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dECEMBER 2011

www.INFERTILITyREPRONEwS.COM

VOL 3, NO 6

ASRM ANNUAL MEETING

CLINIC PROFILE

Innovation and Intimacy at Main Line Fertility Center Interview with Sharon H. Anderson, PhD, HCLD; Michael J. Glassner, MD; and John J. Orris, DO, MBA Main Line Fertility Center, Bryn Mawr, PA

Personhood Amendment Fails in Mississippi, but the Heat Still On in Other States By Wayne Kuznar

Orlando, FL—Personhood legislation or amendments to state constitutions, which would establish legal personhood beginning at any stage of fetal development, remain a threat to reproductive health, believes the National Infertility Association (RESOLVE) and the American Society for Reproductive Medicine (ASRM). Such amendments are clearly intended to outlaw abortion but have the potential to affect assisted reproductive technology, said Barbara Collura, execu-

tive director of RESOLVE, at a press conference during the ASRM’s 2011 annual meeting (3 weeks before the Mississippi vote). Although a ballot measure to amend the Mississippi state constitution that life begins at fertilization (known as Initiative 26) recently failed, the main proponent of the measure, Personhood USA, is pushing similar ballot initiatives in 2012 and beyond in other states. Similar initiatives have failed at the polls twice in Colorado. Continued on page 5

From left: William H. Pfeffer, MD; John J. Orris, DO, MBA; and Michael J. Glassner, MD; Main Line Fertility Center.

M

ain Line Fertility Center has been serving the needs of men and women requiring fertility services in Philadelphia and its surrounding area for more than 20 years, with a commitment to providing the most up-to-date fertility techniques and innovations in patient care and preserving the patient–clinician intimate

interaction. Infertility & Reproductive News asked Drs Anderson, Glassner, and Orris to describe their approach to infertility care.

Q: What motivated you to open your fertility center? We founded our center in November 1998 to pursue our commitment to Continued on page 9

New Eggs for Old?

Coenzyme Q10 May Boost Quality of Older Women’s Oocytes By Rosemary Frei, MSc

Toronto, Canada—The reproductive world is abuzz about research being conducted in Toronto that shows eggs from older women can perhaps be rejuvenated. Studies presented at the 2011 Canadian Fertility and Andrology Society annual meeting indicate that administering coenzyme Q10 (CoQ10) to 1-

year-old mice—the equivalent of women in their 40s—for 3 or 4 months significantly increases the number of ovulated oocytes and the number of successful pregnancies. The same team, from the University of Toronto and the Samuel Lunenfeld Research Institute of Mount Sinai Continued on page 8

The Publicationof of The Official Offical Publication

We thank Watson Pharmaceuticals, Inc., for their gold level support. ©2011 Novellus Healthcare Communications, LLCs

Tranexamic Acid Reduces Heavy Menstrual Bleeding Sleep Interruptions Are Also Reduced By Caroline Helwick

Washington, DC—Menorrhagia was effectively treated, and the effects were durable, in women who received oral tranexamic acid (TA) treatment in a phase 3, randomized, double-blind clinical trial reported at the ACOG 2011 annual meeting. In a separate analysis of this study also presented at the meeting, the drug significantly reduced sleep interruptions in these women. TA is a competitive plasmin inhibitor thought to reduce the excessive fibrino-

lysis in the endometrium of women with heavy menstrual bleeding. The drug is the only oral nonhormonal prescription medication that is US Food and Drug Administration–approved specifically for menorrhagia. “TA is an effective option for women with heavy menstrual bleeding,” said David Archer, MD, of Eastern Virginia Medical School in Norfolk. “The drug significantly reduced menstrual blood loss in this study.” The multicenter US study included Continued on page 7

INS IDE ASRM ANNUAL MEETING

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INFERTILITY UPDATES

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Are your IVF patients following their lifestyle instructions?

Should obesity be a barrier to fertility treatment?

Vaginal progesterone as effective as IM progesterone

Competing PDG technologies presented at infertility meeting

Women of childbearing age lacking fertility knowledge

Primary ovarian insufficiency still often neglected

ART nurses’ practices fraught with interruptions

WOMEN’S HEALTH

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LEGAL UPDATE . . . . . . . . . . . . . . . . .

Breastfeeding important in childhood cancer survivors

Mississippi Initiative 26: implications for reproductive health

Advantage shown for collaborative physician/midwifery OB program

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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


In This Issue WWW.INFERTILITYREPRONEWS.COM PUBLISHING STAFF

Publisher Russell Hennessy russell@novellushc.com 732-992-1888

CLINIC PROFILE Innovation and individualized care focus of Main Line Fertility Center

Editorial Director Dalia Buffery dalia@novellushc.com 732-992-1889

ASRM ANNUAL MEETING Are your IVF patients following their lifestyle instructions?

Associate Editor Lara Lorton 732-992-1892

Vaginal progesterone as effective as IM progesterone in women with PCOS

Editorial Assistant Jennifer Brandt

Women of childbearing age lacking fertility knowledge

Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto

INFERTILITY UPDATES

Should obesity be a barrier to fertility treatment? Competing PDG technologies presented at infertility meeting Primary ovarian insufficiency still often neglected More… WOMEN’S HEALTH Breastfeeding may be compromised but important in childhood cancer survivors

ART nurses’ practices fraught with interruptions Maternal drug exposure declining, less cocaine abuse More… LEGAL UPDATE Mississippi Initiative 26: implications for reproductive health

Advantage shown for collaborative physician/midwifery OB program More…

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 6 times a year by Novellus Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831. Copyright ©2011 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. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issue, $17.00. Orders will be billed at individual rates unless proof of status is confirmed. SUBSCRIPTIONS/CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, OB/GYN Nurse, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831; Fax: 732-656-7938.

ASRM Annual Meeting

Personhood Amendment Fails... ASRM released a statement shortly after the failed Mississippi ballot initiative, saying, “We are pleased the people of Mississippi did not accept this dangerous measure that would have endangered access to reproductive health care. We hope policymakers in other states will take note: the American people do not want government coming between physicians and their patients and will not accept policy on reproductive health care being controlled by extremists. Our members are pleased they will be able to continue to provide the citizens of Mississippi with full access to the reproductive health care they need.” Given the uncertain status of embryos, personhood amendments could hinder in vitro fertilization (IVF) attempts, Ms Collura said. If embryos are full humans, any act that puts an embryo at risk could be a criminal violation, including the practice of cryopreservation. The parties who would have legal responsibility for fertilized eggs created during fertility treatment but not transferred to a woman’s uterus would be unclear. Passage of personhood amendments could increase the number of multiple births and the associated health concerns if all embryos created from IVF cycles had to be transferred. Added Sean Tipton, Director of Public Affairs, ASRM, “Because these amendments are not worded using any clear scientific or legal definitions, it’s impossible to say what they would do. The wording has varied from state to state.”

