February/March 2012, Vol 4, No 1

fEbRuARy/MARch 2012

www.thEobgyNNuRsE.coM

Vol 4, No 1

CTRC-AACR SABCS ANNUAL MEETING

CTRC-AACR SABCS ANNUAL MEETING

Adding Everolimus to Exemestane significantly Prolongs Remission in Patients with breast cancer Updated results of pivotal BOLERO-2: potential paradigm change

By Caroline Helwick

Dual hER2 blockade with Pertuzumab substantially Delays Disease Progression

By Audrey Andrews

San Antonio, TX – It is becoming increasingly clear that 2 agents are better than 1 in treating HER2-positive advanced breast cancer. The latest evidence comes from the results of the phase 3 clinical trial CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), which were presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium by Jose Baselga, MD, PhD, professor of medicine, Harvard Medical School and associate director of the Massachusetts

General Hospital Cancer Center, Boston.

Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy as first-line treatment for patients with metastatic disease extended progression-free survival (PFS) by a median of 6.1 months compared with patients who received only trastuzumab-docetaxel, Dr Baselga reported. “This is huge. It is very uncommon to have a clinical trial show this level of improvement in PFS,” Continued on page 9

Gabriel Hortobagyi, MD, Chair of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Estradiol Route of Administration Does Not Affect Pregnancy Rate

By Wayne Kuznar

San Antonio, TX – Updated results from the phase 3 Breast Cancer Trials of Oral Everolimus (BOLERO-2) showed that adding everolimus to the

treatment regimen with the aromatase inhibitor exemestane more than doubled progression-free survival (PFS) in patients with advanced estrogen Continued on page 6

consider gnRh Agonist to trigger ovulation in women at Risk of ovarian hyperstimulation syndrome

Orlando, FL – The route of estradiol administration does not influence the pregnancy rate in frozen embryo transfer (FET) in vitro fertilization cycles, found investigators at the University of Connecticut Health Center, Farmington.

No studies have been performed comparing pregnancy rates with different routes of estradiol administration, prompting the investigators to perform a review of FET at their institution, comparing pregnancy rates for patients

Continued on page 8

By Wayne Kuznar

Orlando, FL – Consider leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist, instead of a traditional human chorionic gonadotropin

(hCG) as a trigger for final oocyte maturation in in vitro fertilization (IVF) in patients at risk of ovarian hyperstimulation syndrome (OHSS), advised Continued on page 9

The Publicationof of The Official Offical Publication

INS IDE ASRM ANNUAL MEETING . . . . . . . .

Low-intensity IVF: how does it stack up?

NEW WHO GUIDELINES . . . . . . . . . . . .

7 8

Which guidelines should fertility clinics follow when undertaking semen analysis?

13

INFERTILITY UPDATES . . . . . . . . .

We thank Watson Pharmaceuticals, Inc., for their gold level support. ©2012 Novellus Healthcare Communications, LLCs

undergoing cycles with transdermal, oral, or a combination of routes of estradiol administration. They presented their findings in poster format at the 2011 meeting of the American Society for Reproductive Medicine.

There were 479 FET cycles reviewed in women aged 44 years and younger.

Patients on vaginal estradiol or with nonfunctioning ovaries were excluded.

All FET cycles were downregulated with leuprolide acetate starting in the

Viability of single-embryo transfer as method to reduce multiple birth rates

Do low AMH levels rule out in vitro fertilization as an option?

PATIENT AWARENESS AND IDENTIFICATION . . . . . . . . . . . . . . .

14

One fertility center’s approach to testing NONSURGICAL INTERVENTION

.................

A look at pelvic organ prolapse

14

Crinone® 4% Crinone® 8% (progesterone gel) For vaginal use only.

Rx only

BRIEF SUMMARY For full prescribing information, see package insert.

INDICATIONS AND USAGE Assisted Reproductive Technology Crinone 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (“ART”) treatment for infertile women with progesterone deficiency.

Secondary Amenorrhea Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%.

CONTRAINDICATIONS Crinone should not be used in individuals with any of the following conditions: known sensitivity to Crinone (progesterone or any of the other ingredients); undiagnosed vaginal bleeding; liver dysfunction or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders.

WARNINGS The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis).

Should any of these occur or be suspected, the drug should be discontinued immediately.

Progesterone and progestins have been used to prevent miscarriage in women with a history of recurrent spontaneous pregnancy losses. No adequate evidence is available to show that they are effective for this purpose.

PRECAUTIONS General 1. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.

2. In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken.

3. Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.

4. The pathologist should be advised of progesterone therapy when relevant specimens are submitted.

5. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

6. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.

Information for Patients The product should not be used concurrently with other local intravaginal therapy. If other local intravaginal therapy is to be used concurrently, there should be at least a 6-hour period before or after Crinone administration. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage.

Drug Interactions No drug interactions have been assessed with Crinone.

Carcinogenesis, Mutagenesis, Impairment of Fertility Nonclinical toxicity studies to determine the potential of Crinone to cause carcinogenicity or mutagenicity have not been performed. The effect of Crinone on fertility has not been evaluated in animals.

Pregnancy Crinone 8% has been used to support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens in two clinical studies (studies COL1620-007US and COL1620-F01). In the first study (COL1620-007US), 54 Crinonetreated women had donor oocyte transfer procedures, and clinical pregnancies occurred in 26 women (48%). The outcomes of these 26 pregnancies were as follows: one woman had an elective termination of pregnancy at 19 weeks due to congenital malformations (omphalocele) associated with a chromosomal abnormality; one woman pregnant with triplets had an elective termination of her pregnancy; seven women had spontaneous abortions; and 17 women delivered 25 apparently normal newborns.

In the second study (COL1620-F01), Crinone 8% was used in the luteal phase support of women undergoing in vitro fertilization (“IVF”) procedures. In this multi-center, openlabel study, 139 women received Crinone 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer.

Clinical pregnancies assessed at Day 90 post-transfer were seen in 36 (26%) of women.

Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. Of the 47 newborns delivered, one had a teratoma associated with a cleft palate; one had respiratory distress syndrome; 44 were apparently normal and one was lost to follow-up.

Geriatric Use The safety and effectiveness in geriatric patients (over age 65) have not been established.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Nursing Mothers Detectable amounts of progestins have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.

ADVERSE REACTIONS Assisted Reproductive Technology In a study of 61 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Crinone 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women were: bloating (7%), cramps not otherwise specified (15%), pain (8%), dizziness (5%), headache (13%), nausea (7%), breast pain (13%), moniliasis genital (5%), vaginal discharge (7%), pruritus genital (5%).

In a second clinical study of 139 women using Crinone 8% once daily for luteal phase support while undergoing an IVF procedure, treatment-emergent adverse events reported in 5% or greater of the women were: abdominal pain (12%), perineal pain female (17%), headache (17%), constipation (27%), diarrhea (8%), nausea (22%), vomiting (5%), arthralgia (8%), depression (11%), libido decreased (10%), nervousness (16%), somnolence (27%), breast enlargement (40%), dyspareunia (6%), nocturia (13%).

