2015 Obstetrics and Gynecology Update:

The Department of Obstetrics, Gynecology, and Reproductive Sciences

University of California, San Francisco School of Medicine presents

2015 Obstetrics and Gynecology Update:

What Does the Evidence Tell Us?

October 14-16, 2015 Parc 55 Hotel

San Francisco, California

Course Chair Amy (Meg) Autry, MD

of California, San Francisco

University of California, San Francisco School of Medicine

Acknowledgement of Commercial Support

This CME activity was supported in part by an educational grant from the following:

Hologic

Exhibitors

Abbvie, Inc.

Applied Medical

Bayer Healthcare

Cooper Surgical

Hologic

Mallinckrodt Pharmaceuticals

Natera

Olympus America, Inc.

Progenity

Sanofi Biosurgery

University of California, San Francisco School of Medicine Presents

2015 Obstetrics and Gynecology Update: What Does The Evidence Tell Us?

EDUCATIONAL OBJECTIVES An attendee completing this course will be competent to:

Discuss the sensitivity and apply non-invasive prenatal diagnostic testing for the diagnosis of trisomy;

Counsel women with findings of dense breasts on mammography; Order appropriate imaging for women diagnosed with dense breasts; Incorporate evidence-based interventions to reduce preterm labor; Manage pregnancy of unknown location; Manage women with endometrial hyperplasia and early endometrial cancer; Counsel women regarding the appropriate applications for egg freezing; Discuss disparities of BRCA testing.

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 educational activity for a maximum of 22.50 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This CME activity meets the requirements under California Assembly Bill 1195, continuing education and cultural and linguistic competency. The cases used in this course are presented for teaching purposes only. Please observe patient confidentiality. This presentation may be protected under Evidence Code 1156, 1157. Nurses: For the purpose of recertification, the American Nurses Credentialing Center accepts AMA PRA Category 1 Credits™ issued by organizations accredited by the ACCME. Pharmacists: The California Board of Pharmacy accepts as continuing professional education those courses that meet the standard of relevance to pharmacy practice and have been approved for AMA PRA Category 1 Credits™.

ACCREDITATION, CONT. Family Physicians: This Live activity, 2015 Obstetrics and Gynecology Update: What Does the Evidence Tell Us?, with a beginning date of 10/14/2015, has been reviewed and is acceptable for up to 22.50 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. Obstetricians/Gynecologists: The American College of Obstetricians and Gynecologists has assigned 23 cognate credits to this program.

General Information Attendance Verification / CME Certificates Please remember to sign-in on the sign-in sheet on your first day. You only have to sign-in once for the course, when you first check in. After the meeting, please visit this website to complete the online course evaluation: http://www.ucsfcme.com/evaluation Upon completing the online evaluation, your CME certificate will be automatically generated and emailed to you.

Evaluation Your opinion is important to us – we do listen! We have two evaluations for this meeting. The speaker evaluation is the bright yellow hand-out you received when you checked in. Please complete this during the meeting and turn it in to the registration staff at the end of the conference. The overall conference evaluation is online at: http://www.ucsfcme.com/evaluation We request you complete this evaluation within 30 days of the conference in order to receive your CME certificate.

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 or overnight.

Exhibits Industry exhibits are located outside the general session room during breakfasts and coffee breaks.

Lunches Lunches are on your own. A list of nearby options is available at the conference registration desk.

Final Presentations PDF versions of the final presentations will be posted on the course slides website approximately 2-3 weeks post course. Only presentations that have been authorized by the presenter will be included. http://www.ucsfcme.com/2016/MOB16001/slides.html

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

Course Chair

Amy (Meg) Autry, MD Clinical Professor and Residency Director, Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco

Course Faculty

(Department of Obstetrics, Gynecology and Reproductive Sciences unless otherwise noted) Robert B. Baron, MD, MS Professor of Medicine; Associate Dean for Graduate and Continuing Medical Education; Vice Chief, Division of General Internal Medicine Marcelle I. Cedars, MD Professor; Director, Division of Reproductive Endocrinology Lee-may Chen, MD Professor; Edward C. Hill, MD Endowed Chair in Obstetrics, Gynecology and Reproductive Sciences Anna Glezer, MD Assistant Professor of Psychiatry, and of Obstetrics, Gynecology and Reproductive Sciences Mindy R. Goldman, MD, MPH Professor; Director, Women's Cancer Care Program Juan M. González, MD, MS, FACOG Assistant Professor Monica W. Harbell, MD Assistant Professor of Anesthesia and Perioperative Care Megan Huchko, MD, MPH Associate Professor Heather G. Huddleston, MD Associate Professor; Medical Director, Center for Reproductive Health

Alison F. Jacoby, MD Professor; Director, UCSF Comprehensive Fibroid Center Vanessa Jacoby, MD, MAS Associate Professor Karla Kerlikowske, MD Professor, Departments of Medicine and Epidemiology/Biostatistics Jennifer Kerns, MD, MPH Assistant Professor Rachel I. Kornik, MD Assistant Professor of Dermatology Robyn A. Lamar, MD, MPH Clinical Instructor Jennifer M. Lucero, MD Assistant Professor of Clinical Anesthesia Evelyn Mok-Lin, MD Assistant Professor Mary E. Norton, MD Professor and Vice Chair, Clinical and Translational Genetics; David E. Thorburn, MD and Kate McKee Thorburn Endowed Chair in Perinatal Medicine and Genetics Michael S. Policar, MD, MPH Professor

C. Bethan Powell, MD Chief, Gynecologic Oncology Kaiser Permanente San Francisco; Medical Director, Hereditary Women's Cancer Clinic, Kaiser Permanente San Francisco; Clinical Professor, Volunteer Faculty UCSF Melissa G. Rosenstein, MD, MAS Assistant Professor Tami S. Rowen, MD, MS Assistant Professor Kirsten Salmeen, MD Assistant Professor Karen Smith-McCune, MD, PhD Professor; John A. Kerner Chair in Gynecologic Oncology Jody Steinauer, MD, MAS Professor; Co-Director, Family Planning Fellowship Jeffrey A. Tice, MD Associate Professor of Medicine, Division of General Internal Medicine Stefanie Ueda, MD Assistant Professor, Division of Gynecologic Oncology Sara Whetstone, MD, MHS Clinical Instructor Sarah Wilson, MD, MEd Obstetrician-Gynecologist Kaiser Permanente Oakland Marya G. Zlatnik, MD, MMS Professor, Maternal Fetal Medicine & Obstetrics & Gynecology, Program in Reproductive Health & the Environment; Associate Director, Maternal Fetal Health & the Environment, UCSF-Western States Pediatric Environmental Health Specialty Unit

Disclosures 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: Amy (Meg) Autry, MD Robert B. Baron, MD, MS Marcelle I. Cedars, MD Anna Glezer, MD Mindy R. Goldman, MD, MPH Juan M. González, MD, MS, FACOG Monica W. Harbell, MD Megan Huchko, MD, MPH Heather G. Huddleston, MD Alison F. Jacoby, MD Vanessa Jacoby, MD Karla Kerlikowske, MD Jennifer Kerns, MD, MPH Rachel I. Kornik, MD

Robyn A. Lamar, MD, MPH Jennifer M. Lucero, MD Evelyn Mok-Lin, MD Michael S. Policar, MD, MPH C. Bethan Powell, MD Melissa G. Rosenstein, MD, MAS Kirsten Salmeen, MD Karen Smith-McCune, MD, PhD Jody Steinauer, MD, MAS Jeffrey A. Tice, MD Stefanie Ueda, MD Sara Whetstone, MD, MHS Sarah Wilson, MD, MEd Marya G. Zlatnik, MD, MMS

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: Lee-may Chen, MD Independent Contractor Genentech Vanessa Jacoby, MD, MAS Grant/Research Support Halt Medical Mary E. Norton, MD Grant/Research Support Natera Tami S. Rowen, MD, MS Employee (spouse) Genomic Health 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 relationship.

UCSF Obstetrics and Gynecology Update: What Does the Evidence Tell Us?

October 14 – 16, 2015 COURSE AGENDA

Wednesday, October 14, 2015

7:00- 7:45 am Registration / Continental Breakfast 7:45- 8:00 Welcome and Opening Statements Dr. Amy (Meg) Autry 8:00- 8:35 Advanced Laparoscopic and Hysteroscopic Skills: Techniques to Dr. Alison F. Jacoby Make Hard Cases Easier 8:35- 8:45 Q & A 8:45- 9:20 Management of Pregnancy of Unknown Location Dr. Jody Steinauer 9:20- 9:30 Q & A 9:30- 10:05 New Treatments for Uterine Fibroids Dr. Vanessa Jacoby 10:05- 10:15 Q & A 10:15-10:30 Coffee Break 10:30- 11:05 Treatment of Dysplasia Dr. Karen Smith-McCune 11:05- 11:15 Q & A 11:15- 11:50 Complex Contraception Dr. Jennifer Kerns 11:50- 12:00 Q & A 12:00- 1:15 pm Lunch On Own 1:15- 1:50 Evidence-based Treatment of Side Effects of Contraception Dr. Sara Whetstone 1:50- 2:00 Q & A 2:00- 2:35 Pre-Exposure Prophylaxis Guidelines for the Ob/Gyn Dr. Megan Huchko 2:35- 2:45 Q & A 2:45- 3:20 Hormone Replacement and New Regimens Dr. Marcelle I. Cedars 3:20- 3:30 Q & A 3:30- 3:45 Coffee Break 3:45- 4:20 Osteoporosis Dr. Jeffrey A. Tice 4:20- 4:30 Q & A 4:30- 5:05 Current Strategies for Treating Obesity Dr. Robert B. Baron 5:05- 5:15 Q & A 5:15pm Adjourn



Thursday, October 15, 2015 7:30- 8:00 am Continental Breakfast 8:00- 8:35 NIPT Dr. Mary E. Norton 8:35- 8:45 Q & A 8:45- 9:20 Environmental Contaminants & Reproductive Health: What Dr. Marya G. Zlatnik Should We Tell Our Patients? 9:20- 9:30 Q & A 9:30- 10:05 Preterm Labor Dr. Juan M. Gonzalez 10:05- 10:15 Q & A 10:15-10:30 Coffee Break 10:30- 11:05 Advanced Maternal Age - Management of Pregnancy in Dr. Kirsten Salmeen Women over 40 11:05- 11:15 Q & A 11:15- 11:50 Issues Around Periviability Dr. Melissa G. Rosenstein 11:50- 12:00 Q & A 12:00- 1:15 pm Lunch On Own 1:15- 1:50 Depression and Pregnancy Dr. Anna Glezer 1:50- 2:00 Q & A 2:00- 2:35 Anesthesia Considerations for Obstetric Hemorrhage Dr. Jennifer M. Lucero 2:35- 2:45 Q & A 2:45- 3:20 Methods for Labor Induction: Updates on the Evidence Dr. Sarah Wilson 3:20- 3:30 Q & A 3:30- 3:45 Coffee Break 3:45- 4:20 "Can I do this while I'm pregnant?" Searching for Evidence Dr. Robyn A. Lamar Behind Pregnancy Advice 4:20- 4:30 Q & A 4:30- 5:05 Evidence-based Postpartum Visit Dr. Michael S. Policar 5:05- 5:15 Q & A 5:15pm Adjourn



Friday, October 16, 2015 7:30- 8:00 am Continental Breakfast 8:00- 8:35 Infertility Workup for the Generalist Dr. Heather G. Huddleston 8:35- 8:45 Q & A 8:45- 9:20 Egg Freezing Dr. Evelyn Mok-Lin 9:20- 9:30 Q & A 9:30- 10:05 Vulvar Disease Dr. Rachel I. Kornik 10:05- 10:15 Q & A 10:15-10:30 Coffee Break 10:30- 11:05 Disability and Sexual Health Dr. Tami S. Rowen 11:05- 11:15 Q & A 11:15- 11:50 Post-Operative Pain Management Dr. Monica W. Harbell 11:50- 12:00 Q & A 12:00- 1:15 pm Lunch On Own 1:15- 1:50 Surgical Considerations for Obstetric Hemorrhage Dr. Lee-may Chen 1:50- 2:00 Q & A 2:00- 2:35 Endometrial Hyperplasia Dr. Stephanie Ueda 2:35- 2:45 Q & A 2:45- 3:20 Mammographic Breast Density: What You Need to Know Dr. Karla Kerlikowske 3:20- 3:30 Q & A 3:30- 3:45 Coffee Break 3:45- 4:20 Gynecologic Management of Women with BRCA Mutations Dr. C. Bethan Powell 4:20- 4:30 Q & A 4:30- 5:05 Breast Cancer: What the Gynecologist Needs to Know Dr. Mindy R. Goldman 5:05- 5:15 Q & A 5:15pm Adjourn / Evaluations

Advanced Laparoscopic and Hysteroscopic Skills:

Techniques to make hard cases easier Alison Jacoby, MD!

Director, Comprehensive Fibroid Center

No disclosures

• Incorporate new surgical techniques into your practice!

• Review anatomical landmarks for the ureters and Palmer’s point!

!

!

• Share strategies for contained morcellaltion!

• Maximize success in hysteroscopic myomectomy

Learning ObjectivesKeys to success

• Laparoscopic entry: port placement, cosmetic incisions!

• Visualization: seeing around corners!

• Uterine manipulation: delineate vaginal fornices, displace ureters !

• LSH: cervical transection made easy, find those ureters!

• Specimen removal: the most challenging part of surgery today!

• Hysteroscopic myomectomy: enucleation or bust

Laparoscopic entry: Port Placement

Always have your scope higher than the fundus!(with maximum cephalad displacement)

Left Upper Quadrant Trocar Entry: Palmer’s Point

Indications:!

• Prior midline incision!

• Known pelvic adhesions!

• Large pelvic mass!

• Pregnancy!

• Failed umbilical port placement

Left Upper Quadrant Trocar Entry: Palmer’s Point

Relative Contraindications:!

• Prior LUQ surgery!

• Ascites!

• Hepatomegaly!

• Spenomegaly

Laparoscopic entry: Cosmetic incisions

Umbilicus!

• Incision types: Vertical and Omega!

• Cosmetically appealing!

• Minimize # of incisions!

!

Omega Umbilical Incision

Visualization: Seeing around corners

Angled scopes:!

• 0°, 30° & 45°!

• Invaluable for seeing over and around large fibroids

Visualization: Uterine manipulation

• Places tissue on tension!

• Separates ureter and uterine artery!

• Delineates vaginal fornix

Visualization: Identifying the Bladder

• Controlled insufflation of the bladder with CO2

Visualization: Find the ureters

• Practice ureterolysis on your easy cases

Tools for Cervical Amputation

• Electrosurgical loop- monopolar or bipolar!

• Fast but potentially dangerous

Specimen Removal: Before Nov 2013

Specimen Removal: The Controversy

Power Morcellation:!

• November 2013- News story about dissemination of unsuspected sarcoma!

• April 2014-FDA safety warning!

• May 2014- J&J suspends sale of morcellator!

• Nov 2014- FDA requires “black box” warning!

• 2015- Some insurers refuse to reimburse for cases in which the power morcellator is used

Iatrogneic complications from dissemination tissue fragments

• Peritonitis, abscess, obstruction (Lieng, J Minim Invasive Gynecol 2006) !

• Case reports of iatrogenic myomas on bladder, appendix and retroperitoneally (Kho, Obstet Gynecol 2009)

• FDA Warning issued 4/17/2014!

• Prevalence of unsuspected uterine sarcoma in patients undergoing hysterectomy or myomectomy for presumed benign fibroids is 1 in 352, and the prevlance of unsuspected uterine leiomyosarcoma is 1 in 498.!

• “If laparoscopic power morcellation is performed in women with unsuspected uterine sarcoma, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival. For this reason, and because there is no reliable method for predicting

whether a woman with fibroids may have a uterine sarcoma, the FDA discourages the use of laparoscopic power morcellation during hysterectomy for uterine fibroids.”

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ACOG

“Minimally invasive surgery, including with power morcellation, continues to be an option for some patients when performing hysterectomy and myomectomy. At the same time, it is critical to minimize the risk for patients undergoing these surgeries who may have an occult gynecologic cancer.”

Specimen Removal: Vaginal route

• Great option for TLH!

• Less practical for a very large uterus or patient with narrow pubic arch!

• Not an option for LSH!

!

!

Specimen Removal: Supra-pubic mini-lap!

• Addition incision!

• Cosmetically less appealing!

• Increased pain!

!

!

!

Text

Specimen Removal: Options for L/S myo & LSH

• Colpotomy !

• Uncontained power morcellation (with informed consent)!

• Contained scalpel morcellation !

• Contained power morcellation

Contained Power Morcellaltion

Hysteroscopic Myomectomy Pearls

Hysteroscopic Myomectomy: Pearls

• Success is complete enucleation !

• Choose cases wisely!

• Probe technique!

• Minimize intravasation!

• Set infusion pressure as low as possible !

• Vasopressin injection!

• Pause to let the uterus contract

Types of Submucosal Fibroids

`

• Incorporate new surgical techniques into your practice!

• Review anatomical landmarks for the ureters and Palmer’s point!

!

!

• Share strategies for contained morcellaltion!

• Maximize success in hysteroscopic myomectomy

Learning Objectives

Thank you !

UCSF Comprehensive Fibroid Center: 415-885-7788 Questions: jacobya@obgyn. ucsf.edu

10/14/2015

1

Diagnosis and Management of Pregnancy of Unknown Location

Ectopic, Early Pregnancy Loss, or Normal Pregnancy?

Jody Steinauer, MD, MASJuly, 2015

DisclosuresOctober 14, 2015 I have no disclosures.

Objectives1. Define pregnancy of unknown location.2. Describe a thoughtful approach to pregnancy of

unknown location.3. Review the workup of bleeding in the first trimester.4. Review treatment of early pregnancy loss and ectopic

pregnancy.

Patient Case: H&P• Maya is a 26 yo G1P0 presenting to the emergency room

for bleeding in early pregnancy.• Maya’s sure LMP was 9 weeks ago.• She had a positive UPT 2 weeks ago.• This is a desired pregnancy.• Her bleeding is like a “light period” for the past 3 days.• She has no history of STIs or other risk factors for ectopic

pregnancy.• On exam her cervical os is closed.• She is Rh-positive.

What can we tell Maya right now?

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Symptomatic Early Pregnancy Evaluation

Symptomatic Early Pregnancy: Presentation• Urgent or emergency care visit

– Vaginal bleeding– Abdominal or pelvic pain or cramping– Passage of pregnancy tissue from the vagina– Loss of pregnancy-related symptoms– Hemodynamic instability

• Incidental clinical finding– Bimanual exam inconsistent with LMP– Ultrasound suggestive of abnormal pregnancy

Symptomatic Early Pregnancy • Ectopic pregnancy must be ruled out, but we must

be careful to not diagnose a desired IUP as abnormal.

• There are new guidelines for hCG discriminatory zone, as well as EPL ultrasound diagnostic cut-offs.

• Choice of management is a preference-sensitive decision.

Bleeding in Early Pregnancy• Keep the patient informed.

– Reassure - not all vaginal bleeding & cramping signifies an abnormality, but avoid guarantees that “everything will be all right.”

– Assure you are available throughout the process.• What does the bleeding mean?

– Up to 20% chance of ectopic pregnancy– 50% ongoing pregnancy rate with closed cervical os– 85% ongoing pregnancy rate with viable IUP on sono– 30% of normal pregnancies have vaginal bleeding

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Evaluation• History

– Risk factors for ectopic pregnancy• Physical exam

– Vital signs– Abdominal and pelvic exam

• Ultrasound– Transvaginal often necessary

• Lab– Rh factor– Hemoglobin or Hematocrit– β-hCG when indicated

Is the pregnancy desired?

Ectopic Pregnancy • 1-2% of all pregnancies• Up to 20% of symptomatic pregnancies• ½ of ectopic patients have no risk factors• Mortality has dramatically declined: 0.5/100,000

– 6% of pregnancy-related deaths– 21 deaths per year in US

• Early diagnosis important• Concern about management errors

Ectopic PregnancyGOAL: Early Diagnosis • Decreased chance of rupture (rupture can occur at any

level of beta HCG and whether rising, falling or plateauing)• Rupture associated with decreased fertility,

increased morbidity and mortality• More treatment options (eg methotrexate, conservative

surgical treatment) if diagnosed earlier• Methotrexate more effective if diagnosed earlier

Early Pregnancy Loss (EPL)• 15-20% of clinically

recognized pregnancies• 1 in 4 women will

experience EPL in their lifetime

• Includes all non-viable pregnancies in first trimester = miscarriage

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Patient Case: Physical Examination• Maya has stable VS.• She has a small amount of blood in her vagina, a closed os,

a slightly enlarged, nontender uterus, and normal adnexa.• Her pregnancy test is confirmed to be positive.• The ultrasound does not show an IUP or an adnexal mass.

What can we tell Maya now?

Pregnancy of Unknown Location• When the pregnancy test is positive, but no signs

of intrauterine or extrauterine pregnancy on u/s– We try to follow these women until a diagnosis is made– We have to weigh risk of ectopic pregnancy (EP)– Sometimes there is never a final diagnosis as both EPL

and EP may resolve spontaneously • More commonly encountered in symptomatic

early pregnancy, but can also be encountered in asymptomatic women, especially when u/s early

Positive pregnancy test, vaginal bleeding and/or abdominal pain

61% Ongoing IUP28% Spontaneous Abortion 9% Ectopic Pregnancy

Dx upon presentation (80%)

77% Ongoing IUP16% Spontaneous Abortion6% Ectopic Pregnancy

49% of all women with Ectopic Dx at presentation

Dx with additional testing (20%)

11% Ongoing IUP77% Spontaneous Abortion17% Ectopic Pregnancy

51% of all women with Ectopic Dx after outpatient follow-up

Classification of Ultrasound Findings

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5

PUL Outcomes – Clinical Management PUL Outcomes - Summary

PUL: Simplified1. Where is the pregnancy? � U/S (same day)2. If the pregnancy undesired? � uterine aspiration3. If desired and we can’t tell where it is: Is it normal

or abnormal? � quantitative (serial) Beta-HCG– If Bhcg above threshold and no IUP = Abnormal– Serial beta HCGs:

• If Bhcg drops > 50% in 48 hours = Abnormal• If Bhcg rises > 50% in 48 hours = Most likely normal (can be

EP) – Continue to follow and repeat u/s• If between = Most likely abnormal (still can be normal) –

Continue to follow and repeat u/s4. Once pregnancy determined to be abnormal or if

undesired or if patient desires definitive dx �uterine aspiration to determine if IUP, EP tx if not

IUP=Intrauterine pregnancy

β-hCG Utility in Symptomatic Early Pregnancy Diagnosis• β-hCG median serum concentration:

– 4 weeks: 100 mIU/ml (5-450)– 10 weeks: 60,000 (5,000 – 150,000)

Discriminatory Level• Serum β-hCG at which a normal intrauterine

pregnancy should be visualized on ultrasound– If >2000 nl IUP unlikely but possible � new values

• Once beyond discriminatory level, limited role for “following betas”

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6

Discriminatory & Threshold level• 366 ♀with VB/pain� nl IUP

• Highest seen in the study with no sac: 2,300Old values: 1500= 80% & 2000= 91% prob.

of seeing GS in viable IUP

99% Predicted Probability of DetectionDiscriminatory Threshold

Gestational sacYolk sacFetal pole

351017,71647,685

39010941394

Connolly, Obstet Gynecol, 2013.

• HCG 2000 - 3000– Non-viable IUP most likely, 2X ectopic– Ectopic is 19 x more likely than viable IUP– For each viable pregnancy:

• 19 ectopic pregnancies• 38 nonviable pregnancies

– 2% chance of viable pregnancy• HCG > 3000

– Ectopic 70 x and nonviable IUP 140x more likely than viable pregnancy

– 0.5% chance of viable IUP

In women with desired pregnancy consider beta hcg cut-off of >= 3000.

Society of Radiologists in Ultrasound: No Gestational Sac

Balance of Diagnostic Tests• Maximize sensitivity at the cost of diagnosing

some IUPs as Ectopic Pregnancies– Error – interrupting desired IUP

• Maximize specificity at the cost of diagnosing some EPs as IUPs– Error – delay diagnosis resulting in rupture

• Engage the patient in decision-making• Cut-off of 3,000 v. repeat beta hcg +/- u/s








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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 48-hour increase for normal pregnancy = 53% (20% of ectopics increase)

β HCG trends : Other Key Points• Two hcg values may not be enough• If close to the thresholds – check another

Barnhart, Ob Gyn, 2002








If Diagnose as Abnormal…• Presumed ectopic pregnancy – uterine

aspiration before MTX– High HCG nothing in the uterus (50% SAB)– Very low HCG with abnormal rise or definite

fall (25% SAB)

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Role of Ultrasound in Ectopic Diagnosis • Only 2% of u/s are diagnostic for EP

– “Diagnostic” = Gestational Sac with yolk sac or fetal pole visualized outside uterus

• Normal adnexal exam does not exclude ectopic• Suggestive of ectopic

• Empty uterus + hCG above discriminatory zone• Complex mass + fluid in cul-de-sac (94% are EP)• Should still follow them if desired pregnancy

Main role of U/S is to rule in IUP

Ultrasound Findings to R/o EP• Remember that an EP has not been ruled out until

there is an intrauterine pregnancy – Gestational sac with a yolk sac and/or embryo

Incomplete abortion, treat as indicated

Peritoneal signs or hemodynamic

instability

Non-obstetric cause of bleeding identified

EDDiagnose and treat

as indicated

Threatened abortion; repeat TVUS if further

bleeding

Transvaginal ultrasound (TVUS) and β-hCG level

Products of conception(POC’s) visible on exam

Presume ectopic;refer for high-level TVUS

and/or treatment

Viable intrauterine pregnancy (IUP)

Ectopic or signs suggestive of ectopic pregnancy

Nonviable IUP

Embryonic demise, anembryonic gestation,

or retained POC’s;discuss treatment options

Repeat TVUS in one week and/or

follow serial β-hCG’s

Physical exam

Bleeding in desired pregnancy, < 12 weeks gestation

See Figure 2

Figure 1. Evaluation of first-trimester bleeding

Patient stable, no POC’s or other cause of bleeding

No IUP, no ectopic seen

IUP, viability uncertain

IUP seen on prior TVUS?

Yes

No

Completed abortion; expectant

management

Reproductive Health Access Project/October 2013 www.reproductiveaccess.org

First-trimester Bleeding Algorithm

Repeat β-hCG fell< 50% or rose < 53%***

Suggests completed

abortion; ectopic precautions, follow

β-hCG weekly to zero**

β-hCG < 1500 – 2000*

Ectopic precautions, Repeat β-hCG in 48 hours

Suggests viable pregnancy but does not

exclude ectopic; follow β-hCG until

> 1500 – 2000*,then TVUS for definitive

diagnosis

Repeat β-hCG> 1500 – 2000*

Suggests early pregnancy failure or ectopic;

serial β-hCG’s +/- high-level TVUS until definitive

diagnosis or β-hCG zero**

Repeat β-hCGrose > 53%***

Ectopic precautions, repeat β-hCG in 48 hrs

Repeat β-hCG fell > 50%

β-hCG > 1500 – 2000*

Repeat β-hCG< 1500 – 2000*

Repeat β-hCG

fell > 50%

Repeat β-hCG fell

<50%or rose

Single β-hCG > 1500 – 2000*and bleeding history consistent

with having passed POC’s

Obtain high-level TVUS & serial bhCGs to differentiate between ectopic, early IUP, and retained

POCs’ treat as indicated

Single β-hCG > 1500 – 2000*and bleeding history not consistent with

having passed POC’s

Serial β-hCG’s rising and

> 1500 – 2000*

NO IUP or EP seen on TVUS

IUP seen on prior TVUS? Yes

No

Completed abortion; expectant management

Figure 2. Evaluation of first-trimester bleeding with no intrauterine pregnancy on ultrasound

Continued from Figure 1

* The β-hCG level at which an intrauterine pregnancy should be seen on transvaginal ultrasound is referred to as the discriminatory zone and varies between 1500 – 2000 mIU depending on the machine and the sonographer. ** β-hCG needs to be followed to zero only if ectopic pregnancy has not been reliably excluded. If a definitive diagnosis of completed miscarriage has been made there is no need to follow further β-hCG levels. *** In a viable intrauterine pregnancy there is a 99% chance that the β-hCG will rise by at least 53% in 48 hours. In ectopic pregnancy, there is a 21% chance that the β-hCG will rise by 53% in 48 hours.

Repeat TVUS; See TVUS in Figure 1

Modified from Reproductive Health Access Project/October 2013 www.reproductiveaccess.org

First-trimester Bleeding Algorithm

If patient stable repeat bHCG and once higher than 3000 and no IUP – uterine aspiration to rule

out EPL and treat for EP if no IUP

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EPL Diagnosis, Counseling, and Management

EPL – Making the diagnosis

Spontaneous abortionVaginal bleeding + IUP, <20 wks

threatened, inevitable,incomplete, complete

Embryonic demiseEmbryo with no cardiac activity

Anembryonic gestationGestational sac without

embryonic pole

Clinical diagnosis: Ultrasound diagnosis:

Ultrasound Diagnosis of EPL:Anembryonic Gestation

Mean sac diameter >=21mm(20 mm = 0.5% false positive)AND no fetal pole

Abdallah et al 2011 (Aug) Ultrasound Obstet Gynecol

Ultrasound Diagnosis of EPL:Anembryonic gestation

Abdallah et al 2011 (Aug and Oct) Ultrasound Obstet Gynecol

MSD (mm) Specificity False + Growth per day (wk) Specificity False +8mm 64% 36% 0.2mm (1.4mm) 99% 1%16mm 95.6% 4.4% 0.6mm (4.2mm) 90% 10%20mm 99.5% 0.5% 1.0mm (7mm) 45% 55%21mm 100% 0 1.2mm (8.4mm) 24% 76%

MSD, no YS, no embryo

MSD (mm) Specificity False + Growth per day (wk) Specificity False +8mm 35.7% 64.3% 0.2mm 98.6 1.416mm 97.4% 2.6% 0.6mm 87.3 12.720mm 99.6% 0.4% 1.0mm 43.7 56.321mm 100% 0 1.2mm 25.2 74.8

MSD, + YS, no embryoGROWTH:

0 mm/d= 0 False+

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Ultrasound Diagnosis of EPL:Embryonic Demise

Fetal pole >= 5.3AND no cardiac activity

Abdallah et al 2011 (Aug) Ultrasound Obstet Gynecol

Ultrasound Diagnosis of EPL:Embryonic Demise

Abdallah et al 2011 (Aug & Oct) Ultrasound Obstet Gynecol

CRL (mm) Specificity False + Growth per day (wk) Specificity False +3mm 75% 25% 0.2mm (1.4mm) 100% 0%4mm 91.7% 8.3% 0.6mm (4.2mm) 56.3% 63.7%5mm 91.7% 8.3% 1.0mm (7mm) 0*5.3mm 100% 0 1.2mm (8.4mm) 0% 0%

*16 FP, 0 TN. 37 TP, 1 TN

Fetal pole – 7 mm

MSD – 25 mm

Radiologists in Ultrasound: Account for Margin of Error Ultrasound Milestones

Normal IUP findings

When should you see it?

Abnormality if landmark is absent

Gestational Sac Discriminatory Levelβ = 3,000?

Completed EPLMultiple gestationEctopic pregnancy

Yolk sac MSD > 13-16mm Suspicious for EPLFetal pole MSD ≥ 25mm Anembryonic gestation

Cardiac activity CRL ≥ 7mm Embryonic demise

Interval growth (MSD or CRL)

1 mm/day (over 3-7 days)

Confirmed EPL

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EPL Management

Early Pregnancy Loss Management• Three (4) options for the clinically stable patient

1. Uterine aspiration1. Aspiration w/ general/deep sedation (operating room)2. Aspiration w/ local/moderate sedation (office-based)

2. Medication (misoprostol +/- mifepristone)3. Expectant

• All methods are effective, with equivalent safety and patient acceptability = clinical equipoise

NSFG 2004; Chen 2007; Wieringa-de Waard, 2002; Zhang 2005; Trinder 2006

EPL Treatment Options

Misoprostol (800 PV): Success: 80% at 1 wk.Advantages: Privacy, availability, most can avoid surgical tx, ?decreased infection, similar satisfaction as surgicalDisadvantages: multiple visits, 30% require 2nd dose, more pain, N/V & bleeding than surgicalUterine Aspiration: Success: ~100% Advantages: 2-4 hrs, high success rate, less blding & painDisadvantages: less available, rare surgical complications, ?increased infection

Expectant: Success: 60% at 2wks. Advantages: Privacy, some can avoid surgical treatment, ?decreased infectionDisadvantages: up to 6 wks to complete, more bleeding & more visits, less patient satisfaction

EPL Mgt: A Preference-sensitive Decision

• Best choice for management reflects the woman’s values and preferences

• Comprehensive management options can be offered in a typical primary care or outpatient setting

Wieringa-de Waard 2002; Dalton 2006; Smith 2006

Expectant Medication Office-based aspiration

Operating room

aspiration

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Explore the resource page and link to the learning module:

www.earlypregnancylossresources.org

Ectopic Pregnancy Management

Treatment of EPSurgery• If hemodynamically unstable, patient desires surgery,

contraindications to or failed MTX treatment • Laparotomy or laparoscopy• Salpingectomy or salpingotomy

– Salpingectomy if tube compromised– Similar outcomes if not compromised and other tube healthy– If other tube absent or unhealthy – salpingostomy preferred

• 10% failure rate if salpingostomy, require b-hcg followupExpectant management• If beta HCG <200 88% resolve spontaneously• Declining beta HCG - third value less than first• Asymptomatic, informed consent

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Medical Treatment of EPMethotrexate• Antimetabolite that interrupts DNA

synthesis in actively dividing tissues• Successful in 80-95%• Beta HCG levels >5000 higher failure

rate with single-dose tx (14% v. 4% if less than 5000)

• Single-, two-, multi-dose regimens• Start with single-dose if b-hcg <5000• Multi-dose for cervical or interstitial

ectopicsAlso: Inability to follow-up

ACOG Practice Bulletin # 94 Lipscomb et al NEJM 1999

Serum β-hCG Success Rate

<1,000 98% (118/120)

1,000-1,999 93% (40/43)

2,000-4,999 92% (90/98)

5,000-9,999 87% (39/45)

10,000-14,999 82% (18/22)

>15,000 68% (15/22)

Success of Single Dose MTX for EP

Single Dose vs. Multiple Dose

26 Articles PublishedSingle Dose Multiple Dose

Success 88% (940/1067) 93% (241/260)

Range 86% - 90% 86% - 96%

40% of 862 subjects met inclusion criteria.

Barnhart KT, Obstet Gynecol, 2003;101(4):778-84

• Methotrexate is not for everyone• No difference in future IUP or ectopic rates• Single-dose less effective than salpingostomy (OR=0.38)• 5% have rupture despite MTX • Requires significant follow-up

Ectopic Treatment: MTX vs Surgery

Cochrane review, 2007.

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Medical Treatment of EP

ACOG Practice Bulletin # 94

Conclusion

Conclusions• Bleeding in early pregnancy is common.• Take possibility of ectopic pregnancy seriously!• Pregnancy of unknown location takes patience to sort out.

– New beta-HCG cutoffs– New ultrasound measurement cutoffs– If abnormal – do uterine aspiration before giving MTX

• Patient preference is important.

New Treatments For Fibroids

Vanessa Jacoby, MD, MASAssociate Professor

Obstetrics, Gynecology, & Reproductive SciencesUCSF

Disclosure

Principal Investigator, The ULTRA Trial Trial of laparoscopic radiofrequency ablationFunded by Halt Medical under contract with UCSF

*Investigator Initiated Research (IIR)*Study design, implementation, analysis, and publication are independent of Halt Medical

Impact of Fibroids

• 30% of premenopausal women

• #1 reason for hysterectomy (250,000/year)

• $34 billion/year to care for women with fibroids

• $17 billion for lost work and disability after surgery

Outline

• Medical Management• Antifibrinolytics• Hormonal modulations

• Procedures• MR Guided Focused Ultrasound• Radiofrequency ablation

Question 1

A 40 year old P2 presents with heavy menstrual bleeding and 2 intramural fibroids not contacting endometrium, 5cm and 4cm. Hb=11.5. Would you offer her tranexamic acid (lysteda) for heavy menstrual bleeding?

A. Yes

B. No

Y es N o

21%

79%

Antifibrinolytic: Tranexamic Acid

• Nonhormonal medication for heavy menses• Binds to plasmin to inhibit fibrinolysis

Tranexamic Acid: RCT Results

Freeman et al, AJOG, 2011, pg 319. e1-7

2%

26%

39%

N=297

35% had fibroids

Excluded if number/size of fibroids required surgery based on gynecologist opinion

Tranexamic Acid: RCTSubgroup fibroid analysis

• Subgroup analysis of women with fibroids from 2 RCTs• N=96 for TA, 51 for placebo• Decrease in blood loss among women with fibroids

Eder et al, Womens Health (Lond Engl) 2013;9:397–403.

Tranexamic Acid: RCT Adverse Events


• Potential risk of thromboembolism • Not observed in trials of tranexamic acid• Patients at risk have been excluded (including those

on OCPs)• Contraindicated: hx or current thromboembolic

disease

• Headache, GI symptoms, muscle/back pain

Tranexamic Acid: Limitations


• Little known about fibroid subgroup (location/size)• No comparison to OCPs or other medications• May be effective for women with fibroids, more

studies needed• 1300mg tid as needed day 1-5 for heavy

bleeding• Patient can usually tell on day 1 if there is

improvement

Tranexamic Acid during Myomectomy

TA (n = 50) Placebo (n = 50) pPerioperative blood loss (ml)

654 ± 460 (81–2005) 820 ± 558 (213–2544) 0.12

Postoperative blood loss (ml)

150 ± 167 (5–1100) 213 ± 113 (40–535) <0.01

Total blood loss (ml)

804 ± 482 (111–2105) 1047 ± 617 (318–2864) 0.03

Postoperative Hb(g/dl)

9.97 ± 1.5 (7.1–13.2) 9.76 ± 1.4 (7.3–13.0) 0.44

Blood transfusion 0.3 ± 0.8 (0–3) 0.3 ± 0.7 (0–3) 0.60

Caglar et al, Eur J Obstet Gynecol Reprod Biol. 2008;137:227–231

• Randomized trial of 10mg/kg IV TA (up to 1g) versus saline• Given 15 min prior to incision, then 1mg/kg/hr during surgery• No clinically significant differences

Medical Management: Hormonal Manipulation

Drug Targets: Decrease hormone levelsSelectively block hormone action

Estrogen Progesterone

Progesterone Receptor Modulators (PRM)

• Inhibits ovulation, decreases fibroid volume• Does not decrease serum estrogen levels• Ulipristal Acetate

• Studied as 5-10mg tabs• Not available in these doses in U.S.

• Studies underway to gain FDA approval to market 5 and 10mg tabs in U.S. (Watson Pharmaceuticals, NCT02147197)

Progesterone Receptor Modulators: Ulipristal

• Two randomized trials, industry funded, in Europe• Placebo vs. Ulipristal (n=242)• Lupron vs. Ulipristal (n=307)• Participants had heavy bleeding, anemia, uterus

<16 weeks, planning surgery• 13 weeks of medication

Donnez et al, NEJM, 2012: 366:421-32.

Ulipristol Trials

Ulipristal vs. Placebo Ulipristal vs. Lupron

U 10mgN=94

PlaceboN=48

U 10mgN=95

LupronN=93

Amenorrhea 82% 6.3%* 89% 80%

Menstrualbleeding became normal

92% 19%* 98% 89%

Change in fibroid volume

-39% +3%* -42% -53%

Hot flashes

*p<.05 compared with U 10mg

10% 40%*

Donnez et al, NEJM, 2012: 366:421-32.

PRM Risk

• Potential for endometrial hyperplasia or cancer• Mixed results in studies with EMBs • NIH Pathology Panel classified new pattern of

endometrial changes: PRM-associated endometrial changes (PAEC)

• 10-15% of patients develop PAEC• More long-term study needed to assess natural

progression of this entity

Aromatase Inhibitors: letrozole and anastrozole

FibroidAromatase

EnzymeAndrogens Estrogen

• Blocks action of aromatase enzyme in ovaries and peripheral tissue, including fibroids

Letrozole: Decreases Fibroid Volume

Fibroid volume in cc

Parsanezhad et al, Fert Ster: Jan 2010: 93:1

46% decrease

Aromatase Inhibitors

• Side Effects• Estrogen levels in serum remain normal• No hot flashes

• Limitations• Small, uncontrolled trials, none in U.S. • Only 12 weeks of drug

• Long Term Risks• Concern for osteoporosis from data in postmenopasual

women with breast cancer

Larger, long-term, randomized trials needed to assess safety and efficacy

Other Medications

• Antiprogestin Mifepristone• Decreases fibroid size/bleeding• 10% endometrial hyperplasia/PAEC?

• Not available as needed for fibroids (5-50mg)

• GnRH agonist Elagolix• Trial for FDA approval (recruiting, NCT01441635)

• Estrogen Receptor Modulator Raloxifene: • Preliminary studies with conflicting results, concern re: VTE

Other Medications

• Statins?---Stimulate and inhibit cell proliferation

---Mouse model, treated with simvastatin showed decrease fibroid volume

Mostafa et al, Am J Obstet Gynecol 2015;213:196

Question 2

New fibroid surgical devices or procedures are approved by the FDA after comparative clinical trials demonstrate safety and efficacy.

A. True

B. False

T r ue

F a ls e

75%

25%

Fibroid Devices

• Unlike new drugs, FDA does not require comparative trials for new devices

FDA approves new device for fibroids

Insurance considers device experimental: Need RCTsDeclines coverage

RCTs conducted with support from:Industry (concern re: bias)NIH (too $$ to pay for device)

Limits ability to obtain gold standard evidence

Limits access to effective treatments

MR Guided Focused Ultrasound (MRgFUS)

FDA approved 2003, very limited availability across U.S.


Diagnostic ultrasound waves•Focused ultrasound beamheats tissue to 150-1850 F

•Coagulative necrosis occurs

FDA approved 2003, very limited availability across U.S.


• Patient lies prone for 3-5 hours in MRI• Conscious sedation• Foley

• Hand held automatic stop button

What is MRgFUS?

A. B.

C. D.

nonperfused volume (NPV)

MRgFUS vs. UAE

UAE MRgFUS

Ioinizing radiation XHospital admission X (75%)

Return to normal activities

7-10 days 1-3 days

Potential for ovarian failure

X

Post-procedure fever/infection

X

Access to MRgFUS

• Available in 9 states, 12 sites• 9/12 academic medical centers• In California:

UCSF, UCLA, UCSD, Stanford• Reimbursement is major challenge• Some sites offer treatment in research protocol

Current Evidence on MRgFUS

• Largest study 359 women in U.S.A and abroad• Uncontrolled, all women underwent MRgFUS• Treatment volume limited due to FDA regulation• Industry sponsored

Stewart EA, Gostout B, et al, Obstet Gynecol, Aug 2007

Stewart EA, Gostout B, et al, Obstet Gynecol, Aug 2007

MRgFUS Symptom Improvement

Symptoms

MRgFUS Outcomes

Study N NPV Shrinkage Reoperation

Stewart et al 2007

(low treatment volume)

359 Variable 20% average Depends on NPV(24% at 2 years for

45% NPV)

Gorny2011

130 45% N/A 7.4% at 12 mo

LeBlang2010

80 55% 31% at 6 mo N/A

Funaki 2009

91 40% at 24 mo 15% at 34 mo

Adverse Events

Outcome PercentAbdominal pain 33%

Back or leg pain with sonications 13%

Nausea or emesis 11%

Bladder or catheter pain 14%

Abnormal vaginal discharge 11%

Skin burns 5%

Olive D, Obstet Gynecol, March 2008Parker W, Obstet Gynecol, Nov 2007

Pregnancy after MRgFUS

54 pregnancies (51 women)

Ongoing 20% (11/54)

Delivered 41% (22/54)

SAB 26% (14/54)

TAB 13% (7/54)

Antepartum hospitalization

18% (4/22)

Placenta previa 9% (2/22)

Term (14/15)

Rabinovici, et al, Fertility and Sterility, January 2010

Randomized Trials of MRgFUS• PROMISe: Pilot randomized, placebo-controlled trial

MRgFUSN=13

Sham MRgFUSN=7

RandomizedN=20

3 month change in:Fibroid Symptoms, Fibroid Size, Hematocrit

Jacoby VJ, Kohi M, et al, Fert Ster, in press

Change in UFS-QOL Symptom Severity Score

p=.90 p=.20

-13

-31

Jacoby VJ, Kohi M, et al, Fert Ster, in press

Ongoing Randomized Trials

•Placebo-controlled trial for new MR Focused Ultrasound Device underway (Sonavelle device, Philips, NCT01504308)

•The FIRSTT Study: A Randomized Trial of MRgFUS versus UAE (NCT NCT00995878)

•NIH funded•Mayo Clinic (PI E. Stewart), UCSF, Duke•Enrollment closed August 2014

Radiofrequency Ablation

The Radiofrequency Ablation Device

Generator with Foot Pedal

3mm RF Handpiece

Laparoscopic Ultrasound

• FDA approved for fibroids November 2012(Acessa)


• Fibroids identified with ultrasound

• Radiofrequency (RF) probe placed under ultrasound guidance

• RF energy delivered to fibroids

• Tissue heats to 1000 C to cause coagulative necrosis

• Fibroid cells reabsorbed

Advantages of Acessa over Current Treatment

HospitalStay

RecoveryTime

Blood Loss Pain


0 5-9 days

32 cc Minimal

Open Hysterectomy

2-3 nights 4-6 weeks 300-500cc Moderate

Laparoscopicor Vaginal Hysterectomy

1 night 4 weeks 200cc Minimal-Moderate

Open Myomectomy

2-3 nights 4-6 weeks 250-500cc Moderate

LaparoscopicMyomectomy

0-1 2-4 weeks 200cc Minimal-Moderate

RF Ablation: Current Evidence

• Largest study, n=135 • Industry funded, FDA pivotal trial• Uncontrolled, all women treated with RF ablation• 3 year follow-up

Chudnoff et al, Green Jo, May 2013Guido et all, Health and Quality of Life Outcomes 2013, 11;139


UFS-QOL

Symptom SeverityScore

Quality of Life Score

3 months -52% +50%

12 months -57% +53%

24 months -59% +53%

Chudnoff et al, Green Jo, May 2013


Uterine Volume Fibroid Volume

3 months -15% -40%

12 months -25% -45%

Chudnoff et al, Green Jo, May 2013


• Adverse events: 4%

• Pregnancy (“not recommended” per FDA)• Not studied in women who desire future fertility• Insufficient data on pregnancy outcomes

Treatment Failure • <1% at 1 year (1/135) • 4.4% at 2 years (6/129)• 4.5% at 3 years (4/88)• TOTAL 11/135=8%

Chudnoff et al, Green Jo, May 2013Guido et all, Health and Quality of Life Outcomes 2013, 11;139


• Randomized trial of l/s RF Ablation vs. l/s myomectomy • <16 weeks, <10cm fibroid

Hahn et al, Geburtsh Frauenheilk 2015;75:442-449

RF Ablation Myomectomyn=26 n=25

Pain med use(median)

4 days 7 days

Return to normal activities

(median)

20.5 days 28 days


Symptom score decreased in both groups


Hahn et al, Geburtsh Frauenheilk 2015;75:442-449

Women with complete 12 month follow-up– Symptoms decreased in both groups

• 7.5 points RF ablation (n=18)• 17.8 points l/s myomectomy (n=25)

– Difference 10.1, P=0.16

Larger, long-term, randomized trials needed to assess safety and efficacy• TRUST Trial (NCT01563783)

RF Ablation: Ongoing Studies

• ULTRA• Nationwide post-market study of Acessa• 3 years of follow-up to assess change in symptoms,

treatment failure, pregnancy outcomes (NCT02100904)

– Vizablate (NCT01226290): Hysteroscopic RF ablation

Conclusions

• Several new medications, limited data on safety and efficacy

• Surgical treatments focused on minimally invasive approaches that leave fibroids in utero

• Long-term comparative trials are needed to confirm the durability of these treatments

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Treatment of Cervical Intraepithelial Neoplasia

Karen Smith-McCuneProfessor, Department of Obstetrics,

Gynecology and Reproductive Sciences

I have no conflicts of interest

CaseA 26 year old G1P1 woman has an abnormal cytology result. She is referred for a diagnostic workup. Colposcopy is inadequate (unsatisfactory), there is a visible lesion from 12-4 o’clock, and the biopsy shows CIN2. She is on oral contraceptives and has one child. She and her husband want to have another child in the next year.

How would you manage this woman?A. Repeat colposcopy in 6 months B. LEEPC. Ablative therapyD. Cone biopsy

R e pe a t

c o lp o s

c o py i n

6 . .. L E E

PA b l

a t i ve t h

e r ap y

C o ne b i

o p sy

44%

6%6%

44%

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Goals• Review literature about obstetrical outcomes

of treatments for CIN• Discuss strategies for management of CIN 2

and CIN 2/3 in reproductive aged women• Review considerations for determining depth

of treatment

Background• Before the advent of colposcopy, abnormal

Paps were treated by hysterectomy or conization

• With the advent of colposcopy, conservative methods were adopted: – ablative methods such as cryotherapy, laser

ablation, electrocautery or diathermy– excision with CO2 laser (laser conization)

Background• With the introduction of the loop

electrosurgical excision procedure (LEEP, LLETZ) in the 1990’s, the ablative methods were mostly abandoned

• Advantages of treatment with LEEP: – provides a histological specimen– therefore can be used in a “see-and-treat” format

Choice of therapy: excision versus ablation

For ablative therapy (cryotherapy, laser ablation) the following conditions must be present:– satisfactory colposcopy– negative endocervical curettage– lesion fully visualized– no evidence of invasion– no glandular dysplasia or glandular atypia

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Is ablative therapy effective?

