A woman who had a planned home birth of a breech baby and now has retained placenta has just arrived in triage. As you go in to meet her the doula tries to keep you from talking directly to the patient.

Gynecologic Clinic

You are seeing a woman to give her results of her endometrial biopsy: endometrial cancer. As you discuss her basic treatment options she refuses your recommendation of surgery and shows you documents she found on the internet supporting her preference. She then asks dozens of questions.

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Primary Care Clinic

You are seeing a 24 year‐old woman who has had 2 prior abortions who visits your clinic for a pregnancy test. She is now pregnant again. She has not been using contraception and desires another abortion.

• Obstetrics

• Gynecology

• Primary Care

Would any of these patients frustrate you?

Objectives

1. To explore the “difficult” or “challenging” patient

2. To review the literature about judgment and bias

3. To gain practical skills for managing our feelings about patients, improving patient‐centered care, and preventing burnout

Professionalism in Medicine

• Respect, compassion, accountability, altruism

• Patient‐centered care

– Put aside personal values and self‐interest (self‐awareness) in order to prioritize the culture, family, and values of patients

• Challenges us to be empathetic, respectful, and compassionate toward patients, particularly during challenging encounters

ACGME Core Competencies

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Professionalism

• Respect, compassion, accountability, humanism, altruism

• Patient‐centered care– Put aside personal values and self‐interest (self‐awareness) in order to prioritize the culture, family, and values of patients

• Challenges us to be empathetic, respectful, and compassionate toward patients, particularly during challenging encounters


Patient‐centered Care

Patient Physician

Focusing care on patient needs and preferences

Improved patient satisfaction, clinical outcomes

Little, BMJ, 2001; Luxford, Intl J Quality Health Care, 2011.

The “Difficult Patient” The “Difficult Patient”

The Textbook “Difficult Patient”

– The Angry patient

– The Silent Patient

– The Demanding Patient

– The "Yes, But" Patient

Feldman, Behavioral Medicine: A Guide for Clinical Practice, Third Edition, 2008.

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Patient Physician

The Textbook “Difficult Patient”

Angry FrustratedCalm

Elicit the patient’s reason for being angry.

Solicit the patient’s perspective.

Empathize with the patient’s experience.

Happy

High‐quality, patient‐centered care

The Actual “Difficult Patient”

Patient Physician

Actions

Behavior

Speak curtlySpend little timeAvoid patientBody languageComplain about her

FrustratedFrustrated

Low‐quality care

Fatigue, bad moodEmotional reactionWe don’t like herWe feel defensiveWe blame herWe judge her

The difficult patient– The Angry Patient




– The “No” Patient

– The Bad Patient

– The Needy Patient

– The Surprising Patient

The “Difficult Patient” The “NO” Patient

• Disagrees with us

• Does not adhere to medication or tx plan

• “Refuses” our recommendations

– Gynecology patient

• Does not trust us

• Has alternate beliefs about disease

– Obstetrics and gynecology patients

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The Bad Patient

• Lies

• Does bad things

– Uses drugs

– Uses drugs and doesn’t seem ashamed

• Acts irresponsibly

• Acts immorally

BAD

Primary care patient

The Needy Patient

• Asks too many questions

– Gynecology patient

• Takes too much of our time

• Acts entitled

• Has too much pain

Needy

The Surprising Patient

• Appears happy when she should be sad

• Appears sad when she should be happy

• Acts entitled when she shouldn’t

• Is smart when she shouldn’t be

• Has resources but won’t make good decisions

The “Difficult Patient”

The difficult patient– The Angry Patient




– The “No” Patient

– The Bad Patient

– The Needy Patient

– The Surprising Patient

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Think of a time recently when you felt angry or frustrated with a patient...

The “Difficult Patient” Unifying Themes

“The difficult patient is one who makes me feel ineffective.”

Schwartz, “Uncooperative patients,” 1958.

Patients who fail to validate our sense of ourselves, threaten our control or who create "fruitless work" are at risk of being labeled as "bad patients.”

Hill, Philosophy, Ethics, and Humanities in Medicine, 2010.

We judge patients.