Secondary Amenorrhea In three studies, 127 women with secondary amenorrhea received estrogen replacement therapy and Crinone 4% or 8% every other day for six doses. Treatment-emergent adverse events during estrogen and Crinone treatment that occurred in 5% or more of women treated with Crinone 4% or Crinone 8% respectively were: abdominal pain (5%, 9%), appetite increased (5%, 8%), bloating (13%, 12%), cramps not otherwise specified (19%, 26%), fatigue (21%, 22%), headache (19%, 15%), nausea (8%, 6%), back pain (8%, 3%), myalgia (8%, 0%), depression (19%, 15%), emotional lability (23%, 22%), sleep disorder (18%, 18%), vaginal discharge (11%, 3%), upper respiratory tract infection (5%, 8%), and pruritus genital (2%, 6%).

Additional adverse events reported in women at a frequency of less than 5% in Crinone ART and secondary amenorrhea studies and not listed above include: autonomic nervous system–mouth dry, sweating increased; body as a whole–abnormal crying, allergic reaction, allergy, appetite decreased, asthenia, edema, face edema, fever, hot flushes, influenza-like symptoms, water retention, xerophthalmia; cardiovascular, general–syncope; central and peripheral nervous system–migraine, tremor; gastro-intestinal–dyspepsia, eructation, flatulence, gastritis, toothache; metabolic and nutritional–thirst; musculo-skeletal system– cramps legs, leg pain, skeletal pain; neoplasm–benign cyst; platelet, bleeding & clotting– purpura; psychiatric–aggressive reactions, forgetfulness, insomnia; red blood cell– anemia; reproductive, female–dysmenorrhea, premenstrual tension, vaginal dryness; resistance mechanism–infection, pharyngitis, sinusitis, urinary tract infection; respiratory system–asthma, dyspnea, hyperventilation, rhinitis; skin and appendages–acne, pruritus, rash, seborrhea, skin discoloration, skin disorder, urticaria; urinary system–cystitis, dysuria, micturition frequency; vision disorders–conjunctivitis.

OVERDOSAGE There have been no reports of overdosage with Crinone. In the case of overdosage, however, discontinue Crinone, treat the patient symptomatically, and institute supportive measures.

As with all prescription drugs, this medicine should be kept out of the reach of children.

DOSAGE AND ADMINISTRATION Assisted Reproductive Technology Crinone 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Crinone 8% is administered vaginally at a dose of 90 mg twice daily in women with partial or complete ovarian failure who require progesterone replacement. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10-12 weeks.

Secondary Amenorrhea Crinone 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Crinone 8% every other day up to a total of six doses may be instituted.

It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.

HOW SUPPLIED Crinone is available in the following strengths: 4% gel (45 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.

NDC 52544-283-24 - 6 Single-use prefilled applicators.

8% gel (90 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.

NDC 52544-284-12 - 15 Single-use prefilled applicators.

Each applicator is wrapped and sealed in a foil overwrap.

Store at 20-25°C (68-77°F). [See USP controlled room temperature.]

Rx only

Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525 Distributed by: Watson Pharma, Inc., Morristown, NJ 07962 USA Manufactured by: Fleet Laboratories Ltd., Watford, Herts WD18 7JJ UK Revised: July 2010

From the Editor

A

s spring approaches, it is exciting to experience the new beginnings that a fresh season brings.

For me and all my coworkers, this season is muted by the loss of an esteemed mentor, colleague, and friend.

This journal was developed to highlight the multifaceted elements that make OB/GYN extraordinary. These elements may be clinical or personal, and they influence how we structure the care we provide to our patients. In saying this, it is important to take time to reflect on the people who have made an impact in shaping our professional careers and defining how we provide patient care.

As nurses, our role is to provide quality patient care. The care we provide defines us as clinicians and makes a permanent impression on our patients. As nurses advance into clinical management, these responsibilities are expanded. Successful managers have the ability to go beyond a generic job descrip-

tion to elevate the quality of care that is applied to all patients and staff, setting a bar for a standard of care that defines a medical practice. It is very rare to work in partnership with someone who has completed such a monumental task, and in doing so, made a tremendous impact on the practice of fertility nursing.

As an operations manager, Pat Cullen translated her exemplary personal standard of care to establish the practice standard for patient-centered care.

She effectively touched the lives of thousands of patients and staff in her 30+ years of fertility nursing service. I am very proud to have had the honor and privilege of working with one of the leaders in fertility nursing. In tribute to Pat, and the many other nursing leaders that our profession has lost, please remember to acknowledge your mentors, validate your coworkers, strive for quality in everyday care, and appreciate the impact that you are making on the lives of the patients that you touch.

Sue Jasulaitis, RN, MS In memory of Patricia Cullen, RN BSN Director of Operations, Fertility Centers of Illinois

Editorial Board Richard P. Dickey, MD, PhD Director, Reproductive Medicine Fertility Institute of New Orleans, LA

Juergen Liebermann, PhD, HCLD IVF Laboratory Director River North Fertility Centers of Illinois, Chicago

Patricia Rucinsky, RN, BSN Clinical Nurse Manager IRMS at Saint Barnabas, NJ

Gina Paoletti-Falcone, RN, BSN Clinical Services Manager Freedom Fertility Pharmacy Byfield, MA

Mary M. Macgregor, RNC IVF Nurse Coordinator Fertility Institute of New Orleans, LA

Elizabeth A. Shrader, MSN, APN-C IVF Nurse Coordinator DVIF&G Marlton, NJ

Margaret-Rose Agostino, DNP, MSW, RN-BC, IBCLC Assistant Professor Department of Nursing Delaware State University

Donielle Farrington, RNC Clinical Nursing Manager Brunswick Hills OB/GYN, NJ

Jill Marchetti, RN Director, Egg Donor Program IVF New Jersey

Christopher S. Sipe, MD OB/GYN & Reproductive Endocrinology Fertility Centers of Illinois, Chicago

Barbara Alice, RN, APN-C, MSN Nursing Manager, IVF Coordinator South Jersey Fertility Center

Sandra Fernandez, RPh, PharmD Pharmacist Mandell’s Clinical Pharmacy, NJ

Donna Makris, RN, BSN, IBCLC Parent Education Coordinator OB/GYN, St. Peter’s Medical Center, NJ

Dale C. Smith, RN, MPH, MSN NFP Nursing Supervisor DHEC Region 6 Conway, SC

Monica R. Benson, BSN, RNC Nurse Manager Third Party Reproduction, RMA New Jersey

Jennifer Iannaccone, RNC Nursing Manager, IVF Coordinator IVF New Jersey

Norah S. Nutter, MSN, WHNP-BC, IBCLC Women’s Health Nurse Practitioner Magnolia OB/GYN Myrtle Beach, SC

Harvey J. Stern, MD, PhD Director, Reproductive Genetics Genetics & IVF Institute Fairfax, VA

Melissa B. Brisman, Esq Owner Reproductive Possibilities, LLC Surrogate Fund Management, LLC Montvale, NJ

Carolyn E. Keating, BSN, RNC, NP Piedmont Reproductive and Endocrinology Group Greenville, SC

Kutluk Oktay, MD, FACOG Director, Division of Reproductive Medicine & Infertility, Department of Obstetrics & Gynecology, New York Medical College; Director, Institute for Fertility Preservation, NY