• There is a misperception that cryotherapy is not as effective as LEEP

• Cochrane review 2006 indicated similar rates of residual disease for all treatment modalities

Kyrgiou et al 2006 Kyrgiou et al 2006

Treatment outcomes in British Columbia, 6 years of followup

Modality used for treatment of CIN 3

Failure rate 21-29 years



Cone biopsy 5.6% 6.3% 8.5%LEEP 8.6% 9.6% 12.9%Laser 11.7% 13.0% 17.3%Cryotherapy 24.2% 26.5% 34.0%

Melnikow et al JNCI 2009

Choice of treatment modality• Current literature has suggested that

excisional treatment for CIN results in increased risk of preterm delivery

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Obstetric sequelae of cervical therapies:2006

• Systematic review and meta-analysis of the literature regarding obstetric outcomes after excisional therapy for CIN (cone, loop, laser)

• 27 studies were included• Preterm birth defined as less than 37 weeks

Kyrgiou et al Lancet 2006

Obstetric sequelae of excisional therapies: meta-analysis 2006

• Results:• Cold knife cone was significantly associated

with preterm delivery <37 weeks – 14% versus 5%, relative risk 2.6 (statistically

significant)

• LEEP was significantly associated with preterm delivery <37 weeks– 11% vs 7%, relative risk 1.7 (statistically

significant)


Obstetric sequelae of excisional therapies: meta-analysis 2006

– Laser ablation: no significantly increased risks for adverse obstetric outcomes were observed


Cochrane review

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Limitations of the studies:• Comparison groups were mixed: some studies

used “external” controls (population based), which does not control for confounding factors

• Some studies used “internal” controls (women who were treated before birth versus women who were treated after birth) to avoid some of the confounding

Obstetric sequelae of cervicaltreatment: meta-analysis 2011

• Excisional and ablative therapies for CIN • They separated the results based on the

comparison group used in the study: external (population based), internal (birth before versus after treatment), and women with CIN treatment versus no treatment

• 30 studies- 27 were retrospective

Bruinsma and Griffin, BJOG, 2011

Obstetric sequelae of excisional therapy for CIN: meta-analysis 2011

• Results: • As seen in the other meta-analysis, excisional

treatment was associated with a significantly increased risk of preterm labor:

• RR = approx 2 whether the comparison group was external or internal

• The effect of cold knife cone and laser cone (RR 3.41 and 3.58) were more pronounced that LEEP (RR 1.85)


Obstetric sequelae of excisional therapy for CIN: meta-analysis 2011


• Ablative therapy was also associated with a significantly increased risk of preterm labor: RR = 1.47 (statistically significant) when the comparison group was external

• Ablative therapy was not associated with a significantly increased risk of preterm labor when the comparison group was internal

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Meta-analysis 2008: perinatal mortality and other severe adverse pregnancy

outcomes associated with treatment of CIN

• Cold knife cone was associated with significantly increased risk of: – Preterm delivery <28 weeks (RR 5.3)– Low birth weight <2000 gm (RR 2.9)– Perinatal mortality (RR 2.87)

Arbyn et al, BMJ 2008

• LEEP was associated with non-significantly increased risk of perinatal mortality (1.17, 95% CI 0.74-1.87)

• Cryotherapy and laser ablation were not associated with increased risk of perinatal mortality, preterm delivery, or low birth weight

Arbyn et al, BMJ 2008

Meta-analysis 2008: perinatal mortality and other severe adverse pregnancy outcomes

associated with treatment of CIN

LEEP and risk of preterm birth: U.S. data

• 241,701 singleton births at Parkland Hospital from 1992-2008– 511 had previously undergone LEEP– 842 subsequently underwent LEEP

• No differences in rates of preterm birth <34 weeks

Werner et al Obstet Gynecol 2010

Meta-analysis 2014• 19 studies that were restricted to LEEPs only • 2 categories of “unexposed” (no LEEP) women

were identified-– Those with no or unknown history of dysplasia– Those with a known history of dysplasia but no

excision

Conner et al Obstet Gynecol 2014

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Meta-analysis 2014• Pooled RR of preterm labor <37 weeks for

LEEP was 1.6 (95% CI 1.3-1.9)• Pooled RR of preterm labor <34 weeks for

LEEP was 2.2 (95% CI 1.3–3.7)• Risk of perinatal mortality was elevated in

women with a history of LEEP but not statistically significant (pooled RR 1.6, 95% CI 0.95–2.80).


Meta-analysis 2014• There were 4 studies in which the

“unexposed” group were women with a history of dysplasia but no cervical excision

• No statistically significant difference in the risk of preterm birth when the prior LEEP group was compared to this group (10.0% compared with 7.2%, pooled RR 1.08, 95% CI 0.88–1.33).


Conner et al Obstet Gynecol 2014Conner et al Obstet Gynecol 2014

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Fertility and early pregnancy outcomesKyrigou Cochrane reviews 2015

• treatment for CIN did not adversely affect the chances of conception.

• No difference in total miscarriage rate (4.6% versus 2.8%, RR 1.04, 95% CI 0.90 to 1.21; 10 studies, 39,504 participants, low quality)

Fertility and early pregnancy outcomesKyrigou Cochrane reviews 2015

• No difference in first trimester miscarriage rate (9.8% versus 8.4%, RR 1.16, 4 studies, 1103 participants, low quality)

• CIN treatment was associated with an increased risk of second trimester miscarriage (1.6% versus 0.4%, RR 2.60, 95% CI 1.45 to 4.67; 8 studies, 2,182,268 participants, low quality).

Obstetrical outcomes after treatment for CIN: Summary of evidence

• There are no randomized trials• The available studies are limited by

retrospective study designs, by the selection of control groups, and by confounding factors

• The biological mechanisms underlying the associations are not yet well understood

Nevertheless the following results have been observed:

Excisional procedures appear to be associated with an increased risk of preterm delivery and perinatal mortality

Excisional procedures appear to be associated with an increased risk of second trimester miscarriage

The data on cryotherapy and laser ablation do not show a strong association with adverse obstetrical outcomes (and in some cases have not been studied)

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of treatment

CENTRAL TENETS for management of CIN in young women

• The underlying risk of cancer is very low• HPV infection and CIN lesions are common at

the onset of sexual activity• Clearance of HPV is common• Approximately 90% of CIN 1 lesions will regress• Approximately 40% of CIN 2 lesions will regress

ASCCP Guidelines for Management of CIN

New ASCCP guidelines 2013:

• In “young women” with high grade CIN, either treatment or observation is acceptable provided colposcopy is satisfactory (adequate)

• When CIN 2 is specified, observation is preferred

• When CIN 3 is specified, or colposcopy is inadequate, treatment is preferred

ASCCP.com

New ASCCP guidelines 2013:

• “The term ‘young women’ indicates those who after counseling by their clinicians consider risk to future pregnancies from treating cervical abnormalities to outweigh risk for cancer during observation of those abnormalities. No specific age threshold is intended.”

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Management guidelines for surveillance of CIN 2 and CIN 2/3 in young women:

• Perform colposcopy and cytology every 6 months.

• If colposcopy worsens or if HSIL persists for one year, repeat colposcopic biopsy, and if it now shows CIN 3, treatment is recommended

• IF CIN 2 persists for 24 months, treatment is recommended

Figure 17, ASCCP 2013 consensus guidelines




of treatment

Effect of size of excision: • Several studies have shown that the deeper the

LEEP or cone, the greater the risk of preterm birth

• For example, the risk of preterm birth increased 6% for each mm of tissue removed (Noehr et al 2009, Obstet Gyn)

• The height of the cone but not the volume or circumference of the cone was significantly associated with the gestational age at delivery (Ortoft et al BJOG 2010) Anderson and Hartley,

Obstet Gynecol Survey 1979

“CIN 3 with gland neck extension”

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Morphometric studies• Analysis of 319 cone specimens 99.7% of CIN3

lesions were within 4.8 mm of the surface epithelium

• Depth increased with lesion severity: mean depth of CIN1 was 0.4 mm, CIN2 0.9 mm, and CIN3 1.3 mm

Abdul-Karim et al, Obstet Gynecol 1986

Morphometric studies• Analysis of 342 cone specimens revealed that

the mean depth of CIN into the cervical glands was 1.2 mm

• The deepest gland containing CIN that they found was 5.2 mm

• 99.7% of CIN lesions are located 3.8 mm from the surface

• Older women have deeper crypt involvement than younger women

Anderson and Hartley, Obstet Gynecol Survey 1979

Morphometric studies• Conclusion: • In women with satisfactory colposcopy,

excision or ablation to a depth of 5 mm will destroy >99% of lesions even if disease extends into the endocervical glands

Anderson and Hartley, Obstet Gynecol Survey 1979

Choice of therapyABLATIVE EXCISIONAL

Cryotherapy Loop electrosurgical excision (LEEP)

CO2 laser ablation Cold knife cone biopsy

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Cryosurgery (Cryotherapy)• Historically was the 1st outpatient treatment

of CIN• Low cost, high patient safety• Easy to perform, well tolerated• Requires stringent patient selection guidelines• Clearance rates for CIN = 86% to 91.6%• Key predictor of success is depth of freeze

Courtesy E.J. Mayeux


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Cryotherapy

• Goal is top create sufficient thermal injury to kill abnormal cells

• -20 degrees Celsius necessary for cell death• For successful ablation, goal is to freeze

beyond the lesion

Cryotherapy• “Iceball” = freeze depth = lateral spread• Most tissue in this zone will necrose

Cervix

Cryoprobe


Zone of freeze

Laser ablation• CO2 laser is common in dermatology

outpatient settings and used to be common in gynecological outpatient practices but has fallen out of fashion since the advent of the LEEP

• Modern equipment is designed for easy use and storage in the outpatient setting

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LEEP• Given the results from the morphometric

studies, 99.7% of lesions are ≤5mm deep• Therefore, in women with satisfactory

colposcopy, it would be uncommon to need to excise more than 7 mm of canal

• Routine use of the “top-hat” LEEP should be avoided in women of reproductive age

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Multiple passes with the LEEPwire

Donut-shaped ablation with the laser

Case #1A 26 year old G1P1 woman has an abnormal cytology result. She is referred for a diagnostic workup. Colposcopy is adequate (satisfactory), there is a visible lesion from 12-4 o’clock, and the biopsy shows CIN2. She is on oral contraceptives and has one child. She and her husband want to have another child in the next year.


R e pe a t

c o lp o s

c o py i n

6 .. . L E E

PA b l

a t i ve t h

e r ap y

C o ne b

i o ps y

87%

3%7%4%

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Case #2A 26 year old G1P1 woman has an abnormal cytology result. She is referred for a diagnostic workup. Colposcopy is inadequate (unsatisfactory), there is a visible lesion from 12-4 o’clock, and the biopsy shows CIN2. She is on oral contraceptives and has one child. She and her husband want to have another child in the next year.


R e pe a t

c o lp o s

c o py i n

6 .. . L E E

PA b l

a t i ve t h

e r ap y

C o ne b

i o ps y

21%

2%

19%

58%

Case #3A 26 year old G1P1 woman has an abnormal cytology result. She is referred for a diagnostic workup. Colposcopy is adequate (satisfactory), there is a visible lesion from 12-4 o’clock, and the biopsy shows CIN3. She is on oral contraceptives and has one child. She and her husband want to have another child in the next year.


R e pe a t

c o lp o s

c o py i n

6 .. . L E E

PA b l

a t i ve t h

e r ap y

C o ne b

i o ps y

6% 5%

33%

57%

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Questions?

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Complex contraceptionJennifer Kerns, MD, MPHAssistant Professor, UCSFObstetrics, Gynecology and Reproductive SciencesSan Francisco General HospitalOctober 2015

Disclosures• I have no relevant financial disclosures

Objectives• To review resources for assessing the safety of contraceptive methods for particular women

• To review the evidence for selected practice recommendations for women with particular medical issues▫ Contraceptive counseling techniques▫ Contraception for obese women▫ Choosing the best COC▫ Emergency contraception▫ Unscheduled bleeding with nexplanon▫ Updates: Liletta, Essure

Contraceptive Prevalence & Maternal Deaths

Ahmed et al. Lancet. 2012

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Benefits of avoiding unintended pregnancy

Frost and Lindberg Contraception 2012

A. YesB. No

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

Y es N o

38%

62%

Can my patient use this method?1. CDC Medical Eligibility Criteria (CDC MEC)2. U.S. Selected Practice Recommendations (US SPR) for Contraceptive Use, 20133. ACOG Practice Bulletin No. 734. Contraception for the Medically Challenged Patient,

Rebecca Allen, Carrie Cwiak et al.

Just google this

CDC Medical Eligibility Criteria (MEC)

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MEC Categories1 Can use the method No restrictions2 Can use the method Advantages generally

outweigh theoretical/proven risks

3 Should not use method unless no other method is appropriate

Theoretical/proven risks generally outweigh advantages

4 Should not use method Unacceptable health risk

Medical Condition

Birth Control Methods

MEC Category

Where do you find the US MEC?

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Maya

• Maya is a 23 yo G5P2 • 6 weeks post-abortion• Interested in contraception.• 2 NSVDs, 2 abortions• BMI = 41

Approaches to counseling?• Information transfer• Provider recommendation• Allowing patient to decide• Shared decision making

Information transfer Provider recommendationShared decision making

Patient makes her decision

• Paternalistic• Coercion• LARC promotion

• Passive• Unresponsive

Preference-sensitive decision �shared decision making• SDM means the provider does not insert her/his values into the counseling

• Counseling influences method selection• Quality of family planning care associated with use of contraception and satisfaction with method

• Patient-centeredness is the right thing to doElwyn et al. Ann Fam Med 2014Dehlendorf et al. Contraception 2013Durand et al. PLoS One 2014

A. TrueB. False

Combined hormonal methods are considered safe for obese women

Obesity and contraception

T r ue

F a ls e

10%

90%

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Safety of combined hormonal methods in obese women• CDC Medical Eligibility Criteria: 2• Venous thromboembolism (VTE) risk increased:

▫ No evidence of synergistic effect▫ Risk is less than that of pregnancy (29/10,000 ♀yrs)▫ No data on women with BMI>40

• No increased risk of Acute MI or stroke

Safety of other methods in obese women• CDC Medical Eligibility Criteria: 1, except…• DMPA in obese adolescents = 2

A. TrueB. False

Combined hormonal methods have similar efficacy in obese women compared to non-obese women

Obesity and contraception

T r ue

F a ls e

58%

42%

Obesity and oral contraceptives• YES (we think) – conflicting data for COCs

Dinger et al. Obstet Gynecol 2011McNicholas et al. Obstet Gynecol 2013Lopez et al. Cochrane 2010

• N>52,000• RR 1.5 failure / BMI>35• N=1500• RR=1 failure (underpowered)• Longer time to steady state

(10 vs 5 days)• May be related to dosing

(incr risk with prolonged pill-free interval)• Overall risk of failure still low• Can consider continuous dosing

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Obesity and other methods

• Ring: same efficacy• Implant: same efficacy• IUDs: same efficacy• Patch: decreased in women >90kg

Dinger et al. Obstet Gynecol 2011McNicholas et al. Obstet Gynecol 2013Lopez et al. Cochrane 2010

Back to Maya… What other obesity-related conditions does she have?• Diabetes?

▫ Only contraindicated (MEC 3, 4) for all methods if � End-organ disease, or � >20 yrs duration

• Multiple cardiovascular RFs? (age, htn, smoking, DM)▫ Pill, patch, ring, DMPA contraindicated▫ Room for clinical judgment re: what constitutes

multiple RFs

CDC medical eligibility criteria

Maya’s contraceptive choice: COCsApri, Azurette, Caziant, Cesia, Cyclessa, Desogen, Emoquette, Kariva, Mircette, Ortho-Cept, Reclipsen, Solia, Velivet, Viorele, Natazia, Gianvi, Loryna, Ocella, Syeda, Vestura, Yasmin, Yaz, Zarah, Beyaz, Safyral, Kelnor, Zovia 1/35, Zovia 1/50, Altavera, Amethia, AmethiaLo, Amethyst, Aviane, Camrese, Camrese Lo, Daysee, Enpresse, Introvale, Jolessa, Kurvelo, Lessina, Levlite, Levora, LoSeasonique, Lutera, Lybrel, Marlissa, Myzilra, Nordette, Orsythia, Portia, Quartette, Quasense, Seasonale, Seasonique, Sronyx, Triphasil, Trivora, Necon 1/50, Norinyl 1/50, Alyacen 1/35, Alyacen 7/7/7, Aranelle, Balziva, Brevicon, Briellyn, Cyclafem 1/35, Cyclafem 7/7/7, Dasetta 1/35, Dasetta 7/7/7, Estrostep Fe, Femcon Fe, Generess Fe, Gildagia, Gildess Fe, Junel 21 1.5/30, Junel 21 1/20, Junel Fe 1.5/30, Junel Fe 1/20, Leena, Loestrin 21 1.5/30, Loestrin 21 1/20, Loestrin24 Fe, Lo Loestrin Fe, Loestrin Fe 1.5/30, Loestrin Fe 1/20, Microgestin 1/20, Microgestin 1.5/30, Microgestin Fe 1/20, Microgestin Fe 1.5/30, Modicon, Necon 0.5/35, Necon 1/35, Necon10/11, Necon 7/7/7, Norinyl 1/35, Nortrel 0.5/35, Nortrel 1/35, Nortrel 7/7/7, Ortho-Novum 1/35, Ortho-Novum 7/7/7, Ovcon 35, Ovcon 50, Philith, Tilia Fe, Tri-Legest Fe, Tri-Norinyl, Wera, Zenchant, Zenchant Fe, Zeosa, Estarylla, Mono-Linyah, MonoNessa, Ortho Tri-Cyclen, Ortho Tri-Cyclen Lo, Ortho-Cyclen, Previfem, Sprintec, Tri-Estarylla, Tri-Linyah, Tri-Previfem, Tri-Sprintec, TriNessa, Cryselle, Elinest, Lo/Ovral-28, Low-Ogestrel, Ogestrel

Progestin choice• Levonorgestrel� lowest risk of VTE• Remember. . . Absolute risk remains low• Balance with patient choice • No clear benefit of drospirenone with PMDD, acne

• Non-pregnant, no COCs: 2-4 per 10,000 ♀- yrs• Levonorgestrel COCs: 5.0 per 10,000 ♀- yrs• Desogestrel COCs: 6.5 per 10,000 ♀- yrs• Drosperinone COCs: 7.8 per 10,000 ♀- yrs

Lidegaard BMJ 2009 Heinemann Contraception 2007

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Maya’s contraceptive choice: COCsLevonorgestrel-containing COCsApri, Azurette, Caziant, Cesia, Cyclessa, Desogen, Emoquette, Kariva, Mircette, Ortho-Cept, Reclipsen, Solia, Velivet, Viorele, Natazia, Gianvi, Loryna, Ocella, Syeda, Vestura, Yasmin, Yaz, Zarah, Beyaz, Safyral, Kelnor, Zovia 1/35, Zovia 1/50, Altavera, Amethia, Amethia Lo, Amethyst, Aviane, Camrese, Camrese Lo, Daysee, Enpresse, Introvale, Jolessa, Kurvelo, Lessina, Levlite, Levora, LoSeasonique, Lutera, Lybrel, Marlissa, Myzilra, Nordette, Orsythia, Portia, Quartette, Quasense, Seasonale, Seasonique, Sronyx, Triphasil, Trivora, Necon 1/50, Norinyl 1/50, Alyacen 1/35, Alyacen 7/7/7, Aranelle, Balziva, Brevicon, Briellyn, Cyclafem 1/35, Cyclafem 7/7/7, Dasetta 1/35, Dasetta 7/7/7, Estrostep Fe, Femcon Fe, Generess Fe, Gildagia, Gildess Fe, Junel 21 1.5/30, Junel 21 1/20, JunelFe 1.5/30, Junel Fe 1/20, Leena, Loestrin 21 1.5/30, Loestrin 21 1/20, Loestrin 24 Fe, Lo Loestrin Fe, Loestrin Fe 1.5/30, Loestrin Fe 1/20, Microgestin 1/20, Microgestin 1.5/30, Microgestin Fe 1/20, MicrogestinFe 1.5/30, Modicon, Necon 0.5/35, Necon 1/35, Necon 10/11, Necon7/7/7, Norinyl 1/35, Nortrel 0.5/35, Nortrel 1/35, Nortrel 7/7/7, Ortho-Novum 1/35, Ortho-Novum 7/7/7, Ovcon 35, Ovcon 50, Philith, Tilia Fe, Tri-Legest Fe, Tri-Norinyl, Wera, Zenchant, Zenchant Fe, Zeosa, Estarylla, Mono-Linyah, MonoNessa, Ortho Tri-Cyclen, Ortho Tri-CyclenLo, Ortho-Cyclen, Previfem, Sprintec, Tri-Estarylla, Tri-Linyah, Tri-Previfem, Tri-Sprintec, TriNessa, Cryselle, Elinest, Lo/Ovral-28, Low-Ogestrel, Ogestrel

Ethinyl estradiol dose• Nearly all modern-day OCs are “low-dose”• 30mcg EE � higher continuation (vs. 20mcg EE)• Monophasic• Option to shorten or eliminate placebo week

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

a. Ulipristal (Ella)… levonorgestrel (Plan B)… Copper IUDb. Copper IUD… ulipristal… levonorgestrelc. Levonorgestrel… Copper IUD… ulipristal

3 months later…Maya returns asking for emergency contraception because she missed pills

Choose the answer that lists the EC methods in order of most effective to least effective

Oral Emergency ContraceptionLNG: 120 mg x 1, up to 5 days

Ulipristal Acetate:• Selective progesterone receptor modulator• Mechanism:Delayed follicular rupture• Will not harm existing pregnancy• Dosing: 30mg, FDA-approved up to 5 days

1. Brache 2010 Hum Reprod

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29

Levonorgestrel less effective for obese women

Glasier A et al. Contraception. 2011.

Misinformation about LARC

Percent of women pregnant after

taking LNG pills

Emergency contraception

• Used shared decision making for contraceptive counseling

• Reviewed evidence of safety/ efficacy of contraception in obese women

• Used evidence to choose the best COC• Considered obesity in EC recommendation• Gave her resources – BEDSIDER!

Summarizing Maya’s visit

• Discontinuation common, largely because of unscheduled bleeding

• Nearly 80% of women report some unscheduled bleeding with ETG implant

Etonogestrel implant and unscheduled bleeding

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• First 3 months predicts future (but not perfectly)▫ Those w/ favorable bleeding are likely to continue

to have favorable bleeding▫ Those w/ unfavorable bleeding have a 50% chance

of improving• Management:

▫ Expectant ▫ NSAIDs (400-800mg TID, 5-10 days)▫ COCs (cyclic)▫ Estrogen (oral conjugated, estradiol, transdermal)▫ Tamoxifen, mifepristone, doxycycline

Etonogestrel implant and unscheduled bleeding

• Low-cost Mirena• FDA-approved for 3 years

▫ effective 5-7, just like Mirena• No increase in pricing until 2017

▫ Title X clinics - $50▫ Rebate from company if patient pays full price

Liletta

• Pre-marketing studies▫ 2 non-blinded, non-randomized studies w/ no comparator group▫ Analysis was not intention to treat, and 15% had failed attempts at placement▫ Only 85% followed up at 1 yr for effectiveness (and 25% at 2 yrs)▫ 71% followed out to 5 yrs: no pregnancies reported

• Post-marketing studies▫ Stopped early, no follow up, all results redacted on FDA website

• Reports to MAUDE database▫ 5093 reports made: incomplete procedures, chronic pain, device migration, tubal perforation, bleeding, pregnancies

• ~ 5.7% annual risk of pregnancy estimated

Essure update

Dhruva et al. NEJM 2015

Conclusions• Contraception is integral to public health

• Counseling should be patient-centered

• Resources are at your fingertips to help you decide which methods are safe for your patient!

▫ Including the UCSF family planning pager…(415) 443-6318

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Sara Whetstone MD, MHS

BOTHERSOME BLEEDING

Evidence based management of bleeding with contraception

I have no disclosures.

OBJECTIVES

�Describe bleeding patterns expected with initiation and continuation of various contraceptive methods

�State 2 interventions to manage irregular bleeding associated with use of COCs, implant, injection, and IUD

Dissatisfaction with

contraceptive method

Discontinuation of


Delay in resumption of contraception or adoption of less effective

method

UNINTENDED PREGNANCY

CONTRACEPTIVE DISSATISFACTION

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1) COCs2) Vaginal ring3) Implant4) DMPA5) LNG-IUS

a) Weight gainb) Depressionc) Acned) Bleedinge) Headache

AUDIENCE QUESTION

MATCH EACH CONTRACEPTIVE METHOD WITHITS MOST COMMON SIDE EFFECT

(appropriate to use each response more than once)

d) Bleeding

Condom Pill Depo-Provera Norplant

n=705 n=1637 n=579 n=66

% Reporting the following reasonsToo expensive 2.2 3.2 2.1 1Too difficult or messy to use 15.2 5.7 1.2 10.4Partner unsatisfied 38.6 2.8 2.6 1.2Experienced side effects 17.9 64.6 72.3 70.6

Worried about side effects 2 13.1 4.2 4.2

Did not like the changes in menstrual periods 1.5 12.7 33.7 19.3

Experienced contraceptive failure 7.5 10.4 5.7 8.3

Worried about effectiveness 13.2 3 2.2 0

No protection against STIs 1.1 2.1 1.3 0Other health problems/doctor's advice 2.5 8.5 5.7 9.2Method decreased sexual pleasure 37.9 4.1 8.2 1.1Too difficult to obtain 1.5 1.8 2 0Other reason 15.4 10.6 8.1 10.2

Reasons for dissatisfaction leading to pill, condom, Norplant or Depo-Provera discontinuation

Moreau C, et a l . Contracept ion, 2005.

Irregular bleedingIrregular bleeding

Transition from thick to thin

endometriumTransition from

thick to thin endometrium

Fragile and superficial

blood vessels in

endometrium

Fragile and superficial

blood vessels in

endometrium

Unstable endometrial stroma and

glands

Unstable endometrial stroma and

glands

Altered endometrial remodeling

Altered endometrial remodeling

MECHANISM FOR ABNORMAL BLEEDING

�Starting contraception is associated with abnormal bleeding

�No evidence that unscheduled bleeding is associated with decreased contraceptive efficacy or harmful effects

�Consider pregnancy and other etiologies of bleeding including polyps, fibroids, cervicitis, PID, cervical cancer

INTRODUCTION

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CASE 1STUBBORN SPOTTING

ON COCS

CASE 1

�Rates of unscheduled bleeding�10-30% in the first month�Less than 10% by the third

month

�Rates of amenorrhea�Less than 2% in the first year�Up to 5% after 1 year

COCs: SETTING EXPECTATIONS

1. Speroff L, Darney PD. Clinical Guide for Contraception. 4th Ed. 2011

�Take pill at the same time each day� Inconsistent pill use associated with increased risk of unscheduled bleeding1

� Inconsistent use was associated with 60-70% increased risk of spotting/bleeding in first cycle

� Inconsistent use over time was associated with up to 600% increased risk of spotting/bleeding in subsequent cycles

COCs: GENERAL COUNSELING

1. Rosenberg WJ et al. Contraception, 1996.

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�Stop smoking!�Smokers more likely to experience unscheduled

bleeding/spotting1

�Among smokers, bleeding more likely to persist through subsequent cycles

COCs: GENERAL COUNSELING

1. Rosenberg WJ et al. AJOG, 1996.

COCs: SMOKING & SPOTTING

Figure:Proportion of oral contraceptive users with spotting or bleeding, by smoking status.1

1. Rosenberg WJ et al. AJOG, 1996.

�No significant difference in bleeding patterns between immediate start vs. conventional start of COCs1

� Immediate start of vaginal ring was associated with less prolonged bleeding and fewer frequent bleeding episodes in comparison to immediate start of COCs2

COCs: STARTING THE PILL

1. Lopez LM et Al. Cochrane Database of Systematic Reviews, 2012.2. Westhoff C et al. Obstetrics & Gynecology, 2005.

Cyclic Use Extended Cycle

BACK TO THE CASE: STUBBORN SPOTTING

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TREATING BLEEDING ON CYCLIC COCs

Double or triple the birth control pill?

�Supplemental estrogen1� Oral CEE 1.25mg x 7 days� Oral estradiol 2mg x 7 days

� Increase dose of estrogen if woman using COC with < 20mcg estrogen� Several COCs containing 20 mcg ethinyl estradiol resulted in:

� Higher rates of early trial discontinuation� Increased risk of bleeding disturbances2

�Switch to vaginal ring1. Sperof f L , Darney PD. Cl in ical Guide for Contracept ion. 4 th Ed. 2011 .

2. Gal lo , MF. Cochrane Database of Systematic Reviews, 2013.

�Discontinue the COCs for 3-4 consecutive days1

� A 3-day hormone free interval was associated with greater resolution in breakthrough bleeding/spotting in comparison to continuing active pills2

� After the first 21 days of the hormone

TREATING BLEEDING ON EXTENDED COCs

1. Godfrey EM et al. Contraception, 20132. Sulak PJ et al. AJOG, 2006

�Overall improved cycle control1

� Lower rate of breakthrough bleeding and spotting (6%)

� Lower rate of estrogen-related side effects (nausea, breast tenderness) but higher rates of vaginal symptoms

CONTRACEPTIVE RING

1 Lopez LM et al. Cochrane Database of Systematic Reviews, 2013.2 Bjarnadottir RI et al. AJOG, 2002.

Figure: Incidence of cycles with irregular bleeding with contraceptive ring or COC2 BACK

TO CASE 1: STUBBORNSPOTTING

EEDOSE

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CASE 2ANNOYING ABNORMAL

BLEEDING WITH INJECTABLE

CONTRACEPTION

CASE 2

CASE 2

� Abnormal bleeding is common in the first year

� Rates of unscheduled bleeding1� Up to 70% in the first year� Approximately 10% after the first year

� Amenorrhea is more likely over time1

DMPA: SETTING EXPECTATIONS

Within 3 months After 1 year At 5 years

Rate of amenorrhea 12% 46% 80%

1. Speroff L, Darney PD. Clinical Guide for Contraception. 4th Ed. 2011

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�Enhanced pretreatment counseling among DMPA users shown to reduce discontinuation

DMPA: COUNSELING

Percentage of women who discontinued DMPAStructured Counseling

Routine Counseling

Canto De Centina TE et al (2001)1 17% 43% p < 0.05

Lei ZW et al (1996)2 11% 42% p < 0.0001

� Elements of structured counseling include: � expected bleeding patterns� reassurance that these irregularities are not harmful

1. Canto De Centina TE et al. Contraception, 2001.2. Lei ZW et al. Contraception, 1996.

Valdecoxib1

� Dose: 40mg daily x 5d

� More women in the treatment group had cessation of bleeding (77% vs. 33%)

� Treatment group had a higher mean number of bleeding-free days in the following month (17.8 vs.11.5 days)*

*stat ist ical ly s igni f icant

Mefenamic acid2

� Dose: 500mg bid x 5 d

� More women in treatment group had cessation of bleeding in the week following treatment (69% vs. 40%)

� No significant dif ference in bleeding-free days in the following month (16.1 in treatment grp vs. 12.4 in placebo grp)

NSAIDs AND DMPA

1. Nathirojanakun P. Contraception, 2006. 2. Tantiwattanakul. Contraception, 2004.

RCT of DMPA users with unscheduled bleeeding1

Ethinyl estradiol50 mcg

Estrone sulfate2.5 mg Placebo

ESTROGENS AND DMPA

Conclusions� Ethinyl estradiol effective in stopping bleeding during treatment� Bleeding tended to recur after discontinuation of estrogen

1. Said S et al. Human Reproduction, 1996.

% stopped bleeding in 1st wk 88% 8.20%% stopped bleeding in 4 wk f/u 68% 0%Mean number of days of bleeding/spotting 5.7 17.5

TRANEXAMIC ACID AND INJECTABLE CONTRACEPTIVE

RCT of DMPA users with unscheduled bleeeding1

Tranexamic acid250mg qid x 5 days Placebo

1. Senthong AJ et al. Journal of Medical Association of Thailand, 2009.

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�Shortening interval between DMPA injections�No evidence�Not recommended

�Doxycycline �Matrix metalloproteinase inhibitor�RCT showed doxycycline no more effective than

placebo

WHAT DOES NOT WORK FOR DMPA? BACK TO THE CASE: ANNOYING ABNORMAL BLEEDING

Enhanced Counseling•Bleeding patterns

•Reassurance

Enhanced Counseling•Bleeding patterns

•Reassurance

Continue DMPA•More injections, less bleeding

Continue DMPA•More injections, less bleeding

TREAT•NSAIDs x 5-7 days•Estrogen (COCs or supplemental estrogen x 10-20 days)

•Tranexamic acid

TREAT•NSAIDs x 5-7 days•Estrogen (COCs or supplemental estrogen x 10-20 days)

•Tranexamic acid

CASE 3IRRITATING IRREGULAR

BLEEDING WITH IMPLANT

CASE 3

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�Most women experience a reduction of menstrual bleeding1

�Bothersome bleeding reported in 25% of patients2� 6.7% reported frequent bleeding� 17.7% prolonged bleeding

�Rates of amenorrhea3

� Approximately 20% in first year� 30-40% after 1 year

ETONOGESTREL IMPLANT: SETTING EXPECTATIONS

1. Mansour D. Contraception, 2011.2. Mansour D. European Journal of Contraception & Reproductive Health Care, 20083. Speroff L, Darney PD. Clinical Guide for Contraception. 4th Ed. 2011

� Number of unscheduled bleeding days:� Is HIGHEST in the first 3 months

� DECREASES over the first year

� PLATEAUS in the second and third year

CONTRACEPTIVE IMPLANT: BLEEDING PATTERNS

1 Flores JB, International Journal of Gynecology & Obstetrics, 2005.

�More unpredictable bleeding pattern1

�Amenorrhea may not be sustained if achieved� “Favorable” pattern in the first 3 months predicts a

continued favorable pattern�For those with an “unfavorable” bleeding pattern,

50% report improvement over time

CONTRACEPTIVE IMPLANT: BLEEDING PATTERNS

1 Mansour D, European Journal of Contraception & Reproductive Health Care, 2008.

EXPECTANT MANAGEMENT

for 6-12 months

Supplemental estrogen

NSAIDs

CASE 3: IRRITATING IRREGULAR BLEEDING

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10

� Limited data

� Variable efficacy of NSAIDs in LNG implant1,2� Various regimens� Small number of studies and participants

� One RCT evaluated NSAIDs in women with ETG implants3� Randomized to placebo or mefenamic acid (500mg tid)� 65% stopped bleeding within 1 week in NSAID group vs. 21% in the placebo

� Less bleeding in the subsequent 4 weeks in the women who had received NSAIDs

NSAIDS AND ETONOGESTREL IMPLANT

1 Mansour D, European Journal of Contraception & Reproductive Health Care, 2008. 2. Abdel-Aleem H, Cochrane Database of Systematic Reviews, 2013.3. Phaliwong P, Journal of Medical Association of Thailand, 2004.

� Recommendations based on studies of LNG implant

� Systematic review of estrogen vs. placebo treatment for irregular bleeding with LNG implant1� Decreased the days of ongoing bleeding� Effect lasted for several months after treatment

� More side effects in treatment group (nausea, GI upset)

ESTROGEN AND LNG IMPLANT

1. Abdel-Aleem H, Cochrane Database of Systematic Reviews, 2013.

RCT: COCs AND ETG IMPLANT

� Guiahi M et al. Obstet Gynecol, September 2015.� RCT comparing COC vs. placebo for treatment of bothersome bleeding from ETG implant

� N = 32 women, bothersome bleeding for > 7 days� Proportion of women who stopped bleeding during treatment and at the end of treatment

PRAGMATIC APPROACH

REGIMEN EVIDENCE?

First choice COC taken daily x 21 with a 7-day break (up to 3 months) Minimal

Second choice

Cyclic progestin -- medroxyprogesterone acetate 10 mg bid x 21 days with a 7-day break (up to 3 months)

Anecdotal

Third choice POP daily (up to three months) Anecdotal

Fourth choice

NSAIDS, especially COX-2 inhibitors, daily for 5-10 days Minimal

Fifth choice Tranexamic acid 500 mg twice daily for 5 days Minimal

FIGURE: Pragmatic approach to the use of currently available therapies in stopping unscheduled bleeding in users of ETG contraceptive implant (Mansour D. Contraception, 2011)

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for 6-12 months


for 6-12 months



COCs -10-20 days

COCs -10-20 days

Oral estrogen -1.25mg CEE-2mg estradiol

Oral estrogen -1.25mg CEE-2mg estradiol

Transdermal estrogen -0.1mg/day

Transdermal estrogen -0.1mg/day

NSAIDs x 5-7 days

NSAIDs x 5-7 days

US Selected Practice Recommendation for Contraceptive Use, 2013

BACK TO CASE 3: IRRITATING IRREGULAR BLEEDING

CASE 4LASTING LIGHT

BLEEDING WITH LEVONORGESTREL IUS

CASE 4

� Unscheduled spotting or light bleeding is common, especially during the first 3–6 months

� For LNG 52/5, spotting was present in 25% of the users at 6 months and decreased over time.1

LNG-IUS: SETTING EXPECTATIONS

1. Hidalgo M et al. Contraception, 2002.

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LNG IUS: SETTING EXPECTATIONS

•79-97% reduction in bleeding•33% developed oligo/amenorrhea

in first 3 months, 70% at 2 yrs•Amenorrhea at 1 yr: 20%•Amenorrhea at 2 yrs: 30-40%

•Amenorrhea at 1 yr: 6%•Amenorrhea at 2 yrs: 12%

LNG 52/5

LNG13.5/3

LNG 13.5/3 & LNG 52/5:BLEEDING AND SPOTTING OVER TIME

1. Nelson A et al. Obstetrics & Gynecology, 2013.

A/B Mean number of bleeding or spotting days by 30-day reference period during the first year of LNG-IUS

C/D Mean number of bleeding or spotting days by 90-day reference period during the 3 years of LNG-IUS

� Estrogen1

� Estradiol patch weekly x 12 weeks� Greater number of bleeding/spotting days compared to placebo (non-significant)

� More dissatisfaction with treatment

� NSAIDs1� Naproxen 500mg bid x 5 days every 4 weeks for 12 weeks

� Fewer number of bleeding/spotting days compared to placebo (non-significant)

� More dissatisfaction with treatment

LNG-IUS: INTERVENTIONS FOR BOTHERSOME BLEEDING

“No direct evidence was found regarding therapeutic treatments for bleeding irregularities during LNG-IUD use.”-US SPR, 2013

1. Madden T et al. AJOG, 2012.2. Abdel-Aleem H, Cochrane Database of Systematic Reviews, 2013.

�Provide excellent counseling pre-insertion�Discuss bleeding/spotting in

first 3-6 months�Discuss amenorrhea

�Provide reassurance as bleeding likely to improve

�Confirm appropriate location of IUD

BACK TO THE CASE: LASTING LIGHT BLEEDING

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SUMMARYMANAGING

BOTHERSOME BLEEDING ASSOCIATED WITH

CONTRACEPION

GENERAL GUIDANCE

Evaluate for pregnancy, cervicitis, and pathology of cervix and uterus

If appropriate, advise tobacco cessation

If appropriate, reinforce consistent use and decrease missed doses

Reinforce and encourage continuation

Rates of irregular bleedingCOCs • 10-30% in first month of use

• <10% by the third month of useVaginal Ring • Less common in comparison to COCs

• Up to 6% in first yearPatch • Similar to COCs except slightly higher

rate of spotting in first 2 cyclesInjectable • 70% in first year

• 10% after the first yearImplant • Up to 25% in first 2 years

Cu-IUD • Less irregular bleeding compared to LNG-IUS

LNG-IUS • Up to 25% at 6 months• 8-11% at 18-24 months IRREGULAR

BLEEDING BY CONTRACEPTIV

E T YPE

RATES OF AMENORRHEA Within 1st

yearAt 1 year Beyond

COCs <2% Up to 5%

Vaginal Ring Similar to COCs

Patch Similar to COCs

Injectable 12% 46% 80% at 5 yrs

Implant 21% 30-40%

Cu-IUD 0% 0% 0%

LNG-20 20% 30-40% at 2 yrs

LNG-14 6% 12% at 2 yearsAMENORRHEA

BY CONTRACEPTIVE

TYPE

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US Selected Practice Recommendation for Contraceptive Use, 2013

UNINTENDED PREGNANCY

ADDRESSING DISSATISFACTION

Address dissatisfaction& manage bleeding

Continue contraception

Dissatisfaction with


Discontinuation of


Delay in resumption of contraception or adoption of less

effective method

Thank you

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PrEP Guidelines for the Ob/GynMegan J. Huchko, MD, MPH

Obstetrics and Gynecology UpdateOctober 14, 2015

• I have no financial or other conflicts of interest to declare

Outline• The Need for PrEP: HIV Treatment and Prevention

Gap

• What is the evidence?

• What is the role of the Ob/Gyn in PrEP?

• How do I provide PrEP?

• PrEP in Conception, Pregnancy and Breastfeeding

1. How many patient have you discussed PrEP with this year?

A. Over 100B. Between 50 and 100C. Less than 50D. Maybe a coupleE. PrEP? I am ob/gyn, not an

HIV specialist!

O v er 1 0

0B e t

w e en 5 0

a n d 1 0 0

L e s s t h a

n 5 0M a

y b e a c

o u pl e

P r EP ?

I a m o b

/ g yn , n

o t . ..

0% 1%

67%

24%

8%

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Need for HIV prevention methods• Prevention is the most effective and cost-

effective way to prevent morbidity and mortality related to HIV

• 50,000 new HIV-infections in US annually• Women represent >75% of new cases due to

heterosexual transmission– African American women are at highest risk for

heterosexual acquisition of HIV

Antiretroviral Therapy as treatment and prevention

• Extends life expectancy• Reduces complications related to HIV/AIDS• Prevented maternal to child transmission (<1%)• “Treatment as Prevention:”

– Effective ART can reduce HIV viral load and reduce the risk of HIV-transmission

• No documented transmissions between monogomousserodiscordant couples in which HIV+ partner is virally suppressed (HPTN052)1

However….1Cohen MS, HPTN052, International AIDS Society, 2015

HIV in the US:Underdiagnosed and Undertreated

Num

ber

(in ‘0

00s)

Prevalence Diagnosed Treated

1,106,400-1,200,000

874,056-960,000

437,028-489,600

~80%Diagnosed

~40%Treated

Smith MK, et al. PLoS One. 2012;9:e1001260.Gardner EM, et al. Clin Infect Dis. 2011;52:793-800.Burns DN, et al. Clin Infect Dis. 2010;51:725-731.

~20% of AllHIV-Infected Are HIV RNA

<50 copies/mL

209,773-376,992

Viral Suppression

New AIDS Cases and AIDS-Related Deaths in the United States

Num

ber

of C

ases

95 96 97 98 99 00 01 02 03 04 05 06 07 08 09Year

AIDS-Related Deaths

New AIDS Cases

CDC. HIV Surveillance Report, 2010;vol 22. Published March 2012.http://www.cdc.gov/hiv/surveillance/resources/reports/2010report/pdf/2010_HIV_Surveillance_Report_vol_22.pdf.

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Potential Intervention Approachesto Prevent HIV Transmission

• Barrier protection• STI treatment• Blood screening• ART

– Maternal-to-child transmission– Decrease partner’s viral load– Treatment of acute HIV infection

● Barrier protection● STI treatment● Oral PEP● Oral PrEP● Topical microbicides● Vaccines● Infection control● Circumcision

● Condom promotion● Individual intervention● Couples intervention● Community based intervention● Structural intervention

Decrease Sourceof HIV Infection

Decrease Host Susceptibilityto HIV Infection

Alter Risk-Taking Behavior

Mayer KH, et al. Am J Public Health. 2010;100:1867-1876.

What is PrEP?• Pre-exposure prophylaxis with antiretroviral

therapy to reduce the risk of HIV acquisition• Daily, oral antiretroviral therapy given to adults at

high-risk of HIV-acquisition– Tenofovir 300mg and Emtricitabine 200mg (in fixed-

dose combination Truvada, or TDF/FTC)– Once daily dosing

• Has been shown to reduce risk of HIV infection through sexual and IVDU exposures

• Approved in July 2012 by the FDA

Biologic Plausibility• Infants receiving pre and post-exposure

prophylaxis has 68% reduction in perinatal acquisition

• Post-exposure prophylaxis within 72’ of HIV-exposure reduced HIV-risk by 81%

• Animal studies of vaginal and rectal PrEPsuggested efficacy in preventing sexual transmission

• Proof of efficacy study of topical tenofovir gel in women– CAPRISA 004

• First oral PrEP study of emtricitabine/tenofovir DF for MSM– iPrex

• Proof of efficacy studies in heterosexual adults in Africa– Partners PrEP– TDF2 (CDC4940)

• First trial of PrEP in people who inject drugs– Bangkok Tenofovir Study

PrEP Trial Results

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CAPRISA 004 Study:Heterosexual Women

Double-BlindDouble-blind study

South Africa sites(Kwa-Zulu, Natal)

Sexually active HIV-uninfected

women not using barriercontraception

Screened (n=2160)

Randomization1:1

Placebo (n=444)

Tenofovir Gel (n=445)

Abdool Karim Q, et al. Science. 2010;329:1168-1174.

Administration of placebo/tenofovir DF gel•Insert 1 dose within 12 hours before sex

•Insert 1 dose ASAP, within 12 hours after sex

•No more than 2 doses within 24 hours

Similar baseline demographic characteristics, sexual history/behavior,

and contraception use

0 6 12 18 24 30

CAPRISA 004 Results:Cumulative Probability of HIV Infection

Pro

babi

lity

of In

fect

ion

0 6 12 18 24 30Month

Abdool Karim Q, et al. Science. 2010;329:1168-1174.

47% 50% 47% 40% 39%Effectiveness (%):(P=0.064) (P=0.007) (P=0.004) (P=0.013) (P=0.017)

P=0.017

TenofovirGel

PlaceboGel

iPrEx Study:MSM and Transgender Women

Double-Blind

Multinational studyHIV-negative men or

transgender women whohave sex with men

Screened (n=4905)

Randomization1:1

Placebo (n=1248)

TDF/FTC (n=1251)

Study Outcomes•HIV seroconversion•Adverse events•Metabolic effects•HBV exacerbations•Risk behavior and STIs (including HSV)•Adherence

Similar baseline demographic characteristics

(except mean age), sexual risk factors, STIs,and HBV status

Drug resistance, HIV RNA level, immunologic respons e, and CD4 cell count assessed in people whobecome HIV positive during the study.

Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

Follow-Up3324 person-years(median 1.2 years)

iPrEx Study Results:Cumulative Probability of HIV Infection

0 12 24 36 48 60 72 84 96 108 120 132Weeks

Placebo(n=1248)

TDF/FTC(n=1251)

P=0.005

Cum

ulat

ive

Pro

babi

lity

of H

IV In

fect

ion


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Partners PrEP Study:Serodiscordant Heterosexual Couples

Double-Blind

Phase 3, Double-Blind StudyKenya, Uganda

Serodiscordant, heterosexualcouples (n=4758)

(HIV-positive partner not yeteligible for ART)

Normal liver, renal,hematologic values/function

Randomization1:1

Placebo (n=1584)

Tenofovir DF qd (n=1584)

Baeten J, et a. N Engl J Med. 2012;367:399-410.

Follow-Up

Up to 36 months(median 23 months; 7830 person-years)

Tenofovir/Emtricitabine qd (n=1579)

Primary Endpoints

HIV infection in HIV-negative partnerSafety

All patients received comprehensive HIV prevention services.

Partners PrEP Study:Cumulative Acquired HIV Infections

0

0.01

0.02

0.03

0.04

0.05

Cum

ulat

ive

Acq

uire

dH

IV In

fect

ion


0 3 6 9 12 15 18 21 24 27 30 33 36Months

TDF/FTC(n=1568)

Placebo(n=1568)

Tenofovir DF(n=1572)

TDF2 Study: PrEP in Heterosexually Active Young Adults in Botswana

• Phase 2 trial in heterosexual men and women (n=1219)

– Women: 45%– Married: 94%– Completed study: 67%

• Primary results– HIV seroconversion (n=33)

• Daily oral TDF/FTC(n=9 [2 males/7 females])

• Placebo (n=24 [10 males/14 females])

• 62% reduction

• Results in women differed than that seen in the FEM-PrEP study, which showed no benefit

Thigpen MC, et al. N Engl J Med. 2012;367:423-434.

Pro

port

ion

0 1 2 3

HIV Seroconversion (ITT)

TDF/FTC(n=610)

Placebo(n=606)

62%Reduction(P=0.03)

Years

PrEP Effectiveness by Adherence Levels

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6

http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Preexposure-Prophylaxis-for-the-Prevention-of-Human-Immunodeficiency-Virus

PrEP Guidelines Who can benefit from PrEP?• CDC recommends PrEP for:

– Sexually active MSM (IA)– Adult heterosexually active men and women at

high risk of HIV acquisition (IA)– Adult IDU (IA)– “Discussion” for known HIV-discordant couples

attempting conception

CDC/US Public Health Service. Preexposure Prophylaxis for the Prevention of HIV Infection in the US: A Clinical Practice Guideline. 2014

ACOG Committee Opinion1: Who?• Women in known sero-discordant relationships• Sexually active women within a high HIV-prevalence

area2 or social network and one of the following: – inconsistent or no condom use– diagnosis of sexually transmitted infections– exchange of sex for commodities (such as money, shelter,

food, or drugs)– use of intravenous drugs or alcohol dependence or both; – incarceration– partner(s) of unknown HIV status with any of the factors

previously listed1 http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/ Preexposure-Prophylaxis-for-the-Prevention-of-Human-Immunodeficiency-Virus2http://www.cdc.gov/nchhstp/atlas/

10/14/2015

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What is the role of the Ob/Gyn?• Reproductive-aged women often see their ob/gyn as a

primary care provider• Many of our patients are at risk for HIV

– High-risk behavior with HIV-unknown partners– Long-term relationships with HIV+ partners

• HIV providers do not routinely see partners to talk about PrEP

• HIV-risk and partner considerations around pregnancy and lactation are unique– Acceptable risk may increase during conception, decrease

during pregnancy and lactation– Partners may be more engaged in care

HIV prevention is a “core” family planning service

CDC MMWR: Providing quality family planning services, 2014.

Case: MM• 31 yo HIV-negative woman sees you for routine gyn care

– No medical issues– Had been on OCPs until recently– Regular menses, no prior STDs, surgeries

• Partner recently tested positive for HIV, is in care and on ART

• Haven’t been having intercourse since diagnosis• Wants to know options for attempting pregnancy,

breastfeeding and beyond to reduce her risk for HIV

How do you counsel? Manage?

2. Do you think MM is a good candidate for PrEP

A. Yes, definitelyB. MaybeC. NoD. I would probably need to consult

an HIV-specialist

Y e s, d e

f i n it e l y

M ay b e N o

I wo u l

d pr o b

a b ly n

e e d t o .

. .