• We judge patients’ motives, legitimacy of sxs 1

• More likely to judge if doesn’t fit into model of care

• We trust and like some patients more than others2, 3

• We blame patients for medical problems and failed surgery 4

• We judge women in violent relationships 5

• We judge patients who are obese 6,7

1.May, Social Health Illn, 2004;2.Thom, Health Affairs, 2004;3.Hall, Patient Educ Couns, 2002;4. Tait, J BehavMed, 2005;5. Nicolaidis, J Am Bd FamPract, 2005;6.Wear, AcadMed, 2006;7.Persky, I J Obesity, 2011.

We judge patients based on their gender, race, ethnicity and class.

• Provider feelings about pt. varies by patient race 1

• Communication varies by patient race & ethnicity 3‐5

• Tx recommendations vary by race, ethnicity & class 2

1. Moskowitz, JGIM, 2011; 2. Dehlendorf, AJOG, 2010; 3. Johnson, AJPH, 2004; 4. Cene, JGIM, 2009; 5. Beach, JGIM, 2010; 6. van Ryn, AJPH, 2006.

Provider bias partially explains health disparities.

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We judge patients, and it affects care.

• Patients notice judgment – perceive lower quality

• More empathy → higher quality, higher adherence

• More empathy → better diagnostic accuracy

• We treat patients differently– We communicate our discomfort1

• Like patients are more satisfied and adherent 2

1. Persky, Intl J Obesity, 2011; 2. Hall, Patient Educ Couns, 2002.

We all have judgmental feelings.

How do we deal with our feelings in order to provide high‐quality care, model

professionalism and prevent burnout?

Teaching and Learning Professionalism

Self‐awareness

Quality Care and Communication

AcceptancePt. is in your care.

Empathy Compassion

Recognize feelings, judgments

Sympathetic consciousness of another’s distress

Understanding the experience and feelings of another • What was it that bothered you?

• How did you feel?• How did you react? • Do you think the patient noticed? • How did you talk about the patient to colleagues?

Self‐awareness

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Empathy

Compassion

• What do you think is going on with the patient?

• Even if you can’t put yourself in this person’s shoes, do you feel that she might be having a hard time?

Acceptance

• Can you accept that she is in your care? • How can you take care of yourself while taking care of her? • How can you care for her professionally?

Empathy

• Empathy is associated with positive outcomes– Increased dx accuracy, pt. participation, compliance, satisfaction, quality of life

Neumann, AcadMed, 2011; Shapiro, Phil Ethics Humanities, 2008.

Empathy

Empathy Decline

• Empathy is associated with positive outcomes– Increased dx accuracy, pt. participation, compliance, satisfaction, quality of life

• Empathy decreases in once trainees enterclinical practice– Increased vulnerability, distance themselves

– Increased responsibility

– Increased burnout

– Increasingly think of patients as “other”

Neumann, AcadMed, 2011; Shapiro, Phil Ethics Humanities, 2008.

Empathy

Teaching Professionalism through a Case‐based Workshop

• Faculty‐facilitated workshop with 8‐16 learners

• Workshop experience:– UCSF: >400 learners

• Medical students, ob‐gyn residents, faculty physicians, nurses and nurse practitioners students

– 20 other medical schools and residency programs

– 45 trained faculty in US

Professionalism, Empathy & Patient Care

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Professionalism, Empathy & Patient Care

Case‐based workshop– Part 1: Each learner introduces actual case

• Group selects one or two to talk through

• Self‐awareness → empathy → compassion → acceptance

– Part 2: Clinical cases• Family Planning

• Incarceration

• High‐risk obstetrics

• Substance use

1 hour

Part 1: Actual Cases

Tell us about a time recently when you felt angry or frustrated with a patient...


Self‐awareness


Acceptance

Empathy Compassion

How did it make you feel?

Was the patient having a hard time?

What was going on with the patient?

How can you take care of her?

Actual Cases

• Develop awareness of our reactions and buttons– Did patient notice and did it interfere with care?

• Consider theoretical and actual circumstances that contributed to patient’s behavior– Add to the library of potential reasons

– We have a list of good and bad reasons

– If patient acts apologetic or ashamed – we are nicer

– Notice how attached we can be to our expertise and model of medicine

• Discuss how we might act in future

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Part 2: Theoretical Cases

• Abortion ‐ perfect for practicing this framework

– Common in U.S. (1.2 million)

– We come to medicine with opinions

• Many judge women for not using birth control, having one (or more) abortion, presenting in the second trimester, or choosing abortion for specific circumstances.