Kriston Ward, RN, MS, NP-C Strong Fertility Center University of Rochester Medical Center, Rochester, NY

Kit Devine, MSN, ARNP Advanced Nurse Practitioner Fertility & Endocrine Associates, Kentucky

Cheryl Kilbourne, RN Clinical Director Women and Children Services Waccmaw Hospital, SC

Cyndi Gale Roller, PhD, RN, CNP, CNM Program Director, Women’s Health College of Nursing Kent State University, OH

Joan Zaccardi, MS, DrNP Administrative Practice Manager Urogynecology Arts of New Jersey

CO-EDITOR-IN-CHIEF

Sue Jasulaitis, RN, MS Clinical Research Manager Fertility Centers of Illinois, Chicago

CO-EDITOR-IN-CHIEF

Debra Moynihan, WHNP-BC, MSN Women’s Health Nurse Practitioner Carolina OB/GYN, Myrtle Beach, SC

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

5

In This Issue WWW.THEOBGYNNURSE.COM PUBLISHING STAFF

Publisher Russell Hennessy russell@novellushc.com 732-992-1888 Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Jim Scelfo jim@greenhillhc.com Editorial Assistant Jennifer Brandt Senior Production Manager Marie RS Borrelli

NEw who guIDElINEs Which guidelines should fertility clinics follow when undertaking semen analysis?

PAtIENt AwARENEss AND IDENtIfIcAtIoN One fertility center’s approach to testing

INfERtIlIty uPDAtEs Viability of single-embryo transfer as method to reduce multiple birth rates

NoNsuRgIcAl INtERVENtIoN A look at pelvic organ prolapse

Do low AMH levels rule out in vitro fertilization as an option?

AsRM ANNuAl MEEtINg Low-intensity IVF: how does it stack up?

Quality Control Director Barbara Marino Business Manager Blanche Marchitto Editorial Contact: Telephone: 732-992-1536 Fax: 732-656-7938 MISSION STATEMENT The OB/GYN Nurse-NP/PA is the official publication of the American Academy of OB/GYN and Infertility Nurses. The OB/GYN Nurse-NP/PA provides practical, authoritative, cutting-edge information on the physiologic, medical, and psychological aspects of women’s health, focusing on the role of the OB/GYN practitioner, including nurses, NPs, and PAs, in patient care. Our journal offers a forum for nurses, NPs, PAs, administrators, researchers, and all others involved in OB/GYN and women’s health to discuss the entire scope of current and emerging diagnostic and therapeutic options, as well as counseling and patient follow-up for women throughout their reproductive years and beyond. Written by nurses for nurses, The OB/GYN Nurse-NP/PA promotes peer-to-peer collaboration among all nursing professionals toward the advancement of integrated services for optimal delivery of patient care and offers continuing education for all nurses, NPs, and PAs involved in these interrelated fields of women’s health.

The OB/GYN Nurse, ISSN 2153-6562 (print); ISSN 2153-6546 (online), is published by Novellus Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831. Copyright ©2012 by Novellus Healthcare Communications, LLC. All rights reserved. The OB/GYN Nurse is a trademark of Novellus Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher.

Printed in the United States of America.

The ideas and opinions expressed in The OB/GYN Nurse do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in The OB/GYN Nurse should not be construed as an endorsement of the product or the manufacturer’s claims.

Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

SUBSCRIPTIONS/CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, The OB/GYN Nurse, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831; Fax: 732-656-7938.

6

CTRC-AACR SABCS Annual Meeting

Adding Everolimus... receptor (ER)-positive breast cancer whose disease had become refractory to hormonal therapy.

“The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient population,” said lead investigator Gabriel Hortobagyi, MD, chair of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium.

Nearly all ER-positive patients with advanced cancer will develop resistance to hormonal therapies. Resistance to hormonal therapy in breast cancer has been associated with overactivation of the mTOR pathway. Everolimus targets the mTOR pathway, interfering with tumor cell proliferation, angiogenesis, and cell metabolism.

“Everolimus is the first treatment to significantly enhance the efficacy of hormonal therapy in this patient population, where this remains a significant unmet need,” Dr Hortobagyi noted. bolERo Details The new findings represent an additional 6 months of patient follow-up from the data first presented at the European Multidisciplinary Cancer Congress in September 2011, garnering much attention. The updated analysis presented in San Antonio showed that treatment with everolimus plus hormonal therapy more than doubled PFS, from 3.2 months with exemestane alone to 7.4 months with the addition of everolimus, representing a highly significant 56% reduction (P <1 × 10-16) in the risk of

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

Continued from page 1

progression. “While this analysis was done with local tumor assessment, another assessment by central independent review found even greater benefit, with PFS of 11.0 months versus 4.1 months, a 64% risk reduction (P <1 × 10-16),” Dr Hortobagyi reported.

In remarking on the robustness of the findings at a media briefing, Dr Hortobagyi noted that the prolongation

“Everolimus is the first treatment to significantly enhance the efficacy of hormonal therapy in this patient population….The study demonstrated not the 26% reduction in progression, as we had expected, but a 56% reduction in progression events, with a P value for which I don’t have enough fingers to count.”

—Gabriel Hortobagyi, MD

of progression far exceeded the investigators’ expectations. “The study demonstrated not the 26% reduction in progression, as we had expected, but a 56% reduction in progression events, with a P value for which I don’t have enough fingers to count.” Disease-free survival

AT A GLANCE ‰ Nearly all ER-positive patients with advanced cancer will develop resistance to hormonal therapies ‰ The addition of everolimus to hormonal therapy more than doubled PFS, from 3.2 months with exemestane alone to 7.4 months ‰ These new results demonstrated a 56% reduction in disease progression, nearly twice the expected rate ‰ At 1 year, disease-free survival rate is 31% in the everolimusexemestane combination arm versus 10% in the exemestane alone arm

rates at 1 year were 31% in the combination arm versus 10% in the exemestane-alone arm.

Side effects were consistent with those previously reported with everolimus. The most common grade 3 or grade 4 adverse events were stomatitis, anemia, hyperglycemia, dyspnea, fatigue, and pneumonitis, all occurring in <10% of patients receiving the combination. The addition of everolimus did not impact the patients’ quality of life, according to Global Health Scores.

As of December 2011, deaths had occurred in 29.3% of the placebo arm and 23.1% of the everolimus arm. The manufacturer is planning a regulatory submission for everolimus based on the BOLERO-2 results. n

ASRM Annual Meeting

low-Intensity IVf Reduces Pregnancy chances

by Wayne Kuznar

Orlando, FL – Low-intensity in vitro fertilization (IVF), a milder ovarian stimulation that is gaining in popularity, significantly reduces the chance of pregnancy, according to data from a pilot study by Norbert Gleicher, MD. Low-intensity IVF, also known as Eco-IVF, is allegedly more cost-effective and patient friendly while hypothetically producing better embryo quality, say its advocates. But in a poster presentation delivered at the 2011 meeting of the American Society for Reproductive Medicine, Dr Gleicher offered data showing that fewer cryopreserved embryos were produced, resulting in fewer live births, using low-intensity IVF compared with standard IVF. Low-intensity IVF has never been compared with standard IVF in a noninferiority trial. Based on the lower oocyte numbers with mild ovarian stimulation, “one has to conclude that cumulative pregnancy chances from low-intensity IVF have to be lower,” according to Dr Gleicher, medical director of the Center for Human Reproduction, New York City.