88%

5%0%7%

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8

CDC Guidelines forHealthcare Providers

• Before initiating PrEP– Determine eligibility– Counseling on importance of adherence for efficacy

• Beginning PrEP regimen– Dosing and adherence support

• Follow-up while on a PrEP medication is being taken– Monitor for HIV, STIs, risk behaviors and adherence, and safety

– Report any serious adverse events to the FDA’s MedWatch

• Discontinuing PrEP– Patient choice, safety concerns, or HIV infection


CDC Guidelines for Healthcare Providers: Before Initiating PrEP

• Determine eligibility– Take a sexual history!– Document negative HIV antibody test immediately before starting

PreP (within the week)– Test for acute HIV infection if recent exposure and/or symptoms are

present

– Determine pregnancy/breastfeeding status and pregnancy desires• Provide contraception if indicated

– Confirm• Long-term potential for ongoing, high risk for HIV acquisition• Calculated creatinine clearance is >60 mL/min (C-G)

• Other recommended actions– Screen for HBV (offer vaccine if susceptible; treat if present)– Screen and treat as needed for STIs


CDC Guidelines for HealthcareProviders: Beginning PrEP Medication Regimen

• Prescribe Tenofovir DF/Emtricitabine (300/200 mg)– 1 tablet daily

• In general, prescribe no more than a 90-day supply– Renew only after confirming patient remains HIV uninfected

• If HBV infected– Consider TDF/FTC for HBV and HIV prevention

• Provide risk-reduction and PrEP medication adherence counseling and condoms


CDC Guidelines for HealthcareProviders: Follow-Up While on PrEP

• Evaluate and support PrEP medication adherence at each follow-up visit (more often if needed)– For women, assess pregnancy

• Every 2 to 3 months– HIV antibody test (document negative result)– Assess

• Risk behaviors and provide risk-reduction counseling and condoms

• STI symptoms (if present, test and treat as needed)

• Every 6 months– Test for STI regardless of symptomatology (treat as needed)

• Every 3 months after initiation, then yearly while on PrEP– Blood urea nitrogen– Serum creatinine


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CDC Guidelines for HealthcareProviders: Discontinuing PrEP

• Perform HIV test(s) to confirm HIV status– If positive

• Discontinue PrEP

• Order and document CD4+ count, viral load and resistance testing• Establish linkage to care• Help with linkage to partner notification and testing

• For pregnant women, inform prenatal-care provider and coordinate care to maintain HIV prevention during pregnancy and breastfeeding

– If negative• Continue PrEP at least 4 weeks after last exposure

• Establish linkage to risk-reduction support services as indicated

• If active HBV infection at initiation of PrEP– Consider appropriate medication for continued treatment of HBV

infectionCDC/US Public Health Service. Preexposure Prophylaxis for the Prevention of HIV Infection in the US: A Clinical Practice Guideline. 2014

Disco Survey: HIV- in a relationship with an HIV+ desire children

•123 surveys started, 93 completed•90% want children with their HIV+ male partner•25% have tried to get pregnant with their HIV+ male partner•67% had vaginal sex without condom with HIV+ partner

•Condom use: 27% always, 42% half time, 31% never

•42% have seen a provider to discuss ways to get pregnant 45% primary care, 80% HIV specialist, 35% OBGYN, 30% fertility specialist

Most women are willing to use various methods to prevent transmission53% are willing to use PrEP, 51% Timed unprotected sex, 84% ovulation prediction kit, 47% PEP, 62% sperm washing vaginal insemination, 22% IVF, 44% adoption, 9% insemination with donated sperm

Still enrolling: http://hiv.ucsf.edu/care/perinatal/pro_men.html

PrEP in Conception, Pregnancy and Breastfeeding

PrEP in Conception, Pregnancy and Breastfeeding

• Peri-conception and pregnancy are times of increased HIV risk and susceptibility for women in HIV-discordant relationships

• PrEP can be used to reduce the risk of transmission to both mother and baby

• Long-term effects of TDF/FTC on neonate are limited– Most trials excluded or discontinued pregnant women

• PrEP trial showed no difference in pregnancy rates, birth outcomes or infant growth between placebo, TDF and TDF/FTC arms among women with incident pregnancies

– WHO recommends TDF/FTC for all pregnant and breastfeeding women for PMTCT

– TDF or TDF/FTC are widely used in reproductive aged women for HIV care and continued in pregnancy

– No trial or registry data show signals of adverse events

CDC/US Public Health Service. Preexposure Prophylaxis for the Prevention of HIV Infection in the US: A Clinical Practice Guideline. 2014Mugo, et al. JAMA, Jul 2014

ACOG Committee Opinion: Pregnancy and PrEP

• The drug combination of TDV and FTC is commonly used during pregnancy and has a reassuring safety profile.

• Practice vigilance for new HIV infections in lactating women

http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Preexposure-Prophylaxis-for-the-Prevention-of-Human-Immunodeficiency-Virus

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Providing PrEP in Conception & Pregnancy

• Partner should be on effective ART to reduce viral load• Provider should review all options for safe conception, including

assisted reproductive technology• Semen analysis and, if indicated by history, HSG to prevent

unnecessary exposure if likelihood of pregnancy is low• STI screening in both partners• Adherence counseling• Start PrEP 1 month prior and continue 1 month post-exposure• Recommend limiting sex without a condom to peak fertility times

– Cervical mucus checks– Ovulation prediction kits

• If pregnant: HIV testing monthly, with viral load if signs of acute infection and at 36 wks

https://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf accessed October 1, 2015

Financial Considerations• Private and public insurance plans vary in coverage for PrEP• Gilead Sciences has a PrEP medication assistance program

that provides:– Truvada (TDF/FTC) to providers for eligible patients– Access to free HIV testing– Co-pay assistance for medical visits– Free condoms– https://start.truvada.com, 1-855-330-5479

• Billing/ICD-10 Codes:Z20.6 Contact with and suspected exposure to viral HIV/AIDS virus

Z71.7 Human Immunodeficiency Virus Counseling

Our Case: MM• Does she seem like a good candidate for PrEP?

• Screen for HIV, HepB and other STIs; check CrCl• Discuss reproductive desires

– Provide LARC if desired

• Start Truvada• Adherence counseling, continued indication for PrEP at

each visit• Check HIV, BUN/Cr q3 months; STI testing q6 mos

• Questions? NCCC Warmline: 1-888-448-8765

Resources for Providers• Decision-support tools, flowsheets and checklists: http://www.cdc.gov/hiv/pdf/guidelines/PrEPProviderSupplement2014.pdf• ACOG Committee Opinion Preexposure Prophylaxis for Prevention of

HIV, May 2014.• AIDS Info (http://aidsinfo.nih.gov, http://www.aids.gov)• The National Network of STD/HIV Prevention Training Centers (http://nnptc.org/)• The AIDS Education Training Centers National Resource Center (http://www.aids-ed.org).• The National HIV/AIDS Clinicians’ Consultation Service (http://www.nccc.ucsf.edu) • NCCC Warmline: 1-888-448-8765 • HIVE: www.hiveonline.org

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Resources for Patients• Project Prepare Website: www.projectprepare.net• http://www.prepwatch.org/#women• Centers for Disease Control and Prevention:

http://www.cdc.gov/hiv/prep/• Project inform: http://www.projectinform.org/pdf/orderprepbooklets

– A new option for safer loving for women in Spanish and English• San Francisco Department of Public Health: www.prepfacts.org• PrEP watch: http://www.prepwatch.org/#guidance• Bay Area Perinatal AIDS Center: Positive Reproductive Outcomes for Men:

http://hiv.ucsf.edu/care/perinatal/pro_men.html• Positively Negative: https://positively-negative.squarespace.com• www.hiveonline.org

Acknowledgements• Ian McNicholl, PharmD (slides)• Shannon Weber at HIVE• Nika Seidman• Deb Cohan• Jennifer Cocohoba, PharmD

iPrEx Study: ComprehensivePackage of Prevention Services

• All subjects received HIV testing, risk-reduction counseling, condoms, and diagnosis and treatment of symptomatic STIs

• At 24-week intervals, subjects screened for – Asymptomatic urethritis, syphilis, antibodies to HSV-2, genital warts/ulcers– Treatment was provided when indicated

• Sexual partners– Offered treatment of STIs

• As needed, linkage to local prevention and treatment services• Counseled on the use of conventional methods to protect from HIV• HBV vaccination offered to susceptible subjects


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Partners PrEP Study:Comprehensive Prevention Services

• Risk reduction counseling (individuals and partners)• Free condoms and condom counseling• Contraception counseling and provision

• Screening and treatment for STIs• Counseling and referral for other HIV-prevention

interventions (eg, male circumcision), per national policies


Worldwide Treatment andPrevention Gaps (2011)

• On ART: 8 million

• Number needing ART: 15 million

• New infections: 2 million annually• People were waiting to become treatment-

eligible, sicken, or die: ~24 million• Estimated coverage of ART in low- and

middle-income countries: 36%

Granich R, et al. Curr Opin HIV AIDS. 2013;8:41-49.

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New Treatment Strategies for Management of Menopause

Marcelle I. Cedars, M.D.Professor and Director

Division of Reproductive Endocrinology and InfertilityUCSF

Conflict of Interest

• Conflict of Interest– None

• Off –label drug use– Mirena IUD

Problems in Peri-Postmenopausal Women

• Abnormal uterine bleeding

• Vasomotor symptoms

• Genital atrophy

• Decrease in skin collagen• Rapid bone loss

• Increase in coronary heart disease

• Increase in Alzheimer’s disease

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Menopausal Hormone Therapy (MHT) over the decades

1966“Feminine Forever”

1980’s – cohort and case/controlStudies – support MHTreduces CHD and osteoporosis

1992 – American College of PhysiciansRecommends MHT to prevent CHD

1995 PEPI trial

2002WHI – E+P

2004WHI - ERT

WHI vs. Observational studies

Manson JE, et al. 2006; 13:139

Patient Characteristics: Agethe “timing” hypothesis

• Grodstein et al. J Womens Health 2006– Nurse’s Health Study: evaluating time from

menopause – women near menopause reduced CV risk (RR 0.66 CI: 0.54-0.80)

• Manson et al. NEJM 2007– WHI: coronary calcium – women 50-59, coronary

calcium score lower in women on ET vs. placebo (OR 0.69 CI: 0.48-0.98)

• ELITE Trial – Hodus HN 2015– Protection from CIMT changes in younger women

Endothelial dysfunction during MT

Moreau JCEM 2012

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Acceleration of CV risk

El Khoudary Menopause 2012

Ovarian aging and CV risk

Bleil Menopause 2013

Danish Osteoporosis Prevention Study (DOPS)

• 1006 women

• Randomized 45-58 years, last vaginal bleeding 3-24 months prior to enrollment and increased FSH

• Randomized, open-label, trial of estrogen (2mg daily), triphasic estradiol + norethisterone (uterus) vs. no treatment

Schierbeck LL, BMJ 2012

DOPS - 2012

Schierbeck LL, BMJ 2012

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DOPS - 2012

• At 10 years, reduced overall mortality

• Reduced heart failure, MI

• No “apparent” increased risk cancer, VTE

Breast CancerRisk Factors

• Low body weight

• High mammographic breast density

• Late menopause


• Was there truly a “protective” effect of estrogen in the E-only arm – WHI?

• Estrogen– Role of estrogen deprivation

• Whether natural or via anti-estrogens (tamoxifen/aromatase inhibitors)

– Estrogen as a pro-apoptotic

Breast CancerThe ‘Gap’ Hypothesis

• Starting estrogen remote from menopause decreases risk while treatment within 2 years increases breast cancer risk

• The ‘gap hypothesis’ and the ‘timing hypothesis’ are thus in conflict

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• Low body weight

• High mammographic breast density

• Late menopause

• Starting close to menopause

• 2 years after stopping HRT – risk equivalent to never users

The “Menopausal Syndrome”

• Epidemiological Studies: proximity to menopause, not associated with aging, relieved with estrogen– Vasomotor Symptoms– Vaginal dryness/dyspareunia– Difficulty sleeping/insomnia– Mood and depression– Changes in cognitive function

Trouble Sleeping by Cycle Day

Kravitz, H. M. et al. Arch Intern Med

Verbal Memory

Decrement in immediate (A) and delayed (B) verbal recall

Epperson JCEM 2013

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Adjusted OR for CES-D > 16Across Menopausal Transition

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Pre Early Peri Late Peri Post HT Users

Bromberger, J Affect Disord 2007

Hot Flashes worsen Sleep

• 20 healthy premenopausal women receiving GnRHa

• 80% concordance between subjective/objective VMS (sVMS/oVMS)

• Sleep efficiency (actigraphy) worse with oVMS, quality worse with sVMS (questionnaire)

Joffe H, Menopause 2013 PMID 23481119

Estrogen and the Brain

• Direct effects– Enhances synaptic plasticity, neurite growth,

hippocampal neurogenesis and long-term potentiation (memory)

– Protects against apoptosis and neural injury– Stimulates aceytlcholine (memory), serotonin,

noradrenalin– Decrease deposition of β-amyloid– Promotesmorphological and electrophysiological

correlates of learning and memory• Indirect effects

– Vasculature– Immune system

NIA – Frontiers proposal – Bench to BedsideEstrogen as a case-study (2009)

Estrogen and the Brain

• Alzheimer Disease– Early and consistent symptom – loss of

episodic memory (failing to recall appointments and events)

– In the laboratory: estrogen reduces the formation of β-amyloid formation and diminishes hyperphosphorylation of tauprotein

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Estrogen and the BrainAlzheimer Disease

• Observational studies suggest protection• Meta-analyses suggest risk reduction of

approximately 1/3• Contradicted by the WHIMS trial (ages 65-79)

– Risk of dementia increased two-fold with combined HRT

– Impact noted within a few years, suggesting impact primarily on the vasculature

– Past history of use associated with lowered incident risk of dementia (including Alzheimer Disease)

• Initiation in older women WITH disease is not beneficial

HRT/ET and Neuroprotection

• WHIMS (Shumaker et al., JAMA 2003;289:2651-62; Rapp et al., JAMA 2003;289:2663-72)

– increased cognitive impairment and dementia in the oldestpopulation

– Those patients in WHI who had previously taken HRT had LOWER risk of dementia

• Observational/animal studies– role of timing, type– improvement in certain skills (memory and verbal

fluency)– impact of smoking

Estradiol and Depressive Disorders(Soares et al., Arch Gen Psychiatry 2001;58:529)• 50 perimenopausal women aged 40-55 with irregular

menstrual periods and FSH > 25 IU/L meeting criteria for major depressive, dysthymic, or minor depressive disorder by DSM-IV blindly randomized to transdermal estradiol (0.1 mg) or placebo for 12 wks

• Remission of depression observed in 17 of 25 (68%) on E2 and 5% on placebo

• Regardless of DSM-IV diagnosis, subjects responded similarly to E2

Current Thinking• Indication for MHT

– Menopausal symptoms– Prevention of osteoporosis

• Best treatment population– Young women < 60 years of age– < 10 years from menopause

• Individualization– Personal preference– Baseline risk– Characteristics of MHT (route, type, dose)

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Assess Risk

• CV Risk– http://my.americanheart.org/cvriskcalculator

• Stroke Risk– Bushnell, Annals Int Med 2014

• Breast Cancer Risk– http://www.cancer.gov/bcrisktool/– Discuss SERM if 5-year risk > 3%– First degree relative, BRCA+, personal

history of biopsy with atypia

Assess Risk

• Osteoporosis Risk– http://www.shef.ac.uk/FRAX/tool.aspx?country=9

• NAMS decision support tool– Menopause 22(3): 247-253, 2014– MenoPro App

“Lowest Dose”

• Start low– Decreased stroke risk– Positive effects on symptoms

• May take longer to document benefit

– Positive effects on bone– Safety re: endometrial protection when

unopposed not confirmed– Safety re: CVD not confirmed

Route/Type

• Blood pressure – impaired endothelial function– Small impact of oral; no impact for transdermal– beneficial impact suggested with estradiol and

drospirenone

• Metabolic syndrome – menopause diabetogenic– Reduced DM and insulin resistance with estrogen– Advantage of natural progesterone/non-androgenic

progestins (drospeirenone, dydrogesterone)

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Route/Type

• CVD– CRP – increased with oral and not transdermal;

worsening affect with MPA– “first pass” effect on the liver (lipids)– endothelial function - improved with both

(inhibited by MPA and NET)– MMP-9 – increased by oral and not by transdermal

• Thromboembolic events (case-control study)– Increased risk with oral– No increase with transdermal

Route/Type

• Neuroprotection– No differences available between oral and

transdermal

• Breast cancer– No differences available between oral and

transdermal– Increased risk with combined progestational

agent

Route

• Transdermal– Less negative effect on surrogate markers

• Clotting factors, TG, CRP

– Decrease stroke risk– Decreased CV risk – not well documented

• Vaginal– For local symptoms

Type

• Progestogen– Daily combined vs. cyclical

• Improved protection re: endometrial cancer• Increased breast cancer risk

– MPA vs. progesterone• Stroke risk: Progesterone < MPA

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Duration

• 3-5 years

• Stopping guidelines– Breast cancer risk after combined

continuous for 7 years– Bone loss will resume– Vasomotor and vaginal symptoms may

return

• Long-term treatment

Type – New combination therapies

• Activella: E2 1mg + NETA 0.5mg daily

• Femhrt: EE 5 mcg + NET 1mg daily

• Ortho-prefest: E2 1mg + norgestimate 0.09mg– Alternate 3 days unopposed E2 with

combination

• Combi-patch– E2 with LVG or NETA

Type – new alternatives

• Combination – estrogen + SERM– CEE 0.45mg + Bazedoxifene (BZA) 20mg– Vasomotor symptom relief– Vaginal symptom relief– Bone protection – albeit < MHT– Favorable lipid profiles– No adverse risk to bone/endometrium– No long-term studies of events

Lobo RA, Fertil SterilPinkerton JV, J Women’s Health 2014Pinkerton JV, JCEM 2014

Vaginal Relief – new alternatives

• Ospemifene– SERM – local effect on vaginal tissue– Minimal increase endometrial thickness – no

histological changes– Neutral breast– Possible positive bone effect (bone markers)– Possible increased stroke risk

Archer DF, Menopause 2014

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Risks of Menopausal HT:What We Think We Know Now

• Breast cancer– RR 1.1-1.5 (all forms of estrogen) - 8 add’l/10,000 women– Increased with progestogen (especially continuous)– No increased risk with estrogen > 2 years post-menopause

• Endometrial cancer– R 4.0-11.0 (unopposed estrogen)– reduced by progestin

• Venous Thromboembolism (oral therapy)– 2 additional cases per 10,000– Mortality low, 1%

• Gall bladder disease• CVD

– increased risk with existing disease and remote from menopause

Current “Truths” Regarding Menopausal HT and CVD

• The public is largely unaware that CVD is the primary cause of mortality in women.

• Women should not take estrogen to prevent CVD.

• Women with known CVD should not begin HT for treatment of heart disease.

Current “Truths” Regarding Menopausal HT and Breast cancer

• Estrogen-alone (greater than 2-5 years post-menopausally) lowersbreast cancer risk

• 2 years post-cessationof HRT/ET –breast cancer risk is no greater than never-users

Hormone related indicators of the risk of breast cancer

ASRM Practice Committee Report 2008

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Endocrine Society 2010 Endocrine Society 2010

Assessment of Perimenopausal women

• BP• Fasting lipid profile• Fasting glucose• TSH• Assess for metabolic syndrome (decrease in insulin

sensitivity; increase in central obesity)

• Counsel re: maintenance of healthy weight• Assess sleep quality• Screen for depression• Vitamin D deficiency

• IMPORTANCE OF LIFESTYLE

Current “Truths” Regarding Menopausal HT

• The “timing hypothesis” suggests CVD protection MAY be possible if started near the onset of menopause

• The “gap hypothesis” suggests breast cancer risk is HIGHEST when started near menopause.

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Current “Truths” Regarding HRT and CVD

• A statin is the drug of choice for any woman with hypercholesterolemia

• First-line therapies for women with known CVD diseaseinclude risk-factor modification, aspirin, β-blockers, statins and angiotensin-converting enzyme inhibitors - just as in men

Current “Truths” Regarding HRT and Depression

• Psychotherapy is first line treatment

• Psychopharmacology is applied for severe depression or depression in absence of vasomotor symptoms

• Trial of estrogen if onset during perimenopause– Recommend transdermal

Benefits of Menopausal HT:What We Think We Know Now

• Prevents or abolishes hot flashes –still the most effect treatment

• Prevents or improves genital atrophy

• Prevents or slows bone loss

• May reduce risk of Alzheimer’s disease

• May reduce risk of colon cancer• May improve overall quality of life

So Just When Is Menopausal HT Indicated Now?

• For symptomatic women

• For prevention of osteoporosis in those where other drugs may be contraindicated

• ?In women with new onset depression

• ?For those who feel better taking estrogen

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Alternatives and Future Directions for Research

• Estrogen/Progestin Therapy– progestagen-IUD for uterine protection– transdermal estrogen– lower dosages– new progestational agent

• SERM + estrogen combinations• New SERMs

– neurospecific action– bone specific action– anti-estrogenic at breast and uterus– Tissue selective estrogen complex

Updates in Osteoporosis

Jeffrey A. Tice, MD

Associate Professor of Medicine

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

What’’’’s New in Osteoporosis

• Risk stratification

• Under recognition and poor adherence

• New concerns about treatments

• When to start and stop drug therapy

Normal bone Osteoporosis

A disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. World Health Organization (WHO), 1993

What is osteoporosis?

Traditional Risk Factors for Fracture

• The Big Three:– Older age– Postmenopausal female– Caucasian/Asian

• Other important risk factors- Family history of fracture- Low body weight (<127 pounds in women) - Smoker, >3 drinks/d- Certain drugs (steroids, AIs) and diseases (RA, celiac)- Previous fracture (especially hip or spine)

• Bone mineral density (BMD)

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 > -1.0 “normal”– -1.0 to -2.5 “low bone mass” (was called “osteopenia”)– T < -2.5 “osteoporosis”

• Z-score is the number of SDs above or below others of the same age

AGE T-Score

= -1.0

T-Score

= -2.5

50 6 % 11 %

60 8 % 16 %

70 12 % 23 %

80 13 % 26 %

Risk of Fractures Over 10 Years in Women

BMD Does Not Fully Explain The Effect of Age on Fracture RiskBMD Does Not Fully Explain The Effect of Age on Fracture RiskBMD Does Not Fully Explain The Effect of Age on Fracture RiskBMD Does Not Fully Explain The Effect of Age on Fracture Risk

http://www.shef.ac.uk/FRAX/tool.jsp

Calculating Absolute Fracture Risk: FRAXWho Should Have a DXA?

• Guidelines for general population

– All women > 65, men >70

– Postmenopausal with fracture, family history, smoker, weight<127, certain meds

• Usually covered by insurance (Medicare pays $128)

2013 National Osteoporosis Foundation Guidelines

What About Interval Screening?

• Recommendations of q 2 y as interval to measure change

• No evidence based guidelines available

• 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

BMD ResultFemoral Neck

Time to 10% BMD

<–2.5

Normal > –1.0 16.8 y

T = –1.01 to –1.49 17.3 y

T = –1.50 to –1.99 4.7 y

T = –2.00 to –2.49 1.1 y

NEJM 2012; 366: 225-33

Implications for Screening

• BMD results of more than –1.49 at age 65 – Defer repeat screening to age 80

• BMD results of–1.50 to –1.99 at age 65 – Repeat screening BMD at 5 years

• BMD results –2.00 to –2.49– Repeat screening BMD at 2 years

Gourlay ML, et al. NEJM 2012; 366: 225-33

Medical Evaluation

• History and physical to identify underlying problems

• Basic lab tests:– Vitamin D level (25OH-D)

– Serum calcium, creatinine

• Additional tests only if indicated– TSH, PTH, SPEP/UPEP, anti-TTG IgA

Jamal et al, Osteo Inter, 2005

Under Recognition of Osteoporosis

• Among women with fracture or BMD<-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

Summary: OsteoporosisRisk Factors and Evaluation

• Osteoporosis (like hypertension) is silent until something bad happens. Under recognized.

• Routine assessment of risk factors and screening DXA at 65. Extensive lab testing wasteful.

• Everyone should receive lifestyle and nutritional counseling

• Calculation of absolute risk (FRAX) helps clinicians and patients

What Can Be Done To Prevent Osteoporosis? Prevention for everyone

• Little new data

• Smoking cessation, avoid excess alcohol intake

• Physical activity: modest transient effect on BMD – reduces fracture risk

• Fall prevention: targeted PT, home eval.

• Calcium and vitamin D

Calcium and Vitamin D

• Chapuy, 1992: 800 IU D; 1200 mg Ca– Older women in long-term

care– 30% decrease in hip fracture

• Porthouse, 2005: 800 IU D; 1000 mg Ca

– Independent women >70 with 1+ risk factor

– No benefit on hip or other fractures

Chapuy, NEJM, 1992

• MA 25 studies: 14% fewer fractures together, no ben efit alone

News Flash: Calcium Kills!!!

• Pooled 15 calcium trials: cardiovascular events increased 30%

– Not 1° endpoint; trials with vitamin D excluded– Calcium + vitamin D in WHI did not increase risk

• Little supporting scientific data – No effect on other surrogates (coronary calcium on CT)– Dairy calcium not implicated

• ASBMR Task Force: “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

Rational use of Calcium and Vitamin D

• Vitamin D 600 - 1000 IU per day

• Calcium– Ensure adequate intake (1000-1200 mg)

– Focus on adherence

Pharmacologic therapy

Treatment Summary

• FRAX© to identify patients at risk: bone mineral density, age and previous fractures are the strongest independent predictors of fracture risk

• Treatments significantly decrease fracture risk:– “Antiresorptive” therapy: modest BMD increase, yet

decreases fracture risk faster and to a larger extent than predicted by the relatively small change in BMD.

– Anabolic therapy with teriparatide (PTH analog) increases BMD more than antiresorptive treatment, but it is not yet clear that fracture protection is greater

FDA-Approved Therapeutic Options in the USA

PreventionStops bone loss

TreatmentReduces vertebral fractures

Estrogen

AlendronateRisedronateIbandronate

Zoledronic acidRaloxifene

Calcitonin

PTH (teriparatide)Denosumab

Bisphosphonate efficacy

• Bind to bone and prevent absorption and remodeling– Resides in bone for decades

• Four approved agents: alendronate, risedronate, ibandronate, and zoledronic acid– First line therapy

– 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 useful if higher BMD (“low bone mass”)

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 risk

McClung, NEJM, 2001

More Bad News:Adherence with Bisphosphonates is Poor

• 50-60% persistence after one year

– Multiple practice settings (similar to other preventive treatments)

• Reasons for non-compliance

– Burdensome oral administration (fasting, remain upright for 30 minutes)

– Upset stomach and heartburn can occur

– Asymptomatic until fracture

• Trials show clinician interest (but not tests) and regular nursing visits can improve compliance

Clowes, JCEM, 2004

Does Dosing Interval Matter?

• Poor quality data:– Daily to weekly may improve compliance– Weekly to monthly may not

• Yearly dosing available: zoledronic acid– Extremely potent IV bisphosphonate– Fracture reduction after 3 annual injections: hip

40%, spine 60%, non-spine 25%– Precautions: acute phase reaction, renal

insufficiency

• Don’t forget to discuss potential side effects…

Black et al, NEJM, 2007

DEXA to monitor bisphosphonate therapy

• BMD after 1 year of therapy does not accurately predict what will happen over time or reflect fracture reduction

• Effective treatment for osteoporosis should not be changed because of loss of BMD during the first year of use

FIT Trial

• 18% taking alendronate lost BMD during first year

• Women who lost BMD on therapy had 50% fracture reduction

• 92% who lost BMD regained it by next measurement

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?

• Dental exam recommended before Rx, but no need to stop for dental procedures

Woo et al; Ann Intern Med, 2006ADA Guidelines, 2011

Other Things to Worry About

• Atrial fibrillation (zolendronate and alendronate RCTs)

– No association in other trials

– Likely spurious

• Esophageal cancer

– Case series (FDA author) and two conflicting cohorts,

– Might be spurious

• Subtrochantic fracture (with atypical features)

– Likely real…

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?

• Long half-life suggests that life-long treatment may not be necessary

• Ongoing concerns about excessive suppression of bone resorption

• FIT Long-term Extension (FLEX) study– 1099 women with ALN in FIT for 5 years– Randomized to ALN or PBO for 5 additional yrs

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

erce

nt C

hang

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%Hip20%Any

5%

PBO (N = 437)

10% 0.9 (0.6, 1.2)11%Any

Vertebral

Non-spine

Painful

2015 Update:Who to treat and when to stop

• NOF treatment thresholds– Existing hip or vertebral fracture: Yes!

– T-score < -2.5: Yes!

– Low bone mass + FRAX score above risk threshold (10 year risk > 3% hip; 20% any fracture): Probably not…

• Best data: alendronate and zoledronic acid

• After 3-5 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?)

• Hormone replacement

• Denosumab (antibody to RANKL)– SQ q 6 months, not cleared by kidneys

– Effective, but expensive. Less long term data

The Future: Anabolic AgentsTeriparatide (rhPTH) Summary

• The only FDA approved anabolic agent

• Daily SQ rhPTH decreases vertebral and nonvertebral fractures. No hip fracture data.

• Combination PTH and antiresorptive drug less effective than PTH alone in increasing BMD

• PTH followed by alendronate is promising

• Expensive, daily injections– Reserve for severe OP

Take Home Points

• Absolute risk estimates help with decisions

• Aggressive screening and treatment = fewer fractures; start for all women by 65 years

• Interval screening defined by baseline BMD

• Bisphosphonates: treatment of choice– Use for spine/hip fracture or T< – 2.5– Adherence counseling. Intermittent dosing.– Duration of therapy: 3-5 years then off for most– No role for interim monitoring with DEXA

Be Skeptical of Wonder Drugs…

Questions?Thank you!

Denosumab

• Monoclonal antibody to RANKL

• 60 mg subcutaneous injection every 6 months

• 9% increase in spinal BMD after 3 years in the pivotal FREEDOM trial; 4%-5% increase in hip BMD

• Reduction in fracture risk after 3 years:

– 68% decrease in new vertebral fractures

– 40% decrease in hip fractures

– 20% decrease in nonvertebral fractures

• 8-year data: continued increase BMD, reduced bone turnover, good safety

Teriparatide: rhPTH [1-34]

• Only treatment that is anabolic—stimulates bone formation rather than inhibiting bone resorption

• 20 mcg daily subcutaneously for ≤ two years

• Effects:– Increased bone density in spine by 9% and hip by 3% vs

placebo over 18 months

– Reduced incidence of vertebral fractures (65%) and non-vertebral fragility fractures (53%) in women with pre-existing vertebral fractures

– Studies too small to evaluate effect on hip fractures

• Adverse reactions: arthralgia, pain, nausea

New and Emerging Therapies

• Denosumab

• SERMs: lasofoxifene, bazedoxifene

• Strontium– strontium ranelate

– strontium malonate

• Anti-sclerostin antibody

• Cathepsin K inhibitor – odanacatib

• Cyclic analog of PTH (1-31)

• Calcium receptor antagonist – “calcilytic”

Drugs to Treat OsteoporosisCost per Effect on Fracture Risk

Agent year Vertebral Nonvert Hip

Raloxifene $976 � -- --

Calcitonin $1517* � -- --

Brand alendronate $1103 � � �Generic alendronate $108

Risedronate $1110 � � �Ibandronate (oral) $1024 � -- --

Ibandronate (IV) $1938

Zoledronic acid $1249 � � �Denosumab $1650 � � �Teriparatide $9786 � � --�: antifracture efficacy proven in clinical trial --: antifracture efficacy not proven in clinical t rial

Who Should Be Treated?

• Preventive measures for everyone:– Adequate calcium, vitamin D, and exercise

• When to offer osteoporosis medications:– Anyone with hip or spine fracture

– T-score < -2.5

– “Low bone mass” and 10 year fracture risk >20% or hip fracture risk >3%

2013 National Osteoporosis Foundation Guidelines

Current Strategies for Treating Obesity

1

Robert Baron, MD, MS

CURRENT STRATEGIES FOR TREATING OBESITY

Robert B. Baron MD MS

Professor of Medicine

Associate Dean for GME and CME

Founding Director, UCSF Weight Management Program

Declaration of full disclosure: No conflict of inte rest

Prevalence of Obesity 2011-2012

� Obesity prevalence: � Adults 34.9%�Youth 16.9%

� No change since 2003-2004

Ogden Cl, JAMA 2014

Ogden, JAMA 2014

Obesity Disparities: Example: BMI >35

� Women, 40-59: 19.1% �White: 16.9%, Black: 30.4%, Asian 4.6%,

Hispanic 25.5%

� Men, 40-59: 12.2% �White: 12.8%, Black: 15.7%, Asian 0,

Hispanic 8.7%

15%–<20% 20%–<25% 25%–<30% 30%–<35% ≥35%

Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2013

CA

MT

ID

NVUT

AZNM

WY

WA

OR

CO

NE

ND

SD

TX

OK

KS

IA

MN

AR

MO

LA

MI

IN

KY

ILOH

TN

MS AL

WI

PA

WV

SC

VA

NC

GA

FL

NY

VT

ME

HI

AK

NHMARI

CTNJ

DEMD

DC

PRGUAM


2


For a 40 yo woman, with normal BP, lipids, and FBS which BMI is

associated with the lowest all-cause mortality?

A. 18B. 24C. 28D. 34E. 38

1 8

2 4

2 8 3 4 3 8

6%

72%

1%1%

20%

CLASSIFICATION OF OVERWEIGHT AND OBESITY BY BMI

Obesity Class BMI (kg/m 2)

Underweight <18.5Normal 18.5 – 24.9Overweight 25.0 – 29.9Obesity I 30.0 – 34.9

II 35.0 – 39.9Extreme 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


3


For a 40 yo woman, with normal BP, lipids, and FBS which BMI is

associated with the lowest all-cause mortality?

1. 182. 243. 284. 345. 38

Epidemic of Inactivity

60% US adults don ’’’’t exercise regularly

25% are sedentary

Cochrane Collaboration

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

sugarWei, 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 stu dy


4


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 l ost 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; sati ety, hunger, lipids, insulin all equal

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


5


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:

A. 2000 kcalsB. 1800 kcalsC. 1600 kcalsD. 1400 kcalsE. 1200 kcals

2 0 00 k

c a ls

1 8 00 k

c a ls

1 6 0

0 kc a l

s

1 4 00 k

c a ls

1 2 00 k

c a ls

14%

40%

5%

12%

29%

SUCCESSFUL WEIGHT LOSS MAINTENANCE

• High levels of physical activity• Women 2545 kcal/week, men 3293 kcal per 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 kcals2 1800 kcals3 1600 kcals4. 1400 kcals5. 1200 kcals


6


The Neuroendocrinology of Energy Balance

Weight Loss With Weight Loss Medications

Weight loss (% of initial) in excess of placebo:

Phentermine-fenfuramine 11.0%

Sibutramine 5.0%

Phentermine 8.1%

Orlistat 3.4%

Lorcaserin (2012) 3.0%

Phentermine/topiramate (2012) 7.8-9.3%

Buproprion/naltrexone (2014) 2-4%

Liraglutide (2014) 3.7-4.5%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

✜ Results✜ Weight: -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


7


PRINCIPLES OF DRUG THERAPY

• NIH: BMI > 30 kg/m 2 or 27 kg/m 2 with co-morbidity (but in my 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

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)


8


Sleeve GastrectomyLap Band Gastric Bypass Laparoscopic Adjustable Gastric Banding (LAGB)Restrictive Only

Ideal Candidate– BMI 35-40 kg/m2– Wants to lose 50-100 pounds

Benefits– Fewer early risks than other

procedures– One hour procedure– Fully Reversible/Removable– Lowest risk of vitamin deficiencies

Considerations/Risks– Excess Weight Loss (EWL) 50%– 10-year removal or reoperation rate is

>25%– Slower weight loss (1-2lbs/week)

compared to other surgeries– Appetite suppression may be difficult

to achieve– Least effective for resolving diabetes

Sleeve Gastrectomy (Vertical Gastrectomy)Restriction and ResectionIdeal Candidate

– BMI 35-55 kg/m2– Wants to lose 80-150 lbs

Benefits– Excess Weight Loss 70-90%– 1-2 hour procedure– Recovery ranges from days to

weeks– Patients report early and lasting

fullness– Intestines stay intact—No

malabsorption – May cure diabetes

Considerations/ Risks– Removal of a portion of the

stomach is permanent– The remaining pouch may expand

over time

UCSF 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


9


Roux en Y Gastric Bypass (RNY or Bypass)Restrictive and MalabsorptiveMost common procedure performedIdeal Candidate

– BMI 35-55 kg/m2– Wants to lose 100- 150 + lbs– May have severe or prolonged medical

conditionsBenefits

– Excess Weight Loss 70-90%– 2 hour procedure– Recovery of days to weeks– Very effective for diabetes– Approximately 100-200 calories per day

lost through malabsorption– Procedure is reversible

Considerations/Risks– Greater risk for vitamin deficiencies– Dumping syndrome– Smoking, EtOH, NSAIDS use may lead

to ulcers

Years

Bariatric Surgery: Weight Change

Resolution of Comorbidities

0

10

20

30

40

50

60

70

80

90

100

Diabetes Hyperlipidemia HTN Sleep apnea

Band

VBG

GBPD Switch

% R

esol

utio

nC

omor

bidi

ty

Bariatric Surgery – A Systematic Review and Meta-analy sisBuchwald H. et al.

JAMA. 2004; 292(14):1724-37

LABS Consortium, NEJM, 2009

BARIATRIC SURGERY ADVERSE 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%


10


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

� 4047 subjects, surgery vs. matched control. 10.9 y ears

Max weight loss % Final weight loss %Control 2

Gastric bypass 32 25

Vertical banded Gastroplasty 25 16

Banding 20 14

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)

Diet and Exercise After Surgery

Days 1-14

• Thin fluids only• No solid food• 32-60 oz fluids per

day• 400-600 calories

per day• 50-70 grams of

protein• Walk 5-10 minutes

every hour• Wake and walk

after 8 hours

Days 15-30

• Start thick liquids and soft foods

• 32-60 oz fluids• 600 calories per day• 50-70 grams of

protein• Minimal carbs and

fats• Start cardio

exercises and light weight lifting

Day 31 and beyond

• Regular foods as tolerated

• Meats and other foods should be tender, cut and chewed well and eaten slowly

• 60+ oz fluids• 600 calories per day• 50-70 grams of

protein• Increase physical

activity


11


Pregnancy and Weight-Loss Surgery

� Fertility is enhanced after surgery

� Delay pregnancy for 12 to 18 months after surgery

� Use non-oral forms of birth control

� Avoid oral glucose challenge after gastric bypass

SUMMARY

� Environmental and public health changes work.

� Diets work, but not for long in most people (but they do for some).

� Exercise improves health independent of weight change and aid in weight maintenance.

� Continuation of conditions that promote weight loss promotes weight maintenance (no matter what the intervention).

SUMMARY

� Provision of meals and meal replacement products promote greater weight loss (but mostly in the short term, except for a few).

� Medications can help achieve small amounts weight loss for as long as agents can be used (but little is known about long term outcomes).

� Surgery results in long term weight loss and reductions of diabetes and mortality (but with complications in some/many and a high number needed to treat).

GOALS OF MANAGEMENT

� Be as fit as possible at current weight

� Prevent further weight gain

� If successful at 1 and 2, begin weight loss


12


The Magic Formula

10/15/2015

1

Prenatal Aneuploidy Screening Using cell Free DNA

Mary E. Norton MDProfessor, Obstetrics,

Gynecology and Reproductive Sciences

University of California, San Francisco

What Does the Evidence Tell Us? Oct 2015

Disclosures

o Research support from Natera and Ariosa

o No lucrative personal financial contracts

020406080

100120

Detection rate of prenatal screening for Down syndrome has improved over time

Det

ectio

n R

ate

(%)

The questions being debated:

o Is cfDNA screening the best option for low risk patients?

o Is cfDNA screening the best choice for primaryscreening for any or all patients?

10/15/2015

2

Professional Society Opinions: ACOG; ACMG; International Society of Prenatal Diagnosis;

National Society of Genetic CounselorsCommon themes (2012):There are recognized benefits, but…o Not diagnostic

• Needs confirmationo Only detects common trisomieso Requires comprehensive genetic counselingo Should only be used in validated groups (eg high risk)o Need a low risk study before introducing into general

population screening

Rumsfeld on current status of NIPT?“There are known knowns. There are things we know, we know. We also know there are known unknowns. That is to say, we know there are some things we do not know. But there are also unknown unknowns. The ones we don’t know we don’t know.”

-Donald Rumsfeld, 2002

Cell free fetal DNA

o Short segments of fetal DNA (<200 base pairs) circulate in maternal plasma

o Origin is primarily placenta

Maternal DNA

Fetal DNA

Cell free DNA results from apoptosis

10/15/2015

3

Analysis of cell free DNA

Zhong, X, Holzgreve, W, Glob. libr. women's med 2009

Trisomy 21 Non-Trisomy 21

DR: 99.2% (98.5 - 99.6)FPR: 0.09% (0.05 - 0.13)

Trisomy 21 performance cfDNA testing: meta-analysis (Gil et al, Ultrasound Obstet Gynecol, 2015)

Cell free DNA: Biologic ChallengesFalse positives:o Unrecognized or vanishing twino Placental mosaicismo Maternal genetic variation o Maternal malignancyFalse negatives:o Low level of fetal DNA o Placental mosaicismo Maternal genetic variation Failed results: o Increased BMIo Low level of fetal DNAo Fetal aneuploidy

False positive cfDNA results and cancer

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Issues with cfDNA for primary screening

1. Not all abnormalities are detectable• Down syndrome comprises ~50% of aneuploidies

2. The PPV (chance that a positive is a TRUE POSITIVE) depends on maternal age• This is often misunderstood

3. Some tests fail to provide a result• These patients are at HIGH RISK of aneuploidy• Importance of “fetal fraction”

What percentage of chromosome abnormalities will be detected by cfDNAscreening?A. 99%B. 75%C. 50%D. 12%

9 9 % 7 5 % 5 0 % 1 2 %

28%

13%17%

41%

10/15/2015

5

Spectrum of Genetic Disease

Structural Malformations

Autosomal recessiveAutosomal dominant

X-linked

Chromosomal/karyotype

CNV (microarray)

Spectrum of Genetic Disease

Structural Malformations

Autosomal recessiveAutosomal dominant

X-linked

Chromosomal/karyotype

CNV (microarray)

Aneuploidies Present in HIGH RISK Women

Tri 21: 53.2%Sex chromosomal: 8.2%

Tri 13: 4.6%

Tri 18: 17.0%

Other*16.9%

Norton et al, SMFM, 2014

*Not detected by cfDNA

Aneuploidies Present in LOW RISK Women

Tri 21: 49.2%

Sex chromosomal: 9.9%

Tri 13: 5.5%

Tri 18:12.9%

Other*20.8%

Norton et al, SMFM, 2015

*Not detected by cfDNA

10/15/2015

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Rate of abnormalities by maternal age cfDNA Detection Raten=452,901 patients screened in California

Total Cases with Aneuploidy (n=2575)

cfDNADetectable

Not Detected No Result

N=69+560(24.5%)

N=1841(71.4%)

N=105(4.1%)

Not Detectable(False negative+Non-detectable)

In low-risk patients, this is a very accurate test for a rare event.

10/15/2015

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NIPT and diagnostic testing with chromosomal microarray (CMA)

Microarray detects an abnormality in 1.7% of cases (about 1/60)AND:

NIPT detects T13,18, 21 – about 1/500 pregnanciesTHEN:

� If NIPT is the routine screening test, it will detect about 12% of diagnosable chromosomal abnormalities









Your 25 yo patient has cfDNA screening and the result is positive for trisomy 13. What is the chance that the fetus actually has trisomy 13?A. >99%B. 75%C. 50%D. <10%

> 9 9%

7 5%

5 0%

< 1 0%

34%

28%

17%21%

10/15/2015

8

o N=1914 women undergoing standard screeningo Mean maternal age = 29.6 yrso Primary outcome = false positive rates for T18 and T21

cfDNA vs Standard Screening

Bianchi et al, NEJM, 2014

FPR PPVcfDNA 0.3% 45.5% p<.001Standard 3.6% 4.2%

o Only 8 aneuploidy cases in the cohort (5: T21, 2: T18, and 1: T13)

o All were detected

o 15,841 women had cfDNA and first trimester screening

o Mean maternal age = 30.7 yrs

“NEXT” study: 15,841 average risk women

Cell free DNA

screening

First trimester screening

Detection rate 38/38 (100%)

30/38 (79%) P=0.008

False positive rate

0.06% 5.4% P<0.0001

Positive predictivevalue

81% 3.4% P<0.0001

Norton et al, NEJM, 2015

10/15/2015

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Wang et al, Genetics in Medicine, 2014

Aneuploidy No. of positives No (%)confirmed

T21 41 38/41 (93%)T18 25 16/25 (64%)T13 16 7/16 (44%)45X 16 6/16 (38%)

Total 98 67 (67%)

o 6.2% had termination without karyotype confirmation

o Disconcerting if only 67% are true positives

10/15/2015

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Consequences of false positive results

N=100,000 1% false positives

1000 abnormal results6.2% TAB w/o confirmation

62 TAB

42 TP 21 FP

21 TAB of normal fetuses

NIPT

67% PPV

Consequences of false positive results

N=100,0005% false positives

5000 abnormal results

0.2% loss rate (amnio)

10 losses of normal fetuses

N=100,000 1% false positives

1000 abnormal results6.2% TAB w/o confirmation

62 TAB

42 TP 21 FP

21 TAB of normal fetuses

NIPT Serum Screening

67% PPV

If your patient has a positive result:www.perinatalquality.org

10/15/2015

11

The poorly understood PPV Your patient has cfDNA screening, and the lab calls to tell you the test failed to provide a result. What are possible reasons for this?

A. Maternal obesityB. The fetus has a chromosome

abnormalityC. The blood was drawn too earlyD. All of the above

M at e r n

a l ob e s

i t y

T h e f e t

u s ha s a

c h ro m

o . . .T h e

b l oo d

w a s d r a

w n t . .

A l l o f t

h e a b o

v e

16%

71%

12%1%

10/15/2015

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Published Trials of NIPT: failure ratesTrial Failure rate

Chiu et al (2011) 11/764 (1.4%)Ehrich et al. (2011) 18/467 (3.8%)Palomaki et al. (2011) 13/1696 (0.8%)Bianchi et al. (2012) 30/532 (3.0%)Norton et al (2012) 148/3228 (4.6%)Zimmermann et al (2012) 21/166 (12.6%)Pergament et al (2014) 85/1051 (8%)Norton et al (2015) 488/16,329 (3.0%)

All 729/23,182 (3.1%)

Fetal fraction of DNA and test failure

3-5% of samples do not provide a result

• Low fraction fetal DNA, failed sequencing, high variability in counts

• Some association with gestational age (<10 wks) • Low fetal fraction associated with maternal BMI

- 20% at >250 lbs- 50% at >350 lbs

� Low fetal fraction is associated with aneuploidy�Repeating test will provide a result in SOME cases

Obesity in US Adults Pergament et al, 2014

o N=1051 samples were analyzed

o N=85/1051 (8%) samples failed to obtain a result

o 20/85 (22%) were aneuploid

�“No call” cases represent a very high risk group

Obstet Gynecol 2014

10/15/2015

13

No ResultsN = 102(2.3%)

Total Pregnancies SampledN = 4446

Redraw Declined N=39

High Risk N = 157(3.5%)

RedrawnN = 63

Low RiskN = 4187(94.2%)

Low RiskN=32 (50.8%)

High Risk N=5 (7.9%)

No ResultN=26(41.3%)

NO FINAL RESULTN = 65 (1.5%)

Kaiser cfDNA Experience: No Results Cases




High Risk N = 157(3.5%)

RedrawnN = 63

Low RiskN = 4187(94.2%)









High Risk N = 157(3.5%)

RedrawnN = 63

Low RiskN = 4187(94.2%)






KPNC 10/29/12 – 6/30/14Total pregnancies sampled = 4446

Abnormal chromosomes 9/65 (14%)

Normal chromosomes13/65 (20%)

Chromosomes not done43/65 (66%)

Kaiser cfDNA: No Results


10/15/2015

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Failed cfDNA screens indicate increased risk for aneuploidy

Failed tests increase aneuploidy risk:

Author OR for aneuploidyo Norton et al, NEJM 2015: 6.2o Pergament et al, Obstet Gynecol 2014: 2.5o Turocy et al, SMFM 2015: 5.7

The questions being debated:

o Is cfDNA screening the best option for low risk patients?

o Is cfDNA screening the best choice for primaryscreening for any or all patients?