“To RESOLVE, these amendments are antifamily and we’re working hard to defeat them,” said Ms Collura. In Mississippi, ASRM and RESOLVE were members of a coalition to oppose the personhood amendment; RESOLVE recruited women who created their families through IVF to talk about their experience through the media. “We tried to make it very personal,” she said. “In Colorado, we had a woman create a video that was played on the Internet, and we had a family who brought their child to a press conference

“Because these amendments are not worded using any clear scientific or legal definitions, it’s impossible to say what they would do.” —Sean Tipton

talking about the creation of their family through IVF and what personhood would mean to them.” Strategies for defeating such amendments will vary by state, as some bills are being introduced into the legislature and others are appearing on ballots as proposed amendments to state constitutions. In states where personhood bills are in the process of going through the leg-

Continued from page 1

Takeaway quick PoinTs ➤ Initiatives in several states are seeking to establish legal “personhood” for embryos at the time of fertilization ➤ This can potentially threaten access to infertility treatment, including IVF and cryopreservation ➤ ASRM issued a statement saying, “The American people do not want government coming between physicians and their patients and will not accept policy on reproductive health care being controlled by extremists”

islature, RESOLVE prepares physicians for testimony. “We’re focused on trying to get the patient story out there and couple it with information from doctors in that state who are willing to talk to the media,” said Ms Collura. She suggests that professionals who work at fertility clinics or in obstetrics and gynecology offices act as spokespeople to inform the public about the potential ramifications of personhood legislature on the practice of reproductive medicine. Alerting your patient database directly to spread the word about such legislative issues is another strategy. The health professional “does not have to get in the middle but can refer patients to RESOLVE,” she said. “In that way, they can activate former patients or current patients who might like to speak out.” ■

december 2011 I VOLUME 3, NUMBER 6

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From the Editor

Nurses Join Forces

A

s the year draws to an end, I would like to extend a warm thank you to everyone who has contributed articles this year to make our publication a continued success. Your expertise has been enjoyed by many nurses and other fertility clinicians throughout the country. Although we, as nurses, benefit from the wealth of knowledge that physicians can provide, I strongly encourage more nurses to submit articles to our journal. Our original plan was to provide a journal for nurses, by nurses. It is important that we share our experiences, research, and pilot programs with others in the field. We are each other’s support system. By sharing your professional experiences, you may encourage others

to think out of the box. Sometimes we need to see others succeed before we venture out on our own. Don’t be shy. We welcome all nurses who have an interest in infertility and OB/GYN to introduce themselves to our community and share their ideas in helping all of us to provide the best care possible for our patients. Maybe it could be your New Year’s resolution. We would love to hear from you. In closing, I would like to wish everyone a Happy and Successful New Year! Debra Moynihan, WHNP-BC, MSN Co-Editor-in-Chief

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

6

DEcEMbER 2011 l VOLUME 3, NUMBER 6


ACOG Highlights

Tranexamic Acid Reduces Heavy... 196 women (aged, 18-49 years) who had heavy menstrual bleeding, defined as blood loss >60 mL during the first pretreatment cycle, and mean baseline loss ≥80 mL, as measured by a validated alkaline hematin method. The women were randomized in a 2:1 ratio to TA 1.3 g or to placebo 3 times daily for up to 5 days per menstrual cycle. Treatment was initiated at the onset of heavy bleeding and was continued for 6 cycles. Efficacy was determined by measuring menstrual bloodloss volume from all soiled sanitary products collected during the study. Blood loss was significantly Reduced Three fourths of each group completed the study; they were included in the intention-to-treat analysis of women who received at least 1 dose of study drug, had a baseline evaluation, and had sufficient daily primary efficacy data to construct 1 period of data after the first dose of study drug.

“TA is an effective option for women with heavy menstrual bleeding. The drug significantly reduced menstrual blood loss in this study.” —David Archer, MD

often an under-recognized consequence of cyclic heavy menstrual bleeding.” Women in the TA group reported a significant reduction in the mean number of sleep interruptions compared with baseline and compared with the placebo group. The mean reduction was 0.99 with TA and 0.7 with

Continued from page 1

placebo, Dr Muse reported. The most common adverse events that were possibly related to treatment included headache, nausea, menstrual discomfort, and diarrhea. Three women from each arm withdrew from the study due to adverse events. Gastrointestinal and ophthalmic events have been concerns with this

drug, Dr Archer acknowledged, but in this study the incidence of such adverse events was similar for drugand placebo-treated patients. “We believe that TA provides a good first-line, oral, non-hormonal and nonsurgical treatment option for cyclic heavy menstrual bleeding,” Dr Archer said. ■

FOR CYCLIC HEAVY MENSTRUAL BLEEDING...

WHEN SHE WANTS A NON-HORMONAL WAY OUT OF HER HEAVY PERIODS LYSTEDA CAN HELP ®

™LYSTEDA cannot induce clot formation because it acts downstream from coagulation* ™ Efficacy seen as soon as her next period and every period thereafter ™Studied long-term in a 27-cycle study across a range of patients *If a patient were to have a spontaneous thrombus independent of LYSTEDA, the breakdown of that thrombus could potentially be slowed by LYSTEDA. LYSTEDA is contraindicated in women with active thromboembolic disease or a history or intrinsic risk of thrombosis or thromboembolism, including retinal vein or artery occlusion; or known hypersensitivity to tranexamic acid.

TA proved very effective in reducing blood loss, Dr Archer said. The women treated with TA had a significant 40% reduction in menstrual blood loss from baseline, amounting to 69.6 mL less blood. Those randomized to placebo also had a significant, although much smaller, 12.6-mL (8.2%) reduction. The reductions in blood loss with TA were first observed during the first cycle and were maintained for 6 cycles. The improvement observed in the first cycle in the placebo arm was not maintained. Fewer sleep Interruptions “Women who experience heavy menstrual bleeding often present to a healthcare provider because of the subsequent negative impact on their daily lives and activities,” said Ken Muse, MD, of the University of Kentucky, who presented the data on the drug’s impact on sleep interruptions. “Sleep interruptions caused by waking in the night to change sanitary products are

LYSTEDA® (tranexamic acid) tablets are indicated for the treatment of cyclic heavy menstrual bleeding. Prior to prescribing LYSTEDA, exclude endometrial pathology that can be associated with heavy menstrual bleeding. Important Safety Information The risk of thrombotic and thromboembolic events may increase further when hormonal contraceptives are administered with LYSTEDA, especially in women who are obese or smoke cigarettes. Women using hormonal contraception should use LYSTEDA only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event. Do not use LYSTEDA in women who are taking more than the approved dose of a hormonal contraceptive. Concomitant use of LYSTEDA with Factor IX complex concentrates, anti-inhibitor coagulant concentrates or all-trans retinoic acid (oral tretinoin) may increase risk of thrombosis. Visual or ocular adverse effects may occur with LYSTEDA. Immediately discontinue use if visual or ocular symptoms occur. In case of severe allergic reaction, discontinue LYSTEDA and seek immediate medical attention. Cerebral edema and cerebral infarction may be caused by use of LYSTEDA in women with subarachnoid hemorrhage. Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The most common adverse reactions in clinical trials (*5%, and more frequent in LYSTEDA subjects compared to placebo subjects) were: headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle cramps, migraine, anemia, and fatigue. LYSTEDA has not been studied in adolescents under age 18 with heavy menstrual bleeding.

For more information and valuable patient offers, please visit www.LYSTEDA.com. Please see Brief Summary of Prescribing Information on adjacent page.

©2011 Ferring Pharmaceuticals Inc.