To investigate whether low-intensity IVF offered compensatory benefits, Dr Gleicher and colleagues studied 14 lowintensity IVF and 14 age-matched standard intensity IVF cycles in women younger than 38 years with normal ovarian reserve. Women in low-intensity cycles were stimulated with clomiphene citrate, 100 mg daily on days 3 to 7, augmented by human menopausal gonadotropin (hMG), 10,000 IU, until ovulation induction with human chorionic gonadotropin (hCG), 10,000 IU. Women in standard IVF cycles were stimulated with hMG, 10,000 IU, after downregulation with agonist (leuprolide acetate, luteal start, 1 mg once daily until the suppression phase, followed by 0.5 mg daily, until induction with hCG).

Patients using low-intensity IVF used less gonadotropin and had fewer oocytes retrieved (2.7 vs 15.6) resulting in fewer cryopreserved embryos (0 vs 4.7) compared with women using standard IVF. With an identical number of embryos transferred, after adjusting for age, patients using standard IVF demonstrated 7-fold better odds for pregnancy and a cumulative pregnancy rate that was more than 6 times higher than that achieved in patients using low-intensity IVF cycles. There were 10 live births among women using standard IVF compared with 5 among those using lowintensity IVF. The costs per live birth (cumulative) were similar between the 2 groups:

$23,100 when low-intensity IVF cycles were used and $20,333 when standard IVF cycles were used. The significantly reduced chances of pregnancy with lowintensity IVF eliminated the potential cost advantages, said Dr Gleicher. “Even

with normal ovarian reserve, therefore, low-intensity IVF can be considered neither patient friendly nor cost-effective.”

With diminished ovarian reserve, low-intensity IVF should be even less successful, he indicated, even though it

is in this population that low-intensity IVF is used most frequently. “Low-intensity currently lacks clinical and economic foundations, and therefore should be offered only under experimental study conditions,” Dr Gleicher concluded. n

INFERTILITY PROFESSIONALS:

FREE ANSWERS

TO

EMBRYO DONATION’S LIFE-CHANGING QUESTIONS FOR YOU AND YOUR PATIENTS

Embryo Donation Services Center

www.embryocenter.org (719)213-7680

This material was developed and distributed with funding support from the U.S. Department of Health and Human Services under grant #6 EAAPA111017-01-01.The statements expressed are those of the Embryo Donation Services Center and do not necessarily represent the views of the Department.

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

7

Guidelines

New who guidelines for semen Analysis Not up to the task, Expert contends Toronto, Ontario – Which guidelines should fertility clinics follow when undertaking semen analysis? That question is difficult to answer now that two competing systems have been developed. They are the fifth edition of the World Health Organization’s manual for semen analysis, released last year and referred to as ‘WHO5’, and the semen analysis recommendations of the European Society of Human Reproduction & Endocrinology (ESHRE) Andrology Special Interest Group Education Subcommittee, which were first presented in a semen-analysis course in June 2011.

At the Canadian Fertility and Andrology Society’s 2011 Annual Meeting, David Mortimer, PhD, an infertility-clinic consultant and one of the authors of the ESHRE guidelines, described the advantages of the ESHRE approach over WHO5. Paul Claman, MD, a professor of obstetrics and gynecology at the University of Ottawa who attended Dr. Mortimer’s presentation agreed with most of his criticisms of WHO5.

“As a clinician I can’t see how WHO5 helps in the evaluation of the infertile couple. It defines normal sperm parameters based on statistical variances in a population of fertile men, which does not help to define which men are less fertile than others,” Dr Claman said.

“It is sad that this most respected health authority has not considered the practical clinical problem of evaluating the infertile couple when publishing their

updated heretofore important laboratory manual for the evaluation of semen.”

WHO5 contains numerous inconsistencies, errors, and unjustified complications relating to established techniques that unnecessarily increase workload without improving accuracy or precision in the results obtained, Dr Mortimer, President of Oozoa Biomedical Inc, West Vancouver, told meeting attendees. He added, “In addition, the reduction of the differential motility assessment to only three categories by eliminating the assessment of percentage rapid progressive, is a backward step that eliminates this biologically, and hence clinically, important piece of information from basic semen analysis.” Dr. Mortimer also said that almost immediately after WHO5 was published it was “widely criticized….

For example, two of the members of the committee of experts who wrote the revised WHO guidelines wrote refutations of parts of it.”

One of the major problems in WHO5, according to Dr. Mortimer, is that it abandons the distinction between grade A sperm, which swim forward fast in a straight line, and grade B sperm, which swim forward but either slowly or along a curved or crooked path. The reason given for this decision by the WHO committee is that grade A is too subjective and cannot be assessed reliably by eye. However, Dr. Mortimer contends data show that distinction of grade A sperm from others can be learned rapidly by using a standardized

Estradiol Route... midluteal phase of the previous cycle.

Serum estradiol levels were monitored and the doses of estradiol were adjusted accordingly.

Of these 479 women, 37 received oral estradiol only (group A), 244 received transdermal estradiol only (group B), and 198 started on transdermal but had oral estradiol added to achieve targeted estradiol levels during the FET cycle (group C). Intramuscular progesterone was started if the endometrial lining was 7 mm or greater. If the beta human chorionic gonadotropin was positive, estradiol and progesterone supplemen-

8

technique and that many in the field agree this is an essential factor in semen analysis.

Other problems and errors in WHO5 identified by Dr Mortimer are that it uses 4% ‘normal’ forms as a reference limit for sperm morphology; uses misleading terminology such as oligo-

“As a clinician I can’t see how WHO5 helps in the evaluation of the infertile couple. It defines normal sperm parameters based on statistical variances in a population of fertile men, which does not help to define which men are less fertile than others.”

—Paul Claman, MD

zoospermia, “which is not a diagnosis”; and provides multiple methods for some assessments, which “can cause confusion.” Dr Mortimer also said that WHO5 presents protocols in a nonlinear way; uses “illogical, imprecise, and arbitrary” criteria for sperm vitality; requires unnecessary extra work, such as duplicates for vitality assessments and a

new, laborious method for low-concentration samples; and presents problems in its sperm preparation method, including allowing centrifugal washing for “good-quality” semen samples, “although such samples cannot be identified reliably until after the sperm processing has commenced.” In addition, the reference ranges for various parts of the semen analysis do not take into account individual, biological, and methodological variability and ignore the fact that “establishing clear cutoff limits is impossible” due to factors such as overlaps in results between groups of men with and without reduced fertility potential, said Dr. Mortimer.

In contrast, the textbook for the ESHRE semen-analysis course provides consensus-based, “detailed, logical, unambiguous SOP-type methods designed to minimize technical errors, avoid unnecessary effort, and facilitate quality control,” according to Dr Mortimer. These methods include “well-defined criteria for ‘normality’ in sperm morphology and the use of sperm functional analysis in managing infertile couples,” the latter of which he pioneered.

“For semen analysis to be useful, robust validated methods must be employed by trained, competent personnel in order to provide accurate results,” concluded Dr Mortimer.