NIPT is more precise for T13, 18, 21

cfDNA Current NT + serum screen

NIPT is more precise for T13, 18, 21

cfDNA Current NT + serum screen

Other abnormalities

10/15/2015

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cfDNA vs Sequential Screening:Detection and False Positive Rates

Cohort Detection Rate

False Positive Rate

Sequential screening

81.6% 4.5%

cfDNA if “no results” cases = high risk

77.1% 3.7%

cfDNA if “no results” have no follow up

70.7% 0.7%

cfDNA and Ultrasound Abnormalities

Normal U/S Abnormal U/ST13, 18, 21 25 (4.9%) 88 (23.4%)Other chromosomalabnormalities

13 (2.5%) 29 (7.7%)

Total detectable cfDNA

25/38 (66%) 88/117 (75%)

Benachi et al, Obstet Gynecol, 2015

NIPT: Expanded panelsLaboratories have added other trisomies and microdeletionso Trisomies 16 and 22o Microdeletion syndromes

• 22q (diGeorge)• 5p (cri-du-chat)• 1p36• 15q (Prader Willi)• 4p (Wolf-Hirshhorn)

NIPT: Expanded panels

o Trisomies 16 and 22• Rarely seen in viable pregnancies except as mosaics• Common causes of confined placental mosaicism

- Much more common in CVS samples than amniocentesis• Even complete trisomy in the placenta often

associated with a normal fetus• With both, confined placental mosaicism can be

associated with IUGR, so false positive cases should be followed for fetal growth (eg ultrasound at 30-32 wks)

10/15/2015

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Microdeletion syndromes are rareSyndrome Frequency Features22q11.2 (DiGeorge)

1/4,000 Varies: cardiac, palatal, immune, intellectual disability

1q36 1/10,000 Severe intellectual disability (ID), +/- obvious structural anomalies

Angelman 1/20,000 Severe ID, seizures, speech delay

Prader-Willi 1/30,000 Obesity, ID, behavioral problems

Cri-du-chat 1/50,000 Microcephaly, ID, +/- CHDWolf-Hirshhorn 1/50,000 ID, seizures, +/- CL/CP

Testing for Rare Disorders

N=100,000

2 Wolf-Hirschhorn 99,998 not WHS

2 TP; 0 FN 800 FP; 99,198 TN

OAPR = 1/400

Population Risk = 1/50,000(Wolf-Hirschhorn, 4p-: Assume 99% sensitivity and 99.2% specificity)

ACOG/SMFM September 2015o Conventional screening is most appropriate

first line screen for most patientso Ethically any patient may choose cfDNA

screening, but should be counseled regarding limitations and benefits

o Diagnostic testing is required to confirm abnormal results before irreversible decisions

o Testing for microdeletions and in twins should not be performed

10/15/2015

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Important counseling points

o NIPT is NOT diagnostico Extremely high sensitivity and specificity for

Down syndrome o Somewhat lower for trisomy 13, 18 and sex

chromosomeso Approximately 20-30% of chromosome

abnormalities identified with invasive testing are NOT detectable with NIPT

All patients deserve equal access

o ACOG indicates that testing should no longer be stratified by maternal age

o We’ve spent the past decade trying to abolish “advanced maternal age” and the 35 yo cutoff

o It is unethical to withhold this test

All patients deserve equal access

o ACOG indicates that testing should no longer be stratified by maternal age

o We’ve spent the past decade trying to abolish “advanced maternal age” and the 35 yo cutoff

o It is unethical to withhold this test�There is a difference between withholding

something for an individual patient, and recommending it for all patients as policy

All patients should have access to all test options…(the Jim Carrey approach)

10/15/2015

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Ethics, access and counselingo While it is not ethical to withhold tests from one

groupo It is necessary to provide fair and balanced

counseling regarding the pros and cons of ALL test options• cfDNA is very good for the common aneuploidies, but

doesn’t detect other serious chromosome abnormalities

• In low risk patients, a positive result is more likely to be a false positive

• In patients at low risk for the common aneuploidies, other screening options provide broader coverage at lower cost

Appropriate counselingo While it is not ethical to withhold tests from one

















• In patients at low risk for the common aneuploidies, other screening options provide broader coverage for more conditions

10/15/2015

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Thank You!

10/15/2015

1

Program on Reproductive Health and the Environment

No disclosures of any financial nature

2

I moderate a Facebook Page called Pregnancy and Environmental Health


Environmental Contaminants & Reproductive Health: What should we tell our patients?

Marya G. Zlatnik, MD, MMSProfessor, Maternal Fetal Medicine & Program in Reproductive Health & the Environment, UCSFAssociate Director, Maternal Fetal Health & the Environment, UCSF-Western States Pediatric Environmental Health Specialty Unit

'What we have to face is not an occasional dose of poison which has accidentally got into some article of food, but a persistent & continuous poisoning of the whole human environment‘

- Rachel Carson


Do you take an environmental health history for prenatal pts?A. Yes, I ask about occupational exposures

for pt & family, hobbies, fish consumption, smoking & other substances, geomapzipcode to look for superfund sites, etc.

B. Yes, including substance use, occupation, fish consumption, plus more questions based on immigrant status and my local environment

C. Yes, tobacco, occupationD. No

4

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1% 5%

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54%


Objectives• Concerning health trends• Concept of endocrine disruption• Specific chemicals of concern

– BPA, phthalates, PDBEs, pesticides,lead (in syllabus)

• Why we should get involved• Things our pts can do

– Top Ten Changes to make• Resources in syllabus

5

10/15/2015

2


Why does the environment matter to OBs, CNMs? Disturbing Health Trends

Similar trends: low birth weight, GDM, autism, obesity, infertility, gastroschisis, hypospadius, childhood CA, breast/testicular CA, asthma,

http://www.cdc.gov/media/dpk/2013/dpk-vs-child-obesity.html#graphicshttp://www.cdc.gov/ncbddd/autism/data.htmlhttp://seer.cancer.gov/publications/childhood/Van Cleave JAMA 2010

‘88 –’94

2000-6’94 -’00


Our Environment is Changing

Federal reserve data on chemical production (relative production, unit-less). U.S. Federal Reserve Board, Div. of Research & Statistics

Woodruff, 2011. EHP

Chemicals in every pregnant woman

Chemicals in each pregnant woman.

2012: 30,000 lbs. produced annually per person in US (EPA data)


International Group of OB/GYNs Concerned• FIGO publishes statement

October 1st, 2015:– Advocate for policies to prevent

exposure to toxic environmental chemicals

– Work to ensure a healthy food system for all

– Make environmental health part of health care

– Champion environmental justice

8

International Federation of Gynecology & Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals http://dx.doi.org/10.1016/j.ijgo.2015.09.002


Endocrine Disrupting Chemicals:Substances that interfere with normal hormonal activity

• Some examples:– Plastics: BPA,

phthalates– Flame retardants– Pesticides– DES– Lead

9Helmestam 2013

10/15/2015

3


BPA has many biological effects• 1930s: BPA = artificial estrogen,

developed by same chemist who developed DES

• 3.6 million tons/year• Animal/basic science models:

estrogen (ant)agonist• Human epidemiology data:

estrogen (ant)agonist

13Program on Reproductive

Health and the Environment

Gestational urinary BPA & Behaviour

Braun JM 2011

GIRLS BOYS

Fetal BPA exposure associated w/ anxiety, depressive sx, & impaired behavioral regulation at age 3, worse for girls

Beha

viora

l sco

res


BPA: Not just for women & children to worry about…• Chinese workers in BPA factories, Kaiser DOR• The BPA-exposed workers (ave urine BPA 58 mcg/gCreat

vs 1.2 mcg/gCr for unexposed) had – reduced frequency of intercourse (OR = 6.7) – ejaculation dysfunction (OR = 6.3), – reduced satisfaction with sex life (OR = 10.0)– reduced sex drive (OR = 17.7)– reduced ability to have erection (OR = 15.0)

15

Li, et al Human Reprod, 2009Program on Reproductive


Prenatal Phthalate Exposure: Effect on AGI (anogenital distance) in boys

� AGI = sensitive index of desmasculization of male reproductive tract

� Similar studies with smaller penile sizes

� Reproducible in rats

16Swan EHP 2005

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Prenatal Phthalate Exposure & reduced masculine play in boys

Change in play if phthalate metabolite concentration in boy’s mother’s prenatal urine was increased from 10th percentile to 90th percentile. p-value of <0.05

17Swan IIA 2010 (online 2009) Program on Reproductive


Pesticides:Organophosphates

• Prenatal exposure to organophosphate pesticides (OP: dialkyl phosphates) is associated w/:

– Shorter length of pregnancy– Lower IQ in children– Increased risk of attention problems

CERCGH: the CHAMACOS study: Eskanazi 2011, Bouchard 2011


PBDEs – Ubiquitous Exposure (flame retardants)

© Leona Kanaskie

D SLATER. NYT; September 6, 2012

Upholstered Furniture


PBDEs in pregnancy & Low Birth Weight

Harley 2011

-400

-300

-200

-100

00 1 2 3

10x increase PBDE concentration

birth weight decrease (g)Birt

h W

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t Dec

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)

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Maternal Prenatal PBDE Concentrations• Impaired attention age 5 • Poorer fine motor coordination

– particularly non-dominant hand – at age 5 & 7

• Decrements in IQ at age 7 Eskenazi et al. 2012 EHP

• Kids w/ higher concentrations of PDBEs scored lower on tests of mental & physical development (incl. IQ) Herbstman 2010 EHP


Fracking & Pregnancy• Concern raised in media

• Known harmful chemicals used:– 13 known/suspected carcinogens

(benzene, acrylamide) – Developmental neurotoxins– EDCs (Kassotis et al. 2014)– VOCs: including BTEX (benzene,

toluene, ethylbenzene, xylene)

Fracking & environmental (in)justice in a Texas cityFry Ecol. Econ. 2015


Proximity to Fracking & Preterm BirthUnconventional Natural Gas Development & Birth Outcomes in PA

Association between unconventional natural gas development activity & preterm birth (4th quartile OR 1.4)

Casey Epid. 2015 Program on Reproductive Health and the Environment

Proximity to Fracking & SGAPerinatal Outcomes & Unconventional Natural Gas Operations in SW Penn.

Quartiles: Inverse Distance Weighted Well Count

OR

: Sm

all f

or G

esta

tiona

l Age

Stacy PLOS One 2015, see also Hill 2014

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Climate Change and Pregnancy

Medline Trend, accessed 9.11.2015http://dan.corlan.net/medline-trend.html Program on Reproductive


Climate Change and Pregnancy• Extreme heat associated w/ shorter gestation

Barcelona 2001-2005• Higher temperatures associated w/ PTB

– Bay Area: 5-20% increase in PTB for 10F increase in temp

– California 2010• ? Increase in some birth defects

– New York

Dadvand 2011, Basu 2010, Van Zutphen 2012, 2014


Climate Change and Pregnancy• Increased water source salinity & preeclampsia in

Bangladesh

Khan 2015P<0.001


What can we do???

• Image © 2012 Leo Soderman - Creative Commons Non-Commercial

10/15/2015

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Should we panic? No• Effects of these chemicals generally subtle

– Not all routes/types of exposures equally concerning– Not everyone susceptible– Often effect only seen clearly on population level

• Analogies:– Sometimes forgetting sunscreen & risk of skin cancer– Eating eggs/butter & risk of MI– NOT: one exposure to Chernobyl or HPV & cervical Ca



Won’t our patients panic? Maybe• Many providers worried about “scaring” patients

or putting burden of avoiding toxins on already stressed (& caffeine-, wine-, sushi-, turkey-deprived) pregnant women

– Research indicates women want the info• I argue that the burden of change needs to be on a

societal/policy level• I hope to provide tools & resources for clinicians

whose patients are asking questions

33

Morello-Frosch et al., 2009 2014


“If I freak out like, ‘Whoa, look at that kid who’s drinking Coke out of a BPA bottle,’ … which one of those things should I deal with, right?” (Female OB/Gyn)

“Bigger fish to fry”

Stotland 2014

“It’s a little scary barrel to open because I don’t have an answer.” (Female OB/Gyn)

“Pandora’s Box”

OBs views on Counseling Patients:


Does communicating chemical exposures cause undue worry or harm? Lessons from biomonitoring research:Studies say pregnant women want info on personal exposures to environmental chemicals

– Believe they have the right-to-know Morello-Frosch et al., 2009 2014; Nelson et al., 2009a; Sly et

al., 2009; Wu et al., 2009– 97% wanted exposure info even if health implications

are unclear Brody et al., 2007– If you avoid BPA yourself, isn’t it right to tell pts?

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What Can Providers Do? • Educate themselves about

environmental toxins• Establish cross-disciplinary

partnerships• Put a clinical voice into policy

making• Institutionalize change

– Professional societies– Hospital systems


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Societal Change is Possible: Lead


Good News: Policy Change Reduces PBDE Levels in CA Pregnant Women

• 2006: CA bans PDBEs• 2013: Levels lower in 2011-12 samples vs 2008-9

(SFGH)q Zota 2013 EST


Streams of Evidence for Toxicity Assessment

• Putting burden on consumers is not enough (or fair)

• Need regulatory change to prevent harmful chemicals entering our food, etc.

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Public Policy: Current Approach

BPA


Streams of Evidence for Toxicity AssessmentRegulatory Change: Precautionary Approach


Patient level: Actions Matter: Pesticides(see similar results with BPA & fresh food)

47

Lu C et al. 2006. Organic diets significantly lower children's dietary exposure to organophosphorus pesticides. Environ Health Perspect. 2006;114:260-3.

Organic diet Organic diet


PRHE: All That Matters Publications

• UCSF Reproductive Environmental Health & Justice elective for Fellows & Residents

10/15/2015

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So what should we tell our patients?• Clinicians are busy

– Not enough time already to talk about Prenatal & Genetic Screening options, IPV, PTL, etc

• You don’t want to freak pts out– No RCT data, much is out of our patients’ hands– Unintended consequences (avoiding one substance

may inadvertently increase another toxin)• Know resources if pt asks• Ask pts who are high risk (regional-specific risks,

occupational or other exposures)50


So what can our patients do today?-Top 101. Buy organic $$$

– Less pesticide residue

– Wash produce– Avoid fast food &

processed food– Limit foods high in

animal fat

51


2. Avoid food w/ substantial plastic contact: canned foods/sodas, wet foods in plastic pouches/ boxes) $$– Avoid: #3: PVC or vinyl, #6: PS (Styrofoam),

#7 (= other): polycarbonate (some water bottles, & 5-gallon jugs) or may be untested

– Choose: #1 PETE, #2 HDPE, #4 LDPE or #5 PP, likely lower health risks. But, if your community does not recycle these, try to avoid them



2. Avoid plastic: Don’t microwave it! $– Heating increases leaching of chemicals, especially

w/ fatty foods. Use a paper towel or glass lid to cover food in the microwave

53

http://www.healthandenvironment.org/

10/15/2015

11


3. Eat low-mercury fish $-$$$– Smaller fish generally have lower mercury levels– Up to 12 oz/wk of shrimp, catfish, pollock,

canned light tuna, salmon• Consumer Reports says no tuna!

– Check local advisories if eating local fish– http://www.montereybayaquarium.org/cr

/seafoodwatch.aspx



4a. Wash hands prior to eating $– Especially important when hands are exposed

to toxins• Agricultural areas• Pt or spouse works in occupation w/

pesticides, solvents, lead, etc.

55


4b. Avoid carbonless receipts $– Many contain phthalates– Don’t take receipt if you don’t need it– If your patient works as a cashier,

recommend:• wear gloves • wash hands

thoroughly prior to eating

56

Urinary BPA after handing receiptsJAMA. 2014;311(8):859-860. doi:10.1001/jama.2013.283735

No Gloves Gloves


5. Limit pesticide & solvent use in home $– Clean with soap, vinegar– Baking soda for ants, etc.– Keep counters clean– Use integrated pest management strategies

in the garden

57

10/15/2015

12


6. Be thoughtful about body products $-$$– avoid phthalates, fragrances, triclosan– risk stratify (“windows of susceptibility,” dosage,

water vs. fat soluble chemicals)– www.ewg.org (Skin Deep)– http://safecosmeticsact.org/search/products.aspx

(CA Safe Cosmetics Program Database)

58

http://www.ewg.org/skindeep/app/


7. Bust the Dust! $-$$– Dust/damp mop/vacuum daily, take shoes off

outside – Especially important when dust is particularly

likely to have toxins• Agricultural areas• Urban neighborhoods• Pt or spouse works in occupation w/

pesticides, solvents, lead, etc– Commercial grade door mat “Twister”: 75% as

effective as shoe removal (Roberts 1991)59


8. Get rid of old foam furniture $$– Flame retardants worst in foam from prior to

2005 (less likely prior to 1975)•Risk higher if crumbling

– Dust mopping, vacuuming with HEPA filter

– Also, avoid fatty animal foods•Flame retardants are fat soluble•Half-life 1-3 years in human fat



9. Avoid tobacco smoke $– Quit smoking– Avoid 2nd hand smoke– Who knows what’s in e-cigarettes

• Nicotine itself not good for reproduction• Phthalates, etc.• “E-Cigarettes Expose People to More Than

‘Harmless’ Water Vapor: First Comprehensive Analysis Shows that Industry Health Claims are Unsupported by Data”

61

Grana Circulation 2015

10/15/2015

13


10. Avoid lead $-$$$– Frequent dust-mopping– Avoid hobbies, lipstick, other sources – Paint abatement for baby– For women w/ hx lead exposure, Ca2+

supplements to minimize release of lead from bone stores

– Increase dietary Fe, vit C



10b. Lead in unexpected places: ethnic products

• Mexican treatments: Azarcon and greta(also known as liga, Maria Luisa, alarcon, coral, rueda)

• Asian treatments: chuifong, tokuwan, ghasard, bali goli, kandu, bo ying*

• Middle eastern, Ayurvedic treatments or cosmetics: alkohl, saoott, cebagin

• Lipstick: drugstore brands

*


Special situations:• Patient with occupational or home exposures to

lead, mercury, pesticides—or ?s you can’t answer– Work Matters brochure– Local Pediatric Environmental Health Unit

http://www.pehsu.netUCSF/ Western States PEHSU: 1-866-827-3478

– CDC/ATSDR creating app for OBGYNs– Occupational Medicine resources– OSHA



Conclusions• Concerning health trends may or may not be related

to environmental toxins, but the basic science & epidemiology is concerning enough that the precautionary principle makes sense

• Specific chemicals of concern– BPA, phthalates, PDBEs– Lead, TBT, pesticides

• Things we can do– Top Ten Changes to make

65

10/15/2015

14


Do you intend to take more of an environmental health history for prenatal pts?

A. Yes, definitelyB. Yes, if I have reason to suspect a pt

is at riskC. Maybe, if I have timeD. Nope

66

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Which of FIGO’s recommendations are most important for OBGYNs?A. Advocate for policies to prevent

exposure to toxic environmental chemicals

B. Work to ensure a healthy food system for all

C. Make environmental health part of health care

D. Champion environmental justice

67

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Program on Reproductive Health and the Environment68


Other Resources• ACOG/ASRM statement

http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Health_Care_for_Underserved_Women/Exposure_to_Toxic_Environmental_Agents

• Environmental Working Group (& Skin Deep website) http://www.ewg.org/http://www.ewg.org/skindeep/

• EPA/state Pediatric Environmental Health Specialty Units

10/15/2015

15


Other Resources• Collaborative on Health and the Environment (Toxicant &

Disease database) http://www.healthandenvironment.org/• NIH NLM

http://householdproducts.nlm.nih.gov/products.htm• TEDX (includes List of Possible Endocrine Disruptors &

Critical Windows of Development) http://www.endocrinedisruption.com/home.php

• CDC (esp re: lead) http://www.cdc.gov/nceh/lead/publications/LeadandPregnancy2010.pdf

• Preconception Health Council of California http://www.everywomancalifornia.org



Strength of the Evidence

QuickTime™ and a decompressor

are needed to see this picture.

Diamanti-Kandarakis E et al. 2009Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement. Endo Rev 30(4):293-342

Evidence for adverse reproductive outcomes (infertility, cancers, malformations) from exposure to endocrine disrupting chemicals is strong , and there is mounting evidence for effects on … thyroid, neuroendocrine, obesity and metabolism, and insulin and glucose homeostasis.


Prenatal BPA Exposure - Animal Studies

73

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Prenatal BPA Exposure – Human Health



PRHE: All That Matters Publications

• UCSF Reproductive Environmental Health & Justice elective for Fellows & Residents


BPA has many biological effects• 1930s: BPA = artificial estrogen, same chemist who

developed DES• 3.6 million tons/year• Animal/basic science models: estrogen (ant)agonist

– Prenatal BPA exposure � diabetes-changes in adult mice Liu 2013

– BPA increases angiogenesis in human endometrial cellsHelmestam 2013

• Human epidemiology data:– Prenatal BPA & adult diabetes

http://www.ncbi.nlm.nih.gov/pubmed/2367552388


Complex Science: EDCs = SERMs BPA = mixed agonist/antagonist

• Estrogen: stimulates endometrium, breast, bone

• Tamoxifen: stimulates endometrium/bone, down-regulates breast

• Raloxifene: down-regulates endometrium & breast, strengthens bone

• BPA: tissue specific effects, also: -agonist/antagonist depending on concentration

89

Yin EHP 2012

10/15/2015

17


Gestational urinary BPA & Executive Function

Braun JM 2011

GIRLS BOYS

Fetal BPA exposure associated w/ anxiety, depressive sx, & impaired behavioral regulation at age 3, worse for girls

Beha

viora

l sco

res


Perinatal Air Pollutant Exposures & Autism Spectrum Disorder in the Children of Nurses’ Health Study II Participants

91

Association of ASD w/ air pollutant concentration, highest quintilevs lowest quintile Ors. Roberts 2013


Exposure to EDCs via Breast Milk

• Some toxins are found in breast milk, esp. lipophilic compounds

• Studies thus far show benefits to breastfeeding outweigh the risks

92

Amitay JAMA peds 2015

Meta-analysis of breastfeeding and childhood leukemia


Fracking & Pregnancy• Concern raised in media• Known harms from

chemicals used:– 13 known/suspected

carcinogens (benzene, acrylamide)

– Developmental neurotoxins– EDCs (Kassotis et al. 2014)– VOCs: including BTEX

(benzene, toluene, ethylbenzene, xylene)

Fracking & environmental (in)justice in a Texas cityFry Ecol. Econ. 2015

10/15/2015

18


Contemporary Prenatal Exposure to EDCs

100

Percentage of U.S. Pregnant Women with Detectable Level of Analyte

Woodruff, Zota, Schwartz EHP 2011 Program on Reproductive Health and the Environment

So what can our patients do today?-Top 101. Reduce pesticide exposure $-$$

– Food exposures– Home exposures– Occupational exposures

• Wash hands prior to eating at work, returning home

• Remove work clothes & shoes outside the home, wash separately

• Shower after work

111


1b. Limit pesticide & solvent use in home $– Clean with soap, vinegar– Baking soda for ants, etc.– Keep counters clean– Use integrated pest management strategies

in the garden



Reduce Pesticide Exposure1c. Buy organic $$$

– Less pesticide residue

– Wash produce– Avoid fast food &

processed food

113

www.ewg.org

10/15/2015

19


2. Bust the Dust! $-$$– Dust/damp mop/vacuum daily, take shoes off

outside – Especially important when dust is particularly

likely to have toxins• Agricultural areas• Urban neighborhoods• Pt or spouse works in occupation w/

pesticides, solvents, lead, etc– Commercial grade door mat “Twister”: 75% as

effective as shoe removal (Roberts 1991)114


3. Wash hands prior to eating $– Especially important when hands are exposed

to toxins• Agricultural areas• Pt or spouse works in occupation w/

pesticides, solvents, lead, etc.

115


4. Avoid food w/ substantial plastic contact: canned foods/sodas, wet foods in plastic pouches/ boxes) $$

– Avoid: #3: PVC or vinyl, #6: PS (Styrofoam), #7 (= other): polycarbonate (some water bottles, & 5-gallon jugs) or may be untested

– Choose: #1 PETE, #2 HDPE, #4 LDPE or #5 PP, likely lower health risks. But, if your community does not recycle these, try to avoid them



4b. Avoid plastic: Don’t microwave it! $– Heating increases leaching of chemicals, especially

w/ fatty foods. Use a paper towel or glass lid to cover food in the microwave

117

http://www.healthandenvironment.org/

10/15/2015

20


5. Avoid carbonless receipts $– Many contain phthalates– Don’t take receipt if you don’t need it– If your patient works as a cashier,

recommend:• wear gloves • wash hands

thoroughly prior to eating

118

Urinary BPA after handing receiptsJAMA. 2014;311(8):859-860. doi:10.1001/jama.2013.283735

No Gloves Gloves


6. Eat low-mercury fish $-$$$– Smaller fish generally have lower mercury levels– Up to 12 oz/wk of shrimp, catfish, pollock,

canned light tuna, salmon• Consumer Reports says no tuna!

– Check local advisories if eating local fish– http://www.montereybayaquarium.org/cr

/seafoodwatch.aspx

119


7. Be thoughtful about body products $-$$– avoid phthalates, fragrances, triclosan– risk stratify (“windows of susceptibility,” dosage,

water vs. fat soluble chemicals)– www.ewg.org (Skin Deep)– http://safecosmeticsact.org/search/products.aspx

(CA Safe Cosmetics Program Database)

120

http://www.ewg.org/skindeep/app/


8. Repair or Get rid of old foam furniture $$– Flame retardants worst in foam from prior to

2005 (less likely prior to 1975)•Risk higher if crumbling

– Dust mopping, vacuuming with HEPA filter

– Also, avoid fatty animal foods•Flame retardants are fat soluble•Half-life 1-3 years in human fat

121

10/15/2015

21


9. Avoid tobacco smoke $– Quit smoking– Avoid 2nd hand smoke– Who knows what’s in e-cigarettes

• Nicotine itself not good for reproduction• Phthalates, etc.• “E-Cigarettes Expose People to More Than

‘Harmless’ Water Vapor: First Comprehensive Analysis Shows that Industry Health Claims are Unsupported by Data”

122

Grana Circulation 2015Program on Reproductive


10. Avoid lead $-$$$– Frequent dust-mopping– Thoughtful paint abatement for baby– For women w/ hx lead exposure, Ca2+

supplements to minimize release of lead from bone stores

– Increase dietary Fe, vit C

123


10b. Lead in unexpected places: ethnic products

• Mexican treatments: Azarcón and greta(also known as liga, Maria Luisa, alarcon, coral, rueda)

• Candies: Vero Mango, ChacaChaca, PelonPelon Rico, and Pica Limon

• Chapulines (a Mexican snack of grasshoppers)

• Clay pots

SLO County Health Agency Program on Reproductive Health and the Environment

10c. Lead in unexpected places: ethnic products

• Asian treatments: chuifong, tokuwan, ghasard, bali goli, kandu, bo ying*

• Middle eastern, Ayurvedic treatments or cosmetics: alkohl, saoott, cebagin

• Lipstick: drugstore brands*

Prevention of Preterm Delivery: Progesterone,

Cerclage, and Pessaries

Juan M. Gonzalez, MD Assistant Professor

Maternal-Fetal Medicine Department of Ob/Gyn & RS

University of California, San Francisco

Preterm Birth• Single most important cause of perinatal mortality (28 weeks gestation

through 6 days of life) in the U.S. (accounts for approx 75% of these losses)

• Leading cause of neonatal mortality (0-27 days) in U.S.

• Second leading cause of infant mortality in U.S.

• Leading cause of black infant mortality in U.S.

• Major determinant of neonatal and infant illness.

• Major contributor of short and long term morbidity and disability.

Source: National Center for Health Statistics, period linked birth/infant death dataPrepared by March of Dimes Perinatal Data Center, 2006

Preterm is less than 37 completed weeks gestation. Very preterm is less than 32 completed weeks gestation. Moderately preterm is 32-36 completed weeks of gestation. Source: National Center for Health Statistics, final natality data. Retrieved July 11, 2013, from www.marchofdimes.com/peristats.

Preterm births

US, 2000-2010

Preterm Births• Adoption of fertility practices that reduce the

likelihood of multi fetal pregnancies

• Adherence to guidelines IOL only for medical indications

• Progesterone and cerclage in women with a previous PTB

n engl j med 370;3 january 16, 2014Preterm is less than 37 completed weeks gestation. Very preterm is less than 32 completed weeks gestation. Late preterm is between 34 and 36 weeks gestation. Source: National Center for Health Statistics, final natality data. Retrieved July 11, 2013, from www.marchofdimes.com/peristats.

Distribution of all preterm births

US, 2010

Mechanisms of Preterm Birth

Traditional Model of Contractions as the Initial Step Preceding Is Challenged by the following

observations:

Mechanisms of Preterm Birth • Current therapies to treat preterm labor are

largely ineffective.

• Treatment of preterm birth has focused on inhibiting myometrial contractions.

• Growing body of clinical and animal studies now suggests that premature cervical shortening or ripening might be the primary mechanism.

Gabbe 2014

• Cervical Riepening (short cervix)

• Driven by inflammation in the early second trimester is the most common initial manifestation

Goldenberg et al 2000

The preterm parturition syndrome. Multiple pathologic processes can lead to activation of the common pathway of parturition.(Modified from Romero R, Espinoza J, Mazor M, Chaiworapongsa T: The preterm parturition syndrome. In Critchely H, Bennett P, Thornton S (eds): Preterm Birth. London: RCOG Press, 2004, pp 28-60.)

How should women with a previous spontaneous preterm birth be

evaluated for risk of subsequent preterm birth?

Practice Bulletin No. 130 ACOG

• Evaluate obstetrical history

• Most common sequence for spontaneous PTB cervical ripening (short cervix) followed decidual-memebraneactivation and contractions.

• Review of medial records

– Obstetrical: eg, preeclampsia, IUGR– Medical: eg, chronic hypertension, lupus– Fetal: eg, aneuploidy, polyhydramnios, fetal death

Risk Factors and Associations PTB • Smoking • Extremes of bodyweight • Social disadvantage • Maternal depression • Pregnancy stress • Poor diet • Assisted fertility • Peridontal disease

n engl j med 370;3 january 16, 2014

History • Prior pregnancy between 16 and 20 weeks

– risk of recurrent preterm birth that = or exceeds the RR for women whose prior preterm birth occurred after 20 weeks.

• Women with a prior stillbirth are also often considered separately from those with a prior preterm birth– The risk of subsequent spontaneous preterm birth

is also Iams. Care for women with prior preterm birth. Am J Obstet Gynecol 2010.

History • Gyn Hx: Cervical Surgery

• Ovulation promotion (clomiphene) and stimulation (gonadotropins)– associated with a 2-fold increased risk of PTB

• Superovulation /fresh eggs has a GREATER risk of preterm birth than does use of frozen eggs.

Iams. Care for women with prior preterm birth. Am J Obstet Gynecol 2010.

History • The earlier the gestational age, the greater the

risk of PTB

• Ranging from minimal if any for a twin birth after 34 weeks’ versus

40% when the prior twin birth occurred before 30 weeks.

Iams. Care for women with prior preterm birth. Am J Obstet Gynecol 2010.

Interventions supportedby firm evidence

• Smoking-cessation programs

• Screening and treatment for asymptomatic bacteriuria

• Prophylactic administration of progestational agents.

• Cervical Cerclage

• Antenatal administration of corticosteroids

Screening Modalities

• The single most important predictor of preterm birth is a short cervix.

• In a review of 39,284 cases of preterm birth (<37 wk), short cervix was most important single predictor of preterm birth.

Ultrasound Obstet Gynecol 2006; 27: 362–367

Semin Perinatol 33:317-324 Semin Perinatol 33:317-324

How should the current pregnancy be managed in a women with a prior

spontaneous preterm delivery?


Progestational Agents and the Prevention of Preterm Birth

Fonseca et al, UK, Vaginal progesterone administration reduces spontaneous premature delivery in women with a short cervix.

2007

2003

Meis et al, US, 17OHP administration significantly reduces recurrent preterm birth;DaFonseca et al, Brazil, Vaginal progesterone administration reduces preterm delivery in high risk patients.

1990

1979

1962

1958

1985

1953

1970

1975

Elovitz 2008

• Women with a documented history of spontaneous preterm birth at less than 37 weeks

• Treatment started between 16 and 20 weeks

• Continued until 36 weeks or delivery

Meis et al, NEJM 2003

• 17P history of preterm birth at less than 37 weeks. (mean = delivery of index pregnancy 30.7 weeks).

• N = 306 to 17P and n = 153 placebo.


• PTB < 37 weeks 36.3% in progesterone vs54.9% placebo




• NNT = 5 to prevent PTB before 37 weeks, NNT = 12 for PTB before 32 weeks.

• Progesterone group had less BW<2500 g, NEC, need for supplemental O2, and IVH.

• Results greatest for women with a prior PTB < 34 weeks.

Meis et al, NEJM 2003 Spong et al, Am J Obstet Gynecol 2005

• High rate of PTB in placebo group (36.3%)

• Study population was an especially high-risk group of women

17 – hydroxyprogesterone Caproate• While the best evidence for efficacy is for 17P

to be started 21 weeks, beneficial effects have been reported when 17P is started by 27 weeks.

• 17P should not be stopped early as this is associated with increased incidence of PTB.

González-Quintero VH, et al. Gestational age at initiation of 17-hydroxyprogesterone caproate (17P) and recurrent preterm delivery.J Matern Fetal Neonatal Med 2007;20:249-52.

How HY, et al. Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter? Am J Obstet Gynecol 2007;197:260.e1-4. Rebarber A, et al. Increased recurrence of preterm delivery with early cessation of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 2007; 196:224.e1-4.

• MC, RCT examined role serial TV CL with cerclageplacement for those with a short cervix

• Patients with singleton and history of spontaneous preterm birth at less than 34 weeks

• CL q 2 weeks starting at 16 weeks thru 23 weeks

• If length between 25 and 29 mm screening increased to q week.

• Primary Outcome was PTB at 35 weeks– No significant difference RR, 0.78; 95 % CI, 0.58-1.04

• However, cerclage was associated with a reduction in:– Deliveries before 24 weeks RR, 0.44; 95 % CI, 0.21-

0.92 – Deliveries before 37 weeks RR, 0.75; 95 % CI, 0.60-

0.93 – Perinatal death RR, 0.54; 95 % CI, 0.29-0.99

• Secondary Analysis

– Cerclage for cervical length less than 15mm was associated significant decrease in preterm birth at less than 35 weeks (RR, 0.23; 95% CI, 0.08-0.66)

Should a women with a current singleton pregnancy without a

history of preterm birth be screened for a risk of preterm birth?


Proponents • Potential to reduce preterm birth • High quality evidence exists to support efficacy of

treatment for positive test results (cervical length 20 mm or less)

• Cost Effective • Safe • Reliable (Reproducible, variability <10%)• Recognizable early asymptomatic phase• Valid (accuracy of prediction)• Accepted by patients (> 90 % of pts)• Widely available


Opponents • Quality assurance of screening test • Lack of availability of screening and patient

access to qualified imaging • Patient for patients to receive unnecessary

interventions


Cervical Length Education and Review

Cervical Length Education and Review

© 2013 Perinatal Quality Foundation. All rights reserved.

What intervention have been shown to be beneficial for reducing the risk of preterm birth in women who do NOT have a history of preterm birth but who are found to have a short

cervical length?


Progesterone and Short Cervix

• Multicenter RCT • Women underwent CL screening at 20-25 weeks

(median 22 weeks)• 1.7 % of 24,640 screened CL less than or equal to 15

mm • Excluded fetal anomalies, uterine contractions, ROM,

cerclage• Women with CL 15 mm or less randomized to: vaginal

micronized progesterone 200 mg every night vsplacebo between 24 and 34 weeks

Progesterone and Short Cervix • 90 % of the women in the study had a

singleton • 85 % had no prior preterm birth• Less PTB < 34 weeks in progesterone group

(19.2 vs 34.4%; RR, 0.56; 95% CI, 0.36-0.86) • 44 % decrease in spontaneous preterm birth

at less than 34 weeks

Progesterone and Short Cervix

• Number need to avoid one spontaneous preterm birth < 34 week

• Screen - 387 • Treat - 7

Vaginal progesterone reduces the rate of preterm birthin women with a sonographic short cerv ixHassan et al., UOG 2011

Phase III, prospective, randomized, placebo-controlled, double-masked, parallel-group, multi-center, international trial.

ObjectiveTo determine the efficacy and safety of vaginal progesterone gel in reducingthe rate of PTB < 33 weeks in asymptomatic women with a mid-trimester sonographic short cervix.

Journal Club slides prepared by Dr Asma Khalil(UOG Editor for Trainees)

Methodology

Inclusion criteria1) Singleton 2) GA 19+0 – 23+6 weeks 3) Cervical length (TV US): 10 – 20

mm4) Asymptomatic (no symptoms or signs

of preterm labor)

Exclusion criteria

1) Planned cerclage2) Acute cervical dilation3) Allergy to progesterone4) Recent progestogen treatment (within 4

weeks)5) Chronic medical conditions6) Major fetal anomaly or chromosomal

abnormality7) Uterine malformations8) Vaginal bleeding9) Known/suspected chorioamnionitis

Vaginal progesterone reduces the rate of preterm birthin women with a sonographic short cervi xHassan et al., UOG 2011


Outcomes

Primary outcome

Preterm birth <33 weeks

Secondary outcomes• Neonatal morbidity

• RDS• Bronchopulmonary dysplasia• Intraventricular hemorrhage(Grade III or IV)

• Periventricular leukomalacia• Sepsis• Necrotizing enterocolitis

• Perinatal mortality• PTB <28, <35, and <37 weeks • Neonatal biometry at birth• Congenital abnormalities


†Primary study outcome*Adjustment for study site and risk strata

Outcome

ITT analysis Treated patient Compliant analysis

Adjusted*Unadjusted Adjusted*

P value P value P value

PTB < 35 weeks

PTB < 37 weeks

PTB < 33 weeks † 0.02 0.02 0.01

0.02 0.01 0.01

NS NS NS

NSPTB < 28 weeks 0.04 0.04

NS

RDS

Any morbidity/mortality

Birth weight < 1500g 0.01 0.01 0.01

0.03 0.04 NS

0.04 NS

Neonatal morbidity

Preterm birth


Progesterone for the prevention of preterm birth in women with short cervix

0

5

10

15

20

PlaceboN=235

ProgesteroneN=223

16%

9%

45%

25

Pre

term

birt

h

<

33 w

eeks

(%)

0

10

20

30

40

PlaceboN=125

ProgesteroneN=125

34%

19%

44%

50

Pre

term

birt

h

<

34 w

eeks

(%)

N = 250Cervix: ≤ 15 mm (median 11.5 mm)GA: 20 – 25 weeks (median 22 weeks)Progesterone capsule 200 mg PV dailyDuration: 20 – 34 weeksNo serious adverse events

Fonseca EB et al., NEJM 2007

N = 458Cervix: 10 to 20 mm (median 18 mm)GA: 20 – 23+6 weeks (median 22 weeks)Progesterone bioadhesive gel 90 mg PV dailyDuration: 20 – 36+6 weeksNo serious adverse events

Hassan S et al., UOG 2011

Journal Club slides prepared by Dr Asma Khalil

Clinical utility – Number needed to treat (NNT) to p revent adverse outcome

Progesterone for prevention of PTB < 33 weeks*

Progesterone for prevention of RDS*

MgSO4 for prevention of eclampsia†

Antenatal steroids for prevention of RDS‡

22

14

100

NNT

13

Vaginal progesterone reduces the rate of preterm birthin women with a sonographic short cervixHassan et al., UOG 2011

*Hassan S et al., UOG 2011†Altman D et al., Lancet 2002‡Sinclair JC et al., AJOG1995Journal Club slides prepared by Dr Asma Khalil

(UOG Editor for Trainees)

Does cerclage placement be considered in women who do NOT have a history of preterm birth but

who are found to have a short cervical length? (closed internal os)


• Incidentally detected short cervical length is not diagnostic of cervical insufficiency – Cerclage is not indicated

• Vaginal progesterone is recommended in this population


• Cerclage placement in women WITHOUT a prior spontaneous preterm birth and a cervical length less than 25 mm detected between 16 and 24 weeks has not been associated with a significant reduction of preterm birth. (Level A)

Practice Bulletin No. 142 ACOG, February 2014

Cerclage• Low-risk population, cerclage cervical length less than 25

mm – 16 -24 weeks of gestation has not been associated with a

significant reduction in preterm birth at less than 35 weeks of gestation [RR, 0.76; 95% CI, 0.52–1.15]

Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol2005;106:181–9.

• Cerclage for detection of a cervical length of 15 mm or less – 22–24 weeks of gestation has not been shown to significantly

decrease the rate of preterm birth at less than 33 weeks of gestation [RR, 0.84; 95% CI, 0.54–1.31]

To MS, Alfirevic Z, Heath VC, Cicero S, Cacho AM, Williamson PR, et al. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomisedcontrolled trial. Fetal Medicine Foundation Second Trimester Screening Group. Lancet 2004;363:1849–53.

Does cerclage placement or progesterone treatment decrease the risk of preterm birth in women

with multiple gestations ?


• Progesterone treatment does not reduce the incidence of PTB in women with twin or triplet gestations.

• Cerclage may increase the risk of PTB in women with a twin pregnancy and an US detected cervical length less than 25 mm.


Choosing Wisely® is an initiative of the ABIM Foundation

to help physicians and patients engage in conversations to reduce overuse of tests and procedures, and support physician efforts to help patients make smart and effective care choices.

Does a pessary in women with a short cervix decrease the risk of

preterm birth?

Pessary• One trial of women with an incidentally diagnosed

short cervix – less than or equal to 25 mm at 18–22 weeks of gestation

• open-label randomization: cervical pessary or expectant management (no pessary)

• 385 women, the rate of spontaneous delivery at less than 34 weeks of gestation was significantly lower in the pessary group than in the no pessary group (6% compared with 27%; OR, 0.18; 95% CI, 0.08–0.37).

Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomisedcontrolled trial. Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group. Lancet 2012;379:1800–6.

Pessary• If the results of this small trial are validated,

cervical pessary placement may have additional benefit for prevention of preterm birth in otherwise low-risk women with a short cervix.


ClinicalTrials.gov• 7 trails actively recruiting

– Pessary to Prevent Prematurity in Twins in Case of Short Cervix

– Cerclage vs Cervical Pessary in Women With Cervical Incompetence

– Prevention of Preterm Birth in Pregnant Women at Risk Identified by Ultrasound: Evaluation of Two Treatment Strategies

– Arabin Cervical Pessary for Prevention of Preterm Birth in Cases of Twin-to-twin Transfusion Syndrome Treated by Fetoscopic Selective Laser Coagulation: The PECEP Laser Trial

– Prevention of Preterm Birth With a Pessary in Twin Gestations

– Prevention of Preterm Birth With a Pessary in Singleton Gestations

– Efficacy Study of a Cervical Pessary Containing Progesterone for the Prevention of Preterm Delivery

Summary • All women with a singleton and a prior history

of spontaneous PTB should be offered progesterone supplementation starting between 16 – 24 weeks.

• Regardless of TV ultrasound cervical length, to reduce the risk of recurrent preterm birth.


Summary • Vaginal progesterone can reduce the risk of

preterm birth in asymptomatic women with a singleton without prior PTB and short cervix less than or equal to 20 mm before or at 24 weeks.


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Advanced Maternal Age Management of Pregnancy in

Women over 40Kirsten E. Salmeen, MD

Assistant ProfessorObstetrics, Gynecology & Reproductive Sciences

Maternal-Fetal Medicine

I have nothing to disclose.

• Maternal age statistics and trends• Assisted reproductive technologies (ART)• Aneuploidy & Miscarriage Risk• Underlying health problems• Perinatal morbidity • Management

OUTLINE

InfertilityInfertility

Assisted Reproductive Technology

Age MultipleGestations

Medical Co-Morbidities

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MATERNAL AGE – STATISTICS AND TRENDSAge

What percent of births in the United States would you estimate are in women over age 40?

A. < 5%B. 5 – 10%C. 10 – 15%D. > 15%

< 5%

5 – 1 0

%

1 0 – 1

5 %

> 1 5

%

22%

11%

28%

39%

US Birth Rates Among Women ≥ 35

0%2%4%6%8%

10%12%

1997 2002 2008 2013

Deliveries to Women 35-39 Years

Deliveries to Women ≥ 40 Years

CDC, National Center for Health Statistics, National Vital Statistics System. http://www.cdc.gov/nchs/nvss.htm

3%

12%

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1997 2013Total # of Births in US 3,880,894 3,932,181Age 40-44 Years

# of Births (%) 76,084 (2) 109,484 (2.8)Age 45-49 Years

# of Births (%) 3,333 (0.09) 7,495 (0.19)Age ≥ 50 Years

# of Births (%) 144 (0.004) 677 (0.017)

CDC, National Center for Health Statistics, National Vital Statistics System. http://www.cdc.gov/nchs/nvss.htm

93%


Age

Age and Fertility

Practice Committee Committee Opinion No 589 Fertil Steril 2014Data from multiple non-contracepting communities over many decades

By age 40 it is ~ 5% per cycle

At age 30, a woman’s chance of conception

is ~ 20% per cycle

Age and FertilityBirths Resulting from ART Procedures

National Vital Statistics Data 2011Maternal Age Number of

BirthsNumber of Known

ART-Births Percent

< 35 2,273,953 19,285 0.8535-37 228,392 7,949 3.4838-40 117,937 5,905 5.0141-42 33,299 2,354 7.0743-44 11,717 1,379 11.77≥ 45 5,247 1,624 30.95

National Vital Statistics Reports, Vol. 63, No. 8, December 2014

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RISKS ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHNOLOGIES InfertilityInfertility


Age

ART & Multiple Gestation

• 25 – 30% of ART pregnancies are twins • 1.5 – 3% of ART pregnancies are triplets or more • Monozygotic twinning: 1.7 – 2.5% (vs 0.5%)

Kanter et al Trends and correlates of monozygotic twinning after single embryo transfer Ob Gyn 2015; cdc.gov Assisted Reproductive Technology (ART) National Summary Report 2010




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ART is an independent risk factor for which of the following?

A. Birth defectsB. Cesarean sectionC. Placenta previaD. Pre-eclampsiaE. All of the above B i r

t h de f e

c t s C e

s a re a n

s e ct i o n

P l ac e n

t a pr e v

i a P r e

- e cl a m

p s i a A l l

o f t h e

a bo v e

4% 2%

89%

3%1%

Hansen et al. NEJM 346:725-30, 2002

ART & Birth Defects

Figure 1. Cumulative prevalence of diagnosed major birth defects in singleton infants, according to age at diagnosis

301 Infants

837 Infants

4,000 Infants

ART & Birth Defects

Singleton BirthsAssisted Conception

(N = 4333)Spontaneous Conception

(N = 295,220)Adjusted Odds

RatioAny Defect 361 (8.3) 16,989 (5.8) 1.30 (1.16 – 1.45) Multiple Defects 95 (2.2) 4,690 (1.6) 1.24 (1.00 – 1.54) Cardiovascular 78 (1.8) 3,472 (1.2) 1.36 (1.08 – 1.72) Musculoskeletal 130 (3.0) 4,776 (1.6) 1.50 (1.24 – 1.80)Urogenital 95 (2.2) 4,872 (1.7) 1.25 (1.01 – 1.55)Gastrointestinal 34 (0.8) 1832 (0.6) 1.18 (0.83 – 1.68)Central nervous system 22 (0.5) 1,104 (0.4) 1.34 (0.86 – 2.07)Cerebral Palsy 17 (0.4) 496 (0.2) 2.22 (1.35 – 3.63)

Adjusted for age, parity, fetal sex, year, race/ethnicity, country of birth, maternal conditions in pregnancy, maternal smoking during pregnancy, socioeconomic status and maternal and paternal occupation Davies et al. NEJM 366:1803-13, 2012

Multiple BirthsAssisted Conception

(N = 1,830)Spontaneous Conception

(N = 7,591)Adjusted Odds

RatioAny Defect 152 (8.3) 557 (7.3) 1.16 (0.91 – 1.49)Multiple Defects 55 (3.0) 188 (2.5) 1.10 (0.73 – 1.64)Cardiovascular 30 (1.6) 142 (1.9) 0.99 (0.60 – 1.64) Musculoskeletal 25 (1.4) 102 (1.3) 0.92 (0.54 – 1.57)Urogenital 50 (2.7) 173 (2.3) 1.10 (0.74 – 1.65)Gastrointestinal 23 (1.3) 88 (1.2) 1.13 (0.59 – 2.26)Central nervous system 10 (0.5) 42 (0.6) 1.08 (0.39 – 2.96)Cerebral Palsy 16 (0.9) 50 (0.7) 1.39 (0.69 – 2.77)

ART & Birth Defects

Adjusted for age, parity, fetal sex, year, race/ethnicity, country of birth, maternal conditions in pregnancy, maternal smoking during pregnancy, socioeconomic status and maternal and paternal occupation Davies et al. NEJM 366:1803-13, 2012

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ART & Perinatal Risk

Reddy et al. Infertility, assisted reproductive technology, and adverse pregnancy outcomes. Ob Gyn 2007.

ANEUPLOIDY & MISCARRIAGE RISK

Risk of Chromosomal Abnormalities

Maternal Age at Delivery (years)

Risk of Down Syndrome

Risk of Any Chromosomal Abnormality

20 1/1667 1/52635 1/378 1/19240 1/106 1/6645 1/30 1/21

Risk at Live Birth, According to Maternal Age

Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983;249:2034-8

Miscarriage Risk

Nybo Anderson AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:1708–12.