Lysteda.com

09/11

LYS-A16436

DEcEMbER 2011 l VOLUME 3, NUMBER 6

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Infertility Update

new eggs for... Hospital, is now conducting a randomized, placebo-controlled study of CoQ10 in women. The premise of the experiments is that because CoQ10 boosts energy production in the mitochondria, extra doses of this coenzyme may give oocytes the boost they need to go through meio-

Continued from page 1

sis normally and hence become highquality eggs. CoQ10 is produced by every cell in the body, but production starts to drop drastically at about age 30; hence, exogenous sources can begin to play an important role in older women. “We expect a good result from the human studies,” Yaakov Bentov, MD,

LYSTEDA® (tranexamic acid) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please consult package insert for full Prescribing Information INDICATIONS AND USAGE LYSTEDA® (tranexamic acid) Tablets is indicated for the treatment of cyclic heavy menstrual bleeding. Prior to prescribing LYSTEDA, exclude endometrial pathology that can be associated with heavy menstrual bleeding. CONTRAINDICATIONS Thromboembolic Risk: Do not prescribe LYSTEDA to women who are known to have the following conditions: active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis); a history of thrombosis or thromboembolism, including retinal vein or artery occlusion; an intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy). Venous and arterial thrombosis or thromboembolism, as well as cases of retinal artery and retinal vein occlusions, have been reported with tranexamic acid. Hypersensitivity to Tranexamic Acid: Do not prescribe LYSTEDA to women with known hypersensitivity to tranexamic acid [see Warnings and Precautions and Adverse Reactions]. WARNINGS AND PRECAUTIONS Thromboembolic Risk: Concomitant Use of Hormonal Contraceptives: Combination hormonal contraceptives are known to increase the risk of venous thromboembolism, as well as arterial thromboses such as stroke and myocardial infarction. Because LYSTEDA is antifibrinolytic, the risk of venous thromboembolism, as well as arterial thromboses such as stroke, may increase further when hormonal contraceptives are administered with LYSTEDA. This is of particular concern in women who are obese or smoke cigarettes, especially smokers over 35 years of age [see Contraindications and Drug Interactions]. Women using hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of LYSTEDA, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of LYSTEDA with hormonal contraceptives. There have been US postmarketing reports of venous and arterial thrombotic events in women who have used LYSTEDA concomitantly with combined hormonal contraceptives. Women using hormonal contraception, especially those who are obese or smoke, should use LYSTEDA only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event. Do not use LYSTEDA in women who are taking more than the approved dose of a hormonal contraceptive. Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates: LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Drug Interactions]. All-Trans Retinoic Acid (Oral Tretinoin): Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Drug Interactions]. Ocular Effects: Retinal venous and arterial occlusion has been reported in patients using tranexamic acid. Patients should be instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed to discontinue LYSTEDA immediately and should be referred to an ophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination, to exclude the possibility of retinal venous or arterial occlusion. Severe Allergic Reaction: A case of severe allergic reaction to LYSTEDA was reported in the clinical trials, involving a subject who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. A case of anaphylactic shock has also been reported in the literature, involving a patient who received an intravenous bolus of tranexamic acid. Subarachnoid Hemorrhage: Cerebral edema and cerebral infarction may be caused by use of LYSTEDA in women with subarachnoid hemorrhage. Ligneous Conjunctivitis: Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The conjunctivitis resolved following cessation of the drug. ADVERSE REACTIONS Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Short-term Studies: The safety of LYSTEDA in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, double-blind, placebo-controlled studies. One study compared the effects of two doses of LYSTEDA (1950 mg and 3900 mg given daily for up to 5 days during each menstrual period) versus placebo over a 3-cycle treatment duration. A total of 304 women were randomized to this study, with 115 receiving at least one dose of 3900 mg/day of LYSTEDA. A second study compared the effects of LYSTEDA (3900 mg/day) versus placebo over a 6-cycle treatment duration. A total of 196 women were randomized to this study, with 117 receiving at least one dose of LYSTEDA. In both studies, subjects were generally healthy women who had menstrual blood loss of ≥80 mL. In these studies, subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21-35 days, and a BMI of approximately 32 kg/m2. On average, subjects had a history of HMB for approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were Caucasian, 25% were Black, and 5% were Asian, Native American, Pacific Islander, or Other. Seven percent (7%) of all subjects were of Hispanic origin. Women using hormonal contraception were excluded from the trials. The rates of discontinuation due to adverse events during the two clinical trials were comparable between LYSTEDA and placebo. In the 3-cycle study, the rate in the 3900 mg LYSTEDA dose group was 0.8% as compared to 1.4% in the placebo group. In the 6-cycle study, the rate in the LYSTEDA group was 2.4% as compared to 4.1% in the placebo group. Across the studies, the combined exposure to 3900 mg/day LYSTEDA was 947 cycles and the average duration of use was 3.4 days per cycle. The following adverse events occurred in ≥5% of subjects and more frequently in LYSTEDA-treated subjects receiving 3900 mg/day (N=232) compared to placebo (N=139). The total number of adverse events reported with LYSTEDA was 1500 versus 923 with placebo. The number of subjects with at least one adverse event was 208 (89.7%) with LYSTEDA versus 122 (87.8%) with placebo. The following adverse events reported in LYSTEDA-treated subjects receiving 3900 mg/day and placebo, respectively, were (n/%): headache (includes headache and tension headache): 117 (50.4%), 65 (46.8%); nasal & sinus symptoms (includes nasal, respiratory tract and sinus congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis and sinus pain, and multiple allergies and seasonal allergies): 59 (25.4%), 24 (17.3%); back pain: 48 (20.7%), 21 (15.1%); abdominal pain (includes abdominal tenderness and discomfort): 46 (19.8%), 25 (18.0%); musculoskeletal pain (includes musculoskeletal discomfort and myalgia): 26 (11.2%), 4 (2.9%); arthralgia (includes joint stiffness and swelling): 16 (6.9%), 7 (5.0%); muscle cramps & spasms: 15 (6.5%), 8 (5.8%); migraine: 14 (6.0%), 8 (5.8%); anemia: 13 (5.6%), 5 (3.6%); and fatigue: 12 (5.2%), 6 (4.3%). Long-term Studies: Long-term safety of LYSTEDA was studied in two open-label studies. In one study, subjects with physician-diagnosed heavy menstrual bleeding (not using the alkaline hematin methodology) were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 27 menstrual cycles. A total of 781 subjects were enrolled and 239 completed the study through 27 menstrual cycles. A total of 12.4% of the subjects withdrew due to adverse events. Women using hormonal contraception were excluded from the study. The total exposure in this study to 3900 mg/day LYSTEDA was 10,213 cycles. The average duration of LYSTEDA use was 2.9 days per cycle. A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 9 menstrual cycles. A total of 288 subjects were enrolled and 196 subjects completed the study

©2011 Ferring Pharmaceuticals Inc.