“WHO5 has significant limitations in providing reliable methods for performing such testing efficiently and effectively.” n

Continued from page 1

tation were continued until 12 weeks’ gestation.

The mean age in each group was about 35 years. There were no significant differences between the 3 groups in day 3 follicle stimulating hormone or in the number of patients undergoing intracytoplasmic sperm injection. Mean body mass index (BMI) was significantly greater in group A (30.2 kg/m2) compared with group B (25.1 kg/m2) and group C (27.9 kg/m2).

The number of embryos transferred and the implantation rates were not significantly different between the groups.

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

The clinical pregnancy rates were not

Serum estradiol levels were monitored and the doses of estradiol were adjusted accordingly.

significantly different between the

groups: 56.8% for group A; 50.0% for group B; 51.0% for group C. The ongoing pregnancy rates were also not significantly different: 48.6% for group A; 41.0% for group B; 42.9% for group C. There were no differences in the clinical or ongoing pregnancy rates when controlling for BMI. While the route of estradiol administration does not appear to affect pregnancy rates in FET cycles, the authors urge monitoring of estradiol levels, “as increasing the dose or adding a second form of administration maintains pregnancy rates.” n

CTRC-AACR SABCS Annual Meeting

Dual hER2 blockade with Pertuzumab...

Continued from page 1

Dr Baselga emphasized.

Pertuzumab is designed to work in combination with trastuzumab as a dual blockade of the HER2 growth factor. Both drugs are monoclonal antibodies that bind to the HER2 receptor protein in different regions.

Pertuzumab prevents the receptor from linking to HER3, which stops the formation of a “dimer” that could enhance tumor growth.

“Pertuzumab is the first in a new class of drugs called ‘dimerization inhibitors,’ and its combination with trastuzumab produces dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling,” Dr Baselga said. the clEoPAtRA study CLEOPATRA randomly assigned 808 postmenopausal women with metastatic breast cancer, but without previous treatment for metastatic disease, to trastuzumab and docetaxel chemotherapy with the addition of either pertuzumab or placebo. The PFS was 18.5 months for patients receiving pertuzumab along with trastuzumab-

docetaxel compared with 12.4 months for trastuzumab-docetaxel alone, a 38% reduction in the risk of progression.

“Pertuzumab is the first in a new class of drugs called ‘dimerization inhibitors,’ and its combination with trastuzumab produces dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling.”

—Jose Baselga, MD, PhD

Adding pertuzumab to the combination also raised the objective response rate to 80.2% compared with 69.3% for trastuzumab-docetaxel alone.

Although survival outcomes are not

mature, 69 deaths were reported among the 402 patients who were treated with the 3-drug regimen versus 96 deaths among the 406 patients receiving the 2drug regimen; this amounts to a 36% reduction in mortality.

The 3-drug combination was “remarkably safe and well tolerated,” Dr Baselga noted, reporting that pertuzumab added only minimal toxicity.

Enrollment is already underway in a new double-blind, randomized clinical trial, APHINITY, that will test the use of pertuzumab as adjuvant treatment for early-stage HER2-positive breast cancer – “the setting in which you can really cure patients,” Dr Baselga noted.

“We are looking forward to getting pertuzumab approved as soon as possible. The sooner the better,” Dr Baselga commented. Genentech recently submitted a biologic license application for pertuzumab in HER2-positive metastatic breast cancer.

Lisa Carey, MD, medical director, the University of North Carolina Breast Cancer Center, Chapel Hill, moderated a press conference and commented that findings from the

AT A GLANCE ‰ Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy extended PFS by a median of 6.1 months ‰ Pertuzumab is the first in a new class of drugs called “dimerization inhibitors”; its combination with trastuzumab produces dual HER2 blockade ‰ In the CLEOPATRA phase 3 trial, the 3-drug regimen reduced mortality by 36% ‰ Dual HER2 blockade demonstrated a significant advantage over a single blockade BOLERO-2 study that involved another breast cancer drug, everolimus, extend the findings from neoadjuvant studies and smaller, less definitive trials “that dual HER2 blockade has a marked advantage over single blockade of HER2. The challenge will be figuring out which patients need both these drugs.” n

ASRM Annual Meeting

consider gnRh Agonist...

Continued from page 1

Meredith Provost, PhD, MD, at the 2011 meeting of the American Society for Reproduction Medicine.

In her study, retrieval efficiency of oocytes per follicle was equivalent or better with leuprolide acetate compared with hCG. The use of GnRH agonists as a method to trigger ovulation has gained favor in recent years and can “virtually eliminate the risk of ovarian hyperstimulation syndrome,” said Dr Provost, Department of Obstetrics and Gynecology, Banner Good Samaritan Medical Center, Arizona Reproductive Medicine Specialists, Phoenix. Original concerns about a lower pregnancy rate associated with the use of GnRH agonists have been reversed with aggressive luteal phase support. Although, according to Dr Provost, “There still remain some concerns about lower egg retrieval rate efficiencies.”

Dr Provost reviewed 820 cycles (312 IVF and 506 intracytoplasmic sperm injection [ICSI]) with final oocyte maturation triggered using either hCG at a

dose of 5,000 IU or 10,000 IU or leuprolide acetate at a dose of 2 mg or 4 mg in the evening followed by an injection the next morning. All patients were on an antagonist protocol and received follicle stimulating hormone, the starting dose of which was determined by individual criteria. Maturation rate, fertilization rate (IVF and ICSI), and retrieval efficiency were the primary outcomes. Retrieval efficiency was defined in 2 ways: oocytes retrieved/follicle >15 mm (efficiency I) and oocytes retrieved/estradiol level (efficiency II).

“The criteria to use leuprolide acetate varied over time to adapt to changing clinical conditions,” Dr Provost said, with the current criteria being an estradiol level in excess of 3,500 pg/mL and the total number of follicles greater than 11 mm ≥20.

The only demographic factors that predicted outcomes were gravida, which predicted retrieval efficiency I, and estradiol, which predicted retrieval

Table Comparison of Leuprolide Acetate and Human Chorionic Gonadotropin Outcome Retrieval efficiency I Retrieval efficiency II ICSI maturation rate ICSI fertilization rate IVF fertilization rate Embryos/oocyte

LA 2 mg 1.18 5.54 77.8 76.5 65.2 0.33

LA 4 mg 1.20 6.30 82.3 76.2 65.9 0.34

hCG 5,000 1.25 7.74 78.3 73.1 63.9 0.33

hCG 10,000 1.30 7.20 77.2 70.8 66.6 0.30

LA indicates leuprolide acetate; hCG, human chorionic gonadotropin; retrieval efficiency I, oocytes/follicle >15 mm; retrieval efficiency II, oocytes retrieved/estradiol level; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization.

efficiency II. The retrieval efficiency was not different between the leuprolide acetate and hCG groups.

Leuprolide acetate, 4 mg, did perform significantly better on the outcomes of ICSI maturation rate and ICSI fertilization rate compared with hCG at either dose, Dr Provost reported.