Risk of Spontaneous Abortion According to Maternal Age at Conception

Risk o

f Spo

ntane

ous A

borti

on (%

)

Maternal Age at Conception (Years)

40%

80%

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ART Modifies Miscarriage Risk

cdc.gov Assisted Reproductive Technology (ART) National Summary Report 2010

~ 30%

~ 65%

cdc.gov Assisted Reproductive Technology (ART) National Summary Report 2010

Donor Oocytes Further Modify SAB Risk

~ 50%

UNDERLYING HEALTH

PROBLEMS InfertilityInfertility




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Risk of Death Increases with Age

050

100150200250300350400

25-29 30-34 35-39 40-44 45-49 50-54

Number of Deaths/100,000 US Females 2010

Age - YearsCDC, National Center for Health Statistics, National Vital Statistics System. http://www.cdc.gov/nchs/nvss.htm

Percent of US Women With Obesity(BMI > 30) 2007

0%

5%

10%

15%

20%

25%

30%

35%

18-29 yrs 30-39 yrs 40-49 yrs 50-59 yrs

cdc.gov NHANES 2006-2007

Percent of US Females With Hypertension NHANES 1999-2008

0%2%4%6%8%

10%12%14%16%18%20%

20-34 35-39 40-44

aOR = 3.3 (2.1 – 5.2)

aOR = 8.2 (5.0 – 13.3)

Bateman et al. Hypertension in Women of Reproductive Age in the United States: NHANES 1999-2008. PLoS ONE 2012

Adjusted for: race/ethnicity, diabetes, chronic kidney disease, alcohol use, OCP use, BMI

11.1%

3.1%

10.6%

51.1%

39.7%

39.7%

0% 10% 20% 30% 40% 50% 60%

45-54 Yrs

18-44 Yrs

Total

Diabetes Prediabetes

Diabetes & PrediabetesWomen ≥ 18, 2007-2010

cdc.gov NHANES 2007-2010

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9

0.00%

0.50%

1.00%

1.50%

2.00%

2.50%

30-39 yrs 40-49 yrs 50-59 yrs

Colon CancerBreast Cancer

Chance of Being Diagnosed with Breast or Colon Cancer in the Next 10 Years

http://www.cancer.org; http://www.cdc.gov/cancer/colorectal/statistics/age.htm

PERINATAL MORBIDITY





0

50

100

150

20 25 30 35 40 45 50Age (Years)

Perinatal Risk

10/15/2015

10

%Odds

Ratio/Relative Risk

Maternal Age

Reference Age

Non-Chromosomal Congenital Anomalies

Reefhuis 1.1 – 1.9 35-40 25-29Loane 2.3 – 2.5 1 – 1.8 ≥ 40 25-29

Cleary-Goldman 2.8 – 2.9 1.4 – 1.7 ≥ 35 < 35Preterm Birth

Cleary-Goldman (< 37 wks) 8.6 – 11.8 1.0 – 1.4 ≥ 35 < 35Yogev (< 34 wks) 5.6 1.8 40-44 20-29Yogev (< 34 wks) 8.5 3.5 ≥ 45 20-29Luke (< 32 wks) 2.5 – 3.0 1.6 – 2.1 ≥ 40 30 – 34

Obstetrical Risks Associated with Increased Maternal Age

Reefhuis et al. Birth Defects Research (Part A) 70:572–579, 2004; Loane et al. BJOG 116:1111–1119, 2009; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Cleary-Goldman et al. Obstet Gynecol105:983–90, 2005; Luke B et al. Hum Reprod 22(5):1264-1272, 2007

% Odds Ratio/Relativ

e Risk

Maternal Age

Reference Age

Low Birth WeightCleary-Goldman 5.1 – 7.5 1.1 – 1.6 ≥ 35 < 35

Yogev 12.7 0.8 40-44 20-29Luke 7.7 – 9.2 NR ≥ 40 30-34Yogev 16.9 0.7 ≥ 45 20-29Salihu ~ 14 3.0 ≥ 50 20-29


Cleary-Goldman et al. Obstet Gynecol 105:983–90, 2005; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Luke B et al. Hum Reprod 22(5):1264-1272, 2007; Salihu et al. Obstet Gynecol 102:1006 –14, 2003


%Odds

Ratio/Relative Risk

Maternal Age

Reference Age

Pre-EclampsiaCleary-Goldman 2.3 – 3.0 0.9 – 1.1 ≥ 35 < 35

Yogev 2.4 NR 40-44 N/AYogev 10.7 NR ≥ 45 N/APare 13.4 aOR NS > 40 < 35Luke 6.2-7.4 1.3 – 1.6 > 40 30 – 34

Paulson 35 NR ≥ 50 N/A

Cleary-Goldman et al. Obstet Gynecol105:983–90, 2005; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Luke et al. Hum Reprod22(5):1264-1272, 2007; Paulson et al. JAMA;228:2320-2323, 2002


% Odds Ratio/Relativ

e Risk

Maternal Age

Reference Age

Gestational DiabetesCleary-Goldman 5.3 – 7.3 1.8 – 2.4 ≥ 35 < 35

Yogev 10.2 NR 40-44 N/AYogev 17.0 NR ≥ 45 N/A

Paulson 17.5 NR ≥ 50 N/APlacenta Previa

Cleary-Goldman 0.9 – 1.9 1.8 – 2.8 ≥ 35 < 35Yogev 1.4 5.7 40-44 20-29Yogev 5.6 13.4 ≥ 45 20-29

Jacobsson 0.2 – 0.7 1.04 – 4.6 ≥ 40 20-29 Salihu 16.7 NR ≥ 50 N/A

Cleary-Goldman et al. Obstet Gynecol 105:983–90, 2005; Yogev et al. Am J Obstet Gynecol 203:558.e1-7, 2010; Paulson et al. JAMA;228:2320-2323, 2002; Jacobsson et al. Obstet Gynecol 104:727–33, 2004; Salihu et al. Obstet Gynecol 102:1006 –14, 2003

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Mode of Delivery

Cesarean Section

35 – 40 Yrs 40 – 45 Yrs 45 – 50 Yrs > 50 YrsCleary-

Goldman 31.4% 40.5% (aOR 2.0)

Yogev 42.9% (RR 3.7) 78.5% (RR 31.8)Luke

(primiparous) 43% (RR 1.96 54.1% (RR 3.14)

Jacobsson 23.5% (OR 2.8) 30.3% (OR 3.8)

Dulitzki 39.4% (OR 7.3)Paulson

(singletons) 68%

Dulitzki et al. Effect of very advanced maternal age on pregnancy outcome and rate of cesarean delivery. Ob Gyn 1998

Risk Factors for Cesarean Section

• Krieg: Stanford University, 40 pregnancies in oocyte recipients compared to women ≥ 38 yrs who underwent autologous IVF cycles– OR for C/S in oocyte recipients: 2.78 (1.44-5.36)– Each 1 year increase in maternal age was

associated with a 13% increase in the odds of C/S.

Cesarean Section & Oocyte Recipients

Krieg SA, Henne MB, Westphal LM. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil Steril 2008;90:65–70.

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Risk of Intrauterine Fetal Demise

At what gestational age do you offer induction of labor for women who are over 40 without other risk factors?

A. 39 – 40 weeksB. 40 – 41 weeksC. > 41 weeksD. 41 – 42 weeks

3 9 – 4

0 we e k

s 4 0

– 41 w

e e ks

> 41 w

e e ks

4 1 – 4

2 we e k

s

40%

8%

24%28%

Hoffman et al. Pregnancy at or beyond age 40 years is associated with an increased risk of fetal death and other adverse outcomes. AJOG 2006.

Risk of IUFD

35-39 YearsaOR* (95% CI)

N = 13,902

≥ 40 yearsaOR* (95% CI)

N = 3,95332 – 36 weeks 2.03 (1.54 – 2.69) 1.73 (1.05 – 2.83)37 – 39 weeks 1.20 (0.85 – 1.70) 1.63 (0.97 – 2.75)40 – 41 weeks 0.80 (0.44 – 1.45) 2.28 (1.82 – 4.40)

Odds of IUFD by GA compared to women < 35 years (N = 108,547)

* Adjusted for race/ethnicity, parity, chronic hypertension, pre-elcampsia, diabetes

Bateman et al. Higher rate of stillbirth at the extremes of reproductive age: A large nationwide sample of deliveries in the United States. AJOG 2006.

IUFD Risk

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Reddy et al. Maternal age and the risk of stillbirth throughout pregnancy in the United States. AJOG 2006.

IUFD Risk Other Reported Risks

• Intensive care stay• Myocardial infarction• Pulmonary edema• Venous thromboembolism• Postpartum depression

Other Anecdotal Risks

• Anxiety• Difficulty with breastfeeding

A BRIEF DIVERSION TO ADVANCED PATERNAL AGE

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Advanced Paternal Age

Salmeen, Zlatnik. The oldest gravidas: a review of pregnancy risks in women over 45. Obstetrical and Gynecological Survey 2011

Possibly increased risk for other birth defects, autism-spectrum disorders

MANAGEMENT

What I do…

Without a lot of evidence

• Hemoglobin A1c, fasting glucose• TSH• Mammogram• EKG• Lipids• Serial BPs • Cardiac Stress Test/Cardiology evaluation

Preconception Work-Up for Women ≥ 40

(or ≥ 35 with risk factors)

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First Trimester Care for Women ≥ 40

• Determine mode of conception • Assess fetal number, chorionicity of multiples• TSH (if not recently obtained)• Early glucose testing • If hypertensive: baseline pre-eclampsia labs• Genetic counseling (adjust for oocyte-donor age)• Consideration of aspirin prophylaxis

** Aspirin Prophylaxis **

• In “high-risk” women, aspirin prophylaxis may reduce the risk of pre-eclampsia by up to 17%

• I consider women over 40 to be “high risk” and offer aspirin

• Detailed fetal anatomic survey• Low-threshold for fetal echocardiogram• Repeat glucose tolerance testing• Evaluation of fetal growth in the third trimester• Antenatal testing • Labor planning, counseling regarding mode of delivery• Labor induction 39-40 weeks

Prenatal Care for Women ≥ 40 (or ≥ 35 with risk factors) TAKE HOME POINTS

• Age-related risks are actually multifactorial• IUFD increases with increasing maternal age.

Induction for “post dates” may be appropriate after 39-40 weeks for women > 35 – 40 years.

• Age nor donor-oocyte recipient status are indications for cesarean delivery.

• Aspirin prophylaxis is indicated for women at high-risk for pre-eclampsia, including women over 40.

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Questions?

10/15/2015

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Issues Around Periviability: What is an Obstetrician to do?

Melissa Rosenstein, MD, MASUniversity of California, San Francisco

October 15, 2015

Disclosures• I have no financial disclosures to make

Objectives• Review new evidence and recent guidelines

regarding management of periviable birth• Explore the implications of changing

resuscitation thresholds• Present a framework for counseling parents

facing a periviable delivery• Focus on the experience and role of the

obstetrician in making decisions around resuscitation

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Further down the page…• 22-week-old babies did not survive without

medical intervention.– 78 cases with active treatment

• 18 survived• 7 of those did not have moderate or severe impairments. • 6 had serious problems such as blindness, deafness, severe

CP• 755 born at 23 weeks

– 542 cases active treatment• One-third survived• Half of the survivors had no significant problems.

Belluck P. New York Times. 2015 May 6, 2015. Rysavy MA, et al.. N Engl J Med. 2015 May 7;372(19):1801-11.

Rysavy MA, et al.. N Engl J Med. 2015 May 7;372(19):1801-11.

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Impairment Definitions• Severe impairment

– cognitive or motor score (Bayley-III) of less than 70 • (i.e., >2 SD below the scale mean)

– severe cerebral palsy– Gross Motor Function Classification System (GMFCS) level of 4 or 5

• (scale is 0-5)– bilateral blindness (visual acuity, <20/200– severe hearing impairment that cannot be corrected with bilateral

amplification.

• Moderate impairment – Bayley-III cognitive or motor score of 70 to 84

• (i.e., 1 to 2 SD below the scale mean), – moderate cerebral palsy– GMFCS level of 2 or 3.

Neurodevelopmental ImpairmentOutcomeAmongSurvivors

22N=18

23N=173

24N=598

25N=850

WithoutModerate or Severe NDI

7 (39%) 83 (47%) 327 (54%) 523 (61%)

Moderate NDI 5 (28%) 48 (28%) 160 (27%) 198 (23%)Severe NDI 6 (33%) 42 (24%) 111 (19%) 129 (15%)

Adapted from Supplemental Table 2, Rysavy MA, et al.. N Engl J Med. 2015 May 7;372(19):1801-11.

NICHD Joint Statement

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The small print• Between 22 - 25 weeks of gestation, there may be mitigating

factors (IUGR, malformations, aneuploidy, prolonged membrane rupture) that will affect the determination of viability

• The majority of survivors born at 25 6/7 weeks of gestation or less will incur major morbidities, regardless of gestational age at birth;

• Data from recent large studies suggest survival with delivery at 22 0/7 through 22 6/7 weeks of gestation to be 5-6%.

• With survival rates of approximately 26-28% and higher, infants born at 23 0/7 weeks through 25 6/7 weeks of gestation are generally considered potentially viable

Raju TN, Am J Obstet Gynecol. 2014 May;210(5):406-17.

NICHD Survival Data

From: Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012JAMA. 2015;314(10):1039-1051. doi:10.1001/jama.2015.10244

Infant Survival to Discharge

From: Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012JAMA. 2015;314(10):1039-1051. doi:10.1001/jama.2015.10244

Infant Survival to Discharge Without Major Morbidity

Infant Survival to Discharge

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Viability“In general, those born at 23 weeks of gestation should be considered potentially viable…”


Viability• “..viability marks the earliest point at which the State’s

interest in fetal life is constitutionally adequate to justify a legislative ban on nontherapeutic abortions.”

• “Whenever viability may occur, be it at 23–24 weeks, the standard at the time, or earlier, as may be the standard sometime in the future, the attainment of viability serves as the critical fact in abortion legislature.”

– Planned Parenthood of Southeastern PA. v Casey, 505 U.S. 833 (1992).

Viability - California• “the point in a pregnancy when, in the good

faith medical judgment of a physician, on the particular facts of the case before that physician, there is a reasonable likelihood of the fetus’ sustained survival outside the uterus without the application of extraordinary medical measures.”– CA HEALTH AND SAFETY CODE SECTION 123460-

123468

From NICHD statement“importantly, providers and families should understand that initiation of intervention to enhance outcomes (eg, antibiotics for preterm PROM, antenatal corticosteroid administration) does not mandate that all other aggressive interventions (eg. cesarean delivery) be undertaken regardless of clinical circumstances in the periviable period”


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Periviable Cesarean• Increased risk of uterine rupture in a

subsequent pregnancy– 1.8% (8/456) vs. 0.4% (38/10,505)

• Even excluding classical incisions• Mean gestational age in 2nd delivery: 36wks

• Inability to see or hold baby• Painful recovery during difficult time

Lannon SM et al, Obstet Gynecol. 2015 May;125(5):1095-100.

Effect of Method of Delivery• No difference in neurodevelopmental

outcomes at age 2• No difference in mortality • No difference in short-term morbidity

• Reserve CD for obstetric indications

Mercer BM, Semin Perinatol. 2013 12;37(6):417-21.Običan SG et al, Obstet Gynecol. 2015 10;213(4):578.e1,578.e4.

AAP Guide to Counseling• “In addition, whereas previous publications

may have provided specific recommendations based on the anticipated gestational age, this statement emphasizes the limitations of that approach and the need to individualize counseling. “

Cummings J, COMMITTEE ON FETUS AND NEWBORN. Pediatrics. 2015 Aug 31.

Limitations of Gestational Age Cutoffs• Variable and rapid rate of fetal development

during the early third trimester • Inaccuracy of gestational dating• Other factors

– Gender– Steroids– Multiples– Birthweight


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Components of Counseling• assessment of risks• communication of those risks• ongoing support


What information to give?• Institutional vs. Local vs. National?

– Depends on patterns of resuscitation– Depends on numbers of babies

• Range rather than specific number

• Written/Visual aides requested by parents– Consider literacy levels

Gaucher N, Payot A. Paediatr Child Health. 2011;16(10): 638–642

NICHD NRN calculator

Arnold C, Tyson JE. Semin Perinatol. 2014 2;38(1):2-11https://neonatal.rti.org

Hope• Communicating only negative information

perceived as having “given up”• Lack of optimism leads to mistrust and

adversarial relationship• Acknowledge grief and fear• Physicians who express emotion more likely to

be perceived as compassionate and hopeful

Grobman WA et al, Obstet Gynecol. 2010 May;115(5):904-9.Boss RD et al, Pediatrics. 2008 Sep;122(3):583-9.

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“What would you do”• Use as bridge to inquire about patient

– Attitudes– Fears– Preferences– Values– Goals

Tucker Edmonds B et al, Patient Educ Couns. 2015 Jan;98(1):49-54.

Importance of Team Counseling• Divergent estimates given on likelihood of

survival and disability• Different definitions of “intact survival”• Specialists defer to each other on

management questions (steroids)

Tucker Edmonds B et al, J Perinatol. 2015 May;35(5):344-8. Tucker Edmonds B et al, J Matern Fetal Neonatal Med. 2014 Nov 14:1-5.

Patient Desires• Team approach• Time to think• Multiple visits• Expressions of sympathy• Hope• Range of numbers• Ongoing support

Srinivas SK. Semin Perinatol. 2013 12;37(6):426-30. Manley BJ et al, Pediatrics. 2010; 125(3).

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UCSF PolicyResuscitation at limits of viability• >26 weeks – Universal resuscitation (unless lethal

anomaly or other reason not viable)• 25+0 – 25+6 – Resuscitation is default option, with

parental choice for comfort care or resuscitation• 24+0 – 24+6 – Do not recommend resuscitation.

Parental choice for comfort care or resuscitation, based on individual risk factors

• 23+0 – 23+6 – Strong recommendation against resuscitation. Parental choice to be considered IF meets ALL mandatory criteria:

UCSF Criteria for Resuscitation at 23wMANDATORY CRITERIA IN ORDER TO BE OFFERED RESUSCITATION AT 23 +0 -23+6[ ] No major congenital anomalies [ ] No chorioamnionitis on presentation, clinical diagnosis made by obstetrics team [ ] Greater than 24 hours from first dose of BMZ[ ] Category 1 or 2 Fetal Heart Rate Tracing; no evidence of category III tracing on presentation[ ] No prior or current laminaria placement

RELATIVE CONTRAINDICATIONS TO RESUSCITATION AT 23 0/7 – 23 6/7, unless otherwise specified[ ] multiple gestation pregnancy[ ] IUGR (<10%ile)[ ] Unexplained or prolonged oligohydramnios

Counseling Team• Pregnant patient, with partner, intended

parent(s) or other anticipated guardian, if applicable

• MFM Fellow, and/or MFM or OB attending (or Chief OB resident)

• Neonatology Fellow and/or Attending • L&D bedside RN• ICN triage RN• Social worker, as available

Talking Points• Use name and gender of baby• Details vs. Big Picture• NEJM Survival Stats• Obstetric options• Neonatal options• Hospital Course

10/15/2015

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Next Steps

• Northern California Periviability Collaborative • Data collection• Individualize decision-making

Thank you!!

References 1. Ancel PY, Goffinet F, EPIPAGE-2 Writing Group, Kuhn P, Langer B, Matis J, et al. Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr. 2015 Mar;169(3):230-8. 2. Arnold C, Tyson JE. Outcomes following periviable birth. Semin Perinatol. 2014 2;38(1):2-11. 3. Belluck P. Premature Babies May Survive at 22 Weeks if Treated, Study Finds. New York Times. 2015 May 6, 2015. 4. Boss RD, Hutton N, Sulpar LJ, West AM, Donohue PK. Values parents apply to decision-making regarding delivery room resuscitation for high-risk newborns. Pediatrics. 2008 Sep;122(3):583-9. 5. Chervenak FA, McCullough LB. Ethical issues in periviable birth. Semin Perinatol. 2013 12;37(6):422-5. 6. Cummings J, COMMITTEE ON FETUS AND NEWBORN. Antenatal Counseling Regarding Resuscitation and Intensive Care Before 25 Weeks of Gestation. Pediatrics. 2015 Aug 31. 7. Dupont-Thibodeau A, Barrington KJ, Farlow B, Janvier A. End-of-life decisions for extremely low-gestational-age infants: why simple rules for complicated decisions should be avoided. Semin Perinatol. 2014 Feb;38(1):31-7. 8. Gaucher N, Payot A. From powerlessness to empowerment: Mothers expect more than information from the prenatal consultation for preterm labour. Paediatr Child Health. 2011 Dec;16(10):638-42. 9. Grobman WA, Kavanaugh K, Moro T, DeRegnier RA, Savage T. Providing advice to parents for women at acutely high risk of periviable delivery. Obstet Gynecol. 2010 May;115(5):904-9. 10. Haywood JL, Goldenberg RL, Bronstein J, Nelson KG, Carlo WA. Comparison of perceived and actual rates of survival and freedom from handicap in premature infants. Am J Obstet Gynecol. 1994 Aug;171(2):432-9. 11. Kaempf JW, Tomlinson MW, Campbell B, Ferguson L, Stewart VT. Counseling pregnant women who may deliver extremely premature infants: medical care guidelines, family choices, and neonatal outcomes. Pediatrics. 2009 Jun;123(6):1509-15. 12. Kariholu U, Godambe S, Ajitsaria R, Cruwys M, Mat-Ali E, Elhadi N, et al. Perinatal network consensus guidelines on the resuscitation of extremely preterm infants born at <27 weeks' gestation. Eur J Pediatr. 2012 Jun;171(6):921-6. 13. Lannon SM, Guthrie KA, Vanderhoeven JP, Gammill HS. Uterine rupture risk after periviable cesarean delivery. ObstetGynecol. 2015 May;125(5):1095-100. 14. Lantos JD, Meadow W. Variation in the treatment of infants born at the borderline of viability. Pediatrics. 2009 Jun;123(6):1588-90.

References, Cont’d15. Litmanovitz I, Reichman B, Arnon S, Boyko V, Lerner-Geva L, Bauer-Rusak S, et al. Perinatal factors associated with active intensive treatment at the border of viability: a population-based study. J Perinatol. 2015 Sep;35(9):705-11. 16. Manley BJ, Dawson JA, Kamlin CO, Donath SM, Morley CJ, Davis PG. Clinical assessment of extremely premature infants in the delivery room is a poor predictor of survival. Pediatrics. 2010 Mar;125(3):e559-64. 17. Marlow N. The elephant in the delivery room. N Engl J Med. 2015 May 7;372(19):1856-7. 18. Mercer BM. Mode of delivery for periviable birth. Semin Perinatol. 2013 12;37(6):417-21. 19. Moore GP, Lemyre B, Barrowman N,Daboval T. Neurodevelopmental outcomes at 4 to 8 years of children born at 22 to 25 weeks’ gestational age: A meta-analysis. JAMA Pediatrics. 2013 October 1;167(10):967-74. 20. Običan SG, Small A, Smith D, Levin H, Drassinower D, Gyamfi-Bannerman C. Mode of delivery at periviability and early childhood neurodevelopment. Obstet Gynecol. 2015 10;213(4):578.e1,578.e4. 21. Raju TN, Mercer BM, Burchfield DJ, Joseph GF,Jr. Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Am J Obstet Gynecol. 2014 May;210(5):406-17. 22. Ramsay SM, Santella RM. The definition of life: a survey of obstetricians and neonatologists in New York City hospitals regarding extremely premature births. Matern Child Health J. 2011 May;15(4):446-52. 23. Rysavy MA, Li L, Bell EF, Das A, Hintz SR, Stoll BJ, et al. Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med. 2015 May 7;372(19):1801-11. 24. Soll RF. Progress in the Care of Extremely Preterm Infants. JAMA. 2015 Sep 8;314(10):1007-8. 25. Srinivas SK. Periviable births: Communication and counseling before delivery. Semin Perinatol. 2013 12;37(6):426-30. 26. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015 Sep 8;314(10):1039-51. 27. Tucker Edmonds B, McKenzie F, Panoch JE, Barnato AE, Frankel RM. Comparing obstetricians' and neonatologists' approaches to periviable counseling. J Perinatol. 2015 May;35(5):344-8. 28. Tucker Edmonds B, McKenzie F, Panoch JE, Frankel RM. Comparing neonatal morbidity and mortality estimates across specialty in periviable counseling. J Matern Fetal Neonatal Med. 2014 Nov 14:1-5. 29. Tucker Edmonds B, McKenzie F, Panoch JE, Wocial LD, Barnato AE, Frankel RM. "Doctor, what would you do?": physicians' responses to patient inquiries about periviable delivery. Patient Educ Couns. 2015 Jan;98(1):49-54.

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Depression in PregnancyAnna Glezer MDAssistant Clinical ProfessorDepartment of PsychiatryDepartment of OB/GYN and Reproductive Sciences

October 15, 2015

DisclosuresNone

Goals of Today’s Presentation• Recognize the frequency of depression in

pregnancy• Become familiar with the screening and

diagnosis of depression in pregnancy• Learn about treatment options• Review psychopharmacological options for

pregnant patients with depression

Audience Response: How common is depression in pregnancy?A. 5%B. 15%C. 50%D. 75%

5 % 1 5%

5 0%

7 5%

5% 4%

17%

74%

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Depression in Pregnancy is Common

• Reproductive years overlap with depression onset years

• Hormonal impact• Rates vary by trimester• Under and misdiagnosis• Symptoms confused with normal changes of

pregnancy• Co-occurring diagnoses such as anxiety

Schiller, C.E. et al. Psychopharmacology 2014Douma, S.L. et. al. Advances in Nursing Science 2005

Screening Tools

• PHQ-2• PHQ-9• Edinburgh

Edinburgh Postnatal Depression Scale

Risk Factors of Depression in Pregnancy

• Previous episodes of depression• Risk of recurrence high off of medication

• Limited social support• Marital conflict• Multiple other children• Ambivalence about pregnancy

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3

Risk of Medication Discontinuation

• Increased risk of relapse: 26% vs. 68%

Cohen, et. al. JAMA 2006

Audience Response: What are risks of untreated depression in pregnancy?A. Postpartum problems, including PPDB. Delivery complications, including increased

NICU admissions for the infantC. SGA and preterm laborD. SuicideE. 2 of the aboveF. 3 of the aboveG. All of the above

P o st p a

r t u m p r o

b l em s

, i n. . .

D e li v e

r y co m

p l i ca t i o

n s , . . .

S G A a n

d pr e t

e r m l a b

o rS u i

c i d e2 o

f t he a

b o ve

3 of t h

e ab o v

eA l l

o f th e

a b ov e

0% 0% 0%

85%

12%

3%0%

Untreated Depression Effects• Fetal Effects• Neonatal outcomes• Postpartum problems

Gentile, et. al. Neuroscience 2015Grote, et. al. Archives of General Psychiatry 2010Malm, H. et. al. AJP 2015

Treatment Options• Pharmacology• Psychotherapy• Complimentary therapeutic options:

• Omega-3-Fas• L-methylfolate• SAMe• Massage• Exercise• Light therapy• Acupuncture

Delgiannidis and Freeman, Best Practice in Clinical Obstetrics and Gynaecology

10/15/2015

4

Pharmacology: How to Weigh the Risks

• Fetal development/rates of malformation• Neonatal outcomes and complications• Long-term neurodevelopmental consequences

Audience Response: What is your first line medication treatment for perinatal depression?A. WellbutrinB. SertralineC. BenzodiazepinesD. I would not prescribe psychotropic

medication during pregnancy

W el l b u

t r i nS e r

t r a li n e

B e nz o d

i a z ep i n

e s

I w ou l d

n o t p r e

s c r ib e

p s . ..

9% 6%1%

85%

1st Line Psychopharmacology: SSRIs• Major malformations in 1st trimester exposure• Neonatal adaptation syndrome• No increased risk of miscarriage• PPHN• Association with autism• Long-term sequelae• Safety in breastfeeding• Well-tolerated• Mechanism of action: receptor upregulation and

hormonal interaction

Other Psychopharmacologic Options• Bupropion• Mirtazapine• SNRI medications• Augmentation agents• Lamotrigine

10/15/2015

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Take-Home Points• Depression is common in pregnancy.• Depression during pregnancy is associated with a

variety of risks and complications. • All patients at risk should be screened for

depression during pregnancy. • Treatment is available. Pharmacotherapy

requires a risk/benefit analysis on effects of untreated/undertreated mental illness versus effects of medication.

Coming soon…

Expert guidance on emotional wellness for a rewarding pregnancy

10/15/2015

1

Anesthesia Considerations in Obstetric Hemorrhage

Jennifer Lucero, MDAssistant Professor

Division of Obstetric Anesthesia

Post-PartumHemorrhage

• Atony• Retained Placenta• Placenta accreta• Defects in Coagulation• Vaginal laceration• Uterine Inversion

Common Things Being CommonMost Common Cause of Maternal Mortality Worldwide.• In the US roughly 3% rate of PPH• Increasing rates of transfusion Obstetrics

– Increased Cesarean Delivery– Abnormal Placentation

• Atony 80% of causes of Severe PPH

WHO Analysis of Causes of Maternal Death Systematic Review

Khan KS, Wojdyla D, Say L, et.al., Lancet 2006; 367: 1066-74

DevelopedCountries

Africa AsiaLatin Am.Caribbean

Hemorrhage 13.4% 33.9% 30.8% 20.8%

HypertensiveDisorders

16.1% 9.1% 9.1% 25.7%

Infections 2.1% 9.7% 11.6% 7.7%

Abortion 8.2% 3.9% 5.7% 12.0%

Embolism 14.9% 2.0% 0.4% 0.6%

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Flood KM, et al. Am J Obstet Gynecol. 2009; 200: 632

Accreta and Peripartum Hysterectomy

Creanga AA, et al. Obstet Gynecol. 2015; 125: 5-12

Anesthesiology 2014; 121:450-8

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Graphic Source: CMQCC California Maternal Quality Care Collaborative

Source:www.cmqcc.org/ob_hemorrhage

• Developed a Tool Kit for OB services:– Set of Best Practices (short summaries of key aspects of OB

hemorrhage)– Checklist for managing OB hemorrhage– Flow-Chart and Table Chart Summaries of approach– Implementation tools such as sample policies, procedures,

charting examples, implementation hints• All resources on-line at:

www.cmqcc.org/ob_hemorrhage

CMQCC Hemorrhage Task Force:

Source: CMQCC California Maternal Quality Care Collaborative

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• Coagulopathy persisted at ICU admissionPre-ICU resuscitation:

9 ± 1 L crystalloid12 ± 1 units PRBC5 ± 0.4 units FFP

FFP was not given until after 6 units PRBCs• In the ICU during resuscitation, patients received 10 ± 1 units FFP for coagulopathy; the ratio of FFP:PRBC was 1:1. Mean INR < 1.4 within 8 hours

� Volume restoration is accomplished by using thawed plasma as a primary resuscitation fluid in at least a 1:1 or 1:2 ratio with PRBCs� Crystalloid is minimized and serves mainly as a carrier� The blood bank activates the massive transfusion protocol and

deliver 6 units of plasma, 6 units of PRBCs, 6 packs of platelets, and 10 units of cryoprecipitate � Recombinant FVIIa is occasionally used

� “Using the damage control resuscitation approach, the lack of intraoperative coagulopathic bleeding has been remarkable, allowing surgeons to focus on surgical bleeding.”

� “Patients treated in this fashion almost always arrive in the ICU warm, euvolemic, and nonacidotic, with a normal INR and minimal edema.”

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� “In the majority of patients the abnormalities of the lethal triad are absent.”

� “These patients appear to be easily ventilated and more quickly extubated than patients with similar blood loss treated with the standard crystalloid resuscitation volumes and blood component ratios.”

Borgman et al. J Trauma 2007; 63:805-13

2003-2005 Retrospective Data From Iraq War

Volume 50, February 2010 TRANSFUSION

Plasma:RBC product transfusion ratios effect on patient survival

Survival versus ratio. (Dark Gray ) 24-hour survival; (Light Gray ) 30-day survivalVolume 50, February 2010 TRANSFUSION

PLT:RBC product transfusion ratios effect on patient survival

Survival versus ratio. (Dark Gray ) 24-hour survival; (Light Gray ) 30-day survival

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6

Principles to Reducing Maternal Hemorrhage

• Screen and identify patients at high risk• Active management of 3rd stage• Ongoing quantification of blood loss• Ongoing evaluation of patient’s vital signs• Sequential use of medications & procedures• Timely request for blood products • Massive transfusion protocol and team• Periodic hemorrhage drills and simulations

Adapted from CMQCC California Maternal Quality Care Collaborative – OB Hemorrhage Task Force 22Graphic Source: CMQCC California Maternal Quality Care Collaborative

Blood Loss:1000-1500 ml

Stage 2

SequentiallyAdvance through

Medications &Procedures

Pre-Admission

Time of admission

Identify patients with special consideration:Placenta previa/accreta, Bleeding disorder, or those who decline blood products

Follow appropriate workups, planning, preparing

of resources, counseling and notification

Screen All Admissions for hemorrhage risk:Low Risk, Medium Risk and High Risk

Low Risk: Draw blood and hold specimenMedium Risk: Type & Screen, Review Hemorrhage ProtocolHigh Risk: Type & Crossmatch 2 Units PRBCs; Review Hemorrhage Protocol

All women receive active management of 3rd stageOxytocin IV infusion or 10 Units IM, 10-40 U infusion

Standard Postpartum Management

Fundal Massage

Vaginal Birth:Bimanual Fundal MassageRetained POC: Dilation and CurettageLower segment/Implantation site/Atony: Intrauterine BalloonLaceration/Hematoma: Packing, Repair as RequiredConsider IR (if available & adequate experience)

Cesarean Birth:Continued Atony: B-Lynch Suture/Intrauterine BalloonContinued Hemorrhage: Uterine Artery Ligation

To OR (if not there); Activate Massive Hemorrhage Protocol

Mobilize Massive Hemorrhage Team TRANSFUSE AGGRESSIVELY RBC:FFP:Plts 6:4:1 or 4:4:1

IncreasedPostpartum Surveillance

Definitive SurgeryHysterectomy

Conservative SurgeryB-Lynch Suture/Intrauterine BalloonUterine Artery LigationHypogastric Ligation (experienced surgeon only)Consider IR (if available & adequate experience)

Fertility

Strongly

Desired

Consider ICUCare; Increased

Postpartum Surveillance

Verify Type & Screen on prenatal record;

if positive antibody screen on prenatal or current labs (except low level anti-D from Rhogam), Type & Crossmatch 2

Units PBRCs

CALL FOR EXTRA HELPGive Meds: Hemabate 250 mcg IM -or-

Misoprostol 600-800 SL or PO

Cumulative Blood Loss>500 ml Vag; >1000 ml CS>15% Vital Sign change -or-

HR ≥ 110, BP ≤ 85/45

O2 Sat <95%, Clinical Sx

Ongoing Evaluation:

Quantification of blood loss and

vital signs

Unresponsive Coagulopathy:After 10 Units PBRCs and full

coagulation factor replacement,may consider rFactor VIIa

HEMORRHAGE CONTINUES

Blood Loss:>1500 ml

Stage 3

Activate Massive

Hemorrhage Protocol

Blood Loss: >500 ml Vaginal

>1000 ml CS

Stage 1Activate

Hemorrhage Protocol

NO

Stage 0All Births

Transfuse 2 Units PRBCs per clinical signs

Do not wait for lab valuesConsider thawing 2 Units FFP

YES

YES NO

Ong

oing

Cum

ulat

ive

Blo

od L

oss

Eva

luat

ion

Cumulative Blood Loss>1500 ml, 2 Units Given,

Vital Signs Unstable

YESIncrease IV Oxytocin RateMethergine 0.2 mg IM (if not hypertensive)Vigorous Fundal massage; Empty Bladder; Keep WarmAdminister O2 to maintain Sat >95%Rule out retained POC, laceration or hematomaOrder Type & Crossmatch 2 Units PRBCs if not already done

Activate Hemorrhage ProtocolCALL FOR EXTRA HELP

Continued heavy bleeding

Increased Postpartum Surveillance

NO

NO

CONTROLLED

INCREASED BLEEDING

California Maternal Quality Care Collaborative (CMQCC), Hemorrhage Taskforce (2009) visit: www.CMQCC.org for detailsThis project was supported by funds received from the State of California Department of Public Health, Center for Family Health; Maternal, Child and Adolescent Health Division

Obstetric Emergency Management Plan: Flow Chart Format Release 2.0 7/9/2014

23Graphic Source: CMQCC California Maternal Quality Care Collaborative

Blood Loss:1000-1500 ml

Stage 2

SequentiallyAdvance through

Medications &Procedures

Pre-Admission

Time of admission

Identify patients with special consideration:Placenta previa/accreta, Bleeding disorder, or those who decline blood products

Follow appropriate workups, planning, preparing

of resources, counseling and notification

Screen All Admissions for hemorrhage risk:Low Risk, Medium Risk and High Risk

Low Risk: Draw blood and hold specimenMedium Risk: Type & Screen, Review Hemorrhage ProtocolHigh Risk: Type & Crossmatch 2 Units PRBCs; Review Hemorrhage Protocol

All women receive active management of 3rd stageOxytocin IV infusion or 10 Units IM, 10-40 U infusion

Standard Postpartum Management

Fundal Massage

Vaginal Birth:Bimanual Fundal MassageRetained POC: Dilation and CurettageLower segment/Implantation site/Atony: Intrauterine BalloonLaceration/Hematoma: Packing, Repair as RequiredConsider IR (if available & adequate experience)

Cesarean Birth:Continued Atony: B-Lynch Suture/Intrauterine BalloonContinued Hemorrhage: Uterine Artery Ligation

To OR (if not there); Activate Massive Hemorrhage Protocol

Mobilize Massive Hemorrhage Team TRANSFUSE AGGRESSIVELY RBC:FFP:Plts 6:4:1 or 4:4:1

IncreasedPostpartum Surveillance

Definitive SurgeryHysterectomy

Conservative SurgeryB-Lynch Suture/Intrauterine BalloonUterine Artery LigationHypogastric Ligation (experienced surgeon only)Consider IR (if available & adequate experience)

Fertility

Strongly

Desired

Consider ICUCare; Increased

Postpartum Surveillance

Verify Type & Screen on prenatal record;

if positive antibody screen on prenatal or current labs (except low level anti-D from Rhogam), Type & Crossmatch 2

Units PBRCs

CALL FOR EXTRA HELPGive Meds: Hemabate 250 mcg IM -or-

Misoprostol 600-800 SL or PO

Cumulative Blood Loss>500 ml Vag; >1000 ml CS>15% Vital Sign change -or-

HR ≥ 110, BP ≤ 85/45

O2 Sat <95%, Clinical Sx

Ongoing Evaluation:

Quantification of blood loss and

vital signs

Unresponsive Coagulopathy:After 10 Units PBRCs and full

coagulation factor replacement,may consider rFactor VIIa

HEMORRHAGE CONTINUES

Blood Loss:>1500 ml

Stage 3

Activate Massive

Hemorrhage Protocol

Blood Loss: >500 ml Vaginal

>1000 ml CS

Stage 1Activate

Hemorrhage Protocol

NO

Stage 0All Births

Transfuse 2 Units PRBCs per clinical signs

Do not wait for lab valuesConsider thawing 2 Units FFP

YES

YES NO

Ong

oing

Cum

ulat

ive

Blo

od L

oss

Eva

luat

ion

Cumulative Blood Loss>1500 ml, 2 Units Given,

Vital Signs Unstable

YESIncrease IV Oxytocin RateMethergine 0.2 mg IM (if not hypertensive)Vigorous Fundal massage; Empty Bladder; Keep WarmAdminister O2 to maintain Sat >95%Rule out retained POC, laceration or hematomaOrder Type & Crossmatch 2 Units PRBCs if not already done

Activate Hemorrhage ProtocolCALL FOR EXTRA HELP

Continued heavy bleeding

Increased Postpartum Surveillance

NO

NO

CONTROLLED

INCREASED BLEEDING

California Maternal Quality Care Collaborative (CMQCC), Hemorrhage Taskforce (2009) visit: www.CMQCC.org for detailsThis project was supported by funds received from the State of California Department of Public Health, Center for Family Health; Maternal, Child and Adolescent Health Division

Obstetric Emergency Management Plan: Flow Chart Format Release 2.0 7/9/2014

Graphic Source: CMQCC California Maternal Quality Care Collaborative

CMQCC Obstetric Care Summary

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Holcomb et al. JAMA 2015; 313: 471-82

� Multisite, RCT, 12 Level 1 Trauma Centers � 680 Severely Injured Patients� August 2012 – December 2013� Outcomes 24-hour and 30-day mortality



Considerations in Massive Transfusion Protocol - Continued

• Consider arranging for blood salvage• Place large bore IVs (16G-14G)• Place invasive monitoring (a-line & CVP)• Repeat labs frequently (CBC, ABG, lytes, iCa, coags)• Fluid warmers & forced air warmer for patient• Prime rapid infusion pump or pressure bags• Point of care testing (Hb, blood gas, coags, lytes)• Direct communication with blood bank & central lab

Gallos G., et. al. Semin Perinatol 33: 116-123. 2009SFGH Massive Transfusion Policy No 2.06CMQCC Hemorrhage Task Force. www.cmqcc.org

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• Prepare for general anesthesia• Vasopressors immediately available • All uterotonics immediately available• Supply of calcium chloride to prevent low ionized

calcium levels from rapid transfusion• Foley to measure urine & SCDs• Reserve ICU bed

Gallos G., et. al. Semin Perinatol 33: 116-123. 2009SFGH Massive Transfusion Policy No. 2.06CMQCC Hemorrhage Task Force. www.cmqcc.org


• Request additional blood products as needed in “packs” of correct ratio (Prbcs:FFP:Plts)

• Consider cryoprecipitate (Fibrinogen < 100 mg/dL)• Consider factor VIIa (off-label hemostatic use)

– Only after approximately 10 units prbcs and factor replacement• Person for recording/tallying blood products & EBL• Bring “Code Cart” into OR• Plan for Blood Bank to prioritize Transfusion labs• Make time to debrief after event with all disciplines

Gallos G., et. al. Semin Perinatol 33: 116-123. 2009; SFGH Massive Transfusion Policy No. 2.06; CMQCC Hemorrhage Task Force. www.cmqcc.org


Consideration of Cell Salvage

• Cell salvage in obstetrics should be considered in cases at risk for severe hemorrhage or for individuals in whom allogenic blood can not be used…- Placenta accreta / increta / percreta- Massive uterine fibroids- Jehovah’s Witnesses- Difficult cross-matching

Opinion Statements• “If the diagnosis or strong suspicion of placenta accreta is

formed before delivery…Cell saver technology should be considered if available as well as the appropriate location and timing for delivery…”

(American College of Obstetricians and Gynecologists (ACOG), Practice Bulletin, No. 76, October 2006, Postpartum Hemorrhage)

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Opinion Statements• “Cell salvage is recommended for women in whom an

intraoperative blood loss of more than 1500 ml is anticipated. Cell salvage should only be used by healthcare teams who use it regularly and have the necessary expertise and experience. Consent should be obtained and its use in obstetric patients should be subject to audit and monitoring.””

(RCOG Guideline No. 27, October 2005 – Placenta Previa and Placenta Accreta)

TOOLS TO HELP? SOME NEW AND SOME OLD

Role of Interventional Radiology

Uterine Artery Catheterization

Pledgets

Slurry

Coils

n-Butyl Cyanoacrylate

Embolization Agents

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IR for AtonyClinical Success

Study Year n Success %Ornan D et al.Obstet Gynecol

2003 28 96%

Boulleret C et al.CVIR

2004 35 100%

Zwart JJ et al.Am J Obstet Gynecol

2009 114 85%

Kirby JM et al.JVIR

2009 43 79%

Obstet Gynecol 2009;113:992-9

• 100 patients over 13 years

• Outcomes– Clinical success in 89 patients (89%)– 7 of the 11 patients (64%) underwent hysterectomy– Buttock necrosis (1%)

– Puncture site hematoma (1%)

• Conclusion– Patients who failed embolization had higher rate of estimated

blood loss (more than 1,500 mL) and higher transfusion requirements (more than 5 units of PRBCs)

• 28 studies were included in the systematic review

• 460 out of 503 (91.45%) women resumed menstruation

• 168 women desired another pregnancy– 126 (75%) achieved conception following embolization

• Conclusion: Uterine-sparing radiological techniques do not appear to adversely affect the menstrual and fertility outcomes in most women; however, the number and quality of the available evidence is of concern

BJOG 2014;121:382-8

Interventional RadiologyInvasive Placenta

• Different disease process than uterine atony

• Requires a multidisciplinary team– Maternal fetal medicine (OB team)– Surgical gynecology (gyn onc)– Interventional radiology

– Diagnostic radiology (antenatal MRI)– Scheduled deliveries– Use of multidisciplinary team is associated with a significant

reduction in morbidity (p=0.005)

• Need randomized clinical trials/registry dataJ Obstet Gynaecol Can 2013; 35:417–425

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rFVIIaCost: ~ $5000.00

•A review of the FDA’s Reporting System from 1999 to 2004•A total of 431 AE reports for rFVIIa were found, of which 168 reports described 185 thromboembolic events•Unlabeled indications accounted for 151 of the reports, most with active bleeding (n=115)•In 36 (72%) of 50 reported deaths, the probable cause of death was the thromboembolic event•Conclusion: RCTs are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia

� A 2008 review noted 118 cases of massive postpartum hemorrhage treated with rFVIIa.�Median dose was 71.6 mcg/kg� rFVIIa was reported to be effective in stopping or reducing bleeding in 90% of reported cases� Caution in interpreting results as they are from uncontrolled studies� RCTs needed to determine efficacy, dose, & safety

Review of Factor VIIa in Severe Obstetric PPH

Franchini M., et. al., Semin Thromb Hemost 2008; 34:104-112

Butwick et al. Curr Opin Anesthesiol 2015; 28;275-84

�Fibrinogen

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Charbit et al. J Thromb Haemost 2007; 5:266-273 Charbit et al. J Thromb Haemost 2007; 5:266-273

ThromboelastographyROTEM- Thromboelastometry (Germany)

ROTEM

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Butwick et al. Curr Opin Anesthesiol 2015; 28;275-84

PROTOCOL SUMMARY

FULL TITLE OF STUDY: Tranexamic acid for the treatment of postpartum haemorrhage: An international, randomised, double blind, placebo controlled trial

SHORT TITLE: WORLD MATERNAL ANTIFIBRINOLYTIC TRIAL

TRIAL ACRONYM: THE WOMAN TRIAL

PROTOCOL NUMBER: ISRCTN76912190

EUDRACT NUMBER: 2008-008441-38 CLINICALTRIALS.GOV ID: NCT00872469

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Summary• Recognition and Preparedness• Multidisciplinary Team • Good Communication and Team Work• Massive Transfusion Protocols• Role of Cell Salvage in Predictable

Hemorrhage• Potential Role of Devices and Pharmacologic

Interventions

An Evidence-Based Update on Methods of Labor

Induction: How can we improve our care?

Sarah B Wilson Hannay MD MEd


In 2013, 23% of all pregnant

patients in the US underwent IOL

National Vital Statistics Report

pm360online.com

Objectives

• Improved quality of inductions: Tailored patient-centered approach

• Obesity

• TOLAC

• PROM and PPROM

• Termination inductions

• Prolonged pregnancy/Postdates

• Decreased Cost

• Outpatient IOL methods

Clinically relevant

outcomes for IOL studies

• Duration of labor ( cervical ripening and active labor)

• Rates of spontaneous vaginal delivery

• Need for additional augmentation

• Adverse neonatal and maternal outcomes

• Satisfaction (patient and caregiver)

• Length of hospital stay

Induction Methods

• PGE1 Misoprostol

• PGE2 Dinoprostone

• Mechanical dilators

• Foley ballon, Cook cervical ripening balloon, laminaria

• Oxytocin

• Isosorbide mononitrate : nitric oxide donor

• Mifepristone: termination inductions

Labor Induction and Obesity

• Obesity epidemic with childbearing women

• Increased comorbidities requiring IOL

• Increased rates of labor induction by obesity class

• 30.4% class I to 34 % women class III

• Increased failed IOL

• Increased complications with c sections

• Obesity class—> independent predictor of IOL failure —>C section*

• OverWeight OR 1.4 (CI 1.2-1.7 p<0.001), Obese OR 2.3 (1.9-2.7 p<0.001)

Wolfe et al AJOG 2014*Ronzoni et al AM J Perinatol 2015

• Retrospective review 2008-2013

• Misoprostol 25µg vaginal or 50µg oral vs Dinoprostone vaginal insert 10-mg

• 564 women (297 misoprostol, 267 dinoprostone)

• Misoprostol: more successful cervical ripening: 78.1% vs 66.7% (OR 1.79)

p=0.002

• Lower CD rate 39.1% vs 51.3% (OR 0.61) p=0.003

• Significance persisted with multivariate model adjusted for parity, GA, birth weight,

indication for IOL

Differences with obese and non-obese patients

with miso

• Secondary analysis of Misoprostol Vaginal Insert Trial: multisite, double-blind RCT

• 1,273 patients stratified by BMI—> Analyzed duration, characteristics and outcomes of labor

• Obese women:

• Take longer to deliver spont (up to 4 hours longer for morbidly obese patients)

• Higher CD rates: Obese (29.8%) and Morbidly Obese (36.5%) compared to non-obese (21.3%)

• Increased need for oxytocin augmentation and increased amounts of oxytocin for longer time periods

Pevzner et al Obstet Gyn 2009

Labor Induction and TOLAC Labor Induction and TOLAC

• Decreased likelihood of VBAC: less likely with unfavorable cervix

• Potential increased risk of uterine rupture

• ACOG states IOL should be an option for TOLAC (Level B)

• Baseline uterine rupture risk in spontaneous labor: 0.5%

• Which method?

• Prostaglandins (PGE1 and PGE2)

• Misoprostol increased risk of uterine rupture (case reports or halted trials) 1

• Sequential use of PGE2 and oxytocin increased risk of rupture, not PGE2 alone? 2

• ACOG: Against misoprostol, unclear statement about PGE21 ACOG PB 1152 Cahill et al AJOG 2008

Labor Induction and TOLAC

• Which methods?

• Oxytocin

• Unclear risk: No increased risk of rupture vs doubles risk of rupture to 1% 1

• Dose response noted: higher doses associated with increased uterine rupture 2

• ACOG: No established upper limit dose for oxytocin

• Mechanical dilation:

• Limited mixed data: two studies show no increase in risk, one with increased risk of rupture after mechanical dilation

• ACOG: Foley/mechanical dilations can be used1 ACOG PB 1152 Cahill et al AJOG 2008

Induction Methods for PROM and PPROM

• Sparse data on preferred method for PPROM, extrapolate

from PROM evidence

• Conflicting evidence about superiority of prostaglandins vs

oxytocin in PROM

• Prolongation of latency >24 hours —> increased chorio

Packard et al Sem Perinat 2015


• Oxytocin better than PGE2: Kunt et al Taiwan J Obstet Gyn 2010: PGE2 vs pit for PROM

• RCT 240 low-risk, nullips, PROM for ≥12 hours and Bishop ≤ 6

• Mean time from labor induction to active labor and to delivery significantly shorter for pit group

• No difference in neonatal outcomes and c section rates

• Supported previous findings, Butt et al Obstet and Gyn 1999

• Miso better than pit? Lin et al Obstet Gyn 2005: Metaanalysis of miso vs placebo or pit for PROM

IOL

• 15 RCTs (6 studies 453 women miso vs placebo) (9 studies 1130 women miso vs pit)

• Miso compared to placebo increased vaginal delivery rates in < 12 hrs

• Miso better than pit for vag delivery < 12 hrs, equivalent for <24 hrs

• No increased rates of hyperstim or adverse maternal or neonatal outcomes compared to pit

• Decide oxytocin vs miso based on Bishop score.


• Mechanical dilators with ruptured membranes: theoretical concern for ascending infection

• Mackeen et al J Am Osteopath Assoc 2014

• Retrospective cohort: Nullips with ROM, ≥36 wks

• 122 Induced with Foley compared to 33 with miso

• Time to delivery halved in Foley cohort

• Foley group received higher dose of oxytocin compared to miso

• No differences in mode of delivery

• Trend toward higher infection rate in miso group

• Two large multicenter RCTs recruiting patients now: FOLCROM Study and Eval of CRB in PROM

Termination induction in the second and third

trimester

• Dodd et al Cochrane Review 2010

• RCTs compared vaginal misoprostol with other agents

and routes

• Oral miso less effective than vaginal miso for 2nd and

3rd tri induction terminations

• Sublingual miso may be more effective than both oral

and vaginal

Termination induction in the second and third

trimester

• Mifepristone and Miso vs Miso Alone

• Panda et al J Family Reprod Health 2013

• Prospective enrollment of 52 women, 3rd tri IUFD

• IOL to delivery time shorter with combo (p<0.001)

• Total miso dose lower with mifepristone preTx

• No difference in complication of labor

• Chaudhuri et al J Obstet Gyn Res 2015

• RCT 100 patient IUFD ≥20 weeks, mifepristone 200mg vs placebo, then vaginal miso 36-48 h after

• Shorter delivery interval with mifepristone pre treatment: mean 9.8 h vs 16.3 h, (p<0.001)

Induction for

Prolonged pregnancy

• Complicates 15% of all pregs

• Most have an unfavorable

cervix—> increased CD rate

Nitric Oxide Donors: isosorbide mononitrate (IMN)

• IMN vascular dilation, rearranges cervical collagen—> ripening

• Does not induce contractions

• PRIM study: Osman et al AJOG 2006: miso vs IMN inpt: faster cervical ripening with miso, fewer fetal heart changes with IMN

• Agarwal et al Int J Gyn Ob 2012 : improved Bishop scores on admission for IOL in IMN group

• IMOP study: Bollapragada et al BJOG 2009

• 350 pts: Nullips, singleton 37 or > weeks requiring cervical ripening prior to IOL

• Self administered vaginal IMN 48, 32 and 16 hrs before admission—> then induced

• IMN improved Bishop score but did not shorten admission to delivery time interval

• Overall women appreciated home treatment

• Patient satisfaction higher with placebo: IMN group with more headaches

Outpatient Labor Induction?