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DEcEMbER 2011 l VOLUME 3, NUMBER 6

one of the investigators involved in the clinical trial along with lead investigator Robert Casper, MD, told Infertility & Reproductive News. “This is because the ovary is one of the best sites of absorption of CoQ10, and because there have been studies published indicating that other types of function can be restored

through 9 menstrual cycles. A total of 2.1% of the subjects withdrew due to adverse events. The total exposure to 3900 mg/day LYSTEDA in this study was 1,956 cycles. The average duration of LYSTEDA use was 3.5 days per cycle. The types and severity of adverse events in these two long-term open-label trials were similar to those observed in the double-blind, placebo-controlled studies although the percentage of subjects reporting them was greater in the 27-month study, most likely because of the longer study duration. A case of severe allergic reaction to LYSTEDA was reported in the extension trial, involving a subject on her fourth cycle of treatment, who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. Postmarketing Experience: The following adverse reactions have been identified from postmarketing experience with tranexamic acid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Based on US and worldwide postmarketing reports, the following have been reported in patients receiving tranexamic acid for various indications: nausea, vomiting, and diarrhea, allergic skin reactions, anaphylactic shock and anaphylactoid reactions, thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction), impaired color vision and other visual disturbances, dizziness. DRUG INTERACTIONS No drug-drug interaction studies were conducted with LYSTEDA. Hormonal Contraceptives: Because LYSTEDA is antifibrinolytic, concomitant use of hormonal contraception and LYSTEDA may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. Women using hormonal contraception should use LYSTEDA only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event [see Warnings and Precautions]. Tissue Plasminogen Activators: Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both LYSTEDA and tissue plasminogen activators. Therefore, exercise caution if a woman taking LYSTEDA therapy requires tissue plasminogen activators. Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates: LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Warnings and Precautions]. All-Trans Retinoic Acid (Oral Tretinoin): Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy (Category B): LYSTEDA is not indicated for use in pregnant women. Reproduction studies have been performed in mice, rats and rabbits and have revealed no evidence of impaired fertility or harm to the fetus due to tranexamic acid. However, tranexamic acid is known to cross the placenta and appears in cord blood at concentrations approximately equal to the maternal concentration. There are no adequate and well-controlled studies in pregnant women. An embryo-fetal developmental toxicity study in rats and a perinatal developmental toxicity study in rats were conducted using tranexamic acid. No adverse effects were observed in either study at doses up to 4 times the recommended human oral dose of 3900 mg/day based on mg/m2 (actual animal dose 1500 mg/kg/day). Nursing Mothers: Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentration. LYSTEDA should be used during lactation only if clearly needed. Pediatric Use: LYSTEDA is indicated for women of reproductive age and is not intended for use in premenarcheal girls. LYSTEDA has not been studied in adolescents under age 18 with heavy menstrual bleeding. Geriatric Use: LYSTEDA is indicated for women of reproductive age and is not intended for use by postmenopausal women. Renal Impairment: The effect of renal impairment on the pharmacokinetics of LYSTEDA has not been studied. Because tranexamic acid is primarily eliminated via the kidneys by glomerular filtration with more than 95% excreted as unchanged in urine, dosage adjustment in patient with renal impairment is needed. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of LYSTEDA has not been studied. Because only a small fraction of the drug is metabolized, dosage adjustment in patients with hepatic impairment is not needed. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Carcinogenicity studies with tranexamic acid in male mice at doses as high as 6 times the recommended human dose of 3900 mg/day showed an increased incidence of leukemia which may have been related to treatment. Female mice were not included in this experiment. The dose multiple referenced above is based on body surface area 2 (mg/m ). Actual daily dose in mice was up to 5000 mg/kg/day in food. Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. Mutagenesis: Tranexamic acid was neither mutagenic nor clastogenic in the in vitro Bacterial Reverse Mutation Assay (Ames test), in vitro chromosome aberration test in Chinese hamster cells, and in in vivo chromosome aberration tests in mice and rats. Impairment of Fertility: Reproductive studies performed in mice, rats and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. In a rat embryo-fetal developmental toxicity study, tranexamic acid had no adverse effects on embryo-fetal development when administered during the period of organogenesis (from gestation days 6 through 17) at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. In a perinatal-postnatal study in rats, tranexamic acid had no adverse effects on pup viability, growth or development when administered from gestation day 6 through postnatal day 20 at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. The dose multiples referenced above are based on body surface area (mg/m2). Actual daily doses in rats were 300, 750 or 1500 mg/kg/day. Animal Toxicology and/or Pharmacology: Ocular Effects: In a 9-month toxicology study, dogs were administered tranexamic acid in food at doses of 0, 200, 600, or 1200 mg/kg/day. These doses are approximately 2, 5, and 6 times, respectively, the recommended human oral dose of 3900 mg/day based on AUC. At 6 times the human dose, some dogs developed reversible reddening and gelatinous discharge from the eyes. Ophthalmologic examination revealed reversible changes in the nictitating membrane/conjunctiva. In some female dogs, the presence of inflammatory exudate over the bulbar conjunctival mucosa was observed. Histopathological examinations did not reveal any retinal alteration. No adverse effects were observed at 5 times the human dose. In other studies, focal areas of retinal degeneration were observed in cats, dogs and rats following oral or intravenous tranexamic acid doses at 6-40 times the recommended usual human dose based on mg/m2 (actual animal doses between 250-1600 mg/kg/day).

Rx only This summary provides important information about LYSTEDA. For full prescribing information, please visit www.Lysteda.com.

LYS-14746-A

“We used to think that egg ‘quality’ was something that is fixed, but with CoQ10, there is a shift in the paradigm about how we think about eggs, in that there might now be a way to change egg quality, and that is exciting.” —Jason Hitkari, MD

by administering CoQ10, such as correction of muscle weakness.” Jason Hitkari, MD, attended the presentation of the data at the meeting. Dr Hitkari is Codirector of Genesis Fertility Centre and Clinical Associate Professor, University of British Columbia, Vancouver, and is not involved in these studies. “We used to think that egg ‘quality’ was something that is fixed, but with CoQ10, there is a shift in the paradigm about how we think about eggs, in that there might now be a way to change egg quality, and that is exciting,” said Dr Hitkari. The team conducted 4 sequential animal experiments. Each involved 80 1year-old mice which had been bred previously and hence were known to be fertile. Half of the mice acted as controls and the other half were given twiceweekly CoQ10 injections for 3 or 4 months before oocyte analysis or mating. “We found the treated mice had nearly double the number of ovulated oocytes of the controls,” said Andrea Jurisicova, PhD, lead investigator and Associate Professor of Obstetrics and Gynecology, University of Toronto. As a result, the treated mice also had an average of 11 pups per litter compared with 6 per litter for the agematched controls. Furthermore, 100% of the treated mice became pregnant compared with 70% of the controls. The team is now conducting a human study. More than 30 women of an expected 54 have been recruited. The women in the study arm will receive oral CoQ10 600 mg daily for 2 months, after which they will begin in vitro fertilization (IVF) treatments. “We still do not know what the ideal treatment period is with CoQ10. It may be as long as 6 months, since this is how long it takes for follicles to mature in humans. But it would be unethical to ask women to delay their IVF this long,” noted Dr Bentov. ■


Clinic Profile

Innovation and Intimacy at Main line... high-quality patient care for people with fertility problems. Our center has become the largest fertility program in Pennsylvania. We emphasize individualized care, without losing the intimacy of the doctor–patient relationship. We have a dedicated team of nurse practitioners who help to maintain the care continuity. In addition to dealing with the aspects of medical treatment, we also focus on the emotional well-being of the patient throughout the fertility treatment process. In our practice, we never overextend ourselves. We maintain our integrity at the core to stay strong in all aspects. We do not gamble with trying to become something that we are not. We serve the Main Line area in the greater Philadelphia region, but we are attracting many new patients from outside the area via our website. We pride ourselves on proactively pursuing new and innovative technologies to be the first to introduce them in our region. We are most proud that our center has grown. We have diligently kept up with staffing our center with people who are kind and caring, and who understand the importance of what we do. Patients come because they do not feel like they are a number.