The IVF fertilization rate and the number of oocyte embryos transferred

and retrieved were also similar between the groups. “None of our LA [leuprolide acetate] cycles had no oocytes retrieved; there were oocytes retrieved in every cycle that we did,” Dr. Provost said. The better safety profile of a GnRH agonist with respect to OHSS argues for consideration of leuprolide acetate instead of a traditional hCG trigger, she concluded. n

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

9

Crinone® 4% Crinone® 8% (progesterone gel) For vaginal use only.

Rx only

BRIEF SUMMARY For full prescribing information, see package insert.

INDICATIONS AND USAGE Assisted Reproductive Technology Crinone 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (“ART”) treatment for infertile women with progesterone deficiency.

Secondary Amenorrhea Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%.

CONTRAINDICATIONS Crinone should not be used in individuals with any of the following conditions: known sensitivity to Crinone (progesterone or any of the other ingredients); undiagnosed vaginal bleeding; liver dysfunction or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders.

WARNINGS The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis).

Should any of these occur or be suspected, the drug should be discontinued immediately.

Progesterone and progestins have been used to prevent miscarriage in women with a history of recurrent spontaneous pregnancy losses. No adequate evidence is available to show that they are effective for this purpose.

PRECAUTIONS General 1. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.

2. In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken.

3. Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.

4. The pathologist should be advised of progesterone therapy when relevant specimens are submitted.

5. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

6. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.

Information for Patients The product should not be used concurrently with other local intravaginal therapy. If other local intravaginal therapy is to be used concurrently, there should be at least a 6-hour period before or after Crinone administration. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage.

Drug Interactions No drug interactions have been assessed with Crinone.

Carcinogenesis, Mutagenesis, Impairment of Fertility Nonclinical toxicity studies to determine the potential of Crinone to cause carcinogenicity or mutagenicity have not been performed. The effect of Crinone on fertility has not been evaluated in animals.

Pregnancy Crinone 8% has been used to support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens in two clinical studies (studies COL1620-007US and COL1620-F01). In the first study (COL1620-007US), 54 Crinonetreated women had donor oocyte transfer procedures, and clinical pregnancies occurred in 26 women (48%). The outcomes of these 26 pregnancies were as follows: one woman had an elective termination of pregnancy at 19 weeks due to congenital malformations (omphalocele) associated with a chromosomal abnormality; one woman pregnant with triplets had an elective termination of her pregnancy; seven women had spontaneous abortions; and 17 women delivered 25 apparently normal newborns.

In the second study (COL1620-F01), Crinone 8% was used in the luteal phase support of women undergoing in vitro fertilization (“IVF”) procedures. In this multi-center, openlabel study, 139 women received Crinone 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer.

Clinical pregnancies assessed at Day 90 post-transfer were seen in 36 (26%) of women.

Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. Of the 47 newborns delivered, one had a teratoma associated with a cleft palate; one had respiratory distress syndrome; 44 were apparently normal and one was lost to follow-up.

Geriatric Use The safety and effectiveness in geriatric patients (over age 65) have not been established.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Nursing Mothers Detectable amounts of progestins have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.

ADVERSE REACTIONS Assisted Reproductive Technology In a study of 61 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Crinone 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women were: bloating (7%), cramps not otherwise specified (15%), pain (8%), dizziness (5%), headache (13%), nausea (7%), breast pain (13%), moniliasis genital (5%), vaginal discharge (7%), pruritus genital (5%).

In a second clinical study of 139 women using Crinone 8% once daily for luteal phase support while undergoing an IVF procedure, treatment-emergent adverse events reported in 5% or greater of the women were: abdominal pain (12%), perineal pain female (17%), headache (17%), constipation (27%), diarrhea (8%), nausea (22%), vomiting (5%), arthralgia (8%), depression (11%), libido decreased (10%), nervousness (16%), somnolence (27%), breast enlargement (40%), dyspareunia (6%), nocturia (13%).

Secondary Amenorrhea In three studies, 127 women with secondary amenorrhea received estrogen replacement therapy and Crinone 4% or 8% every other day for six doses. Treatment-emergent adverse events during estrogen and Crinone treatment that occurred in 5% or more of women treated with Crinone 4% or Crinone 8% respectively were: abdominal pain (5%, 9%), appetite increased (5%, 8%), bloating (13%, 12%), cramps not otherwise specified (19%, 26%), fatigue (21%, 22%), headache (19%, 15%), nausea (8%, 6%), back pain (8%, 3%), myalgia (8%, 0%), depression (19%, 15%), emotional lability (23%, 22%), sleep disorder (18%, 18%), vaginal discharge (11%, 3%), upper respiratory tract infection (5%, 8%), and pruritus genital (2%, 6%).

Additional adverse events reported in women at a frequency of less than 5% in Crinone ART and secondary amenorrhea studies and not listed above include: autonomic nervous system–mouth dry, sweating increased; body as a whole–abnormal crying, allergic reaction, allergy, appetite decreased, asthenia, edema, face edema, fever, hot flushes, influenza-like symptoms, water retention, xerophthalmia; cardiovascular, general–syncope; central and peripheral nervous system–migraine, tremor; gastro-intestinal–dyspepsia, eructation, flatulence, gastritis, toothache; metabolic and nutritional–thirst; musculo-skeletal system– cramps legs, leg pain, skeletal pain; neoplasm–benign cyst; platelet, bleeding & clotting– purpura; psychiatric–aggressive reactions, forgetfulness, insomnia; red blood cell– anemia; reproductive, female–dysmenorrhea, premenstrual tension, vaginal dryness; resistance mechanism–infection, pharyngitis, sinusitis, urinary tract infection; respiratory system–asthma, dyspnea, hyperventilation, rhinitis; skin and appendages–acne, pruritus, rash, seborrhea, skin discoloration, skin disorder, urticaria; urinary system–cystitis, dysuria, micturition frequency; vision disorders–conjunctivitis.

OVERDOSAGE There have been no reports of overdosage with Crinone. In the case of overdosage, however, discontinue Crinone, treat the patient symptomatically, and institute supportive measures.

As with all prescription drugs, this medicine should be kept out of the reach of children.

DOSAGE AND ADMINISTRATION Assisted Reproductive Technology Crinone 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Crinone 8% is administered vaginally at a dose of 90 mg twice daily in women with partial or complete ovarian failure who require progesterone replacement. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10-12 weeks.

Secondary Amenorrhea Crinone 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Crinone 8% every other day up to a total of six doses may be instituted.

It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.

HOW SUPPLIED Crinone is available in the following strengths: 4% gel (45 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.

NDC 52544-283-24 - 6 Single-use prefilled applicators.

8% gel (90 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.

NDC 52544-284-12 - 15 Single-use prefilled applicators.

Each applicator is wrapped and sealed in a foil overwrap.

Store at 20-25°C (68-77°F). [See USP controlled room temperature.]

Rx only

Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525 Distributed by: Watson Pharma, Inc., Morristown, NJ 07962 USA Manufactured by: Fleet Laboratories Ltd., Watford, Herts WD18 7JJ UK Revised: July 2010

Infertility Updates

single-Embryo transfer Associated with higher birth Rates and fewer Multiple births But single-center data appear unlikely to cause policy to spread

By Rosemary Frei, MSc

Toronto, Ontario – Allowing couples to have only single-embryo transfer (SET) during each cycle of in vitro fertilization (IVF) can be a viable policy, according to a study at the Center for Advanced Reproductive Care, University of Iowa Carver College of Medicine, Iowa City, Iowa. Data released at the Canadian Fertility and Andrology Society’s 2011 annual meeting, and in press in Fertility and Sterility, show that the live-birth rate has slightly increased since this policy was implemented on June 1, 2004, whereas multiple-birth rates have decreased by 50%.