• Ideal agent: cervical ripening without significant uterine

contractions

• Important outcomes:

• Safety profile

• Patient experience

• Cost-saving: decreased hospital time

• Any inherent physiologic differences?

• Does outpt cervical ripening at 41 wks with isosorbide mononitrate reduce c section rate in nullips with an unfavorable cervix

• Powered to detect a 25 % reduction in tx group, 685 women in each group

• Treatment: 40mg vaginal dose at 41wks, 41+2, 41+4—> induced with miso or oxytocin at 41+5 if not yet in labor

• Equivalent CD rate: ( 27.3% tx, 27.2 % plac)

• Tx increases SEs: HA, n/v

>

Outpatient Vaginal gels/vaginal insert (PGE2)

• O’Brien et al AJOG 1995

• RCT compared 2mg intravaginal PGE2 to placebo placed as outpatient over 5

consecutive days

• 100 low risk patients, well-dated between 38-40 weeks, Bishop score ≤ 6,

• PGE2: significantly shorter mean time to delivery (4 d vs 10d p=0.002)

• 54% of PGE2 group admitted in spont labor, vs 20% of placebo group

• Hyperstim noted in one PGE2 patient

• Biem et al J Obstet Gyn Can 2003

• RCT compared outpatient vs inpatient vaginal CR PGE2

• 300 term women, Bishop score ≤ 6

• Similar times to labor onset and spontaneous delivery by 24 hours in both

groups

• Outpatient group with higher levels of satisfaction (56% to 39 % p<0.008)

• Outpt group at home for median 8 hours before labor

• 827 women, outpatient vs inpatient PGE2

• No differences in pit use, CD rate, epidural use and NSVD within 24 hours

• Outpt women : increased hyperstim and non reassuring monitoring, < half went home and remained home overnight

• Cost analysis: Adelson et al Aust Health Review 2013 Outpatient care: cost saving of $433/woman, offset by costs of “priming” clinic—> overall savings $156

BJOG 2015

Outpatient Misoprostol: Background

• Misoprostol (PGE1)

• Effective cervical ripening agent compared to dinoprostone, oxytocin or placebo 1

• Trend to more c sections for fetal distress and fewer for failure to progress 1

• Miso compared to Foley 2,3

• Trend to higher rates of tachysystole with miso

• No difference in CD rates or adverse fetal outcomes

• Miso compared to dinoprostone 4

• Miso: Higher vaginal delivery rates within 12 and 24 hrs, similar heart rate changes and CD rates 1 Hofmeyr et al Cochrane Review 2010

2 Fox et al BJOG 20113 Jozwiak et al Am J Perinat 20144 Austin et al AJOG 2010

Outpatient Misoprostol

• Stitely et al Obstet Gyn 2000: 25 µg vaginal miso for 2 days vs placebo, then IOL on day 3

• Small RCT: Low risk singleton pregnancies ≥41 wks, low Bishop

• 88.9% miso patients entered active labor within 48 hrs of 1st dose, compared to 16.7%

• Additional studies show efficacy, all too small to be powered for safety

• Increased rates of tachysystole with and without fetal heart rate changes

Outpatient Foley Balloon: Background

• Effective method with lower rates of uterine hyperstim

compared to prostaglandins

• Oxytocin needed more often in labor IOL with Foley compared

to misoprostol

• —> Capitalize on cervical ripening with fewer contractions for

outpatient setting

Jozwiak et al Am J Perinat 2014

Outpatient Foley Balloon

• Sciscione et al Obstet Gyn 2001

• RCT 61 patients, Bishop score ≤5

• Inpatient vs outpatient Foley: no difference in duration or dose of oxytocin, IOL time, neonatal outcomes

• No adverse events in either group

• Outpatient group in hospital an average of 9.6 hours less

• Sciscione et al Am J Perinatol 2014

• Retrospective char review of 1,905 term singleton preg with Foley, excluded TOLAC, ROM, fetal anomaly, HTN, IUFD

• Looked at timing of adverse outcomes: CD for NRFHT, VB, placental abruption and IUFD after for interval of Foley

• No adverse outcomes—> Safe mechanism for IOL as an outpatient

Conclusions

• Obesity: Miso more effective than PGE2

• TOLAC: Pitocin and mechanical dilator can be used, no misoprostol, PGE2?

• PPROM/PROM: Decide on oxytocin vs miso based on need for cervical ripening, Foley ballon?

• Termination Inductions: Vaginal miso over oral, consider adding mifepristone 24 -48 hrs before IOL

• Post dates: Nitric oxide donor—> no difference

• Outpatient IOL: Mechanical Dilator most promising option: need more data Questions? Thank you.

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“Can I do this while I’m pregnant?”

Searching for EvidenceBehind Pregnancy Advice

Robyn Lamar, MD, MPHAssistant Professor,

Obstetrics & Gynecology at UCSF

Disclosures• I have nothing to disclose

Objectives• Consider how we discuss risk related to

lifestyle choices in pregnancy• Evaluate pregnancy related advice concerning:

– seafood– sleep position– caffeine– alcohol

Communicating Risk in Pregnancy

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Laundry list? Public Health Campaign Poster?

Economics-style Risk-Benefit Analysis? Medical Ethics framework?

• Ethical principles:– Autonomy– Beneficence & nonmaleficence– Justice

Ethical Decision Making in Obstetrics andGynecology*

Number 390 • December 2007

A C O G C O M M IT T E E O P IN IO N

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Communicating Risk in Pregnancy:Common pitfalls

1 Falsely dichotomizing a range of risk into “low risk” and “high risk” exposures

2 Letting any risk to the fetus trump considerations related to the wellbeing of the pregnant woman

3 Emphasizing the risks of taking certain actions, but ignoring the risks of avoiding those actions

Lyerly, A. D. et al. Risks, values, and decision making surrounding pregnancy. Obstet Gynecol 109, 979–84 (2007).

Decision-making in pregnancy• Pregnant women deserve care that is both

evidence-based and patient- centered. • We should avoid reinforcing distortions of risk • We can do this by:

– acknowledging the range of values that pregnant women bring to decisions

– Identifying a range of well-considered options and allowing women to make decisions in the context of their own priorities and life circumstances


Case Examples

Can I eat seafood?

Retrieved from: http://www.montereyfish.com/

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Seafood: Official AdviceACOG: “pregnant women . . . should eat at least 8 and up to 12 ounces per week of a variety of fish lower in mercury.”

ACOG Practice Advisory: Seafood Consumption During Pregnancy

Seafood in PregnancySeveral issues to consider:• From nutrition standpoint: high protein, low

fat, high in DHA• From contamination standpoint: mercury

levels, other pollutants• From food safety perspective: contamination

risk if raw/undercooked?

Seafood: History2001 FDA Advisory

• Don’t eat 4 fish high in mercury– Shark– Tilefish– King mackerel– swordfish

• Limit overall fish consumption to 12oz/week

Seafood: Early Evidence1990s: cohort studies published in • Faroe islands• New Zealand Correlated increasing levels of mercury in mother’s hair & decrements in child’s language skills, memory, motor speed, and visuospatial function

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Seafood: Early Evidence

– Unusual consumption patterns (Faroe islands: pilot whale meat/blubber; NZ shark)

– Reanalysis looking at seafood consumption itself (not mercury level) did NOT show link

Seafood: Seychelles Cohort study

Davidson P, Cory-Slechta D, Thurston S, et al. Fish consumption and prenatal methylmercury exposure: Cognitive and behavioral outcomes in the main cohort at 17 years from the Seychelles child development study. NeuroToxicology 2011;32(6):711717.

Seafood: Seychelles Cohort study• High fish diet (12 servings/wk), no

consumption of marine mammals/shark• Predictor variable: maternal hair mercury• Outcome variables: neurocognitive &

behavioral testing done from age 6mo – 17yo• Results: as maternal mercury increases . . .

– 26 of 27 outcomes: no difference or better scores– 1 of 27 outcomes: Higher risk of referral to school

counselorDavidson P, Cory-Slechta D, Thurston S, et al. Fish consumption and prenatal methylmercury exposure: Cognitive and behavioral

outcomes in the main cohort at 17 years from the Seychelles child development study. NeuroToxicology 2011;32(6):711717.

Seafood: Systematic Review of prenatal fish & neurodevelopment

• 8 cohort studies identified– Published between 2000-2014– Predictor variable: maternal seafood consumption– Evaluated offspring from age 3 days – 9 years– Sample sizes ranged from 135 to over 25,000

• Findings– One study showed no association– 7 studies showed improved outcomes as maternal

seafood consumption increasedStarling P, Charlton K, McMahon AT, Lucas C. Fish intake during pregnancy and foetal neurodevelopment--a systematic review of the

evidence. Nutrients 2015;7(3):2001–14.

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Seafood: Current Consumption

None20%

less than 2 oz40%

2 to 4oz20%

4+ oz20%

Seafood consumption in last week among 1000 Pregnant Women

S Ostroff. (2014, June 10). Why We Want Pregnant Women and Children to Eat More Fish. Retrieved from http://blogs.fda.gov/fdavoice/index.php/tag/environmental-protection-agency-and-food-and-drug-administration-advice-about-eating-fish/

The women in the highest consumption category aren’t necessarily even eating 1 serving a week!





Lyerly, A. D. et al. Risks, values, and decision making surrounding pregnancy. Obstet Gynecol 109, 979–84 (2007). Retrieved from: https://www.washingtonpost.com/national/health-science/2012/04/03/gIQABd16sS_graphic.html

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This looks complicated.Should I just take fish oil instead?

Fish Oil: EvidenceRecent Meta-analysis looked at omega-3 supplementation during pregnancy & childhood neurodevelopment• 11 RCTs with 5,272 participants• No difference in cognitive, language, or motor

development– Except for cognitive scores in subgroup of 2-5 year

olds; but driven by 2 studies rated high risk for bias

Gould J, Smithers L, Makrides M. The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr.

2013;97(3):531–44. doi:10.3945/ajcn.112.045781.

OK, I’ll eat fish. What about sushi?

Raw Seafood: Advice• ACOG says no• NHS says raw fish is fine, if frozen first

– Deep freezing kills parasites (anasakis, tapeworm)– FDA requires freezing fish intended to be eaten raw

• Seafood causes a tiny percent of food poisoning in the US

• Raw shellfish is responsible for the vast majority of seafood-associated “food poisoning” – can be contaminated with vibrio cholera or norovirus

“Seafood Choices: Balancing Benefits and Risks.” IOM report brief, Oct 2006.http://www.nhs.uk/chq/pages/is-it-safe-to-eat-sushi-during-pregnancy.aspx?categoryid=54

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Seafood: Summary• Eat seafood• Not too much, but not too little• Eat some types, but not others• Cook shellfish thoroughly• Enjoy fish if it’s been well frozen

. . . Is it any wonder women give up?

Can I sleep on my back?

Sleep Position: The Official advice

About 1,560,000 results (0.59 seconds)

Feedback

The best sleep position during pregnancy is “SOS” (sleep on side).Even better is to sleep on your left side. Sleeping on your left side willincrease the amount of blood and nutrients that reach the placenta andyour baby. Keep your legs and knees bent, and put a pillow betweenyour legs.

Sleeping Positions During Pregnancyamericanpregnancy.org/pregnancy.../sleeping-positions-during-pregnancy/

Web Images Videos News Shopping Search toolsMore

sleep position while pregnant

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Sleep Position• Theory: simple & compelling

– As uterus enlarges, supine position causes compression of vena cava, decreasing venous return & cardiac output

– Familiar practice for c/s & ACLS in pregnancy, and to ameliorate fetal heart tracing changes

• Evidence: limited

Sleep Position: Stacey et al2011 prospective case-control study in New Zealand• Cases: 155 singletons with 3rd tri stillbirth• Controls: 301 ongoing singleton pregnancies matched

for GA• Results: OR for stillbirth

– Supine vs left: 2.54– Nocturia once or less vs more: 2.28– Daytime napping vs not: 2.04

• Absolute risks of stillbirth if go to sleep on:– Left 1.96/1000– Back or right 3.93/1000

Sleep Position: Stacey et al• Some things to consider about Stacey’s study:

– Recall bias? • Controls were asked about last night’s sleep• Cases interviewed an average of 25 days after delivery

– Reverse causality?• Before pregnancy, cases & controls equally likely to

sleep on their back, left, or right sides• “What would reduce normal progression toward the

preference of a more lateral tilt, [and] reduce the need to go to the bathroom at night?”

IUGR?Froen JF et al. “No need to worry about sleeping position in pregnancy—quite yet.” BMJ 2011;342;d3404

Sleep Position & IUGR: Theories• So is supine sleep part of the “triple risk” that

increases stillbirth?– 1: maternal risk factors (obesity, smoking, age)– 2: fetal & placenta risk factors (IUGR)– 3: stressor (sleeping position?)

• Or is IUGR actually the real risk factor that leads to both supine sleep & stillbirth?

Stacey T, Thompson JM, Mitchell EA, Ekeroma AJ, Zuccollo JM, McCowan LM. Association between maternal sleep practices and risk of late stillbirth: a case-control study. BMJ. 2011 Jun 14;342:d3403.

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Sleep Position: Owusu et al2013 Cross-sectional study looking at sleep practices & pregnancy outcomes (birthweight preeclampsia, etc) among 234 women in Ghana• Results:

– Supine sleep as a risk for IUFD:• OR adjusted for maternal factors: 8.0 (1.5-43)• OR also adjusted for IUGR: 4.9 (0.8-34)

– Percent of women who slept supine at term:• Low birthweight: 25%• Normal birthweight: 6%

Owusu JT, Anderson FJ, Coleman J, et al. Association of maternal sleep practices with pre-eclampsia, low birth weight, and stillbirthamong Ghanaian women. Int J Gynaecol Obstet 2013;121(3):261–5

Sleep Position: Sydney Stillbirth Study2015 prospective case-control study in Australia• Cases: 103 singletons with 3rd tri stillbirth• Controls: 192 singletons matched for GA• Asked about “usual” sleep position in last month• Results for supine sleep: aOR 6.26 (1.2-34)• Of the 10 stillbirths among back sleepers, none

was classified as “unexplained”• Infection (3), hemorrhage (1), PPROM (1), IUGR (3), maternal

condition (2)Gordon A, Raynes-Greenow C, Bond D, Morris J, Rawlinson W, Jeffery H. Sleep position, fetal growth restriction, and late-pregnancy

stillbirth: the Sydney stillbirth study. Obstet Gynecol 2015;125(2):347–55.

Sleep Position: UpcomingOngoing research study:

MiNESS(Midland and North of England Stillbirth study)

• larger case control-study• powered to detect interaction between

variables (i.e., IUGR & sleeping position)

Sleep Position: SummaryWomen who sleep on their back in the 3rd

trimester have a higher risk of stillbirthBut . . . .• Few women with normal size bellies go to

sleep on their back in the 3rd trimester• If there is an attributable risk from supine

sleeping, the absolute value is very smallGet sleep as you’re able in the 3rd trimester!

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When you were pregnant, did you drink coffee?

A. NeverB. OccasionallyC. 1-2 cups a day on averageD. More than 2 cups a day on

average

N e ve r

O c ca s i o

n a l ly

1 - 2 c u p

s a d a y

o n a v e

r a ge

M or e t

h a n 2 c

u p s a d

a y .. .

18%11%

46%

26%

Coffee: The Official Advice• ACOG: “Moderate caffeine consumption (less

than 200 mg per day) does not appear to be a major contributing factor in miscarriage or preterm birth. The relationship of caffeine to growth restriction remains undetermined.”

• Other societies: less than 200-300mg/day

ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy.

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12

Coffee: Research Challenges• American women who drink coffee are:

– Older– More likely to smoke & drink– Less healthy conscious– Lower SES

• “Pregnancy signal” hypothesis: bad nausea is correlated with lower risk of miscarriage, but amy lead to aversion to coffee

Coffee: IUGR EvidenceBech et al: sole RCT regarding coffee intake• Double blind, controlled trial of 1207 women

drinking 3+ cups of coffee/day in 2nd tri• Design: randomized to either decaf or regular

instant coffee at 20wk of pregnancy• Results: (for caffeinated vs decaf groups)

– Dropout rates similar (5 vs 8%)– Mean caffeine intake differed (117mg vs 317mg)– Absolutely no difference in birthweight or GA

Bech BH, Obel C, Henriksen TB, Olsen J. Effect of reducing caffeine intake on birth weight and length of gestation: randomisedcontrolled trial. BMJ 2007

Coffee: IUGR EvidenceSystematic review & meta-analysis 2014• Risk of low birthweight:

Caffeine consumption RR• Low (50-149mg) 1.13 (1.06, 1.21)• Moderate (150-349mg) 1.38 (1.18, 1.62)• High (≥350mg) 1.60 (1.24, 2.08)

• Absolute birthweight difference in grams was small• Low (50-149mg) -9 (-35, 16)• Moderate (150-349mg) -33 (-63, -4)• High (≥350mg) -69 (-102, -35)

• The better the study design (larger; cohort; European?) the smaller the effect (RR ~1.1 vs 1.2-1.3)

Chen L-W, Wu Y, Neelakantan N, Chong M, Pan A, van Dam R. Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose–response meta-analysis. BMC Med 2014;12(1):174

Coffee: SAB evidenceBrent et al. systematic review of studies since 2000• Human data: 17 studies

– Most showed no increased risk for <300mg/day– Those that did often had incomplete control of

confounders (ex: 11/17 did not control for nausea)• Animal data: no increased risk of SAB until levels

well above usual human consumption (i.e., more than 10 cups/day), and even then risk was small

Brent R, Christian M, Diener R. Evaluation of the reproductive and developmental risks of caffeine. Birth Defects Research Part B: Developmental and Reproductive Toxicology 2011;92(2):152–87.

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Caffeine: Unique EvidenceDanish National Birth Cohort study • periconception use of Letigen (ephedrine + 600mg caffeine)

• Result:– Maternal age adjusted HR for SAB = 1.1 (0.8, 1.6)

Klebanoff MA, Levine RJ, DerSimonian R, Clemens JD, Wilkins DG. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. New England Journal of Medicine [Internet] 1999;341(22):1639–44.

Can I drink coffee?• Yes, enjoy your coffee . . . If you’re able

Can I drink a glass of wine? When you were pregnant, did you drink alcohol?

A. NeverB. I had 1 drink a few times during the

pregnancyC. I had 1 drink a few times a monthD. I had 1 drink a few times a weekE. More than that

N ev e r

I h ad 1

d ri n k

a fe w

t i me s .

. .

I h ad 1

d ri n k

a fe w

t i me . .

.

I h ad 1

d ri n k

a fe w

t i me s .

.M o

r e t h a

n th a t

46%

38%

3%4%9%

10/16/2015

14

Alcohol: Official Advice• ACOG: “no safe level of alcohol use during

pregnancy.”• NICE: none in the 1st trimester, and no more than

1-2 units, 1-2 times a week after that• SOGC: “Abstinence is the prudent choice,” but

“there is insufficient evidence regarding . . . harm at low levels of alcohol consumption.”

• Australia: in 2009 reverted to abstinence messaging after 8 years of saying small amounts were ok

Alcohol: Teratogenicity• FAS is common & likely underdiagnosed:

Study of 1st graders with active ascertainment:– FAS 6-9 per 1000– Partial FAS 11-17 per 1000– FASC 24-48 per 1000

• Drinking among US women age 18-44 is common:In last month . . . Used alcohol: Binged:

– Non-pregnant: 52% 15%– Pregnant: 7.6% 1.4%May PA et al. Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics. 2014 Nov;134(5):855-66.

MMWR. Alcohol Use and Binge Drinking Among Women of Childbearing Age — United States, 2006–2010

Alcohol: the dilemma• Challenging to research

– American women who drink in pregnancy are much more likely to smoke & use drugs

• Unclear how drinking amount, pattern, nutrition, and genetics interact to produce FAS in some cases but not others

Despite this, data regarding impact of light to moderate drinking on the fetus is largely reassuring

Alcohol: Recent EvidenceIn September 2012, BJOG published 5 articles from the same prospective cohort study examining alcohol & neurodevelopmental outcomes in young children

10/16/2015

15

Alcohol: Cohort StudyThe Lifestyle During Pregnancy Study (LDPS): prospective cohort study, sampled from the larger Danish National Birth Cohort (>100,000)• Of note: some alcohol consumption during pregnancy was

considered acceptable to Danish women at that time• Design: recruited 1617 women, sampled to represent 20

different drinking patterns– Phone interview at 12 & 30wk to ascertain weekly alcohol

intake, and any binge (5+) drinking– Controlled for smoking, diet, SES, maternal IQ, medical &

obstetric history– Assess cognitive, behavioral, emotional & social functions in

children at age 5Kesmodel US et al. Lifestyle during pregnancy: neurodevelopmental effects at 5 years of age. The design and implementation of a

prospective follow-up study. Scand J Public Health 2010;38(2):208–19Kesmodel U, Kesmodel PS. Drinking during pregnancy: attitudes and knowledge among pregnant Danish women, 1998

Alcohol: LDPS ResultsAll results are based on assessment

of children at age 5

LDPS Results: IntelligenceOutcome measure: IQ assessed with the Wechsler Primary and Preschool Scales of Intelligence• By average number of drinks per week:

– 1-4, or 5-8 drinks: no difference by any analysis• Mean IQ of 106 or 104, versus 105 in nondrinkers• No higher risk of low IQ (OR 0.9-1.1)

– 9+ drinks: • Mean IQ of 99 (not statistically significant from 105)• Higher risk of low IQ (OR 4.6)

• By binge drinking: – no differences except that binge drinking at GA 1-2wk

reduced risk of low IQ (OR 0.5)Eriksen H, Mortensen, Kilburn, et al. The effects of low to moderate prenatal alcohol exposure in early pregnancy on IQ in 5-year-old

children. BJOG 2012;119(10):1191–200.Kesmodel, Eriksen H, Underbjerg, et al. The effect of alcohol binge drinking in early pregnancy on general intelligence in children. BJOG

2012;119(10):1222–31.

LDPS Results: AttentionAttention was measured using the recently developedTest of Everyday Attention for Children at Five Average attention score = 0, higher is better• By average number of drinks per week:

– 1-4, or 5-8 drinks: no difference by any analysis• Mean score difference: (+0.03 and +0.03)• No higher risk of low score (OR 1.17, and 1.37)

– 9+ drinks: • Mean score difference of -0.45 (-1.08, 0.18)• Higher risk of low score, OR 3.2 (1.08, 9.53)

• By binge drinking: – no differences on any measures

Eriksen H, Mortensen, Kilburn, et al. The effects of low to moderate prenatal alcohol exposure in early pregnancy on IQ in 5-year-oldchildren. BJOG 2012;119(10):1191–200.

Kesmodel, Eriksen H, Underbjerg, et al. The effect of alcohol binge drinking in early pregnancy on general intelligence in children. BJOG 2012;119(10):1222–31.

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16

LDPS: Executive FunctionExecutive function assessed using the Behaviour Rating Inventory of Executive Function, an 86-item questionnaire, completed by both a parent & a teacher• No association with any drinking pattern

So can I have a glass of wine? • Public health messaging is a nightmare

– Australia reversed its more lenient stance on alcohol not in the face of new evidence of harm, but due to worries the advice was too confusing

• We’re not all Vikings– variations in genetics and nutrition might leave some

populations more vulnerable to alcohol's harms than others

• Perhaps research is most helpful in reassuring women who inadvertently drank before recognizing pregnancy?






Conclusions

10/16/2015

17

My Two Cents• Focusing too much on pregnancy taboos:

– Creates an unfounded aura of hazard & mystique around pregnancy

– Distorts perception of risk– Distracts from more important health behaviors– Implies a level of control women may not have

over outcome of their pregnancy

OK, maybe more than 2 cents:• Those laundry lists are likely unavoidable,

given limited visit time• When patients ask what to do when pregnant,

I purposely just focus on healthy living• When they press me on specific issues, I say:

– You can’t make your risk of anything zero– Some risks can be lessened by changing behavior– Changing behavior has its own risks

The Evidence Based Post-Partum Visit: New Guidelines, New Quality Metrics

Michael Policar, MD, MPHClinical Professor of Ob, Gyn, and RSUCSF School of [email protected]

UCSF ObGyn Update: What Does the Evidence Tell Us?October 15, 2015 Disclosure

• I am a litigation consultant to Bayer Healthcare relating to the Mirena IUD

Postpartum Care• What currently happens at post partum visits?

– Maternal postpartum history– Breast feeding status and plans– Screening for postpartum depression– Follow-up of medical problems managed during

pregnancy (e.g., gestational diabetes)– Contraception counseling and method initiation– Physical exam, as medically indicated– Discussion re: return to primary care provider

Why Should Family Planning Be the “Centerpiece” of the PP Visit?

• “It’s all about the IPI”…interpregnancy interval• Conventional wisdom…

– At least two years between kids• Evidence-based wisdom…

– > 18 months from delivery till next conception– > 27 months between deliveries

In the US, 1/3 of all repeat pregnancies are conceived within 18 months of the previous birth

What Are the Risks of A Short IPI?• Mother

– Less time to recover from metabolic demands of pregnancy– Less time to stabilize c medical conditions (e.g., diabetes)

• Newborn• More likely that next offspring will be delivered preterm or

have low birth weight• Negative impact on older siblings

• DHHS Healthy People 2020: reduce the proportion of pregnancies that were conceived within 18 months of a previous birth by 10% in 2020

Interpregnancy Intervals: Impact Of Postpartum Contraceptive Effectiveness And Coverage

Thiel H, et al. Am J Obstet Gynecol 2014;210

Method Odds ratio estimates (95% confidence interval)

Tier 1 (IUC, implant) 3.89 (3.55–4.26)Tier 2 (OC, CVR, patch, DMPA) 1.89 (1.80–1.98)Tier 3 (barrier methods) 1.00 (Reference) No method 0.66 (0.63–0.69)

Likelihood of optimal IPI

Postpartum Contraception

Control No BTLPostpartum contraception 41.1% 42.8%Postpartum visit 20.3% 18.8%% pregnant at 12 months 22.3% 46.7%

Thurman AR et al. Obstet Gynecol. 2010(116):1071-77

� University of Texas, San Antonio, Dec. 2007-May 2008� 1460 deliveries tracked� 296 requested and got tubal ligation (BTL)� 133 requested but did not get BTLs

Improving Postpartum Care• Every Woman California

– Interconception Care Project guidelines• CDC Medical Eligibility Criteria (MEC) for Contraception,

2010…safety of postpartum contraception• CDC Selected Practice Recommendations for Contraception

(SPR) 2012…effective use of postpartum contraception

everywomancalifornia.org http://everywomancalifornia.org/content_display.cfm?categoriesID=120&contentID=359

Post-partum Ovulation Patterns• Resumption of ovulation in non-lactating women

– Ovulate in 6-7 wks (median= 45 days)– None before 25 days from the delivery

• Resumption of ovulation in lactating women – Intensity, frequency, duration of suckling– Time elapsed since delivery– Maternal nutritional state– Rate of weaning: rapid > gradual weaning– Introduction of supplementary feeding (ovulation usually

begins 6 weeks later)

Lactational Amenorrhea Method (LAM)• Effectiveness

– Pregnancy rate: 1-2% by 6 months postpartum– 7% by 12 months; 13% by 24 months

• Bellagio Conference Consensus (1989)– Nurses "on demand" ( > 5 feeds/day; > 65 min total)– Breast milk is only nutrition to newborn; no

supplementary bottle feedings or other foods– No bleeding episode beyond 56 days from delivery– Nursing of newborn for less than 6 months

LAM: Summary

• LAM works well, but return of fertility is multifactorial and unpredictable

• Ovulation may precede bleeding > 10 wks post-partum– LAM is less effective from 10 wks-6 months

• LAM is unforgiving of imperfect use• Use another method at 6 months, or sooner if

menstrual bleeding occurs

Delivery -10 weeks

10 weeks - 6 months

Beyond 6 months

Lactational Amenorrhea Method

Post-partum OC's: Effect on Lactation• Quality (composition) of breast milk

– No change, including iron and copper levels• Quantity of breast milk

– If started before establishment of lactation, high dose estrogen decreases quantity

– If started after lactation is established, low dose OCs have minimal effect on quantity

• POPs have no effect on quantity or content milk• Duration of breast feeding

– 3.7 months in OC users vs. 4.6 months controls

Post-partum OC's: Newborn Risk• 1% of ingested drug secreted in milk• Ethinyl estradiol dose reaching newborn is comparable

to daily ovarian estradiol production• Effect of OCs on development of infants

– No short term metabolic differences vs. controls– A long term (5 year) study shows no effect on

neurological development• Newborn growth rates not affected by OC use

– Any loss of milk volume compensated by increased suckling or food supplements

Post-partum OC's: Maternal Risk• Changes in maternal clotting factors persist for up to 6 wks

– Causes increased VTE risk up to 6 week post-partum• Concern that coagulation effects from each of pregnancy

and OC's may increase risk of VTE– VTE rates not studied in pp low-dose OC users vs controls

• VTE risk of OC always > benefit if less than 3 weeks pp• Greater VTE risks not expected with progestin only

methods, since no change in clotting factors

Absolute Risk VTE: SOGC 2010 Estimates Per 10,000 Women per Year

Reproductive age women non-users 4 - 5

Oral contraceptive users 9 - 10In pregnancy - overall 29Postpartum 300 - 400

Reid R. J Obstet Gynaecol Can. 2010;32(12):1192-204

� OCs actually decrease overall rate of VTE in the population compared with rates in populations without access to effective contraception

Post-Partum CHC: Non-BreastfeedingUS MEC 2011 Revision

US MECa) < 21 days postpartum 4 b) ≥ 21 days to 42 days postpartum

i) with other risk factors for VTE 3ii) without other risk factors for VTE 2

c) > 42 days postpartum 1

Post-Partum CHC: BreastfeedingUS MEC 2011 Revision

US MECa) < 21 days postpartum 4 b) 21-29 days postpartum

i) with other risk factors for VTE 3ii) without other risk factors for VTE 3

c) 30-42 days postpartumi) with other risk factors for VTE 3ii) without other risk factors for VTE 2

c) > 42 days postpartum 1

USMEC: Risks of Post-partum DVT/PE• Age ≥35 years• Previous VTE• Thrombophilia• Immobility• Transfusion at delivery• BMI ≥30• Postpartum hemorrhage, postcesarean delivery• Preeclampsia• Smoking

Post-Partum Women: Progestin OnlyUS MEC 2011 Revision

Days from delivery POP DMPA Implant<21 days 2* 2* 2*21-29 days 2* 2* 2*30-42 days> 42 days

1 1 1

*2 In breast feeding women; 1 in non-breast feeding women

Post-partum Long-acting Progestins• DMPA

– Mildly lactogenic; no change in milk content• Implant (Implanon, Norplant studies)

– No effect on milk volume, content, or growth• Administration before hospital discharge

– Advantage•Protected if post-partum visit is missed

– Disadvantages•Unnecessary for first 4 weeks•Anatomic bleeding vs. drug side effect

POC Use Among Breastfeeding Women: A Systematic Review

• Review of 47 studies• “Evidence fails to demonstrate adverse breastfeeding

outcomes or negative health outcomes in infants such as restricted growth, health problems, or impaired development”

• Evidence newly added to this review was largely consistent with previous evidence

Phillips SJ, Tepper NK, Contraception. Sep 24, 2015

Breastfeeding and Hormonal Contraceptives: Striking a Balance

• Pro– Opportunity to initiate contraception when the risk of

unplanned pregnancy or loss to follow-up is high• Con

– Exclusively BF women are extremely unlikely to become pregnant in the first 6 weeks post-partum

– The period of exclusive breast feeding (12 weeks) is critically important and varies among women

• Hence: shared decision making is paramount and must be tempered by the interval since delivery

Proposed MEC Updated Comment• Discussions about contraception for breastfeeding

women should include information about risks, benefits, and alternatives while considering each woman’s desire to breastfeed, risk of breastfeeding difficulties and risk of unintended pregnancy

• Women at risk for breastfeeding difficulties, include women with previous breastfeeding difficulties, certain medical conditions, certain perinatal complications, and those who deliver preterm

Risk Factors for Lactation Problems• Previous BF problems or breastfed

infant with slow weight gain• Perinatal complications (hemorrhage,

infection, LBW or preterm (<37wks)• Hormone related infertility• Med illnesses: hypothyroidism,

diabetes, cystic fibrosis• Maternal age: advanced or

adolescent• Psychosocial problems, especially

depression

• Obesity (BMI >30 kg/m2)• Lack of breast enlargement

during pregnancy• Previous breast surgery that

severed ducts or nerves• Previous breast abscess• Extremely or persistently

sore nipples • Mother and infant

separation or mother needing to pump

Breastfeeding Handbook for Physicians, AAP & ACOG 2013

Postpartum IUC InsertionUS MEC 2010

Postpartum (BF or non-BF women) including C/S

LNG-IUS Cu-IUD

<10 min after delivery of placenta

2 1

10 min after delivery of placenta to <4 wks

2 2

>4 wks post partum 1 1Puerperal sepsis 4 4

How Is Postpartum IUC Insertion Done? • IUC placement after vaginal delivery– Insert IUC within 10 minutes of placental delivery– Use sponge forceps on cervical lip; 2nd forceps to place

IUC at uterine fundus– Cut string flush with external cervical os

• IUC placement at caesarean section– Manually place IUC at fundus; tuck strings thru cervix– Repair uterus and complete c-section– Trim strings at postpartum visit

Postpartum IUC Placement• Pros

– One procedure, rather than delivery and delayed placement

– Pregnancy prevention if patient doesn’t return for visit– Cost saving to health system, including adolescents

• Cons– Higher rate of expulsion (15-20%) vs. delayed placement– Delivery room challenges, until system established– Pushback from hospital administration if not line-item

reimbursement from payer

Uterine Perforation RatesEuropean Active IUD Surveillance Study (EURAS)

• Multinational, prospective, non-interventional cohort study• New IUD users

– Baseline information– Follow-up at 12 months

•User and clinician– Loss to follow-up 2%

• 61,448 women in 6 countries– 70 % LNG; 30 % copper (30 types)

Heinemann K, et al. Contraception. 2015;ahead of print.

Uterine Perforation RatesEURAS, 2015

• Perforation: Partial (20%); complete (80%)• Perforation: 50% diagnosed first 2 months• Perforation rates by 12 months

– LNG: 1.4/1,000– Copper: 1.1/1,000– Adjusted risk ratio: 1.6 (95% CI 1.0-2.7)

•Adjusted for age, breastfeeding, pregnancy


Uterine Perforation RatesEURAS, 2015

• Breastfeeding significantly increased risk– RR 6.1 (9.5% CI 3.9-9.6) in breastfeeding vs. non-

breastfeeding– No difference between IUD types

• 63/81 perforations had risk factors– Breastfeeding– Time since delivery < 36 weeks

• No serious injury to intraperitoneal or pelvic structures


Uterine Perforation RatesEuropean Active IUD Surveillance Study

Heinemann K, et al. Contraception. 2015

Time Since Last Delivery

BreastfeedingRR (95% CI)Yes No

≤ 36 weeks 5.6 1.7 3.3 (1.6-6.7)> 36 weeks 1.6 0.7 2.2 (0.3-16.1)RR (95% CI) 3.4 (0.5-24.8) 2.3 (1.1-4.7)

Red Italicized numbers: perforation rate per/1000 insertions

Factors That did Not Affect Perforation RiskEuropean Active IUD Surveillance Study

• Cervical dilation at time of placement• Use of anesthesia• Ever Cesarean section• Last delivery by Cesarean section


CMS: Improving Postpartum Care Action Learning Series

Aim: Improve postpartum care visit rate and content by July 2015• California one of 11 participating states Measure:• Postpartum care visit 21-56 days after delivery• Number of postpartum care visits with content bundle

� Counsel on family planning and provide contraception� Support breast feeding � Screening for postpartum depression �Hand-offs/care transitions for medical conditions �General health messages—smoking cessation, weight

reduction, exercise

How Is Quality Currently Measured in Sexual And Reproductive Health

• 2013 HEDIS measures (NCQA)– Cervical cancer screening– Breast cancer screening– Chlamydia screening – HPV vaccine for female adolescents– Management of urinary incontinence in older adults– Osteoporosis testing in older women– Entry into prenatal care– Postpartum care

A National Quality Metric for Family Planning?Front runners1. Question regarding pregnancy intendedness

– Would you like to become pregnant in the next year?2. Contraceptive method mix

– % of women using Tier 1 + Tier 2 methods, and– % of new starters using Tier 1 methods

3. Postpartum contraceptive use within 100 days after delivery

Infertility for the Generalist

Heather Huddleston, MD

Associate Professor

UCSF Center for Reproductive Health

I have nothing to disclose

Outline

• Fecundability and age

• Advice for the person about to start trying to conceive

• Workup of the patient with fertility problems

• What is new in fertility treatment

Knowledge Gap: Age and Fertility

Survey by American Fertility Association 2001

• 12,382 women responded to 15 questions• 1 responded correctly to all• More than ½ of all questions answered

incorrectly• 85% overestimated by 5-10 years the point at

which fertility declines

Fecundability declines with age

Menken, et al., Science 1986, 233:1389-94 Homan, G.F. et al. Hum Reprod Update 2007 13:209-22 3;

Fecundability and natural fertility in humans

Chance of Natural Conception per Month

24%22%

20%

16%13%

10%7%

5%3% 2%

25%

18%

24 26 28 30 32 34 36 38 40 42 44 46

Age

Per

cent

cha

nce

per

mon

th

•

3 mo 6 mo 9 mo 12 mo

Hassan and Killick, Fertility and Sterility 2003

Evaluation of Time to Pregnancy in 2012 women

35-39

Time to Pregnancy and Age

28 % of pregnant women 35-39 will not have conceived in a

year

Cumulative pregnancy rate (CPR) according to patien t's age (years).

Ferrara I et al. Hum. Reprod. 2002;17:2320-2324

Risk of Fetal Loss According to MaternalAge

Andersen A N et al. BMJ 2000;320:1708-1712

�Denmark Registry�1978 to 1992 �34 272 women and�1 221 546 pregnancy outcomes.

Abnormalities in the oocyte increase with age

Pellestor et al, Eur J Med Genet 2006

Advice for the person about to start

� Timing

� Lifestyle

Dunson D B et al. Hum. Reprod. 2002;17:1399-1403

Timing of Intercourse Smoking and Fertility

• Average age of menopause 3-4 years earlier than non-smokers

• Nicotine and Cotinine found in follicular fluid

• Direct damage to oocytes/follicles suspected

Smoking and Fertility

3.2

3.9

2.6

No Smoking <10/per day >10 per day

Average Time to Conceive by Smoking Status

Mon

ths

.

Metanalysis: smoking and fertility

Odds Ratio of infertility in smokers: 2.27 (1.34,1. 91)

Body Weight and Fertility

Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004

6.9

10.914

25

<19 19-24 25-39 >39

• 1,200 consecutive pregnant women.

• A questionnaire inquiring about time to pregnancy

•Contraceptive use, pregnancy planning, previous subfertility/pregnancies, age, and lifestyle characteristics examined

Adjusted Months to Conception

BMI

Body Weight and Fertility

BMI Adj RR Infertility p

<19 4.8 (1.2 - 19.7) .03

19-25 1.0

25 – 39 2.2 (1.6-3.2) <0.001

>39 6.9 (2.9-16.8) <0.001

Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004

Lifestyle Factors

�Alcohol: Evidence that >7 drinks per week is deleterious to fertility

�Exercise: No evidence that moderate amounts are deleterious

The Infertility Evaluation

�<35 years old: after one year of trying to conceive

�>35 years old: after six months

�Patient with irregular cycles, known tubal disease or partner with known subfertility

ASRM Practice Committee 2006

The Basic Infertility Work-up

Ovary Tubes Semen Other Endocrine

Ovulation

And Cycles

Ovarian Reserve ???

HSG

Semenanalysis

TSH

Uterus

Ultrasound

Tubal/Uterine Factor

Normal Filling Defect

Blocked Tube Septum

Semen Analysis

• Volume 1.5-5ml• Concentration>20million/ml• Motility>50%

WHO,1992

If Abnormal Repea t

Is Ovulation happening?

�Regular Cycles with moliminal symptoms

�Timing of ovulation:

� Basal body temperature

� Ovulation predictor kits

�Anovulation suggested by cycle length 36

�Progesterone <3 seven days after predicted ovulation

�Inadequate luteal phase <10 days or extended spotting

Endocrine

�TSH

�Prolactin

Ovarian Reserve

�Antral Follicle Count

�AntiMullerian Hormone

�FSH

Ovarian Reserve

Anti-Mullerian Hormone

Antral Follicle Count (AFC)

Inhibin

Hypothalamus

PituitaryEstradiol

FSH

FSH and ANTI-MULLERIAN HORMONE are indirect measure s of the ANTRAL FOLLICLE COUNT

FSH and Response to Gonadotropin Treatment

Broekmans F et al. Hum. Reprod. Update 2006;12:685-7 18

Not predictive

Highly Predictive

FSH useful in predicting poor

response

Basal FSH and Pregnancy During Treatment

Broekmans F et al. Hum. Reprod. Update 2006;12:685-7 18

Day 3 FSH not predictive of pregnancy

during treatment

Age specific nomogram of AFC in infertile women

Antral Follicle Count in the Community

Rosen et al F and S 2010

AMH: conception to menopause

Kelsey TW: PLoS ONE 2011

Ovarian Reserve Testing: Summary

�FSH, Antral Follicle Count, etc – arose as a predictive tool during infertility treatment

�Unclear and likely small relationship to possibility of natural pregnancy

�Strong relationship with degree of ovarian response during treatment

�Minimal relationship to live birth rate in IVF in women under 40

What is new for Treatment?

Optimal Treatment of Anovulatory Infertility

Clomiphene Citrate (Clomid)

• Synthetic Anti-estrogen

• Convenient

• Inexpensive

• Long-standing first choice for ovulation induction in women with PCOS

Imani, B. et al. J Clin Endocrinol Metab 1998;83:2361- 2365

How Many Women Will Ovulate With Clomid?

About ¾ of women

with PCOS will

ovulated with clomid

Imani, B. et al. J Clin Endocrinol Metab 1999;84:1617- 1622

� 160 patients

� Normogonadotropic anovulation

� Successful response to clomid

� Normal SA

� BMI >18.5

Clomid: Chances for conception?

Metformin For Ovulation

• Biguanide Insulin Sensitizer

• Category B

• Not FDA approved

Results of RMN PPCOS Trial

P<.001

P<.001

Legro et al. NEJM 2007; 35:551-66

Aromatase InhibitorsLetrozole versus Clomiphene for

Infertility

• RCT of 750 women comparing letrozole of cloniphene for five treatments

• Cumulative Ovulation Rate higher in Letrozole(61.7% vs. 48.3%)

• No differences in pregnancy loss rate or twin pregnancy rate.

28%

19%

0%

5%

10%

15%

20%

25%

30%

Letrozole Clomid

Live Birth Rate

Legro et al NEJM 2014

The Withdrawal Bleed Could Be a Hindrance

• Secondary analysis of RMN PCOS trial

• Use of withdrawal bleed prior to cycle start was up to discretion of site investigators

0%

10%

20%

30%

Preg/cycle Preg/Ov LB/cycle LB/OvSpont menses 3% 5% 2% 3%Withdraw 2% 7% 2% 5%No Withdraw 8% 27% 5% 20%

*

**

* * P<.001

Diamond et al Obset Gyncol 2012 119: 902-905

Treatment of Unexplained

Expectant4%

Clomid4%

IUI5%

Clomidand IUI

8%

GonadotropinIUI

15%

IVF25%

Guzick Fertility and Sterility 1998

Clomid for Unexplained Infertility

• 100 mg for five days (typical: 3-7)• Acts as estrogen antagonist• Assist in production >1 oocyte

Practice committee ASRM, Fertil Steril, 2004

Risks/Side Effects:

•Headache

•Hot Flash

•Mood Changes

•Ovarian Cysts

•Twins

Clomid alone vs. IUI

Battacharya BMJ 2008

580 women randomized (avg age 32)

Clomidalone IUI alone Expectant

14% 23% 17%

Not statistically different

6 months

Unexplained Infertility: Clomid & IUI

Deaton et al, Fertil Sterility 54:1083 1990

3.3%

9.5%

Clomid and IUI Timed Intercourse

•Number of cycles to achieve one pregnancy: 16

Pregnancy rate per Cycle •Randomized Controlled Trial

•298 cycles

•67 patients with unexplained Infertility

Treatment of Unexplained Infertility

o Treatment effect of clomid without IUI is quite modest compared to timed intercourse

o Recommend for patients if:

�No time constraints (ie young)

�Patients who wish to avoid additional intervention

Amigos Trial

FORT-T Trial • 154 women randomized to Clomid/IUI, FSH/IUI or IVF

0

10

20

30

40

50

60

Clomid IUI FSH IUI IVF First

Clinical PregnancyLive Birth

Results after first two treatment cycles

FORT-T Trial

0

10

20

30

40

50

60

70

80

Clomid IUI FSH IUI IVF First

Clinical PregnancyLive Birth

Results by the End of the Study

Summary

•Fertility Declines with Age

Natural Fecundity by age of 35 is almost ½ that of a 22 year old woman

•Miscarraige Rates increase

A pregnancy conceived by a 35 yo is twice as likely to miscarry as a woman age 22 .

•These changes are thought to be due to a decrease oocyte quality

Summary: Patient Care

•Counseling regarding implications of age

•Counseling regarding other factors associated with fertility: smoking and BMI

•Basic fertility workup at age 35 recommended after six months:

•Semenanalysis and HSG most high yield

Summary: Treatment

•Clomid alone not more effective than no treatment

•Clomid and IUI reasonable first step

•IVF is the more cost effective than Gonadotropin IUI as next step after Clomid IUI

•Preimplantation Genetic Screening not recommended on basis of maternal age

Thank you

10/16/2015

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Oocyte Cryopreservation

(aka Egg Freezing)

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Evelyn Mok-Lin, MDAssistant Professor

Department of Obstetrics, Gynecology and Reproductive SciencesDivision of Reproductive Endocrinology and Infertility

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Disclosure

No one involved in the planning or presentation of this activity has any relevant financial relationships with a commercial interest to disclose.

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Audience Poll

In the last year, how often have you discussed egg freezing with your patients?

A. NeverB. RarelyC. At least once per monthD. At least once per week

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R a re l y

A t le a s

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43%

5%

13%

39%

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Overview

• Indications

– Why, who, when?

• The Science

– Embryo vs egg freezing

– Success rates

• The Procedure

– Timeline and logistics

– Risks

– How to prepare your patient

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Indications: Why?

• Why consider egg freezing?

– To preserve a woman’s current fertility and increase their chances of achieving pregnancy at a later age

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www.elle.com

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Wallace and Kelsey, PLoS 2010

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Heffner, NEJM 2004

Indications: Who?

• Who should consider egg freezing?

– Women who require medical or surgical treatments that reduce ovarian reserve

• Cancer

• Other conditions requiring chemotherapy (SLE, thalassemia)

• Complex and/or recurrent ovarian cysts

• BRCA mutation carriers

– Women at risk for early menopause

• Family history of primary ovarian insufficiency (POI)

• Personal history of diminished ovarian reserve (DOR)

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Indications: Who?

• Elective (“Social”) Egg Freezing

– Women who wish to delay childbearing due to personal or professional circumstances

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Indications: Who?

• Elective (“Social”) Egg Freezing

– Women/couples who want to have more than 1 child

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Indications: When?

• What is the optimal age?

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Franasiak et al. Fertility and Sterility 2014

Optimal timing for elective egg freezing

• Decision-tree model for egg freezing vs no action

– ages 25-40 yrs, attempting procreation 3, 5 or 7 years after

– unassisted attempts for 6 months and then IVF

– conception rates and cost estimates for fresh IVF cycles vs egg freezing, storage and subsequent usage

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Mesen et al. Fertility and Sterility 2015

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• Live birth rate (LBR) highest when egg freezing perf ormed at <34 yrs (>70%)

– Steadily declines with increasing age to 26.2% at age 40 yrs

• Greatest improvement in LBR at age 37 yrs

– 30% difference in chance of live birth with egg freezing compared to no action (51.6% vs 21.9%)

• Little benefit at ages 25-30 yrs (2.6-7.1% increase )

• Egg freezing was most cost-effective at age 37 yrs

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Mesen et al. Fertility and Sterility 2015

Indications: When?

• When should a woman undergo egg freezing?