What are some of these technologies and innovations? We had the first program in the area to do array comparative genomic hybridization (aCGH) testing, which is generating tremendously improved pregnancy rates. Doing the aCGH allows us to study embryos for aneuploidy and improve our success. We perform a day 5 blastocyst biopsy for aCGH, followed by a day 6 fresh embryo transfer, which has led to excellent pregnancy rates compared with the conventional day 3 embryo biopsy. We also are doing a preimplantation genetic diagnosis (PGD) study to see if PGD of embryos improves pregnancy rates. In addition, we work with the Tay Sachs Foundation and with the Fragile X Foundation to assist people in preventing propagation of genetic diseases through the use of PGD. As a private institution, we have been able to pioneer certain technologies, such as the egg-freezing program, which now is branching into creating a frozen egg bank, similar to the frozen sperm bank. The frozen egg bank cuts the price of fresh donor egg by almost half. Furthermore, just as fresh sperm insemination using donors is restricted by the US Food and Drug Administration, we believe the same restrictions will eventually be applied to the egg bank.

We also take pride in our pro bono work with the Children’s Hospital of Philadelphia (CHOP), where we are actively involved in fertility preservation for young men and women who have cancer.

Sharon H. Anderson, PhD, HCLD

It is thought that young people should take the time to have a reproductive health physical. Having this information about one’s personal health has an advantage down the road when they want to achieve pregnancy.

Could you elaborate on your work with fertility preservation? We work with oncologists at CHOP, and treat young male patients who are diagnosed with cancer and wish to preserve their sperm. This is done with little or no fee to the patient, with the hope to provide them the ability to procreate later in life, once their cancer treatment is over. For the boys, we simply freeze their sperm. They have to reach puberty and to be able to generate sperm, which is the one limitation. As far as fertility preservation for women, if the patient is old enough (again at puberty), we do controlled ovarian hyperstimulation to extract their eggs and freeze them through vitrification. If the patient had at least one period, we can stimulate the ovaries and extract eggs from her.

How do the kids react to the fertility preservation process? It is a little scary for them, but the

Continued from page 1

hospital offers very good education for fertility preservation. They offer excellent emotional support to the parents and the children to provide them the confidence they need to proceed with the procedures. Our goal is to bring normality to their future, which we hope will allow them to have a genetic child of their own. It is one of the best things one can do to give back to society. The experience they had battling cancer, overcoming it, and then having offspring, is going to make them excellent human beings in the way that they conduct themselves and give back to society. We do a great deal for women undergoing treatment for breast cancer, such as the removal of their ovaries. When they are scheduled for chemotherapy or radiation, we make every effort to get the patient in to our clinic the next day to set up a treatment plan to optimize their chances of fertility preservation. We are not freezing ovarian or testicular tissue. We are on the front-lines of retrieving the oocytes and the sperm, so that they can be used at a later date.

What have you learned from your work with young people with cancer? It has made us realize the importance of fertility awareness for youth. It is our thought that young people should take the time to have a reproductive health physical. Having this information about one’s personal health has an advantage down the road when they want to achieve pregnancy. Understanding their reproductive health today will allow young people to proactively address any potential problems in the future. Most insurance companies will cover a reproductive health physical to validate one’s fertility capacity. We recommend that young men and women in their late 20s or 30s do a reproductive health physical, because the majority of people we know that would contemplate getting pregnant are in that age range. We also see a second tier coming in their late 30s, but it is beneficial to get a reproductive physical in the mid- to late-20s.

What does a reproductive physical include? In men, we would look at the use of anabolic steroids and the use of medications that could compromise sperm function. Men are taking medications to reduce androgens, treat hair loss, or men who have had trauma to their testicles, and those who have had inguinal hernia repairs or have had undescended testicle surgery as a child. We see many problems with kids, who

had undescended testicles or inguinal hernias when they were infants and had surgery, with compromised semen parameters. This can be identified, proactively, through a simple semen analysis. Having chronic diseases later in life, including diabetes, hypertension, or being overweight, could affect their fertility. So, a man may want to find out if he has low sperm count in his 20s, and this is all covered by insurance. For women, it will be helpful to see evidence of endometriosis in a woman who is 25 years old, or a uterine fibroid that is small. She will eventually need more surveillance than a manual examination. Anyone with a tubal occlusion should undergo a laparoscopy to find the reason for that and not be surprised when she is 36 and wants to have a child. A good history and physical examination, as well as a few cost-effective blood tests, will give them insight into their reproductive potential and if needed, do things that will preserve their reproductive potential.

Your center is also involved in clinical trials. What do you hope to achieve by that? The state of the economy and our desire to be academically competitive has led us to partner with many organizations and companies with meaningful clinical trials that will afford patients the ability to participate in trials and undergo procedures that are more advanced and often prohibitive from a cost perspective for many individuals. This is a win–win situation. We serve to advance science, accumulate knowledge, and improve our field. At the same time, it opens the door for patients who could not afford assisted reproductive technologies on their own. We are involved in several clinical trials, which also help us to reach success in pregnancies that would have otherwise not been possible. We are currently participating in an international, multicenter trial in which we are looking at substances found in follicular fluid, substances secreted by the embryos or the cells around the eggs to see if they are associated with embryo quality. Some of our current studies offer free or highly discounted fertility medications which, in turn, helps the patient and is also an incentive to participate in the trial. All studies at Main Line Fertility Center are approved by an Institutional Review Board and patients have given their consent voluntarily knowing that they may withdraw at any time. We have been awarded a grant to study the effect of egg vitrification on Continued on page 10

DEcEMbER 2011 l VOLUME 3, NUMBER 6

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Clinic Profile

Innovation and Intimacy at Main line... embryo development. We are also involved with a national multicenter PGD study. The study is looking at the impact of PGD on implantation rates and pregnancy rates after selecting the genetically normal embryos for transfer. We have published many articles and studies. In a competitive marketplace, one is either a leader or a follower. Being a follower can lead to losing sight on what is new and exciting in the field. And the pregnancy rates suffer from that. In addition, patients are quite knowledgeable these days, and they know who is at the top of the field. We believe it is our duty to know what is right and good, as well as to be able to answer any patient who asks, “Why do you not offer this service?” and explain our reason. If we believe a technique or a procedure is beneficial, we offer it.

Is IVF your primary focus? Yes, our main focus is on in vitro fertilization (IVF) technologies. We do the standard IVF and intracytoplasmic sperm injection (ICSI). What sets our program apart is our active egg vitrification program. We also do blastocyst biopsy with aCGH, which is a form of PGD. After we biopsy or remove cells from a blastocyst-staged embryo, the biopsy is tested for aneuploidy, which helps us to select the normal embryos for transfer. In addition, we have a special laser at our center and the highly trained embryologists needed to perform blastocyst biopsy. The advantages of the blastocyst biopsy are that we can biopsy more cells and it is less stressful to the embryo. We

have seen a very significant increase in our pregnancy rates with the use of blastocyst biopsy and aCGH. Blastocyst biopsy and aCGH allow us to select the chromosomally normal embryo for transfer, and thereby minimize the chance of multiple gestations. We have been using this procedure for about 1 year now. Many clinics are not able to offer this cutting-edge technology, because of the high cost of the equipment and the lack of fully trained embryologists on staff who can properly perform blastocyst biopsy.

bank. We can freeze or vitrify eggs from screened donors. Then we have an immediate availability of frozen donor eggs for infertile couples. With an egg bank there is no need to synchronize the recipient cycle with the egg donor’s cycle. We simply prepare the recipient’s lining, thaw the donor eggs, perform ICSI to fertilize them, and then perform an embryo transfer. This reduces the wait time for the recipient couple, which could be up to 1 or 2 months at other centers.

What is your pregnancy success rate?

Blastocyst biopsy and aCGH allow us to select the chromosomally normal embryo for transfer, and thereby minimize the chance of multiple gestations. We have been using this procedure for about 1 year now.