After implementation of mandatory single-embryo transfer (mSET) at the center, live-birth rates increased from 51.1% to 55.9% and multiple-birth rates fell from 34.8% to 17.5%. The center mandates SET for women who are the best candidates for successful IVF, including those who are younger than 38 years and have never failed IVF. “Insurance companies are now giving us a bonus – they have for a few years – because we’re costing them less money since we’ve lowered our rates of twins and triplets, and they’re associated with higher levels of morbidity,” explained Ginny Ryan, MD, MA, assistant professor, Division of Reproductive Endo-

crinology and Infertility, University of Iowa Carver College of Medicine.

However, Carol Wheeler, MD, Center for Reproduction and Infertility, Women & Infants, Warren Alpert Medical School of Brown University, Providence, Rhode Island, commented that it is unlikely this policy will be implemented in other centers. “It is a

“Insurance companies are now giving us a bonus – they have for a few years – because we’re costing them less money since we’ve lowered our rates of twins and triplets, and they’re associated with higher levels of morbidity.”

—Ginny Ryan, MD, MA

very hard sell for patients; if they think there’s even a 1% higher chance of getting pregnant by having 2 embryos transferred rather than 1 – even if the data

show that’s not correct – they’re going to want 2,” said Dr Wheeler. “I can’t imagine mSET will spread in this country.…

It is a very competitive field, and while in Iowa there aren’t a lot of other clinics, in other states there are, so people will vote with their feet.”

Although the University of Iowa is 1 of only 2 fertility clinics in the state, Dr Ryan and her colleagues are hoping the policy will proliferate. “It is one strategy to stop the epidemic of iatrogenic multiple pregnancies,” she said, and added, “An effort has to be made to lobby local insurers to improve coverage based on mSET and the associated reduction in costs. I think it would be great if insurance companies said to patients, ‘We will fund your IVF if you go to this clinic because they follow best practices and have mSET.’” Meanwhile, Dr Ryan is hoping the data might bring some other clinics on board. Iowa is one of the majority of states in the US where insurance coverage is not mandated for IVF. In July 2004 the clinic brought mSET into effect for women who: • Are under age 38 and using autologous oocytes in a fresh embryo transfer • Have no history of failed IVF at the University of Iowa

• Have at least 6 blastocysts that are fit to be cultured • Have at least 1 ‘good’ or ‘excellent’ blastocyst on the day of embryo transfer The women who meet these criteria are given significant education about the benefits of SET and the risks associated with having twins.

Dr Ryan and her colleagues compared the 5-year period prior to mSET implementation, June 1, 1999, to May 31, 2004, to the 5-year period immediately after, June 1, 2004, to May 31, 2009.

They found their clinic’s volume was not significantly changed, with 2412 cycles in the first time period and 2389 in the second. Overall, they performed SET in 33.8% of cycles in women under 38 years of age. The live-birth rate significantly increased, despite a decrease in the average number of embryos transferred from 2.10 to 1.65. Furthermore, the multiplebirth rate dropped drastically.

The team also surveyed 462 patients in a separate study (Fertility and Sterility, in press). They found 94% of the patients supported the mSET policy. Moreover, 95% felt they had the “right amount of input” in their IVF treatment, and 87% said they believed they had the correct number of embryos transferred. n

Extremely low AMh levels Do Not Rule out In Vitro fertilization

by Wayne Kuznar

Orlando, FL – An extremely low level of anti-Müllerian hormone (AMH) is not an absolute contraindication for in vitro fertilization (IVF). Data obtained from women referred to the Center for Human Reproduction, New York City, for an evaluation for infertility revealed clinical pregnancies and live births in women with AMH levels ≤0.4 ng/mL, found Andrea Weghofer, MD, PhD. The data confirm the Center’s prior findings that suggested “surprisingly robust pregnancy chances, even at undetectable to extremely low AMH levels.” Dr Weghofer presented her findings in a poster at the 2011 meeting of the American Society for Reproductive Medicine. The study included 128 women with AMH levels ≤0.4 ng/mL who were referred for an infertility workup and subsequently started an

IVF cycle. An AMH level of ≤0.4 ng/mL was chosen because it was shown in the published literature to be a predictor of poor response to controlled ovarian hyperstimulation. The mean age of the patients was 40.8 years.

Prior to IVF, all women with diminished ovarian reserve were supplemented with dehydroepiandrosterone (DHEA), 25 mg 3 times daily, for at least 6 weeks. All women who underwent IVF received microdose agonist stimulation with a daily gonadotropin dosage of 600 IU. Ovulation induction and oocyte retrieval were performed in all women who presented with at least 1 follicle of 17 mm.

There were 20 clinical pregnancies recorded (7.9% per cycle start), 15.6% cumulatively, resulting in 13 live births in 12 women. Eight women miscarried.

Eight deliveries occurred after the first IVF cycle (6.3% per cycle start) and 4 after subsequent IVF cycles (3.2%).

In the 70 women 42 years old and younger, there were 16 clinical pregnancies that resulted in 10 deliveries. In the 58 women older than 42 years, there were 4 clinical pregnancies that resulted in 2 deliveries, which was a significantly lower rate of pregnancy chance and delivery compared with the younger cohort.

The data demonstrate a “moderate but still reasonable pregnancy chance and live birth rates” in women with AMH levels up to 0.4 ng/mL, according to Dr Weghofer, an attending faculty physician, Department of Gynecological Endocrinology and Reproductive Medicine, Medical University of Vienna; and an affiliate at the Center

for Human Reproduction. She also noted, “To the best of our knowledge, this represents the largest cohort of women with extremely compromised AMH levels who conceived and delivered in the course of assisted reproductive technology.”

Supplementation with DHEA has been demonstrated to improve pregnancy chances in women with diminished ovarian reserve. The findings in this study, therefore, may not apply to all women with low AMH levels, Dr Weghofer cautioned, but she concluded, “Though these post hoc observations need further confirmation in other (not treated with DHEA) patients, extremely low AMH levels do not seem to represent an appropriate marker for withholding fertility treatment.” n

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

13

Patient Awareness

fertility Awareness checkup

By Meike L. Uhler, MD

I

nfertility affects approximately 15% of the reproductive-age population, which is currently estimated at about 7.5 million people. Because of the high prevalence of this condition, as well as the media and Internet attention to this problem, young women and men are becoming increasingly aware of their own fertility potential.

In relation to other species, humans are poor reproducers, with an estimated 20% chance of conception monthly.

Meike Uhler, MD.

When the potential for miscarriage is factored in, the actual chance of conception falls to approximately 10% to 12% each month. This is largely due to the prevalence of chromosomal abnormalities of the oocytes, causing failed conception or miscarriage. In a woman younger than 35 years, it is estimated that 60% of eggs contain inherent chromosomal abnormalities. By age 40, this percentage increases to more than 80%, and by age 45, it is estimated that 90% of a woman’s eggs are affected.