– Early to mid-30s is ideal

– Take personal timeline into consideration

– No absolute age cut-off

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Embryo versus Egg Freezing

• Embryo cryopreservation

– Well-established

• Most data

• Highest success rates

– Higher survival

– Pre-implantation genetic screening (PGS)

– Limitations:

• Requires male partner or donor sperm

• Legal and ethical issues

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Embryo versus Egg Freezing

• Oocyte cryopreservation

– More practical

• Future sperm of choice

• Lower initial cost

• Logistically more simple

– No longer “experimental” (ASRM 2012)

– Limitations:

• Less long-term data

– Short-term data with no increased risk of chromosomal or congenital anomalies

• Lower success rates

– Unknown fertilization rates and embryo quality

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Success Rates

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Success Rates

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Egg Freezing Procedure

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1 3 5 7 9

FSH+LH

hCGtrigger

EggRetrieval

11 13

Days

• The procedure is typically completed within 2 weeks

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• Each visit during ovarian stimulation involves monitoring of estradiol levels and follicle sizes

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• Egg retrieval is performed under MAC anesthesia

• Mature eggs are cryopreserved (unless cancer)

• Once frozen, quality of eggs does not change

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Risks of Egg Freezing

• Ovarian hyperstimulation syndrome (OHSS)

• Ovarian torsion

• Bleeding

• Infection

• Damage to adjacent organs

• No association with long-term risks to the patient:

– Breast cancer

– Ovarian cancer

– Premature menopause

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Preparing your patient for egg freezing

• Initial work up

– Ovarian reserve testing (AMH, day 3 FSH/E2)

– *Additional labs: T+S, CBC, ID panel

– Formal pelvic ultrasound not necessary

– Updated healthcare maintenance: pap smear, mammogram

• Hormonal contraceptives

– Stop long-term OCPs temporarily

– Hold on replacing LARCs (except Paragard)

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Summary

• A woman’s egg quantity and quality decline with increasing age, particularly after her mid-30s

• Egg freezing offers women the opportunity to delay childbearing for medical or elective reasons

• Egg freezing is a safe, non-experimental procedure that is typically completed within 2 weeks

• The ideal candidate is a healthy woman in her early to mid-30s with high ovarian reserve who is able to freeze 20 mature eggs

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Thank you

Vulvar Disease: An Update

Rachel Kornik MD

Assistant Professor of Dermatology

Disclosure

• I have nothing relationships to disclose

• Will be discussing off label use of medications

Goals

• Identify clinical findings and associated conditions of lichenoid vulvar disease and lichen simplex chronicus

• Develop evaluation and management strategy

• Recognize pitfalls and learn how to minimize complications

Lichen Sclerosus (LS)

• Chronic dermatosis with predilection for anogenital area

– ?Autoimmune ?Inflammatory

• Most common in post menopausal women

• Prevalence estimated at 1/300 to 1/1000 but could be as high as 1/30

• Accounts for 1/3 of patients presenting to a specialty clinic with vulvar complaintsBall BS, and Wojnarowska F. Vulvar Dermatoses: Lichen Sclerosus, Lichen Planus, and VulvalDermatitis/Lichen Simplex Chronicus. Semin Cutan Med 1998: 17 (3): 182‐188.

LS: Clinical Findings

• Periclitoral edema• Wrinkling and/or hyperkeratosis of skin• Fusion of labia minora leading to resorption• Fissures• White/pallor • Scarring of the clitoral hood• Introital narrowing• Sparing of mucous membranes• Genital melanosis

Lichen Sclerosus Associated with Autoimmune Disease

• 22‐28% of women with LS have associated autoimmune disease

• Most common is thyroid disease

– 8‐30% of patients

– Check TSH

• Alopecia areata (9%)

• Vitiligo (6%)

• Pernicious anemia (2%)Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol2013: 14: 27–47

LS: Other Associations

• Morphea 1

– 50% of pts presenting with generalized morpheahad LS

• Psoriasis 2

• Celiac 3

• IBD

1. Lutz V. et al. High frequency of genital lichen sclerosus in a prospective series of 76 patients with Morphea. JAMA Dermatol. 2012;148:24‐28

2. Walls A. and Qureshi A. Psoriasis and concomitant fibrosing disorders: lichen sclerosus, morphea, and systemic sclerosis. J Am Acad Dermatol. 2012;67:1079‐83.

3. Jacobs L et al. Association between lichen sclerosus and celiac disease: A report of three pediatric cases. Ped Dermatol.2014;31:e128‐131

Squamous Cell Carcinoma in Lichen Sclerosus

• Lifetime risk estimated at 5%

• Cohort study of 253 women followed over 69 months found prevalence of 3%

• Between 7‐60% of vulvar SCCs occur on vulvar lichen sclerosus

• Thought to be secondary to chronic inflammation

• Patients should be advised to monitor for ulcers or lumps

• Erosion or area of hyperkeratosis not responding to therapy warrants biopsy

• Patients require long term follow up

• Treatment is thought to reduce the risk

Gutiérrez‐Pascual M. Lichen sclerosus and squamous cell carcinoma. Actas Dermo‐Sifilio 2012: 103: 21‐8.

Cooper at al. Does treatment of lichen sclerosus influence its prognosis? JAMA Derm 2004: 140 (6):702‐706

LS: Management update

• Study of 67 patients

• Randomized to 5 x weekly mometasone fumarate for 12 weeks vs tapering schedule (5 per wk for 4 weeks then every other day for 4 weeks then twice weekly)

• No difference in clinical/symptom/ improvement

• No difference in adverse reaction

• Prospective longitudinal study of 507 women with biopsy proven LS

• Topical therapy tailored to degree of hyperkeratosis but most pts used potent to ultrapotent topical steroids

• Avg time to skin normalization – 4.9month

• No SCCs in compliant pts• 7 pts who reported they were not compliant developed SCC or VIN

• Sx did not correlate with disease progression– Asymptomatic progression

• Bottom line: no standardized tx for LS• Need regular follow up until stable then maintenance therapy and then 6 month follow ‐up

LS: Complications

• Iatrogenic Infections– HSV: if pos hx, prophylactic antivirals while on clobetasol

– Candida/tinea: itch, erythema, fissuring or scale perform KOH or culture for candida

– Culture for strep/staph if sx not improving

• SCC

• Atrophy– If steroids are used correctly risk of atrophy is very low

• Steroid irritant/allergic contact dermatitis– Reduce potency, switch to desoximetasone 0.25% ointment, consider patch testing

Lichen Planus (LP)

• LP is an inflammatory disorder of skin, mucous membrane and nails

• Unknown prevalence

• Pathogenesis thought to be Tcell mediated immunologic response to basal cells

Types of Vulvovaginal LP

• 3 main types– Erosive

• Erosions, erythema or desquamative vulvitis/vaginitis. May have surrounding wickham striae (lacy reticulations)

– Papulosquamous• Pruritic, vilaceous, papules with wickham striae

– Hypertrophic• Extensive, white, thick, hyperkeratotic plaques and erythematous macules and patches

Ginat M and Goddard A. Dermatol Clin28 (2010) 717–725

Vulvovaginal LP

• Similar clinically to to oral LP

• Oral LP + vulvovaginal LP = vulvovaginal‐gingival syndrome (VVG)

• 43‐100% of vulvovaginal cases may have oral involvement

At least 3 criteria should be present to make the diagnosis

DDX: Erosive Vulvar Diseases

• Lichen Planus

• Immunobullous Disease

– Pemphigus, mucous membrane pemphigoid

• Graft Versus Host Disease

• HSV

• Aphthae

• VIN/SCC

Check Hep C (Lodi et al Br J Dermatol 151 (2004) 1172‐81)

Vulvovaginal LP

Ginat M and Goddard A.Dermatol Clin. 2010;28: 717–725

Management Strategies: LP

• Eliminate irritants/allergen• Topicals mainstay of therapy

– Suprapotent topical steroids (clobetasol proprionate 0.05%) – Tacrolimus 0.1%– Hydrocortisone 25mg suppository (anusol)– Compounded hydrocrotisone intravaginal cream (10%)

• Systemic medications: prednisone, methotrexate, hydroxychloroquine, acitretin, mycofenolate mofetil

• Topical/intravaginal estrogen• Dilator therapy• Check and recheck for candida/strep

Ginat M and Goddard A. Treatment of vulvovaginallichen planus. Dermatol Clin. 2010;28: 717–725

Wet Mount• Important to diagnose vaginal involvement and monitor for resolution

• 1wbc per squamous epithelial cell = normal

http://www.bacterialvaginosis.net/

Additional Sites of Involvement

• Esophageal LP (ELP) is likely under‐recognized

• Predilection for middle aged women

• Associated with oral and/or genital dz

• Prevalence unknown (may be as high as 25‐50%)

• Pt with oral LP and dysphagia or weight loss EGD

AND GYNECOLOGISTS

Genital Tract Graft Versus Host Disease

• 60‐70% of patients who receive allotransplant manifest GVHD (Lee et al. Chronic graft‐versus‐host disease. Biol Blood Marrow Transplant 2003)

• Incidence of female genital tract cGVHD~50%

• Patients with genital disease more likely to have extensive cGVHD

• May be first presenting sign of GVHD

Zantomio et. al. Female genital tract graft‐versus‐host disease: incidence, risk factors and recommendations for management. BMT 2006: 38: 567‐572.

GVHD: Have a High Index of Suspicion

• Ask the patient about sx

• Diagnosis made by clinical‐pathologic correlation

• Lichenoid GVH may mimic lichen planus or lichen sclerosus clinically and histologically

• Include hx of transplant on path requisition and talk to the pathologist

Lichen Simplex Chronicus (LSC)

• Clinical

– May be subtle

– Lichenified, thickened plaques

– Hypopigmentation or hyperpigmentation

– Linear excoriations (scratches), secondary erosions

LSC

• Due to “itch‐scratch‐cycle”• Repair barrier – eliminate irritants and scratching implements, add emollient

• Rule out underlying cause of itch (yeast, irritant, other dermatosis, allergic contact dermatitis)

• Associated with atopic dermatitis• Address both skin issue and behavioral component– Treat with mid to high potency topical steroids and antihistamine at night

• Hydroxyzine 10‐30mg

– Consider addition of tricyclic or SSRI if not improving• Doxepin 10mg

Vulvar Disorders: Multifactorial

• Eliminate irritants– Assess for incontinence, hygiene practices, wipes etc

• Repair the skin barrier (emollient, topical estrogen)

• Correct initial infection and monitor for iatrogenic effects– Candida, HSV, HPV, bacteria

– 1 dose fluconazole not enough in setting of topical steroids

– Applying topical steroids to an infection will exacerbate it

• Any lesion that has not responded to therapy should be biopsied

Principles of Management

• The modified mucous membranes are relatively resistant to steroid atrophy

– Keratinized skin are not

• Ointments are better tolerated than creams ‐ a little goes a long way

• Treatment failure often due to non compliance or incorrect application

• Little risk of atrophy if use 30 gram tube over 6 ‐12 months

Thorstensen K., Birenbaum D. Recognition and managament of vulvar dermatologic conditions: Lichen sclerosus, lichen planus and lichen simplex chronicus. JMWH. 2012

Stewart K. Clinical Care of Vulvar Pruritus, with Emphasis on One Common Cause, Lichen Simplex Chronicus Dermatol Clinic. 2010; 28(4) 669‐680.

Demonstrate Where and How to Apply

Thank you!

Contact info:

[email protected]

Sexual Health Concerns of Disabled Women ISSWSH 2011 Annual Meeting, February 10

Mitchell Tepper, PhD, MPH 1

Sexual Health and Women with Disabilities

Tami Serene RowenUCSF Department of ObGyn and Reproductive SciencesUCSF Gynecologic Fall CourseOctober 16, 2015

Financial Disclosures- None

Outline• Review some gynecologic health concerns

unique to women with disabilities• Review the Definitions and Models of Sexual

Health• Review the current treatments available for

treating sexual dysfunction

Definition and Scope of Disability• ADA (1990) definition of disability• Physical or Mental impairment• Substantially Limits one or more major life activities42 U.S. Code § 12102 - Definition of disability

• Prevalence of disabilities among civilian noninstitutionalized U.S. adults:21.8% stable from 1999

• ~48 million Americans with disabilities

• Largest and poorest minority

• US Census Bureau 2005



Pervasive Cultural Constructs(Myths)

Asexual Childlike

Not interested in sexual pleasure

Not acceptable candidates for reproduction

Photo courtesy of Intimate Encounters, by Belinda Mason http://www.belindamason.com/

Call To Action on People with Disabilities

� Sexuality and sexual needs often ignored

� PWD too often exploited and abused

� Serious underutilization of existing assistance developed for vulnerable populations

� Additional materials and programs needed

� Further research needed

High Risk for Averse Sexual Health Outcomes

Summary of 2002-2003 NSFG: Compared to people without disabilities, people with disabilities are . . .• More likely to have been assaulted

– 33% : 15% heterosexual vaginal intercourse • More likely to have had 10 or > lifetime partners• More likely to have had same sex experiences

– 17% : 10% • May be more likely to have an STI

– with disabilities; 13% : 9% – who have been raped; 24% : 17%

High Risk to Miss STIs

• WWD often not asked about sex

• STIs mistaken for UTIs• Woman may not be able to see

discharge/lesions • Woman may have unperceived

or atypical physical symptoms

STI’s often go

undetected or

diagnosis is delayed

Welner Sex Trans Dis 2000



Importance of Contraception� Ask if there is a need for contraception� Consider who is requesting contraception and

make sure there is no coercion involved� Consider the patient’s capability to consent to

sexual relations� Important to think about role of immobility in

prescribing medication� VTE� Long term osteoporosis risk

� Also consider role of AUB as a AE from specific forms of MOC

Kaplan C. Special issues in contraception: caring f or women with disabilities. J Midwifery Womens Health. 2006

Systems Contributing to Sexual Response & Expression in WWD

Systems RespiratoryCardiovascularNervousMusculoskeletalSensoryEndocrineReproductive

Seduction/flirtationDesire

Excitement/ArousalSensationsMovement

Orgasm

Response & Expression

Sexual Health RightsWorld Association of SexualityDeclaration of Sexual Rights:� Grounded in universal human rights� Sexuality is a source of pleasure & well-being,

contributes to fulfillment & satisfaction� Sexual health is a state of physical, emotional,

mental, and social wellbeing (WHO), not just absence of disease or dysfunction� Sexual health requires positive and respectful

approach/relationships, protection of diversity

Models of Sexual Function



Masters and Johnson’s (1966) EPOR ModelFemale Male

Modified by Kaplan (1974) and Georgiadis et al. (20 12)

Alternative Cycle of Female Sexual Response

Basson. J Sex Martial Ther 2001.

Emotional Intimacy

Sexual Stimuli

Sexual Arousal

Sexual Neutrality

Emotional & Physical

Satisfaction

Sexual Desire & Arousal

Psychological/biological influences govern

“arousability”

Seeks/is receptive to

+ Motivates sexuallyneutral woman

Spontaneous Sexual Desire

Do Women Care about Sex?• Largest study(13882 women, 29 countries)• 65% women sexually active in last year

– 38% in last week(inverse age relationship)– Agrees with US data

• 20-37% reported sex was very/extremely important to life

• 76% women felt satisfactory sex is essential to maintain a relationship

• Sexual well being significantly correlated to self perceived overall health

• Laumann et al, 2006; Nicolosi et al, 2004; Lindau 2007

Whom do Patients Ask?Physician specialties approached for help.Who did you ask for help?(n =3,807)• Gynecologist/obstetrician 42% (1,616)• General practitioner 24 % (925)• Psychiatrist 12% (439)• Urologist 3% (107)• Endocrinologist 8% (116)• Other 8% (297)• Did not seek help 40% (1,519)

Berman. Seeking help for sexual complaints. Fertil Steril 2003.



Do Gynecologists ask about Sex?

Cross sectional study of 1,154 US Gynecologists• 63% ask about sexual activity• 40% ask about sexual function• <30% ask about sexual orientation &

satisfaction• ~25% express disapproval with patients’ sexual

practices• Older physicans less likely to ask about sexual

healthSobeicki et al What we don’t talk about when we don’t talk about sex J Sex Med 2012

Female Sexual Dysfunction: How common is it?

• Laumann 1999: 1,749 US women age 18-59– ~43% prevalence based on 7 single item dichotomous

questions

• Bancroft 2003: Interview of 987 women 20-65– 24% prevalence of self reported “distress”

• Shifren 2008: 31,581 US women >18 years– 43% reported sexual problem– 22% reported sexual distress– 12% reported both sexual problem and distress

Distressing Sexual Problems: Age Stratified (PRESIDE)

Age-stratifiedprevalence

Desire 2,868/28,447

Arousal 1,556/28,461

Orgasm 1,315/27,854

Any3,456/28,403

18 - 44 years 8.9 3.3 3.4 10.8

45 - 64 years 12.3 7.5 5.7 14.8

65 years or older

7.4 6.0 5.8 8.9

Shifren JL, et al. Obstet Gynecol. 2008.

Bottom Line• Our patients would like to discuss sex• More than 10% likely have a

distressing problem• Many of us don’t ask about it

–Unsure how to ask–Uncertainty what to ask–Unfamiliar with treatment options



Female Sexual Dysfunction:DSM-IV-TR Definitions and ICD Definitions

Sexual desire disordersHypoactive sexual desire disorder

302.71 or 799.81

Absence or deficiency of sexual interest and/or desire

Sexual aversion disorder 302.79 Aversion to and avoidance of genital contact with a sexual partner

Sexual arousal disordersFemale sexual arousal disorder

302.72 Inability to attain or maintain adequate lubrication-swelling response of sexual excitement

Orgasmic disordersFemale orgasmic disorder 302.73 Delay in or absence of orgasm after a normal

sexual excitement phasePain disordersDyspareunia 302.76 or

625.0Genital pain associated with sexual intercourse

Vaginismus 306.51 or 625.1

Involuntary contraction of the perinealmuscles preventing vaginal penetrationAm Psych Assoc 2000; Buck, et al. 2008.

Female Sexual Disorders: DSM 5Female Orgasmic Disorder

302.73 (F52.31)

Presence of either of the following on all or almost all (75%-100%) occasions of sexual activity:1.Marked delay in, marked infrequency of, or absence of orgasm.2.Markedly reduced intensity of orgasmic sensations

Female Sexual Interest/Arousal disorder

302.72(F52.22)

Lack of, or significantly reduced, sexual interest/arousal as manifested by 3 of the following:1. Absent/reduced interest in sexual activity2. Absent/reduced sexual/erotic thoughts or fantasies3.No/reduced initiation of sexual activity and unreceptive to partner’s attempts to initiate4. Absent/reduced sexual excitement/pleasure during sexual activity in almost all or all (75%-100%) sexual encounters5. Absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues (written, verbal, visual)6. Absent/reduced genital or nongenital sensations during sexual activity in almost all or all (75%-100%) sexual encounters

Symptoms persisted a minimum of 6 months and not better explained by a nonsexual mental disorder or consequence of severe relationship distress or other significant stressors and not due to effects of substance/medication or other medical conditionAmerican Psychiatric Association, DSM 5, 2013

Female Sexual Disorders: DSM 5Genito-Pelvic Pain/Penetration Disorder

302.76(F52.6)

Persistent or recurrent difficulties with 1 or more of the following:1.Vaginal penetration during intercourse2. Marked vulvovaginal or pelvic pain during intercourse or penetration attempts3. Marked fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of vaginal penetration4. Marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration.

Symptoms persisted a minimum of 6 months and not better explained by a nonsexual mental disorder or consequence of severe relationship distress or other significant stressors and not due to effects of substance/medication or other medical condition

American Psychiatric Association, DSM 5, 2013

Predictors of Sexual Health • Physical and Emotional Health status is #1 predictor!

Laumann et al, 1999; Laumann et al, 2006; Nicolosi et al, 2004; Lindau et al, 2007

• Role of age

– Other factors:– Delivery Type: worse with OVD and episiotomy– Relationship length (inverse correlation), education,

mental health status, HRT and surgical menopauseHayes,et al 2008; Dennerstein 2008

Filled circle =desireopen triangle= arousalfilled square= orgasmopen diamond=any.

Shifren et al, Obstet Gynecol 2008



Evaluation• Focused history and physical• May be useful to ask patient to describe most

recent sexual experience• Surveys may be of use-FSDS, domains of FSFI• Physical Exam:

– consider vulvoscopy– screen for vag infxn– PFMD

• Laboratory testing as indicated by H&PGoldstein ISSWSH, 2005

Medication Side Effects• SSRIs

– Exception is buproprion• Anti Psychotics

– Exception is mirtazepine• CHC• Anti-HTN• Antihistamines• ChemotherapyACOG Practice Bulletin 2011, Parrish ISWWSH 2013

Treatment of sexual concerns– Treat underlying disorders– Address relationship– Address psychosexual issues– Sex Education– Recalibrate expectations– Sexual Enhancement treatments: gels and

devices– Pharmacotherapy?

Hormones• Estrogens

– Demonstrated effect on vaginal vascularity and baseline moisture– Regular use associated with increased sex activity– May improve other health measures– Can use

• Cream (cEE vs Estradiol 3/week)• Estring q 3 months• Vagifem 2-3/week

• SERMs– Ospemafine: until 8/15 only FDA approved tx for FSF– Tibolone: has P, E, & T activity

• Not approved in USGass et al, 2011; Kovalevsky 2005, Lobo 2003, Basson 2004, Shifren 2000, Davis 2006, Nappi 2006



Off-label Testosterone• Data: IMS Health• Two million prescriptions written for ♀ 2006-7• Increased since 2004 (U.S. FDA Intrinsa Advisory

Committee Briefing Document)• 21% of prescriptions for branded male testosterone

products written for ♀• Figures do not include substantial number of

prescriptions for compounded T• Compounded products have no systematic trials to

support safety concerns and no black box warningsSnabes M , Simes SJ Sex Med 2009.

QuestionDo you prescribe testosterone for your patients?

A. YesB. No

Y es N o

63%

37%

Relationship Between Age and Androgens in Women

Davison et al. J of Clin Endocrinology & Metabolism, 2005

0

5

10

15

20

25

30

35

40

45

18-24 (n=22) 25-34 (n=97) 35-44 (n=153) 45-54 (n=140) 55-64 (n=74) 65-75 (n=109)

TT (ng/dl)

FT (pmol/L)

DHEA-S (µmol/L)

Androstenedione (nmol/L)

Davison, S. L. et al. J Clin Endocrinol Metab 2005

Free T Significantly Lower in Premenopausal Women with Desire Disorder

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

totalT freeT totalDHT freeDHT

nmol

/L o

r %

Control(n=15)

desire disorder

P=0.02

Riley and Riley, J Sex Martial Med 2000.



Summary of Testosterone Patch RCTsSSE PFSF-

ArousaPFSF-Desire PDS AE

Braunstein 2005 447, SM 140-450 mcg/d NR 8* ~5* NS 6%

Simon 2005 562 SM 300mcg/d 1.1† 5† 5† -7.7† -2%

Davis 2006 77 SM 300 mcg/d 0.5 19† 10† -19.3† -1%

Shifren 2006 238 NM 300 mcg/d 1.6† 26%† 5.8† -9† 6%

Davis 2008 814 no E2‡ 150 or 300 mcg/d 1.4* ~10† ~8† ~-11† 0%

Panay 2010 272 NM (26% E2) 300 mcg/d 1.2† ~14† 7.6† 11.5† 9%

†= Sta�s�cally Significant (p<0.05) * = Significant differences only with 300 mcg/daily patch ‡ = women taking vaginal estrogens continued on stable dosing regimens

Study n= TreatmentDifference versus placebo in…

AE= Incidence of Adverse Events, FSFI=Female Sexual Function Index, FSDS=Female Sexual Distress Scale, NR= Not Reported, NS= Not significant, PFSF =Profile of Female Sexual Function, PDS= Personal Distress Scale, SSE=Satisfying

Summary of Known Safety Data• Van Kesternen et al 1997: 297 F-M Transsexuals given T for 2 mo-41

years – No difference in CAD rate compared to control Dutch women

• Braunstein 2007 : Review of TRT in women– Major AE in women appear to be hirsutism, acne, and lowering of HDL

with oral T over 1-2 year time frame

• Tamimi et al 2006: 70,444 post-menopausal women in Nurses Health Study taking E, E+P, E+T, or no hormones over 24 years– Multivariate RR for breast CA was 1.77 (CI 1.22-2.56) for E+T, 1.15 (CI

1.05-1.27) for E, and 1.58 (CI 1.44-1.73) for E+P

• Ness et al 2009: 31842 women in WHI, E+T vs no HRT– Adjusted HR BC 1.42; 95% confidence interval, 0.95-2.11 p=.67)

Testosterone Therapy Options• Can use cream (compounded 1%) , spray , male pellets/gels

• Libigel: daily 1% gel application– Committed to long term safety trial

• 5 year f/u– BLOOM phase III trials

• 1172 women– no significance in ANY endpoint

– Company went bankrupt– did not release safety dataShifren ASRM 2013,; Shafer 2011, El Hague 2007, Davis 2008

Testosterone Bottom Line• End of Libigel meant end of Testosterone solo

therapy for FDA approval of FSD• Data insufficient to demonstrate sig AE, incl

breast ca• Off-label use: what our societies say

– NAMS (2005): “Postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause may be candidates for testosterone therapy. Testosterone treatment without concomitant estrogen therapy cannot be recommended because of a lack of evidence”

– ACOG: Practice Bulletin (2012) : “Transdermal Testosterone has been shown to be effective for the short term of hypo-active sexual desire disorder, with little evidence to support long term use (longer than 6 months) Level A



Flibanserin• Flibanserin is a mixed post-synaptic 5HT1A agonist and 5HT2A antagonist– 5HT1A agonists could have pro-sexual effects.– Stimulating 5HT2A receptor has been associated with decreased sexual behavior (male rodents)• Additionally, Flibanserin has activity at dopamine D4 receptors moderate affinity for 5HT2B and 5HT2C receptors.• The precise mechanism of action of flibanserin for HSDD is not fully understood• Flibanserin is thought to produce region-specific elevations in dopamine and norepinephrine, and may help to offset inhibitory serotonergic activity impacting desire pathways

Flibanserin: 4 RCTs, >11K Women

Flibanserin for postmenopausal women

Simon et al SNOWDROP trial Meonapuse 2014

Flibanserin Major AE



So What Happened?• 2010 Application Denied

– Benefits did not outweigh risks-• including CNS effects

• Not enough sexual benefit– based only on SSE

• not on other domains of sexual health– Controversy re: how to measure improvement Kingsberg and Althof, J Sex Med 2011

• Taken up by new company (Sprout)• FDA again denied (2013)

So What Happened Next?• 2014-2015

– Hearings on importance of Female Sexual Health– June 2015: FDA advisory committee recommends

approval of Flibanserin– August 18 2015 FDA approved ADDYI for daily use – Treatment for acquired, generalized hypoactive sexual

desire disorder (HSDD) in premenopausal women.– First approved medication for HSDD, and is classified as a

multifunctional serotonin agonist antagonist (MSAA)

QuestionWho plans to prescribe flibanserin?

A. YesB. No

Y es N o

38%

62%

Addyi needs REMS• Risk evaluation and mitigation strategy• Based on data showing severe hypotension in

women drinking 2-4 drinking within 10 minutes

• www.addyirems.com– Need to fill out prescriber registration– Knowledge Assessment– Set to be online by Spring 2016



Summary of Recent Drug Development Conclusions• Women with Disabilities comprise a large and

important subest of our patient population• Female Sexual Health is complex but very

important to women• New research has opened door to physiologic

factors• Any treatment should be both medical and

psychosocial• Reliable and proven medical therapy for women

with sexual problems is just now getting approved– Delays based on both outcomes and safety concerns

Questions?

10/16/2015

1

Monica W. Harbell, MD

WHAT’S NEW IN POST-OP PAIN FOR

GYNECOLOGIC SURGERY?

October 16, 2015

2015 UCSFWhat Does

The Evidence Tell Us?

�None

DISCLOSURES

� Describe the current impact of post-op pain after gynecologic surgery

� Provide an overview of options for post-op analgesia� Non-opioid analgesics

� Regional anesthesia:

� Spinal

� Epidural

� Transversus Abdominus Plane Blocks

� Discuss the rationale and benefits of multimodal analgesia and Enhanced Recovery After Surgery (ERAS) pathways

OBJECTIVES

� 40% of laparoscopic gynecologic surgery patients have inadequate pain control after discharge

� 45-51% of major gynecologic surgery patients reported inadequate pain control on POD#3

�After 2 weeks, 23% report inadequate pain control

�By 6 weeks, ~50% feel recovered

PAIN AFTER GYNECOLOGIC SURGERY

Lovatsis D et al. J Obstet Gynaecol Can 2007; 29(8): 664-7.Evenson M. Obstet Gynecol. 2012; 119(4): 780-4.

10/16/2015

2

� 5-32% incidence of chronic pelvic pain 1 year after hysterectomy

�Chronic post-surgical pain (CPSP)

� Lasts at least 2 months after surgery

� Most consistent patient factors are preoperative and postoperative pain

ACUTE � CHRONIC PAIN

Brandsborg B et al. Acta Anaesthesiol Scand 2008; 52: 327-31.Brandsborg B et al. Anesthesiology 2007; 106: 1003-12.

RISK FACTORS FOR CPSP AFTER HYSTERECTOMY

Brandsborg B et al. Anesthesiology 2007; 106: 1003-12.

�Surgical approach was not a risk factor

�Abdominal, vaginal, laparoscopic

�Total vs. subtotal abdominal hysterectomy

�Unclear effect of spinal vs. GA on CPSP

�Spinal associated with less pain than GA in a nonrandomized study (OR 0.42, CI: 0.21-0.85)

�No difference in pain scores after 12 weeks in one RCT

CHRONIC PAIN AFTER HYSTERECTOMY

Brandsborg B et al. Acta Anaesthesiol Scand 2008; 52: 327-31.

Respiratory DepressionRespiratory Depression

PONVPONV

Paralytic ileusParalytic ileus

Delay of early

mobilization

Delay of early

mobilization

Immuno-suppresionImmuno-

suppresion

OPIOIDS

10/16/2015

3

� Optimize additive effects of various

agents

� Utilize different modes of analgesia

�Non-opioid analgesics

�Regional anesthesia

� Minimize side effects

� Facilitate patient recovery and

ambulation

MULTIMODAL ANALGESIA

A. AlwaysB. SometimesC. RarelyD. Never

HOW OFTEN DO YOUR PATIENTS HAVING GYNECOLOGIC SURGERY RECEIVE POST-OP NSAIDS?

A l wa y s

S o me t i m

e s

R a re l y

N e ve r

93%

0%0%7%

�NSAIDS and COX2 inhibitors have opioid-sparing activity

�22-50% in patients undergoing gynecologic surgery

�NSAIDS reduce opioid-related side effects

�Undesirable side effects include platelet dysfunction, renal impairment, and GI irritation.

� 2.4% surgical-related bleeding vs. 0.4% with placebo

� Does ketorolac increase postoperative bleeding?

NSAIDS AND COX2-INHIBITORS

Maund E et al. Br J Anaesth 2011; 106: 292-7.Bauchat JR, Habib AS. Anesthesiology Clin 2015; 33: 173-207.

Effect of Ketorolac on perioperative bleeding

Gobble RM et al. Plast Reconstr Surg. 2014; 133(3): 741-55.

10/16/2015

4

Fixed interval NSAID dosing provides more effective post-operative cesarean analgesia and results in higher patient satisfaction than on-demand dosing.

NSAIDS: ON DEMAND VS. FIXED INTERVAL

Jakobi P, et al. Am J Obstet Gynecol 187(4):1066-9. 2002

� 30-40% opioid-sparing effect in gynecologic surgery

with 1g once or twice daily dosing regimen

�Max dosing 4g/day

�Equal efficacy as NSAIDS

� Improved analgesia and reduced PONV when

combined with NSAIDS compared with either drug

alone

ACETAMINOPHEN

Maund E et al. Br J Anaesth 2011; 106: 292-7.Ong CK et al. Anesth Analg 2010; 110: 1170-9.

�Higher peak plasma concentrations

� Increased cost

�No current analgesic outcome benefit

IV VS. PO ACETAMINOPHEN

Jibril F et al. Can J Hosp Pharm 2015; 68(3): 238-47.

A. AlwaysB. SometimesC. RarelyD. NeverE. Don’t know

HOW OFTEN DO YOUR PATIENTS HAVING GYNECOLOGIC SURGERY RECEIVE GABAPENTIN?

A l wa y s

S o me t i m

e s

R a re l y

N e ve r

D o n’ t k

n o w

1%

13%16%

54%

16%

10/16/2015

5

� Structural analog to GABA

� Perioperative gabapentin reduces acute postop pain and opioid use.

� 35% reduction in total opioid use over 1st 24 hours post-op

� Reduces preop anxiety, PONV, pruritis

� Increases patient satisfaction

GABAPENTIN

Ho et al. Pain 2006; 126(1-3): 91-101.Peng PW et al. Pain Res Manag. 2007: 12(2): 85-92.Doleman B et al. Anaesthesia 2015; 70(10): 1185-204.Alayed N et al. Obstet Gynecol 2014; 123: 1221-9.

�Side effects:

� Sedation (RR 1.65)

� Dizziness (RR 1.4)

� Visual disturbances

�Optimal dose unclear:

� Most studies: Gabapentin 600-1200mg given 1-2 hours preop

� Minimal effective dose of Preop Gabapentin = 600mg

GABAPENTIN

Alayed N et al. Obstet Gynecol 2014; 123: 1221-9.

� Reduced postoperative pain scores and opioid use in 1st

24 hours

� Optimal dose unclear: 100mg-300mg once or q8-12 hours

PREGABALIN

Yao Z et al. Clin Ther 2015; 37(5): 1128-35.

GABAPENTINOIDS REDUCE CPSP

Clarke H et al. Anesth Analg. 2012; 115(2): 428-42.

10/16/2015

6

�Spinal

�Epidural

� Transversus Abdominus Plane (TAP) Block

REGIONAL ANESTHESIA

� Spinal anesthesia reduces postop opioid use for 48 hrs

� Likely due to IT morphine

� More cost-effective than GA ($969 savings/patient)

� Shorter PACU stay (median 282 vs. 234 min)

� Improved quality of life scores

� Unclear effect on hospital length of stay:

� No difference for vaginal hysterectomy

� Shorter LOS in abdominal hysterectomy (2.2 vs. 3.3 days)

SPINAL ANESTHESIA

Bauchat JR, Habib AS. Anesthesiology Clin 2015; 33: 173-207.Borendal Wodlin et al. Am J Obstet Gynecol 2011; 205(326): e1-7.Sprung et al. Can J Anaesth 2006; 53: 690-700.Massicotte et al. Acta Anaesthesiol Scand 2009; 53: 641-7.

INTRATHECAL MORPHINE DOSES FOR POST-CESAREAN ANALGESIA

Analgesia Pruritus

• Nausea and Vomiting 10% to 50%• Respiratory Depression < 0.25%

Palmer, CM, et al. Anesthesiology 90:437-44. 1999Palmer, CM, Tech in Reg Anesth & Pain Mgmt 7(4):213-21. 2003

Lower pain scores than with PCA opioidsReduced opioid useHigher patient satisfactionFaster return of bowel function

Did not reduce hospital length of stay

EPIDURAL ANALGESIA

Ferguson SE et al. Gynecol Oncol 2009; 114: 111-6.Katz J et al. Anesthesiology 2003; 98: 1449-60.Jorgenson H et al. Br J Anaesth 2001; 97: 577-83.

10/16/2015

7

� Epidurals may inhibit tumor spread and growth due to:

� Intrinsic tumor suppression properties of local anesthetics

� Minimize opioid induced and surgically induced immunosuppression

� Suppression of adrenergic stimulation during surgery

� Avoidance of GA, which suppresses NK cell activity

� RCT of women for ovarian CA: Patients with combined epidural + GA have higher antitumorigenic cytokines and NK cell cytotoxicity than those with GA alone

DO EPIDURALS IMPROVE SURVIVALAFTER GYN CANCER SURGERY?

Hong JY, Lim KT. Reg Anesth Pain Med 2008; 33: 44-51.Dong H et al. J Int Med Res 2012; 40(5): 1822-9.

� GA + Epidural associated with lower rate of ovarian cancer recurrence vs. GA alone (72 vs. 85%, p= 0.028)

� Longer DFS associated with >48h of epidural use

� Use of Desflurane vs. Sevoflurane associated with lower rate of recurrence (63 vs. 84%, p = 0.01)

EPIDURALS AND SURVIVAL

Elias KM et al. Ann Surg Oncol 2015; 22: 1341-8.

TRANSVERSUS ABDOMINIS PLANE (TAP) BLOCK

Figure from Ultrasound For Regional Anesthesia, 2008

A. YesB. NoC. Don’t know

ARE TAP BLOCKS ROUTINELY USED AT YOUR INSTITUTION FOR POST-OP ANALGESIA?

Y e s N o

D on ’ t

k no w

29%22%

49%

10/16/2015

8

� Placed between subcostal margin and i l iac crest

� Blind or US guided techniques

� 20-30mL of local anesthetic injected incrementally on each side

� Complications:� Intravascular injection

� Bowel perforation

� Liver trauma

� Intraperitoneal injection (18% with blind technique)

TAP BLOCK TECHNIQUE

McDonnell et al. Anesth Analg 2008; 106: 186-9.McDermott G et al. Br J Anesth 2012; 108: 499-502.

TAP BLOCK: US-GUIDED TECHNIQUE

Gray AT et al. Atlas of US-Guided Regional Anesthesia. 2nd Edition. Elsevier-Saunders, 2013

TAP BLOCK: US TECHNIQUE

Gray AT et al. Atlas of US-Guided Regional Anesthesia. 2nd Edition. Elsevier-Saunders, 2013

� 5 RCTs, n = 225

� Reduced pain scores

� Reduced opioid use

� Limited effect to first 24 hours

TAP BLOCKS FOR ABDOMINAL HYSTERECTOMY

Champaneria R et al. Eur J ObstetGynecol Reprod Biol 2013; 166: 1-9.

10/16/2015

9

� 10 RCTs, n = 633

� 3 gynecologic

� TAP blocks reduce pain scores and opioid use.

� Preoperative TAP blocks had greater effects on early (0-4 hr) pain and opioid consumption

TAP BLOCKS FOR LAPAROSCOPIC SURGERY

De Oliveira GS Jr et al. Anesth Analg 2014; 118: 454-63.Calle GA et al. Acta Obstet Gynecol Scand 2014; 93(4): 345-50.

ENHANCED RECOVERY AFTER SURGERY (ERAS)

http://www.erassociety.org/index.php/eras-care-system/eras-protocol

� Types of studies:

� RCT (1), Nonrandomized prospective (2), Retrospective pre and post-intervention (6)

� Types of cases:

� Abdominal hysterectomy (5), vaginal hysterectomy (1), laparotomy for gynecologic cancer surgery (3)

� ALL of these studies have found reduced hospital length of stay in ERAS group

� However:

� High variation in ERAS interventions

� Lack of standardization of interventions

ERAS FOR MAJOR GYNECOLOGIC SURGERY

Bauchat JR, Habib AS. Anesthesiology Clin 2015; 33: 173-207.

� 2015 Retrospective cohort study (n=223):

� Open gynecologic surgery for non-malignant lesions

� Increased POD1 discharges post-ERAS (34% vs. 7%)

HYSTERECTOMY ENHANCED RECOVERY PATHWAYS

Miller EC et al. Can J Anaesth 2015; 62(5): 451-60.

10/16/2015

10

Control (n=26) ERAS (n=27)Preop: Paracetamol, NSAID, COX2

inhibitorParacetamol, NSAID, COX2 inhibitor

Carbohydrate drink < 2h before surgery

Intraop: GA (Nitrous + Volatile agent) Spinal bupivacaine + morphine 100mcg

PONV PPx: Ondansetron Betamethasone + droperidol + ondansetronIV fluid restricted to 500mL/h

Postop: Paracetamol + Morphine PCA Paracetamol + NSAIDIV fluids stopped with oral intake

ERAS FOR HYSTERECTOMY - RCT

Kroon UB et al. Eur J Obstet Gynecol Reprod Biol 2010: 151(2): 203-7.

� Lower rate of PONV (11% vs. 50%, p<0.01)

ERAS FOR HYSTERECTOMY - RCT

Kroon UB et al. Eur J Obstet Gynecol Reprod Biol 2010: 151(2): 203-7.

� No bowel prep. Boost Breeze unti l 2 hours

� Gabapentin, APAP, NSAIDs periop

� Fluids <2L

� TAP blocks or l idocaine gtt

� Temperature >36

� PONV PPx (decadron, zofran, scopolamine)

� Goals: � Foley out by 6hrs

� Regular diet on POD#0

� Early mobilization

� Discharge by noon

UCSF ERAS FOR GYN-ONC

LAPAROSCOPY� Improved pain scores

� Reduced opioid consumption

� Reduced PONV rate

� Higher rate of Regular diet on POD#0

� Foleys removed 10 hours earlier

� 100% of patients discharged on POD#1

� Future plans: Expansion to open gynecologic cancer surgery and benign gynecologic surgery

ERAS FOR GYN-ONCLAPAROSCOPIC SURGERY

10/16/2015

11

� Pain after gynecologic surgery affects quality of life and can lead to chronic pain.

� Improved acute pain management may help decrease development of CPSP.

� Multimodal analgesic techniques and ERAS pathways decrease opioid consumption, improve patient satisfaction, and can reduce length of stay.

� Use neuraxial analgesia when possible. TAP blocks for those who cannot have neuraxial.

SUMMARY

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

10/16/20151

Surgical Considerations for Obstetrical Hemorrhage

10/16/15

Lee-may Chen, MDDivision of Gynecologic OncologyUCSF Helen Diller Family Comprehensive Cancer CenterDepartment of Obstetrics, Gynecology and Reproductive Sciences

2 Surgical Considerations for Obstetrical Hemorrhage 10/16/15

I have no financial disclosures

Audience Response


�Have you been involved in a postpartum hemorrhage in the last 6 months?

A. YesB. No

�Have you diagnosed a placenta accreta/percreta in the last year?

A. YesB. No

� Have you performed a postpartum hysterectomy in the last year?

A. YesB. No

Learning Objectives


�To describe patterns of pregnancy related mortality, and the impact of postpartum hemorrhage

�To recognize patients at risk for postpartum hemorrhage, including preoperative and intraoperative management strategies

�To describe the role of multidisciplinary teams in the management of C-section deliveries for abnormal placentation


10/16/20152

Pregnancy-related Mortality


CDC Pregnancy Mortality Surveillance System: 16.0 deaths per 100,000 live births

Obstetrical Hemorrhage


26%

10%10%3%12%

2%2%

16%

19%

Ruptured ectopicUterine rupture orlacerationPlacental abruptionPlacenta previaAccreta/increta/percretaRetained productsCoagulopathyAtonyOther/unspecified

Hemorrhage accounts for 11% of pregnancy related mortality



26% increase in postpartum hemorrhage, primary due to atony



26% increase in postpartum hemorrhage, primary due to atony


10/16/20153

A California Toolkit


National Partnership for Maternal Safety: Consensus Bundle on Obstetric Hemorrhage


Main et al, Obstet Gynecol 2015Main et al, Anesth Analg 2015Main et al, J Midwifery Womens Health 2015Main et al, J Obstet Gynecol Neonatal Nurs 2015


Readiness: Establish a Response Team


�Anesthesia

�Blood bank

�Pharmacy

�Advanced gynecologic surgery

�Critical Care Medicine

�Operating room

� Interventional radiology

�Nursing

� (Tissue banking)

� (Pathology)


10/16/20154

Recognition and Prevention: Common Errors


�Failure to identify at risk patients

�Delayed response from medical team

• Protocols for activating response teams

�Underestimation of blood loss

• Quantitative versus estimated

�Delay in blood product administration

� Lack of readily accessible or working equipment

�Need for organized and standardized team approach

Access to hemorrhage medications, blood products


�Oxytocin 10-40 units per 500-1000mL IV infusion

�Methylergonivine 0.2mg IM (not IV) q 2-4 hours

� 15-methyl PG F2a 250mcg IM or intramyometrial (not IV)

�Misoprostol 600-800mcg sublingual or PO

�Packed red blood cells: longer to crossmatch with antibodies

�Fresh frozen plasma: especially if > 2 units PRBCs

�Platelets: especially if < 50K

�Cryoprecipitate: especially if Fib < 80

Uterine tamponade


� Internal balloons may be used where uterotonics not effective or not available (2012 WHO guidelines)

• Fill with 500-750mL fluid

• 60-80% success in 20-30 minutes

• Maximum dwell 24 hours

�Uterine packing may be an option in poor resource settings

Uterine tamponade


�Compression sutures with 1-Chromic or 1-Monocryl

• Manually squeeze the uterus from top to bottom

• May combine with intrauterine balloon

• May also be used for focal accretas


10/16/20155

Uterine artery ligation


�O’Leary stitches

• Include part of the myometrium

• May also ligate utero-ovarian vessels

Kominiarek, Hospital Physician 2008

Uterine artery occlusion


�Hypogastric artery ligation

N=110 women with PPH underwent hypogastric artery ligation

39% required hysterectomy

None required re-operation; 1 iliac vein injury

Joshi et al, Br J Obstet Gynecol 2007

Uterine artery occlusion


� Interventional Radiology techniques

• Vaso-occlusive balloons

‒ Better EBL and less transfusion in prophylaxis for percreta

‒ Complications of pseudoaneurysm, vessel rupture, thrombus

• Embolization

Cali et al, Eur J Obstet Gynecol ReprodBiol 2014Bishop et al, Int J Obsetet Anesth 2011Urquia et al, ECR 2012

Cell Saver


�Commencement after removal of fetoplacental unit

�Minimal contamination of fetal elements

�Higher postoperative hemoglobin concentrations

�Shorter hospital stay

�Requires set up time

Rainaldi et al, Br J Anesth 1998


10/16/20156

Readiness: Multidisciplinary Team


�The invasive placenta, a spectrum of abnormal adherence

� 1/533 incidence

�Associated with prior C-section, other uterine surgery

�Concurrent placenta previa in 90%

�Possible defect of trophoblastic function leading to invasion

� Leading cause of C-hysterectomy

Invasive Placenta


�Ultrasound is primary screening tool

• Prominent placental lacunae

• Loss of space between uterus & placenta

• Interruption of bladder-myometrium interface

• Increased vascularity

• Aberrant surface vessels

• Sensitivity: 77-93%

• Specificity: 71-96%

Invasive Placenta


�MRI is used for preoperative planning

• Abnormal uterine bulging

• Heterogeneous placental signal intensity

• Dark intraplacental bands

• Sensitivity: 80-88%

• Specificity; 65-100%

Invasive Placenta


Bladder involvementComplete previa & percreta


10/16/20157

Invasive Placenta


�Traditional therapy is hysterectomy

• Typically admitted after bleeding.

• Steroids for fetal lung maturity

• MRI for surgical planning

• MFM, Gyn Onc, IR, Neonatal consults

�Schedule delivery @ 34-35 weeks

• Unscheduled patients deliver earlier, more likely to have vaginal bleeding, uterine activity

Preoperative considerations

Bowman et al, Am J Obstet Gynecol 2014

Invasive Placenta


�Schedule delivery @ 34-35 weeks

‒ Arrange for cell saver

‒ T&C 6 units PRBCs, 2 units FFP

• Lithotomy position, 3 way Foley

• Regional anesthetic� general

• Consider vertical skin incision, uterine incision based on fetal position

• Consider vascular balloon occlusion

• Consider ureteral stent placement

• Consider internal iliac ligation

Intraoperative considerations



�Gynecologic Oncology

�Maternal Fetal Medicine

�Obstetrical Anesthesia

�Radiology

� Interventional Radiology

�Nursing

�Pathology

UCSF Multidisciplinary Abnormal Placentation Service (MAPS)



3 Tertiary care hospitals between 2000-2013

Multidisciplinary management introduced in 2011

90 patients with placenta accreta

Multidisciplinary group, n= 57, versus 33 historical controls

More percreta cases

Less EBL

Less likely to be delivered emergently

Retrospective Cohort Study

Shamshirasaz et al, Am J Obset Gyncol 2015


10/16/20158


Silver et al, Am J Obset Gyncol 2015

Consider referral/delivery at accreta center for:

Suspicious for accreta on ultrasound

Placenta previa with abnormal ultrasound

Placenta previa with > 3 prior C-section deliveries

h/o classical C-section & anterior placenta

h/o endometrial ablation or RT

Centers of Excellence for Placenta Accreta Centers of Excellence for Placenta Accreta


Delay uterine incision if findings abnormal

Set up OR team

Consider transfer to Teritary Center if stable

Close hysterotomy, leaving placenta in situ

If percreta is discovered at laparotomy

Silver et al, Am J Obset Gyncol 2015

Conclusions


�Early recognition

�Elective delivery pre-term

�Don’t delay intervention—transfusions, activation of surgical teams

�Review and debrief for quality improvement

1

Management of Endometrial Hyperplasia

Stefanie M. Ueda, M.D.Assistant Clinical Professor

UCSF Division of Gynecologic Oncology


Female Malignancies in the United States

New Cases Deaths

Breast 231,840 40,290Lung/Bronchus 105,590 71,660Colorectal 69,090 23,600Uterine Corpus 54,870 10,170Ovary 21,290 14,180Cervix 12,900 4,100Vulva 5,150 1,080

2015 American Cancer Society

Uterine Cancer

• Increase in deaths from 3,000 in 1988 to more than 10,000 in 2015

• 2.6% lifetime risk• 25% premenopausal 1

– 2.5%-14% younger than 40

• 80% low grade endometrioid histology– Unopposed estrogen major risk factor

1Gadducci A et al, Gynecol Endocrinol 2009

2

Factors Associated with Hyperplasia & Cancer

1Gressel GM et al, Int J Gynaecol Obstet 2015

Characteristic Increased Ris k

Obesity 3 –10xNulliparity 2xLate menopause 2.4xDiabetes 2.8xHypertension 1.5xUnopposed estrogen 9.5xPCOS 3x

PrognosticatorsPrognosticators

Obesity and Health Outcomes 1

1Beavis AL et al, Gynecol Oncol Rep 20152Campagnoli C, Gynecol Endocrinol 2013

BMI>30 with 4 fold increased risk of hyperplasia, and 13 fold if BMI>40 2

Weight Loss in Endometrial Cancer and Hyperplasia Patients

• Prospective cohort study of 121 obese women with CAH or early stage endometrial cancer 1

• 91% felt acceptable for physician to discuss weight loss and 10% loss of body weight beneficial– 35 accepted medical referral– 8 accepted referral to bariatric specialist

• At 3 months– Compliance with 16 medical, 1 surgical referral– 59% initiated weight loss attempt

1Jernigan AM et al, Am J Obstet Gynecol 2015

3

Natural History of Endometrial Neoplasia

Estimated prevalence as high as 132/100,000Simple Hyperplasia Complex Hyperplasia

Atypical Hyperplasia

Risk of Progression to Cancer

• Hyperplasia – Simple 1%– Complex 3%– Simple with atypia 8%– Complex with atypia 29%

Risk of having concurrent cancer ~30-40%

Endometrioid Grade

Grade 3Grade 1

4

Do you offer medical or conservative management to patients with

hyperplasia before referring to a gynecologic oncologist? For how long?