In addition, if we have several highquality blastocyst embryos that are chromosomally normal, we have a blastocyst vitrification protocol with very high survival rates. They can remain cryopreserved just about indefinitely. Another thing that is new at our center is the impending launch of an egg

Main line Fertility center

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DEcEMbER 2011 l VOLUME 3, NUMBER 6

Our current success rate is significantly higher than the national average. It has increased as a result of the new technologies and the dedication of our entire team. One thing we do differently is individual embryo culture, as opposed to group culture. We culture each embryo in individual drops of culture medium and then evaluate each one daily. When we select embryos for embryo transfer, our decision is based on each embryo’s individual developmental progression during the 3 or 5 days in culture.

Your center is involved with the Puah Institute. What is it and how is it linked to infertility? There are certain halachic (ie, Jewish law) restrictions based on the Torah on what can and cannot be done in terms of reproduction. For many observant Jews, certain levels of technology were unavailable, because it was breaking halachic law. Puah is centered in Jerusalem. We were the 13th center in North and South America to be approved by the Puah Institute in Israel. This required certain adjustments in the laboratory, such as having someone trained by Puah at the laboratory when a sperm sample is given, to make sure that the sperm is carefully labeled, and that no other sperm sample is processed concurrently. These trained personnel also have to be present in the embryology laboratory during egg retrieval to ensure that the eggs are the patient’s eggs, and to make sure the husband’s sperm is used. Next, we have to place the embryos in special lockboxes in the incubator. The next morning the Puah representative comes and makes sure the lockbox was not disturbed, so that no embryos were mistakenly put in there. It involves much education of the staff, and it cannot be done on Saturday. This has allowed us to provide treatment for rabbis from the Chabad community in the United States, Canada, and Europe.

See also article on PGD technologies on page 22

We have also had some non-Jewish couples ask for the Puah supervision, for an extra set of eyes making sure that everything goes well.

What are the biggest challenges and rewards for your center? In terms of challenges, it is upsetting that we cannot help everybody. We try to treat anyone we can, especially in this tough economy. Pennsylvania does not have a mandate for infertility treatment. We have to be creative with ways to help people who could otherwise not afford fertility treatment. We must pay attention to the psychological disposition of our patients to do a good job. The biggest rewards are seen in our community. Although the community is very spread out, there are not many degrees of separation between people who know a doctor from Main Line Fertility Center, because there is somebody who has a friend or a family mem-

To see the impact we had on patients’ lives makes us more driven to keep putting out not only a good technological product, but also a good people product, where we are emotionally invested in each individual’s treatment.

ber that we have treated. We know our community. We meet people at our kids’ schools, and we know we are responsible for helping many of those parents and teachers achieve pregnancy. That is very rewarding. To see the impact we had on patients’ lives makes us more driven to keep putting out not only a good technological product, but also a good people product, where we are emotionally invested in each individual’s treatment. Valuing family puts an intrinsic pressure on us to create families. If you love family, you are going to go that extra mile to deliver for your patients. ■


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ASRM Annual Meeting

AsRM, sART Bulletin equips Fertility specialists with Information to Avoid Multiple gestations By Wayne Kuznar

Orlando, FL—The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) have issued a report during the 2011 ASRM annual meeting—“Multiple Gestation Associated with Infertility Therapy: An ASRM Practice Committee Opinion”— with the intent of helping fertility specialists to reduce the number of multiple gestations and to aid in the counseling of patients regarding the associated risks. Among the recommendations of the ASRM/SART Practice Committee are: • An increased use of single embryo transfer (SET) during in vitro fertilization (IVF) cycles • Moving patients directly from lowdose ovulation induction drugs to IVF cycles more quickly (rather than going through repeated or higherdose cycles). “Single embryo transfer is not for every patient, but in a select group of patients, there is ample evidence that the same live birth rate can be achieved with SET versus transfer of 2 or more embryos,” said Eric Widra, MD, chair of the SART Practice Committee and a reproductive endocrinologist at Shady Grove Fertility Center, Washington, DC. “It is especially true when you con-

“Single embryo transfer is not for every patient, but in a select group of patients, there is ample evidence that the same live birth rate can be achieved with SET.” —Eric Widra, MD

sider the ability to replace frozen embryos after an initial IVF cycle if the patient is not pregnant from the transfer of a single fresh embryo.” According to the Practice Committee, “The risks for fetal demise during the third trimester, perinatal morbidity, preterm birth, and both low (<2500 g) and very low birth weight (<1500 g) increase with the number of fetuses in a multiple gestation.” The risks associated with multiple gestations include the consequences of preterm birth, such as cerebral palsy,

retinopathy, and bronchopulmonary dysplasia, and those of fetal growth restriction, such as polycythemia, hypoglycemia, and necrotizing enterocolitis. In addition, the economic costs of multiple gestations are significant and include the costs of maternal hospitalization, neonatal intensive care, and lifetime costs associated with the care for chronic illnesses and rehabilitation. Although the ASRM/SART Practice Committee says that transferring a single embryo is the most direct way to limit the risk of multiple gestations from assisted reproductive technologies, it admits that identifying the single embryo most likely to implant itself and develop is not yet possible. The most appropriate candidates for SET, according to the Practice Committee’s listed selection criteria, are women younger than 35 years, women with more than 1 quality embryo available for transfer, women in their first or second IVF treatment cycle, and women who receive embryos created from donated eggs. “These patients all have an excellent prognosis for conception and do not need to expose themselves to the risk of a multiple pregnancy by transferring 2 or more [embryos],” said Dr Widra.

TAkEAWAY qUIck POINTS ➤ The ASRM/SART Practice Committee recommends the increased use of single embryo transfer to reduce multiple gestations ➤ Patients should proceed directly from low-dose induction drugs to IVF and avoid repeated higherdose cycles ➤ The best candidates are women under age 35 years who have more than 1 quality embryo from donated eggs and are in their first or second IVF cycle Other ASRM/SART recommendations for reducing the number of multiple gestations after infertility treatments are an increased use of low-dose gonadotropins in ovulation induction insemination cycles and extensive and improved patient education and counseling on the dangers for multiple gestation pregnancies. “When other strategies fail and treatment results in a high-order multiple pregnancy, multifetal pregnancy reduction offers an option for reducing the risk for the remaining fetuses,” according to the report. ■

Few Patients with High-Quality embryos choose single embryo Transfer, Despite equal Pregnancy Rate with Dual embryo Orlando, FL—Few women at high risk of multiple pregnancies during in vitro fertilization (IVF) cycles choose elective single embryo transfer (SET), even though the pregnancy rate with SET is similar to that with elective double embryo transfer (DET) in these women. In an ongoing prospective case cohort study over 4 years, “less than one third of our study population chose to transfer 1 embryo compared to 2,” said Christine Briton-Jones, PhD, Embryology Laboratory Director, Assisted Reproductive Technology (ART) Reproductive Center, Beverly Hills, CA. She presented her data at the 2011 American Society for Reproductive Medicine (ASRM) annual meeting. The finding comes at a time when ASRM and the Society for Assisted Reproductive Technology are encouraging the use of SET for women aged younger than 35 years who have more than 1 quality embryo available for transfer, are undergoing their first or

12

second IVF treatment cycle, and have received embryos from donated eggs. The United States continues to lag behind most European countries in SET, she said. Consequently, the rate of multiple births is far higher in the United States.