The single most important factor in predicting pregnancy is the age of the female partner. It is commonly known that as age increases, the chance of pregnancy decreases. At the same time, the rate of spontaneous miscarriage and chance of having a child with chromosomal abnormality increases with increasing age. Both the age at which women are having their first child and the age of marriage are noted to be increasing. A recent study by the CDC showed that women in the US and other developed countries are waiting significantly longer before becoming pregnant than women of a generation ago. The average age of first-time mothers in the US jumped from 21.4 years in 1970 to 25 in 2009. The average age of marriage has similarly increased from 23 years in 1970 to 28.2 in 2010. As women choose to delay marriage and childbearing, the likelihood of future infertility increases. The monthly chance of achieving pregnancy gradually but significantly begins to decline at age 32 and decreases more rapidly after age 37.

The Fertility Awareness checkup at Fertility Centers of Illinois is a simple test performed on cycle day 3 that is composed of blood tests to check follicle stimulating hormone (FSH) and estradiol levels, an antral follicle count to measure ovarian reserve, and semen analysis to assess sperm parameters.

Ovarian reserve refers to the ability of the ovary to respond to ovulation induction treatment and produce a reasonable quantity and quality of oocytes, therefore enabling a woman to achieve

pregnancy. There are several methods to test for ovarian reserve, and the simplest include day 3 FSH and estradiol.

FSH is elevated due to the aging ovary not producing adequate amount of inhibin, the hormone that suppresses FSH. Estradiol is elevated due to an increase in FSH earlier in the menstrual cycle. An FSH level <10 mIU/mL and an estradiol level <70 pg/mL are considered within the range for normal

Patients are made aware that these tests do not guarantee future fertility, although the results may help them answer questions about when to start planning their family and what direction their family planning could most likely take.

ovarian reserve. Antral follicle count is another test of ovarian reserve performed on day 3 of the cycle. It uses transvaginal ultrasonography to measure small follicles <10 mm in diameter.

A bilateral total number of small follicles between 10 and 20 is considered within the range for normal ovarian reserve.

Since male infertility is a factor in

approximately 40% of all couples with difficulty achieving pregnancy, a semen analysis is an important step in the fertility assessment. The standard reference range for normal semen analyses is: volume 1.5 to 5 mL, concentration >15 million/mL, motility >40%, and strict morphology >14%. An abnormal test will most likely result in a recommendation to repeat the semen analysis with further follow-up as indicated.

This simple combination of 4 tests to check for ovarian reserve and semen quality constitutes the Fertility Awareness checkup. The results may be helpful to patients who will be making family planning decisions currently or in the near future. This evaluation is provided to patients at a low cost, and they receive the completed results within 1 week. The results do not give a definitive answer but may provide an estimate of a patient’s fertility potential. Patients are made aware that these tests do not guarantee future fertility, although the results may help them answer questions about when to start planning their family and what direction their family planning could most likely take. If patients decide to consult further with a physician, the evaluation fee is credited toward future treatment services.

While the exact causes of roughly one third of all fertility problems are still unknown, there are many reproductive dysfunctions that can be overcome with treatment. Identifying patients who require treatment is necessary to prevent future compounded infertility, and it all starts with a fertility assessment. n

Pelvic organ Prolapse May Respond to Nonsurgical treatments

By Rosemary Frei, MSc

E

vidence is accumulating that alternate approaches may give surgery a run for its money in treating pelvic organ prolapse.

A Cochrane Review examined whether selective estrogen receptor modulators (SERMs) are effective for preventing or treating pelvic organ prolapse in postmenopausal women (Ismail SI, et al. Cochrane Database Syst Rev. 2010;9:CD007063). Although only 1 meta-analysis and 2 original trials met the investigators’ inclusion criteria and

14

had “meaningful” data, the researchers concluded that 1 SERM, oral raloxifene (Evista, Lilly USA), may reduce the need for pelvic organ prolapse surgery in women aged older than 60 years.

However, they stressed that long-term, rigorous, randomized, controlled trials are needed to verify whether estrogen preparations are indeed useful in this application.

The review was conducted by a team led by Sharif Ismail, MD, attending physician, Urogynecology Unit,

FEbRUARY/MARCH 2012 l VOLUME 4, NUMBER 1

Singleton Hospital, Swansea, Wales. Dr Ismail noted that the study was undertaken because estrogens are used in clinical practice – often as adjuncts to improve the prolapse outcomes from other treatments, such as surgery or diaphragm-type devices – without clear evidence to support these practices.

Overall, the 2 trials and 1 secondary analysis of 3 studies included in the Cochrane Review showed a significant reduction in the need for surgery for pelvic organ prolapse in women aged

older than 60 years treated with raloxifene and tamoxifen.

“I’d like to stress that raloxifene is not normally used for pelvic organ prolapse, and hence, this potential reduction in the need for pelvic organ prolapse surgery needs further investigation,” Dr Ismail said.

Matthew Barber, MD, associate professor of surgery, Center of Urogynecology and Reconstructive Pelvic Surgery, Cleveland Clinic Lerner Continued on page 15

Nonsurgical Intervention

Pelvic organ Prolapse…

Continued from page 14

College of Medicine, Case Western Reserve University, and vice-chair of clinical research, OB/GYN & Women’s Health Institute, Cleveland Clinic, agreed that more research is needed. “I don’t think we have enough information to say whether estrogen or SERMs are going to be helpful for treating or preventing prolapse,” Dr Barber said. “Some studies have suggested that postmenopausal hormone replacement can actually predispose women to stress urinary incontinence, a condition related to prolapse, so it is important that more rigorous studies be performed before advocating estrogen or SERMS for prolapse generally.”

“Raloxifene is not normally used for pelvic organ prolapse, and hence, this potential reduction in the need for pelvic organ prolapse surgery needs further investigation.”

—Sharif Ismail, MD

Dr Ismail’s co-investigator, Suzanne Hagen, PhD, led an earlier Cochrane Review on conservative management of pelvic organ prolapse (Hagen S, et al.

Cochrane Database Syst Rev. 2006;4:CD003882). She and her colleagues had also concluded that there was insufficient evidence to make a recommendation and could not advise clinicians whether their patients should receive pelvic floor muscle training.

Ingeborg Hoff Braekken, PhD, PT, and colleagues at the Department of Sports Medicine, Norwegian School of Sport Sciences in Oslo, Norway recently attempted to fill this void with a medium-sized trial (Braekken IH, et al.

Am J Obstet Gynecol. 2010;203:170.e1-

7). They randomly assigned 59 women with prolapse stages I, II, and III to pelvic floor muscle training, and randomized another 50 women to standard treatment, including learning how to contract their pelvic floor muscles before and during increases in abdomi-

nal pressure.

Among women in the pelvic floor muscle training group, 19% (11) improved by 1 Pelvic Organ Prolapse Quantification System stage, compared with 8% (4) in the control group. The pelvic floor muscle training group also experi-

enced a significantly greater elevation in the bladder and rectum, and re-duced frequency and bother of symptoms.

“Pelvic floor muscle training is without adverse effects and can be used as treatment for prolapse,” the investigators concluded. n

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Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

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