A. Yes, for 3 monthsB. Yes, for 6 monthsC. Yes, for 9-12 monthsD. No

Y e s, f o

r 3 m o

n t hs

Y e s, f o

r 6 m o

n t hs

Y e s, f o

r 9 -1 2 m

o n th s N o

29%

12%

24%

35%

Do you perform any additional diagnostic work-up prior to

offering treatment?

A. Pelvic ultrasoundB. MRIC. HysteroscopyD. D&CE. Combination of above

P e lv i c

u l t ra s o

u n d M RI

H y st e r o

s c op y D &C

C o mb i n

a t i on o

f a bo v e

16%

0%

54%

23%

7%

What is your preferred treatment option in endometrial hyperplasia?

A. ProveraB. MegaceC. MirenaD. Hysteroscopic resectionE. Combination of above

P r ov e r

aM e

g a ce

M i re n a

H y st e r o

s c op i c

r e se c t

i o n

C o mb i n

a t i on o

f a bo v e

33%

15%17%

0%

35%

Predictors of Malignancy

• Multi-institutional cohort study of 813 women with endometrial polyps 1

– Older age and history of AUB associated with risk o f malignancy

– Risk estimated to be 0.3-4.8%

• Multicenter study of model predicting presence of carcinoma with CAH 2

– Age>50– BMI>30– Menopausal status– Endometrial thickness>12 mm– Score>5 (Higher BMI & thicker endometrium held more weight)

1Litta P et al, Gynecol Oncol 20142Gungorduk K et al, Gynecol Obstet Invest 2015

5

Predictors of Concurrent Cancer

• Case control study of 211 with endometrial hyperplasia who underwent hysterectomy 1

• Predictors of concurrent cancer– Age>60 (OR 6.7)– BMI>35 (OR 2.3)– Diabetes mellitus (OR 2.5)– CAH (9.0)

• Risk increased with more risk factors identified– 7.0% for 1– 17.6% for 2– 35.8% for 3– 45.5% for 4

1Matsuo K et al, Gynecol Oncol 2015

Screening for Women at High Risk

• 1.5-2x risk if first degree family member with endometrial cancer

• Lynch syndrome (DNA mismatch repair and microsatellite instability) most common mutation– 30-70% lifetime risk of endometrial cancer– Earlier age of onset than sporadic cases

• Cowden syndrome (PTEN mutation) rare condition leading to 5 fold increase

• BRCA1 associated with 1.9x risk• Consideration of annual ultrasonography starting at

age 35 and biopsy if appropriate

1Gressel GM et al, Int J Gynaecol Obstet 2015

• Normal endometrial stripe:Postmenopausal 4- 8 mmPostmenopausal on HRT 4-10 mm

• U/S detection of any uterine pathologySensitivity 85-95%Specificity 60-80%PPV 2-10%NPV 99%

Diagnosis by Ultrasound Findings on Pelvic Ultrasound

Normal endometrial stripePostmenopausal 4- 8 mmPostmenopausal on HRT 4-10 mm

6

Endometrial Sampling

Sufficient material obtained in about 90.6% with pipelle 1

Diagnostic rates similar with pipelle or curettage in abnormal uterine bleeding (~95%)In up to 60% of curettages, less than half endometrium sampled

1Ben-Baruch G et al, Gynecol Obstet Invest 1994

• Detection of endometrial hyperplasia 1,2

Sensitivity 76.4%-81%Specificity 76.9%-96%PPV 73.1%-87%NPV 79.1%-93%

• Detection of endometrial cancer 2,3

Sensitivity 63-83%Specificity 97-99%PPV 77%NPV 95%

Hysteroscopic Assessment in Endometrial Thickening

1Korkmazer E et al, Prz Menopauzalny 20142Loiacono RM et al, Gynecol Obstet Invest 2015

3Gkrozou F et al, Arch Gynecol Obstet 2015

Assessment of Extent of Disease

• 156 women with CAH or grade 1 endometrial cancer who underwent hysterectomy– Hysteroscopic directed biopsies higher accuracy

than EMB for differentiating hyperplasia from cance r (92% vs 58%)

– Deep myometrial invasion better assessed by MRI than ultrasound (82% vs 74%, p<0.02)

– Hysteroscopic biopsies better evaluated cervical involvement than MRI or ultrasound (94% vs 84% and 80%)

– Combination of MRI and hysteroscopic directed biopsies identified women at highest risk (83%)

1Ortoft G et al, Acta Obstet Gynecol Scand 2015

Conservative Management in Hyperplasia & Low Grade Cancer

• Society of Gynecologic Oncology recommends imaging be performed to exclude concurrent carcinoma– Ultrasound, CT, MRI– Confined to corpus, exclude synchronous ovarian

tumors or adenopathy

• MRI more sensitive than ultrasound for evaluation of myometrium but may miss up to 5% of adnexal masses 1

• Residual hyperplasia at 6 months increases the likelihood of failure of progestin therapy 2

1Gressel GM et al, Int J Gynaecol Obstet 20152Mentrikoski MJ et al, Am J Clin Pathol 2012

7

Role of Conservative Management

• Frequency of surveillance remains under debate– Repeat biopsy after 3 months commonly recommended

• Diffusion-weighted imaging-T2 MRI can improve diagnostic performance in predicting deep myometrial invasion in review of 15 studies 1

– Age, preoperative tumor grade, and myometrial invasion<50% on MRI not associated with lymph node metastasis 2

– Diagnostic accuracy in detecting myometrial involve ment significantly lower in premenopausal women (0.42 ve rsus 0.73, p=0.006), but no difference in deep myometria l invasion (0.94 versus 0.95, p>0.99)

1Deng L et al, IJ Comput Assist Tomogr 20152Son JH et al, Obstet Gynecol Sci 2015

3Lin G et al, Clin Radiol 2015

Type Dosage/Duration

Provera 10-20 mg daily12-14 days/month

Depo Provera 150 mg IM Q3 monthsMicronized vaginal 100-200 mg dail y

12-14 days/monthMegace 40-200 mg dailyMirena 1-5 years

Hormonal TreatmentHormonal Treatment

Progestins in Non-Atypical Hyperplasia

• Meta-analysis of 7 randomized trials 1

• Mirena achieved significant treatment response– 3 months (OR 2.3)– 6 months (OR 3.2)– 12 months (OR 5.7)– 24 months (OR 7.5)

• Improved response of Mirena compared to oral progestins (OR 2.5)– Fewer hysterectomies (OR 0.26)

• No difference in vaginal bleeding between Mirena and oral progestins

1Abu Hashim H et al, Am J Obstet Gynecol 2015

Type of Progesterone in Hyperplasia

• Randomized, multicenter trial comparing Mirena to continuous or cyclic Provera 1

– 153 women (75% under age 51)– 73% with complex hyperplasia

• Response rates at 6 months– 100% Mirena– 96% continuous Provera– 69% cyclic Provera

• Side effects– 78% irregular bleeding– 35% nausea– 52% pain

1Orbo A et al, BJOG 2014

8

Progestins in Hyperplasia & Cancer

• 34 observational studies with 408 women with early stage endometrial cancer and 151 CAH 1

• Endometrial cancer– Pooled regression rate of 76.2%– Relapse of 40.6%– Live birth rate of 28%

• Complex atypical hyperplasia– Pooled regression rate of 85.6%– Relapse of 26%– Live birth rate of 26.3%

• IVF resulted in 39.4% live birth rate compared to 1 4.9% spontaneous conception

• 1.9% progressed to higher than Stage I cancer, from which 2 died

1Gallos ID et al, Am J Obstet Gynecol 2012

Regression and Relapse of Hyperplasia with Mirena

• Cohort study of 344 women treated with Mirena or oral progestins for complex hyperplasia 1

– Median follow-up 58.8 months (IUD) and 95.1 months (oral)

• 221 with complex hyperplasia regressed (96.5%) with Mirena– BMI>35 associated with failure (32.6% relapsed)– 12.7% overall relapsed (only 3.3% with BMI<35)

• Delivers 20 µg/day of progestin directly to endometrial cavity

1Gallos ID et al, Obstet Gynecol 2013

Oncologic Outcomes with Progestin

• Systematic review of 45 studies of 391 patients 1

– Provera (49%), Megace (25%), Mirena (19%), Makena ( 0.8%)– 39 months median follow-up

• Complete, durable response in 53.2%– Higher in hyperplasia than carcinoma (65.8% vs 48.2 %)– Median time to complete response 6 months

• Less persistent disease in hyperplasia– 14.4% vs 25.4%

• Recurrence after initial response higher in carcino ma– 23.2% vs 35.4%

• Reproductive outcomes not different between cohorts (41.2% vs 34.8%, p=0.39)– 117 live births recorded

1Gunderson CC et al, Gynecol Oncol 2012

Prognostic Factors in Fertility Sparing Treatment

• Chinese women <40 with CAH or grade 1 endometrial cancer (EC) 1

– 32 patients (13 CAH)– Mean follow-up 32.5 months

• Complete response in 84.4%• Patients with elevated HgbA1C more likely to

experience complete response– Decreased effectiveness in patients with PCOS

• 9 of 21 patients experienced clinical pregnancies– 8 with assisted reproductive technology (ART)

1Zhou R et al, Gynecol Oncol 2015

9

Hysteroscopic Resection for Fertility Preservation

• Retrospective study of 23 women up to age 45 1

– 3 patient with grade 1 endometrial carcinoma– 20 patients complex atypical hyperplasia– Hysteroscopic resection followed by Megace 160 mg/d ay

• Remission of disease– 52.2% after 3 months– 39.1% after 6 months– 8.7% after 9 months

• 6 underwent second hysteroscopic resection• 4.3% relapsed at median follow-up of 25 months• 6 pregnancies with average time of 7.4 months

after completion of progestins

1De Marzi P et al, J Minim Invasive Gynecol 2015

Concurrent Carcinoma with Preoperative Hyperplasia Biopsy

• Prospective GOG cohort study of 306 women with preoperative community biopsy of atypical hyperplasia 1

– Independent review by 3 gynecologic pathologists– Hysterectomy within 12 weeks without interval treat ment

• Change in diagnosis– 25.6% less than atypical hyperplasia– 29.1% diagnosed as endometrial carcinoma

• 42.6% found to have concurrent carcinoma in hysterectomy specimens– 30.9% myometrial invasion– 10.6% with >50% myometrial invasion

1Trimble CL et al, Cancer 2006

Clinically Significant Outcomes in CAH

• Retrospective review of 150 patients with CAH 1

– 36.7% found to have carcinoma at time of hysterecto my

• Change in diagnosis– 43.5% with preoperative office biopsy– 28.1% with D&C

• Endometrial cancer risk– 1.8% grade 3 – 7.3% lymphovascular space invasion– 10.9% deep myometrial invasion– 10 patients underwent lymphadenectomy, 1 nodal

metastases• 1.6%-2.1% estimated risk of cancer node involvement

with preoperative CAH1Costales AB et al, Gynecol Oncol 2015

Uterine Cancer Staging

• Clinical Stage I will be upstaged 30% of the time at time of primary surgery– 9% pelvic nodes– 6% para-aortic nodes– 5% adnexa– 12% positive cytology– 6% other ( e.g. cervical or

abdominal disease)

• Clinical Stage II or III will be upstaged 60% of time

10

Surgical Staging• Hysterectomy, BSO +/- Pelvic/Para-aortic LND• Risk factors to consider

� Invasion >50% myometrium� High grade, serous, clear cell� >2 cm tumor size� LVSI (lymphovascular space invasion)� Cervical involvement� Clinically bulky lymph nodes

• If none of these present, risk of + nodes <10% and survival >90%

Clinical Considerations

• Progestin therapy remains the most tested fertility-sparing option in CAH and early stage endometrial cancer– Conservative management should be complemented

with referral to an infertility specialist

• Surgical management remains the standard of care for those patients done with childbearing, as up to 40% of patients harbor a co-existing adenocarcinoma and approximately 40% fail treatment

What treatment would you offer patients with hyperplasia who desire fertility?

A. MirenaB. Cyclic ProveraC. MegaceD. Hysteroscopic resectionE. Still recommend

hysterectomy

M i re n a

C y cl i c P

r o ve r a

M eg a c

e

H y st e r o

s c op i c

r e se c t

i o n

S t i ll r e

c o mm e

n d h y s

t e r e. . .

83%

6% 3%4%5%

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Gynecologic management of women with inherited risk of

gynecologic cancerC. Bethan Powell MD

Kaiser Permanente Northern California Gynecologic Oncology Program

I have nothing to disclose

∗ Take a basic family history∗ Refer to a multidisciplinary hereditary

women’s cancer risk center if available∗ Provide follow up care and support for early

menopause∗ Identify family members who may benefit

from testing

Key RecommendationsGene Ovary uterus Cervix Other gyn Breast

BRCA1 40% 49-57%

BRCA2 18% 49-57%

RAD51D RAD51CBRIP1

10-15%

PALB2CHEKATM

? nonconfirmed 58%48%52%

HBOC related genes

Powell, 2015

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Gene Ovary uterus Cervix colon BreastLynch MLH11 4-20% 20-54% 41%

MLH2 7.5-24% 21-49% 48%MSH6 0-13.5% 16-71% 12-31%PMS1 small 15% 15%

Cowden PTEN 19-28% 50%Peutz-Jeghers

STK11/LKB1 21%Sex cord stromal tumors

10%Adenoma malignum

Other DICER1SMARCA4

Sertoli-leydig

Small cell carcinoma

Other genes associated with ovarian cancer

Powell, 2015

Ovarian Cancer Risk Breast Cancer Risk

At age 30 BRCA1 BRCA2 BRCA1 BRCA2

By age 40 2.2% <1% 10% 6.6%

By age 50 8.7% 2.4% 28% 20%

By age 60 22% 7.4% 44% 35%

By age 70 39% 16% 54% 45%

Ovarian and Breast Cancer risk by gene and decade of life

Chen, JCO 2007

∗ Young age∗ Multigenerational cancers∗ Personal history of non-mucinous ovarian cancer or

breast cancer under age 50∗ Multiple cancers, bilateral breast∗ Male breast cancer∗ Ashkenazi Jewish

Who Should be Considered for Hereditary Cancer Risk Assessment: HBOC

Syndrome?

∗ Families with few females∗ Families with females with early hysterectomy∗ Adoption∗ Paternal as well as maternal history∗ Need to test an affected relative

Don’t be fooled

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∗ Hispanic: 3.5% BRCA1∗ US Ashkenazi Jews: 8.3% BRCA1∗ African American: 1.3% BRCA1∗ African American, with breast cancer age <35: 16.7% BRCA1∗ Asian: 0.5% BRCA1

John, E JAMA: 2007, 2869

American Women with Breast Cancer

Non-AshkenaziBreast cancerBreast cancer

<40yrsOvarian cancer

2%<10%

10-15%Ashkenazi

Breast cancerBreast cancer

<40yrsOvarian cancer

10%30-35%

41%

Likelihood of being a BRCA carrier by personal cancer history

King et al 2003 Moslehi et al 2000 Malone et al 2006 and Papelard et al 2000

∗ Triple negative breast cancer:< age 50, with any family history: 29% BRCA1< age 40: 23% BRCA1

∗ Tubal cancer: 28% BRCA

∗ Non-mucinous ovarian cancer: 16-21% BRCA

Pathologic Features of BRCA1 cancer

Cass, I GynOnc, in pressLakhani, S Cl Can Res: 2005

Strategies for ovarian cancer risk reduction

Woman with BRCA mutation

Surveillance

CA125, Ultrasound

Chemoprevention

OCPs

Surgery

RRSO, salpingectomy, BTL

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Ovarian cancer risk reductionParity > 4breastfeeding

No associationBMI, alcohol, age at menarche,

first birth under age 30

Lifestyle modification for ovarian cancer

∗ OR =0.58 (95% CL 0.46 to 0.73)∗ Risk reduction for BRCA1 and BRCA2∗ Greater reduction of risk with years of use (3-6)∗ No clear increased risk of breast cancer

?age< 25, BRCA1?prolonged use?increase in early breast cancer, in BRCA1

Oral contraceptive pills

Moorman,JCO 2012Iodice, Euro Jl of Cancer, 2010

Kostsopoulos, Breast Can Research 2014

RR 0.43 in BRCA1 OR 0.39 in BRCA1Risk reduction not confirmed in BRCA2

Antoniou, 2009Narod, 2003

Tubal ligation

∗ UK Familial ovarian cancer screening study3563 women at 10% risk: annual CA 125 and ultrasound

26% stage IIIC as compared with 86.7% in unscreenedPPV 25.5%overall survival: 72 vs 48.4mo60% of those with stage 1 had Lynch syndrome

All screen negative cancers, were BRCA related

Surveillance

Rosenthal, JCO 2013

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∗ Post-menopausal women, ave risk∗ 4051 women, 11 year follow up∗ CA 125 q 4mths, with ultrasound for abnormals.∗ PPV 40%

Surveillance: ROCA testing

Lu K, Cancer, 2013

∗ Symptoms if occurring greater than 12 times in a month were associated significantly with ovarian cancer were∗ pelvic/abdominal pain, ∗ urinary urgency/frequency,∗ increased abdominal size/bloating, ∗ difficulty eating/feeling full

Goff, B Cancer 2007

Symptom Diary

∗ 5783 women with BRCA1 or BRCA2∗ 69% reduction all cause mortality∗ 77% reduction in mortality, if no prior breast

cancer∗ Risk per year .9% brca1 peak 50-59∗ Risk per year .3% BRCA2 peak 60-69

Risk Reducing surgery: BSO

Finch A, JCO 2014

∗ RRSO under age 40OR = 0.44 BRCA1OR = 0.57 BRCA2

RRSO: Breast cancer risk reduction

Eisen A, JCO 2005

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∗

∗ Laparoscopic ∗ Inspection of all peritoneal surfaces, diaphragm, liver

and pelvic peritoneum∗ Collection of peritoneal cytology ∗ resection of the entire ovary with a retroperitoneal

approach, removing all adhesions with the adnexa, resection of the tube as close to the uterus as possible and gentle handling of the specimen with removal in a endoscopic bag.

∗ The entire tube and ovary should be submitted with micro-sectioning of the entire specimen in 2-3mm cuts.

∗ Attention in particular should be paid to the fimbria and immunohistochemistry staining with Ki67 and P53 for confirmation of precursor lesions.

Technique for risk reducing salpingo-Oophorectomy in women with BRCA1 and

BRCA2 mutations:

∗ 2035 cases∗ 3.0% STIC∗ 2.7% invasive cancers

Risk of peritoneal primary3.9% BRCA11.9% BRCA2

Risk of cancer at RRSO and after

Finch A, Powell, GO 2014

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.

SEE-FIM Protocol

Medeiros et al, Am J Surg Path, 2006

Sectioning of RRSO Specimens

Should Hysterectomy be performed with RRSO?

∗ PROSEnsures removal of all tubeSimplifies hormonal managementIncreased risk of uterine cancer with BRCA? and TamoxifenOther gyn pathology

∗ CONSIncreased risk, cost, hospitalizationNo reports of cancer in cornual portion of fallopian tubeEndometrial cancer can be detected in early stage with vaginal bleeding

Salpingectomy in women with BRCA mutations

If a young woman is not ready for men0pause or may even want the possibility of a childWhat about removing the tube first and removing the ovaries at a later time?

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Salpingectomy

Pros∗ Avoid a portion of pelvic

serous cancers∗ Avoid premature menopause∗ Option when patient will not

agree to RRSO∗ Maintain option for IVF

pregnancy

Cons• Two stages to surgery• Result in a delay of removing

the ovaries• May not be as effective as

removing both tubes and ovaries

• Removal of ovaries in young BRCA carriers reduces breast cancer by 50%

∗ Inspect entire abdomen∗ Peritoneal cytology∗ Remove adjacent ovarian capsule∗ Remove all the fimbria∗ Place in an endoscopic bag for removal∗ Pathology processing with SEE-FIM protocol

Salpingectomy Technique

�Early menopause�Increase in osteopenia/osteoporosis –70%�Cardiovascular disease, hyperlipidemia – 30%�Sexual symptom, decreased pleasure and

satisfaction and increased dyspareunia.

Long term health outcomes

PROSE study: no impact on Breast cancer riskmay reduce the protective effect of RRSOreduction still significant: HR 0.37 (CI 0.14-0.96)

427 women with BRCA1 had no increased risk of breast cancer on HRT, decreased risk on estrogen onlyRebbeck JCO 2005Eisen JNCI 2008

HRT in women with BRCA mutations

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Menopausal symptomsHormone replacement therapy after BSO in women

without breast cancer, stopping by age 45-50.

Recommendations after RRSO

�Primary peritoneal cancer: ?annual pelvic examCA 125 q 6mths

�Bone HealthDXA scan at 2-3 years, then q 5 yearsWeight bearing exerciseVitamin D 1000 IU and Calcium 1500mg

�Cardiovascular diseaseLipids q 1-3 years if no HRT and family history

Recommendations after RRSO

∗ Premature ovarian failure∗Menopause at 48 vs 50∗ Increased rate of premature menopause (under age 40)

∗ Breast cancer∗ Prenatal diagnosis:

PGD for those undergoing IVFPND at 12-16 weeks gestation

Fertility and reproduction

Finch, Fert Steril 2013

Challenges: how to identify and test family members at risk

New directions: Cascade Testing

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Mary Claire King: LaskerAward: JAMA, 9-2014

Women do not benefit by practices that “protect” them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.

The future: Population-Based Screening forBRCA1

andBRCA2Did any of your first-degree relatives have breast or ovarian cancer?

Did any of your relatives have bilateral breast cancer?Did any man in your family have breast cancer?Did any woman in your family have breast and ovarian cancer?

Did any woman in your family have breast cancer before age 50 y?

Do you have 2 or more relatives with breast and/or ovarian cancer?

Do you have 2 or more relatives with breast and/or bowel cancer?

FHS-7: validated questionnaire

Study N Population Mutation testing

BRCA1 BRCA2 Personal breast cancer history

BRCA1/2 in breast cancer subjects

First degree family history of breast/ovarian cancer

Goshen et al. 2000

56 Canadian 4 common 0 0 6 (10.7%) 0 16 (28.6%)

Levine et al. 2001

17 Ashkenazi Jewish

3 founder 0 0 Not reported Not reported Not reported

Goldman et al. 2002

9 American Full sequence

0 3 (33.3%) 9 (100.0%) 3 (33.3%) 1 (11.1%)

Biron-Shental et al. 2006

22 Israeli Jewish

3 founder 3 (13.6%) 3 (13.6%) 7 (31.8%) 3 (42.9%) 5 (22.7%)

Lavie et al. 2010

59 Ashkenazi Jewish

3 founder 7 (11.9%) 1 (1.7%) 15 (25.4%) 3 (20.0%) 35 (59.3%)

Pennington et al. 2013

151 American BROCA panel

3 (2.0%) 0 22 (16.4%) 2 (9.1%) 40 (29.9%)

Uterine Serous Cancer related to BRCA mutations

Adapted from Lavie In t jl of gyn cancer 2010 Pennington Cancer 2013

∗ Small cancers and precancers found in the tubes in 6% of patients. Precancerous changes in the tube from atypia, dysplasia to STIC.

∗ Fallopian tube abnormalities more common than Ovarian abnormalities.

∗ STIC associated with 70% of Ovarian Cancer

∗ Ovarian cancers rare without tubal abnormality. No pre-invasive disease.

∗ Recurrence of cancers is 17-47% in 5-7 years, rare if STIC.

Occult Cancer at the time of RRSO

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Breast Cancer: What the Gynecologist Needs to KnowMindy Goldman, MD

Clinical ProfessorDept. of Ob/Gyn and Reproductive Sciences

Director, Women’s Cancer Care Program, UCSF Breast Care Center

and Women’s HealthUniversity of California, San Francisco

•I have nothing to disclose

–Mindy Goldman, MD

• What does the gynecologist or women’s health provider need to know?

What’s safe for treating hot flashes?

Case• 34 yr. G2P2 presents with a palpable breast mass –

you send her for a FNA which returns positive for carcinoma. She has no other medical history and no family history of breast cancer. She undergoes a lumpectomy for a 1.8 cm infiltrating ductal carcinoma that is ER+/PR+ and Her2Neu negative. She receives adjuvant chemotherapy with AC followed by Taxol, then radiation, and is placed on Tamoxifen. Her menses stop with chemotherapy and return 6 mos later.

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Questions• 1. Is she at risk for endometrial cancer by taking

Tamoxifen?

• 2. Will Tamoxifen affect her menstrual cycles?

• 3. Would you recommend routine ultrasound surveillance?

Breast Cancer Epidemiology-• Most common invasive cancer in US women

• 231,840 new cases invasive Breast ca in US in 2015

• Median age of diagnosis is 61

• 12% diagnosed in reproductive years (ages 20-44)

• More than 25,000 cases per yr in California

• 89% women diagnosed alive at 5 yrs – 98.6% alive for localized breast cancer

Breast Cancer Treatments• Breast surgery – either breast conserving

lumpectomy or modified mastectomy. May also include immediate or delayed reconstructive procedures

• Radiation

• Chemotherapy

• Hormonal Therapies

• Many of these treatments have gynecologic effects

Gynecologic Issues Related to Breast Cancer

• Chemotherapy induced menopause

• Gynecologic effects of hormonal therapies

• Treatment of menopausal symptoms– Hot flashes– Vaginal dryness/discomfort– Sexuality issues

• Gynecologic uses of hormonal therapies

• Ovarian suppression

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Breast Cancer Treatments and MenopauseMenopausal complaints often more severe

• Surgical treatments may include oophorectomy with immediate onset of menopause

• Premenopausal women with normal menstrual functioning may get put into menopause with chemotherapy

• Postmenopausal women taking HRT tend to abruptly stop when diagnosed with breast cancer

• Vasomotor symptoms common with hormonal drugs like Tamoxifen or Aromatase Inhibitors

Chemotherapy Induced Menopause• Incidence of ovarian failure dependent on

chemotherapy regimen, cumulative dose and age of patient

• Most ovarian toxicity due to alkylating agents -cyclophosphamide

• Moderate ovarian toxicity with doxurubicin or cisplatin

• Less ovarian effects with 5-FU, methotrexate, vincristine, taxol and taxotere

Chemotherapy Induced Menopause

• Overall incidence of chemotherapy-induced amenorrhea ranges from 53% to 89%

• 50% women < 35 resume normal menses post chemotherapy

• 70 -90% women > 40 have permanent ovarian failure post chemotherapy

• Longterm cytotoxic effects - women who menstruate post chemotherapy still at increased risk for premature menopause

Can Ovarian Toxicity be Prevented?

• POEMS (Prevention of Early Menopause, phase 3 prospective trial) – presented at ASCO 5/2014

• 2004-2011, 4 year follow up

• 218 women with Stage 1-3 hormone negative breast cancer given Goserelin (GnRH agonist) with chemotherapy vs. chemotherapy alone

• primary endpoint - ovarian failure

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Can Ovarian Toxicity be Prevented?• Results: More pregnancies and more live births with goserelin

– Ovarian failure: 22% chemo arm vs 8% goserelin arm (P = .04)

– Attempted pregnancy: 12 (11%) chemo arm and 22 (21%) goserelinarm became pregnant (P = .03)

– Live Births: 8 chemo arm (7%, 12 babies) and 16 (15%) in the goserelin arm (18 babies, P = .05)

– 4-year DFS: 78% in the chemo arm and 88% in goserelin arm (P = .04)

– 4-year OS: 82% chemo arm vs 92%, goserelin arm(P = .06)

Breast Cancer Tumors• Breast tumors are all sent for ER/PR status and to

see whether over-expression of Her2neu

• Estrogen and Progesterone positivity tells you the tumor will benefit from drugs that manipulate the hormonal environment

• 2/3 of breast cancers are hormone positive

HER-2 Tumors• The HER2 gene makes the protein HER2 receptor which

is important in controlling epithelial cell growth, cell differentiation and possibly angiogenesis

• HER2 tumors overexpress Her2-neu and are oncogene driven and a marker of more aggressive tumor

• 18-20% of breast cancers over express HER2-neu

HER-2 Tumors• Anti-angiogenic drug Trastuzumab (Herceptin) - attaches to

HER2 receptors on the surface of breast cancer cells and prevents them from receiving growth signals

• Biologic targeted therapy

• Typically used with either anthracycline-based or docetaxeland carboplatin (TCH) chemotherapy

• Studies have shown Improved 5-year disease-free survival and overall survival but more cardiotoxicity

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HER-2 Tumors• Similar drug pertuzumab (Perjeta) given with Herceptin and

chemotherapy has shown improved survival for metastatic Her2-positive disease

• Perjeta approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer

• FDA approved in 2013 for neoadjuvant treatment with HER2-positive, locally advanced, inflammatory or early stage breast cancer who are at high risk for recurrence

Who Sleeps the Most in a Day?• Dogs

• Cats

• Monkeys

• First year medical students

Who Sleeps the Most in a Day?

• Cats - average 16 hours of sleep a day, more than any other mammal.

Hormonal Treatments and Breast Cancer

• Used to reduce recurrences and overall breast cancer mortality in women with hormone receptor positive breast cancer

• Biologic goals of hormonal therapy

• Block production of estrogen• Block action of estrogen• Down-regulate the estrogen receptor

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Hormonal Treatments of Breast Cancer

• SERMS: Tamoxifen (Soltamox), Raloxifene (Evista), Toremifene (Fareston)

• Estrogen Receptor Downregulators: Fulvestrant(Faslodex)

• Aromatase Inhibitors: Anastrozole (Arimidex), Letrozole (Femara), Exemestane (Aromasin)

Hormonal Treatments of Breast Cancer - Tamoxifen

• Complex drug with estrogen and anti-estrogen properties

• Originally made as contraceptive then found to suppress mammary tumors in rats

• By 1992 shown to increase disease free interval and decrease contralateral breast ca in pre and postmenopausal women

Benefits of Tamoxifen• 5 years of tamoxifen reduces breast cancer recurrence by 40%-

50% in PMP women and 30%-50% in premenopausal women

• 5 years of tamoxifen reduces risk of a new contralateral breast cancer by about 50%

• 5 years of tamoxifen has shown improved overall survival with more than 15 years of follow up

• 5 years of tamoxifen has been found to better than 2

• Can be used as neoadjuvant therapy to shrink large, hormone-receptor-positive breast cancers prior to surgery

Tamoxifen – Longer Treatment• Earlier international trials showed differences in benefits with

longer treatment

• Adjuvant Tamoxifen, Longer vs Shorter (ATLAS) looked at >15,000 women, 5 or 10 yrs of Tam

– Reductions in recurrence, mortality, contralateral breast cancer with 10 vs 5

– More endometrial cancer, PE and Ischemic Heart Disease

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Tamoxifen - Longer Treatment• Adjuvant Tamoxifen To Offer More (aTTOM) trial looked at

7000 women given 5 or 10 yrs of Tam – results 2013

– Decreased recurrence with 10 yrs, not seen until year 6– Trend toward decreased mortality after year 10– Increased endometrial cancers and endometrial cancer

death

• Standard of care changing to 10 years of adjuvant tamoxifen

Stopping Tamoxifen for Pregnancy• Given the recommendations for longer treatment and trials

showing safety of pregnancy after breast cancer, more oncologists recommending stopping tamoxifen for pregnancy and then resuming post partum

• Typically recommended to do at least 2 years of tamoxifentherapy

• Stop for at least 2 mos (wash out) prior to attempting pregnancy

• Tamoxifen may slow milk production and should not be used when breastfeeding

Tamoxifen – Adverse Events• Increased rate of venous thromboembolic events, particularly

in first two years

• Additional pro-coagulant effect when tamoxifen is added to chemotherapy

• Overall 2-3 fold increased RR for DVT and PE

• If Factor V Leiden mutation 5 –fold increased risk of thromboembolism

Tamoxifen – Adverse Events• Increased risk for arterial thromboembolism (stroke)

• Stroke risks thought to be counterbalanced by favorable effects on ischemic heart disease: – Overview of RCT of adjuvant tamoxifen showed non-significant

increased stroke deaths (3 extra per 1000 women in first 15 yrs) was exactly balanced by a non-significant reduction in cardiac deaths (3 fewer per 1000 women during the first 15 years)

• Most recommendations are to discontinue tamoxifen for few days before surgery or long travel

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Tamoxifen – Common Gyn Side Effects

• Weight Gain- initially thought 7-10 lbs– Not clear if this is true, but likely harder to lose weight

Common Side Effects:Hot FlashesVaginal DischargeVaginal DrynessJoint PainHeadaches

Tamoxifen- How to treat vasomotor side effects?

• Low dose antidepressants – Venlaflaxine, Paroxetine, Fluoxetine, Citalopram, Escitalopram, Desvenlafaxine(1/10-20th doses for depression )

• Antihypertensive Clonidine• Gabapentin – or pregabalin but less well studied• Vitamin E (800 IU daily)• Soy supplements• Herbal Products: best studied Black Cohosh• Tibolone (in Europe)• Chinese Herbs• Alternative Therapies- CBT, mindfulness, acupuncture,

stellate ganglion blocks, relaxation techniques

Clinical Pearls for Hot Flash Management• If using Venlaflaxine, start with low doses to avoid

discontinuation – lowest is 25 mg but scored, most effective dose 75 mg typically in divided doses

• For pure SSRI’s start with 10 mg

• If using Gabapentin – 900 mg most well studied, use at night as sedation common side effect. Start with 100-300 mg and increase up to a max of 2400 mg in divided doses

• Only FDA approved (2013) alternative is low dose Paroxetine 7.5 mg (Brisdelle) . Studies showed improvements in VMS frequency /severity up to 24 months, improvements in sleep without negative effects on libido or weight gain

Fast Food Trivia• McDonald's was forced to apologize to

customers in Japan in January 2015 after what was found in their food?

• a. Human Teeth• b. Finger Nails• c. Eye Lashes• d. Dog Hairs

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And the Answer Is……

• Human Teeth - McDonald’s serves about 68 million people every day.

Tamoxifen - Biologic Effects

• Agonist and Antagonist effects

• Effects of Tamoxifen vary depending on hormonal environment

Tamoxifen and Premenopausal Women

• Induces estrogen production and ovulation - has been used for ovulation induction for IVF. If need contraception, non-hormonal recommended - Copper IUD a great option

• Reports of ovarian cysts in upwards of 30% women

• Menstrual irregularities- mainly oligomenorrhea or amenorrhea (but affected by prior chemotherapy)

• Growth of endometrial polyps, fibroids, endometriomas

• Not thought to increase the risk of endometrial cancer

Tamoxifen and Postmenopausal Women

• Increased endometrial proliferation, cystic changes, polyp formation, adenocarcinoma and uterine sarcoma

• Frequency of cancer dependent on endometrial surveillance: TVS vs. EMB and criteria for surveillance – symptomatic vs. asymptomatic

• The reported risks of endometrial cancer in Tamoxifen users have ranged from 1.3-7.5 in RCT, and increase with longer use

• Meta-analysis of 32 RCT trials showed RR 2.7, primarily in women > 50

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Tamoxifen and Endometrial Cancer• Absolute risks - about 4 cases of endometrial cancer per

1000 women taking Tamoxifen each year

• 95% of Endometrial Cancers present with Vaginal Bleeding

• Risks are thought to decrease as soon as tamoxifen is stopped

• Most women get a much greater benefit to their breast than risk to their uterus

Tamoxifen and Other Types of Endometrial Cancer

• Recent studies show more aggressive endometrial cancer subtypes in Tamoxifen users: sarcomas, papillary serous, clear cell, and mixed mullerian tumors

• Cancer registry data has shown that shorter time to development of cancer and more aggressive subtypes but no differences in endometrial cancer specific survival

• Overall felt that tamoxifen does not affect endometrial cancer survival

Endometrial Surveillance with TVS – what are the concerns?

• Increased endometrial thickness, irregular echoes, cystic changes (‘Swiss-cheese appearance”), polyps and hyperplasia

• Findings do not correlate with malignant histology

• Thickened endometrium can be atrophic. Mechanism may be stromal hypertrophy, enlargement of subendometrial glands

• No prospective data on what is normal endometrial thickness for women on tamoxifen

What are the problems with routine surveillance?

• Absence of a defined endometrial thickness cut-off for the tamoxifen patients reduces ultrasound accuracy and increases the number of patients referred for unnecessary hysteroscopy

• Overtreatment with unnecessary surgeries

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Ultrasound of Patient on Tamoxifen Endometrial Surveillance – Other Imaging for patients on Tamoxifen

• Saline Sonogram – useful in distinguishing polyps from cystic endometrium, overall improved sensitivity

• MRI useful for evaluating myometrium but less accurate in looking at intra-cavitary lesions - sensitive in evaluating endometrium but not specific enough to assess cancer vs. other pathology

• Lack of good data looking specifically at Tamoxifen

Clinical Pearls for Tamoxifen and Imaging• Get baseline sono for comparison because there are many times

that “things come up” –bloating, pain, bleeding that may require imaging- recommended in ACOG guidelines

• Do not get routine surveillance

• Do not use endometrial thickness as an indicator for intervention

• Consider saline sonograms to improve PPV but no stated guidelines

• Endometrial effects are thought to stop once tamoxifen is stopped and risks back to baseline in about 5 years

What about levonorgestrel-releasing IUD (Mirena) for women on Tamoxifen?

• Cochrane review to determine effectiveness of Mirena in preventing endometrial hyperplasia, polyps, and adenocarcinoma in pre and postmenopausal breast cancer patients taking tamoxifen

• Looked at only RCT, 2 met search criteria

• Results:– Mirena led to significant reduction in the incidence of endometrial polyps OR

0.14– Neither trial powered to detect changes in rate of endometrial hyperplasia or

adenocarcinoma or whether Mirena led to increased risk of breast ca recurrence

– More vaginal bleeding in the Mirena treatment group in the first six months only

• Chin J, et al. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007245. Review.

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What about levonorgestrel-releasing IUD (Mirena) for women on Tamoxifen?

• RCT 2013 in China showed similar reduction in polyps, no differences in hyperplasia or cancer and not powered to assess breast cancer recurrence

• Many oncologists feel uncomfortable based on risks of progestins to the breast

Tamoxifen and CYP Testing• Tamoxifen is converted into its active metabolites in the liver by

the CYP2D6 liver enzyme, part of the P450 detoxification pathway

• CYP2D6-mediated drug metabolism is variable. 7-10% of individuals have decreased enzyme production - Concern whether poor metabolizers may not benefit from tamoxifen and have increased risk for recurrence

• Trials have not yet shown that CYP testing is clinically useful

• Some concerns with co-administration of pure SSRI’s that are potent inhibitors of CYP - Paroxetine, Fluoxetine- doesn’t imply that tamoxifen isn’t effective

Aromatase Inhibitors• Tamoxifen competes with estrogen at receptor binding site in

the breast preventing receptor activation

• Aromatase Inhibitors prevent conversion of androstenedioneand testosterone into estrogens and decrease peripheral circulating estrogen

• Not useful in premenopausal women because blocking aromatase in the ovaries reduces negative feedback to the pituitary (in the short term) with increased FSH output, and increased follicular development and increased estradiol

Aromatase Inhibitors

• Third generation AI’s used:

• Anastrozole (Arimidex) • Letrozole (Femara)

• Exemestane(Aromasin)

Nonsteroidal - reversible

Steroidal –irreversible inhibitors

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Anastrazole, Tamoxifen, Alone or in Combination (ATAC) trial

• 9000 PMP women with early stage breast ca, treated with 5 yrsof Anastrazole vs. Tamoxifen, first interim analysis presented in 2001 with now 13 years of follow up.

• Anastrazole had improved Disease Free Survival (HR .90 at 100 mos)

• Anastrazole had improved time to recurrence (HR .81 at 100 mos)

• Anastrazole had lower incidence of contralateral breast cancer (HR .68 at 100 mos)

Anastrozole vs. Tamoxifen - Adverse Effects

• Only about 60% of women continue full recommended treatment because of side effects

• More arthralgia, myalgia, and bone loss with AI

• Increased cardiovascular risks with AI, but no difference in MI, or MI related death

• Increase risks of fracture with AI during treatment but not seen after completion

• More colorectal and lung cancers with AI, not significant

• More vaginal dryness, dyspareunia and decreased libido

Anastrozole vs. Tamoxifen - Beneficial Effects

• Better with AI:

• Fewer CVA in AI group but did not persist after treatment

• Lower thromboembolic events with AI

• Fewer endometrial, ovarian cancer and melanoma in AI - only significant for endometrial cancer

• Aromatase Inhibitors thought to prevent endometrial cancer

How to manage all the Vaginal Dryness• Vaginal Moisturizers – retain water and provide longer term relief -

Replens, Rephresh, Luvena, JuvaGyn• studies (with Replens) show improvement in vaginal itching, irritation

and dyspareunia

• For vulvar discomfort – marketed mainly for vulvodynia- V Magic, Neo gyn, OTC lidocaine 1% Ela Max

• Vaginal Lubricants for sexual activity, provide short term relief –gels, liquids, water or silicone based. Consider iso-osmalar for women on AI as may have less mucosal irritation (Pre-Seed)

• Hyaluronic acid vaginal gel, studies suggest just as effective as local estrogen cream (Hyalofemme, Hyalo Gyn)

• I am not promoting any of these products and remember these are classified as cosmetics, not FDA approved drugs!

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How to manage all the Vaginal Dryness• Oils to the tissue- mineral, olive, coconut (particularly if on AI)

• Hormonal Options:

• Vaginal Preparations of Estrogens or Testosterone• Avoid typical intra-vaginal doses for estrogen creams• Testosterone preparations not FDA approved and need to

be compounded - Typical dosing 1% micronized cream using ½ gm PV 2-3x per week

• Estring (best data, limited), Vagifem

• SERMS – Ospermifene (Ospehena), contraindicated in breast cancer patients per labeling

Aromatase Inhibitors - 2015• Many international trials have now shown efficacy of

aromatase Inhibitors in adjuvant treatment for postmenopausal women

• FDA approved Anastrazole (Arimidex) as first-line adjuvant therapy in PMP women with hormone positive breast cancer

• FDA approved Letrozole (Femara) for extended adjuvant use in women with early-stage, hormone-receptor-positive breast cancer after five years of tamoxifen

• Both Exemestane(Aromasin) and Anastrozole (Arimidex) have showed reduction in ER-positive invasive breast ca compared to placebo in large trials, not yet FDA approved for prevention

Aromatase Inhibitors – Gynecologic Uses• Ovulation Induction – studies have shown pregnancy rates similar to

gonadotropins

• Ovulatory Dysfunction – PCOS. Meta-analysis of 4 published trials showed pregnancy rates similar to Clomiphene

• Treatment of Pelvic Pain and Endometriosis – aromatase is expressed at higher levels in endometriosis implants than in normal endometrium. Letrozole and Norethindrone reported to improve symptoms and histologic diagnosed endometriosis – No RCT compared to standard medical therapies

• Treatment for Fibroids – documented aromatase in myoma cells

• ACOG Technical Bulletin on Aromatase Inhibitors in Gynecologic Practice - Aug 2008

Nature Trivia• Bamboo is known for being?

• a. Growing only at night• b. The fastest growing plant in the world• c. Having above ground roots• d. Having two colors of flowers

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And the Answer Is…..• The fastest growing plant in the world -• Bamboo is part of the grass family.

Breast Cancer – What’s New in 2015• Individualized Treatment - Advances in gene expression

technologies improves predictions of prognosis and treatment benefit

• Oncotype DX ,Mammoprint , PAM50 test - genomic tests that predict risk of cancer recurrence and likely benefit from adjuvant chemotherapy

• Targeted therapies- Drugs that target HER2, anti-angiogenesis drugs, or biologic targeted therapies being used more

• Breast cancer treatments are becoming more individualized

Ovarian Suppression and Ablation

Ovarian Suppression and Ablation • Ovarian ablation oldest form of systemic treatment for breast ca,

first described 1896

• Methods – Surgical, Radiation-Induced, Medical with GNRH analogs (Zoladex)

• Many studies looking at ablation as adjuvant therapy

Overview of trials:

– Ovarian suppression (OS) and ovarian ablation (OA, via surgical oophorectomy) significantly decreases recurrence and improves survival in women < 50 with hormone positive tumors

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Ovarian Suppression and Ablation• OS and OA thought to be comparable to chemotherapy alone

– but data based on older regimens and not established for current anthracycline or taxane baseed regimens

• But main questions have been whether OS provides an additive benefit to endocrine therapy in premenopausal women with hormone positive disease

SOFT - Suppression of Ovarian Function Trial

• Largest trial conducted on OS in premenopausal women• 3,066 premenopausal women with early stage hormone positive

breast ca randomized to 5 yrs of either Tam, Tam + OS or AI OS

• After a median follow-up of 67 months disease-free survival rates were: – 86.6% for all women treated with tamoxifen and ovarian

suppression – 84.7% for all women treated with tamoxifen alone (hazard

ratio for disease recurrence, second invasive cancer, or death, 0.83, P=0.10)


• Most recurrences occurred in patients who had received prior chemotherapy

• After a median follow-up of 67 months the numbers of women who had not had a recurrence were:– 78.0% of the women treated with tamoxifen– 82.5% of the women treated with tamoxifen plus ovarian

suppression (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02).

– 85.7% of the women treated with Aromasin plus ovarian suppression (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87)


• Women younger than 35 who had been treated with chemotherapy seemed to get the most benefits from Aromasin plus ovarian suppression – One in three women of this age treated with tamoxifen alone had a

recurrence within 5 years – One in six women of this age treated with Aromasin plus ovarian

suppression had a recurrence within 5 years

• 30% of the women in all three treatment groups reported severe side effects. Women taking Aromasin were slightly more likely to withdraw from the studies because of side effects

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Should the Ovaries Come Out?

• If recurrent disease after tamoxifen and planned AI therapy –YES

• If high risk disease and long term hormonal therapy planned with minimal likelihood of remaining ovarian function – YES

• If low risk disease and likelihood of ovarian function when treatment complete – NO

• ? Counterbalancing risks of subsequent heart and osteoporosis

Ovarian Suppression and Fertility• Recent studies showing ovarian suppression

prior to chemotherapy preserved ovarian function

• Many fertility programs focused on assisted reproductive techniques to preserve fertility –ovarian stimulation with Tamoxifen or Letrozole and embryo cryopreservation, ovarian tissue or oocyte cryopreservaton prior to chemotherapy

Final Thoughts……

• Common questions about breast cancer

Do Fertility Drugs increase the risk of Breast Cancer? - NO

• Large Danish cohort showed no association Cancer Epidemiol Biomarkers Prev. 2007

• Israeli cohort of IVF found women over age 40 and those who underwent > 4 cylces had a higher risk of breast cancer Ann Surg Oncol. 2008

• Large British cohort with ovulatory disorders showed higher risk of primary breast cancer but no increased risks with fertility drugs Br J Cancer. 2009

• US cohort of 12,000 women from 1965-1988 showed no increased risk except for women using >12 cycles of Clomid Cancer Epidemiology, Biomarkers & Prevention, April 2014.

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Is it safe to get pregnant after having Breast Cancer? -YES

• Large population registry studies have shown no increased risks of recurrences for women who get pregnant after prior treatment for breast cancer

• Typically recommended to wait at least 2 years from diagnosis

• Pregnancies more often in women with early stage disease so possible selection bias “healthy mother effect”

Can Women Breastfeed after Breast Cancer? - MAYBE

• Most patients report inadequate lactation in affected breast

• May have asymmetric breasts due to inadequate hypertrophy

• Breast conserving surgeries may allow for lactation

• Less likely with:

– Centrally located tumors– If prior radiation - induces fibrosis of lobules with decreased

milk production

Is MHT after Breast Cancer safe? MAYBE

• Many observational studies suggested no risks

• Qualitative review of 10 prospective and 2 randomized trials in Belgium- no increased risks Human Reproduction 2007 22(2):616-622

• Retrospective study from large HMO in Washington lookingat pharmacy data showed no increased risk of recurrence or mortality J Natl Cancer Inst. 2001 May 16;93(10):754-62

• Review from Germany of four prospective randomized studies and 15 observational studies – all but one showed no risks

Is MHT after Breast Cancer safe? MAYBE

• Only 2 large randomized trials showed conflicting results:

• Hormonal Replacement Therapy after Breast cancer: Is iT Safe (HABITS) –stopped early because of increased risk of breast cancer in HT arm. Median follow-up of 4 years, new breast cancers occurred almost twice as often in the HT group compared with the non-hormone group (39 of 221 versus 17 of 221, HR 2.4) J Natl Cancer Inst. 2008;100(7):475

• Stockholm Trial stopped early after HABITS published but after 10.8 years of follow-up there was no significant difference in new breast cancer events, 60 in the HT group and 48 in the controls (HR 1.3, 95% CI 0.9-1.9) but increased risk of contralateral breast cancer with HT (RR 3.6) Different progestins used in this study. Eur J Cancer. 2013 Jan;49(1):52-9

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MHT and Breast Cancer

• MHT safe if DCIS only and bilateral mastectomies

• MHT and breast cancer complicated: studies using estrogen therapy to reverse acquired antihormonalresistance in the treatment of metastatic hormone positive breast cancer Clin Breast Cancer. 2008 Apr;8(2):124-33

Is breast imaging needed after bilateral mastectomies? NO

• If complete mastectomy no need for imaging

• If skin sparing, nipple sparing procedure, some centers may still recommend screening mammography

• MRI can be helpful to establish the presence of residual breast tissue after bilateral mastectomy, and routine screening not recommended if no residual breast tissue is seen

• With saline or silicone implants or autologous reconstruction procedures imaging typically not recommended

Case• 34 yr G2P2 presents with a palpable breast mass –

you send her for a FNA which returns positive for carcinoma. She has no other medical history and no family history of breast cancer. She undergoes a lumpectomy for a 1.8 cm infiltrating ductal carcinoma that is ER+/PR+ and Her2Neu negative. She receives adjuvant chemotherapy with AC followed by Taxol, then radiation, and is placed on Tamoxifen. Her menses stop with chemotherapy and return 6 mos later.

Questions• Is she at risk for endometrial cancer by taking

Tamoxifen? • NO

• Will Tamoxifen affect her menstrual cycles? • MAYBE

• Would you recommend routine ultrasound surveillance?

• NO

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Hopefully now, you will….• Know more facts about breast cancer• Understand the gyn issues related to breast ca• Understand when Tamoxifen and Aromatase Inhibitors are used • Understand the gyn implications of Tamoxifen and the Aromatase

Inhibitors• Know how to treat hot flashes and vaginal dryness • Know about the role of ovarian suppression• Know about fertility drugs and breast cancer• Know about safety of pregnancy and use of MHT after breast ca• Know something new about breast cancer that you didn’t know

before this talk……or at least the TRIVIA

2015 Obstetrics and Gynecology Update:

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