“We need to get them to buy into the concept that the risk associated with a twin pregnancy is a bad outcome, particularly the young physicians.” —Christine Briton-Jones, PhD

The study included patients who presented for infertility treatments at her ART clinic, all of whom had high-quality embryos for transfer and fell into the high-risk category for multiple pregnancy. All patients were offered SET; those who declined were offered DET.

DEcEMbER 2011 l VOLUME 3, NUMBER 6

“We targeted those who were at high risk of multiples. Our study population would represent about 15% of the treatment cycles that come through our clinic, so it was a highly selected population,” said Dr Briton-Jones. Of the 820 IVF cycles, only 21% of patients chose SET compared with 79% who chose DET. “We found that the implantation potential of both embryos is very high, around 70% per embryo,” she said. The clinical pregnancy rate was 80.7% with SET and 79.0% with DET. Multiple pregnancies were achieved in 70.9% of the DET group but in only 11.5% of those using SET. The rate of SET use was physicianspecific. “We’re a fairly large embryology service with 4 doctors on site, but the lab is used by another 12 outside physicians,” said Dr Briton-Jones. “Only 2 of the doctors, the most senior doctors, consistently get their patients to agree to have single embryo transfers. They’re stronger in educating their patients

about the risks of twin pregnancies.” Therefore, managing patient and physician expectations is important. “We need to get them to buy into the concept that the risk associated with a twin pregnancy is a bad outcome, particularly the young physicians, who are starting their practices and tend to want the success and are willing to be aggressive to achieve success,” she said. The role of the nurse in patient education, which would begin early in the treatment cycle, is to instill the idea that twins is not a desirable outcome, she believes. “We can make a decision as the cycle goes on,” she said. “If it’s looking like they have these really highquality embryos, their pregnancy rate is not increased by transferring 2.” The psychological consequences of a twin pregnancy must also be communicated early. These consequences include an increased prevalence of parental depression, poorer physical well-being, and a higher rate of divorce.—WK ■


ASRM Annual Meeting

Are your IVF Patients Following Their lifestyle Instructions? By Wayne Kuznar

Orlando, FLâ&#x20AC;&#x201D;A large proportion of women undergoing in vitro fertilization (IVF) report lifestyle behaviors that are inconsistent with recommendations from their infertility physicians and nurses, according to findings from a prospective study released at the 2011 annual meeting of the American Society for Reproductive Medicine. â&#x20AC;&#x153;This is the first prospective study to examine lifestyle behaviors during an IVF cycle,â&#x20AC;? said lead investigator Alice D. Domar, PhD, Director of the Domar Center for Mind/Body Health, Boston IVF. â&#x20AC;&#x153;We tracked patientsâ&#x20AC;&#x2122; lifestyle habits every day as they went through an IVF cycle. We also had asked them what they had done the month before.â&#x20AC;? The lifestyle behaviors of 118 women scheduled to undergo an ART cycle were assessed by a survey. Eligible patients were 18 to 44 years old, were undergoing an IVF cycle using their own eggs, and had daily access to the Internet. Patients completed the online Lifestyle and Health Habits Questionnaire, which asked about the following health behaviors: exercise; smoking; sleep; consumption of alcohol, caffeine, herbs, and fruits/vegetables; and use of acupuncture. â&#x20AC;&#x153;One hundred percent of patients exercised during their IVF cycle even though patients are told to dial back on their exercise,â&#x20AC;? said Dr Domar. Nearly half (49.5%) consumed alcohol, even though patients seen at Boston IVF are told in writing to eliminate alcohol consumption completely while cycling. Those who consumed alcohol reported having 1 to 2 drinks per week. Although the impact of caffeine consumption on fertility is not established, patients at Boston IVF are advised in writing to limit caffeine consumption to a maximum of 50 mg daily. Yet, three fourths (76.5%) reported caffeine consumption during their IVF cycles, and almost half drank caffeine daily, most often coffee, which has 60 to 200 mg of caffeine per cup. â&#x20AC;&#x153;The most surprising finding to me was that 12% took herbs during the IVF cycle, even though theyâ&#x20AC;&#x2122;re explicitly told not to take herbs. Our acupuncturists on contract canâ&#x20AC;&#x2122;t even mention herbs to their patients,â&#x20AC;? said Dr Domar. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s worrisome to me that patients continue to have potentially detrimental lifestyle habits, especially since they are told in writing not to exercise vigorously, not to drink alcohol, not to drink caffeine, and not to take herbs, yet a huge number of patients are still doing it. We believe that lifestyle factors can

have an impact on outcome, yet a lot of women arenâ&#x20AC;&#x2122;t listening to their physicians in terms of what they should not be doing during their cycle.â&#x20AC;? Dr Domarâ&#x20AC;&#x2122;s advice is that nurses

should have a personal discussion with their patients before the IVF cycle begins and that they should â&#x20AC;&#x153;be explicit about what [the patients] should and shouldnâ&#x20AC;&#x2122;t do.â&#x20AC;? â&#x2013;

â&#x20AC;&#x153;The most surprising finding to me was that 12% took herbs during the IVF cycle, even though theyâ&#x20AC;&#x2122;re explicitly told not to take herbs.â&#x20AC;? â&#x20AC;&#x201D;Alice D. Domar, PhD

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DEcEMbER 2011 l VOLUME 3, NUMBER 6



13


ASRM Annual Meeting

Vaginal Progesterone as effective as, More convenient than, IM Progesterone in women with Pcos By Wayne Kuznar

Orlando, FL—Vaginal progesterone is as effective as intramuscular (IM) progesterone for luteal support in women with polycystic ovarian syn-

drome (PCOS), achieving similar pregnancy rates in a randomized comparison, reported Angie Beltsos, MD. Patient satisfaction was greater with

the vaginal progesterone inserts, with markedly more patients reporting more convenient dosing and greater ease of dosing compared with IM progesterone

Nature’s Active Folate for Prenatal Care NeevoDHA® is a medical food for use only under medical supervision for the dietary management of impaired metabolic processes in women under a doctor’s care who face high to intermediate risk pregnancies and are unable to fully metabolize or absorb folic acid.

Adverse Reactions While allergic sensitization has been reported following both oral and parenteral administration of folic acid, allergic sensitization has not been reported with the use of Metafolin®.

Description NeevoDHA® is an opaque blue gelatin capsule.

Drug Interactions Pyridoxine hydrochloride should not be given to patients receiving the drug levodopa, because the action of levodopa is antagonized by pyridoxine hydrochloride. However, pyridoxine hydrochloride may be used concurrently in patients receiving a preparation containing both carbidopa and levodopa. While the concurrent use of phenytoin and folic acid may result in decreased phenytoin effectiveness, no such decreased effectiveness has been reported with the use of Metafolin®. Capecitabine (Xeloda®) toxicity may increase with the addition of leucovorin (5-formyltetrahydrofolate) (folate).

Description of Primary Ingredients: Algidha TM proprietary blend ........................................... 687mg¥ Calcium (tricalium phospate) .......................................... 200mg Vitamin C (acorbic acid) ................................................. 40mg Elemental iron (ferrous fumarte) ..................................... 27mg Vitamin B6 (pyridoxine HCl) ......................................... 25mg Vitamin E (d-alpha-tocopherol) ...................................... 30IU L methylfolate Calcium (as Metafolin®) .......................... *1.13mg** Vitamin B12 (methylcobalamin) ..................................... 1mg Vitamin B9 (folic acid) .................................................... 400 mcg ¥

AlgidhaTM is a proprietary blend containing algal oil and soy lecithin.