Family Planning Case

A 24 year‐old woman who has had two abortions comes to you with an undesired pregnancy and wants an abortion.


Self‐awareness


Acceptance

Empathy Compassion

What upsets you about her having had many abortions? How does it make you feel?Why would someone have three

unintended pregnancies? What might be going on in her life?

Do you think she’s having a hard time? Can you feel for her?

How can you care for her professionally?

Strategies to Teach/Learn Empathy

• Mindfulness‐based Stress Reduction1

• Balint groups,2 support groups,3 self‐awareness training

• Reflection4 and narratives

• Home visits, service programs

• Perspective‐taking5 – put yourself in patient’s shoes

• Prioritizing empathy in clinical team discussions

• Unconscious bias literature – recommends approaching each patient with fresh perspective

• Our workshop – positive, qualitative outcomes

1. Krasner, JAMA, 2009; 2. Adams, AJOG, 2006; 3. Harris, Soc Science Med, 2011; 4. Learman, AJOG, 2008; 5. Blatt, AcadMed, 2010.

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Professionalism

• Respect, compassion, accountability, humanism, altruism

• Patient‐centered care– Put aside personal values and self‐interest (self‐awareness) in order to prioritize the culture, family, and values of patients

• Challenges us to be empathetic, respectful, and compassionate toward patients, particularly during challenging encounters.


Conclusion

• Patients who challenge us offer an opportunity to develop empathy, compassion and self‐awareness.

• We must prioritize this dimension of patient care in our clinical settings.

• Feel free to use this schema!

Self‐awareness

CompassionEmpathy

Department: MedicineCourse Number: MDM14M01Course Name: Essentials of Women's Health:

An Integrated Approach to Primary Careand Office Gynecology

Cours Chair: Robert B. Baron, MD, MSCourse Date: June 30-July 5, 2013

Date Time From # of Hrs./Credits # of Min. Speaker30-Jun

5:00 0.17 10 Baron/JacobyGERIATRIC 5:10 0.83 50 JacksonGERIATRIC 6:00 1.17 70 Jacoby

ADJOURN at 7:10 PM

Total Credits for June 30, 2013: 2.25

Date Time From # of Hrs./Credits # of Min. Speaker1-Jul

GERIATRIC 7:00 0.83 50 TiceGERIATRIC 7:50 0.83 50 Baron

BREAK at 8:40 AMGERIATRIC 9:00 0.83 50 Perez-Stable

9:50 0.83 50 SteinauerADJOURN at 10:40 AM

Total Credits for July 1, 2013: 3.50


GERIATRIC 7:00 0.83 50 Steinauer7:50 0.83 50 Jackson8:40 0.83 50 Jacoby

BREAK at 9:30 AM

Concurrent Workshops: A & B9:50 1.50 90 Jacoby / Baron

ADJOURN at 11:20 AM



GERIATRIC 7:00 0.83 50 Perez-StableGERIATRIC 7:50 0.83 50 BaronGERIATRIC 8:40 0.83 50 Tice

BREAK at 9:30 AM

Concurrent Workshops: C & DGERIATRIC (Workshop D only) 9:50 1.50 90 Steinauer / PerezStable

ADJOURN at 11:20 AM



GERIATRIC 7:00 0.83 50 TiceGERIATRIC 7:50 0.83 50 Perez-Stable

8:40 0.83 50 JacobyBREAK at 9:30 AM

Concurrent Workshops: E & F9:50 1.50 90 Jackson-Tice

ADJOURN at 11:20 AM



7:00 0.83 50 Jackson7:50 0.83 50 Jacoby

GERIATRIC 8:40 0.83 50 SteinauerADJOURN at 9:30 AM


Maximum CME Credits (June 30 - July 5, 2013): 20.25

Maximum Geriatric Credits (June 30 - July 5, 2013): 11.75

Calculated by J. BorjalDate: 2/13/2013; 6/19/2013Source of Calculation: Brochure ReviewPlanner: M. Trojnar

ESSENTIALS OF WOMEN'S HEALTH: - Continuing Education

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