*CAS# 151533-22-1 is the registry of the absolute stereochemistry of L-methylfolate calcium. **1.13mg L-Methylfolate (calculated as L-methyltetrahydrofolic acid) is the molar equivalent of 1.0mg folic acid. *Metafolin® (L-methylfolate calcium) is a substantially diastereoisomerically pure source of L-methylfolate containing not more than 1% D-methylfolate which results in not more than 0.011 milligrams of D-methylfolate in NeevoDHA®. Indication and Usage NeevoDHA® capsules are for the specific dietary management of impaired metabolic processes in those women with distinct nutritional requirements for any of the following conditions: hyperhomocysteinemia during pregnancy4, 5, 6, 7; high risk recurrent pregnancy loss5, 7; risk of anemia due to impaired folic acid absorption2,3,15, 16,17,18 ; and impaired metabolism due to 677C-T mutations in the methylenetetrahydrofolate reductase gene8, 10, 11 ; NeevoDHA® should only be used under medical supervision. Rationale for Distinct Nutritional Requirements Medical foods are intended for a patient who has a limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone. NeevoDHA® contains folate in the form of L-methylfolate which is the biologically active folate isomer. L-methylfolate is the body’s preferred form of folate because it is directly usable by the human organism for certain metabolic processes. There are well documented studies 2, 3, 6,8,12 which have established folic acid’s ineffectiveness regarding inherited disorders of folate transport and metabolism. These disorders limit and impair the capacity to ingest, digest, absorb or metabolize folic acid. Folic acid, the synthetic form of folate, must be metabolized in a four step process by the body to become the biologically active L-methylfolate. Unmetabolized levels of folic acid were found in 78% of plasma samples from women given >400 mcg of folic acid per day 1. Unmetabolized folic acid has a high affinity to bind to the cellular folate transport mechanism. This has been shown to reduce the transfer of the active metabolite L-methylfolate across the blood brain barrier 2,3. D-methylfolate or 6(R)-5-methyltetrahydrofolate [6(R)-5-MTHF] is the other diastereoisomer of folate. Studies administering doses of 2.5 mg per day or higher resulted in plasma protein binding of D-methylfolate higher than L-methylfolate causing a significantly higher renal clearance of L-methylfolate when compared to D-methylfolate.4 Further, D-methylfolate is found to be stored in tissues in the body, mainly in the liver. D-methylfolate is not metabolized by the body and has been hypothesized to inhibit regulatory enzymes related to folate and homocysteine metabolism and reduces the bioavailability of L-methylfolate.5 Hyperhomocysteinemia is an independent risk factor of vascular and endothelial dysfunction in maternal patients. Although hyperhomocysteinemia is not due to folate deficiencies alone, it can be indicative of dietary deficiencies of essential nutrients, increased catabolism, clearance and excretion of essential nutrients, hormonal influence on folate metabolism or an intrinsic metabolic disorder. Increased homocysteine levels can also increase the risk of recurrent early pregnancy loss as well as increase maternal complications. Disturbed homocysteine metabolism has also been shown to have a greater effect in women with early pregnancy losses 4,5,6,7. In the cell, 6(S)-5-MTHF (L-methylfolate) is used in the methylation of homocysteine. The prevalence of the 677C-T mutations in the methylenetetrahydrofolate reductase gene in pregnant women was shown to be 53% 8. Studies show that enzyme activity necessary to convert folic acid to its active form (L-methylfolate) can be reduced by as much a 72% in patients with the 677C-T mutation in the methylenetetrahydrofolate reductase gene 9. In certain studies, women with the 677C-T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) had significantly higher risk for recurrent pregnancy loss, congenital abnormalities and other adverse pregnancy outcomes 10,11. Other MTHFR gene variants (A1298C and MTHFD) that affect folic acid bioavailability have been associated with folate metabolism and the incidence of congenital anomalies 11, 12. Contraindications Known hypersensitivity to any of the components in this product is a contraindication. Warnings Ingestion of more than 3 grams per day of omega-3 fatty acids has been shown to have potential antithrombotic effects, including bleeding time and INR. Administration of omega-3 fatty acids should be avoided in patients on anticoagulants and in those known to have an inherited or acquired bleeding diathesis. WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately. Precautions Folates, when administered as a single agent in doses above 0.1mg daily, may obscure pernicious anemia in that hematologic remission can occur while neurological manifestations remain progressive.

Patient Information NeevoDHA® should only be used under medical supervision. NeevoDHA® is certified kosher by Triangle K and Associates. Contains Soy Dosage and Administration Usual adult dose is 1(one) gelatin capsule daily or as directed by your physician. How Supplied Available as a blue, soft gelatin capsule with “Neevo DHA” imprinted on one side in white ink. Commercial product (0525-0621-30) is supplied in bottles of 30 capsules. Sample product (0525-0621-04) is supplied in bottles of 4 capsules.

In this study, patient satisfaction was greater with the vaginal progesterone inserts compared with IM progesterone in oil.

Commercial Product (30 capsules) 0525-0621-30* Use under medical/physician supervision. Professional samples-not for sale Sample Product (4 capsules) 0525-0621-04* * Pamlab, LLC does not represent this product code to be a National Drug Code (NDC) number. Instead, Pamlab has assigned a product code formatted according to standard industry practice to meet the formatting requirements of pharmacy and health insurance computer systems. Storage Store at controlled room temperature 15oC to 30oC (59oF to 86oF) (See USP). Protect from light and moisture. Dispense commercial product in original container. Dispense sample product in original container.

KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Patents Some or all of the following patents may apply: U.S. Patent No. 6,011,040 U.S. Patent No. 6,207,651 U.S. Patent No. 5,563,126 U.S. Patent No. 6,254,904 U.S. Patent No. 6,297,224 U.S. Patent No. 5,795,873 U.S. Patent No. 6,528,496 U.S. Patent No. 5,997,915 and other pending patent applications.

and a mean of 2.9 blastocysts were transferred in the women receiving vaginal progesterone versus 3.1 in women who received IM progesterone. Clinical pregnancy was achieved in 50.9% of women in each group, and a similar proportion of women in each group experienced ongoing pregnancy (47.2% in the vaginal progesterone group vs 49.1% in the IM progesterone group). At the last study visit, 71.8% of the women who received the vaginal inserts indicated that they were very satisfied with the treatment compared with 18.2% of the women who received IM injections. Some 71.8% of women assigned to vaginal progesterone reported that administering the insert was “very easy.” In contrast, only 13.8% of women randomized to IM progesterone indicated that dosing was “very easy.” Patients receiving vaginal progesterone reported greater convenience of dosing, with 53.8% indicating that it was “very convenient” compared with only 6.8% who indicated that IM progesterone was “very convenient” to administer. ■

References 1. Troen A, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cells cytotoxicity among postmenopausal women. J Nutr 2006; 136:189-194 2. Wu D, Pardridge W. Blood brain barrier transport of reduced folic acid. Pharmaceutical Research 1999; 16(3):415-19. 3. Reynolds E. Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry 2002; 72:567-571. 4. Stroes E, van Faasen E, Circ Res 2000;86:1129-34. 5. Willems FF et al. BR J Pharmacol 2004;141(5):825-30. 6. Wen S, et al. Folic acid supplementation in early second trimester and the risk of preeclampsia. Am J Obstet Gynecol 2008; 198:45.e1-45.e7. 7. Nelen W, et al. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obste Gynecol 2000; 95:519-24. 8. Tamura T, Picciano M. Folate and human reproduction. Am J Clin Nutr 2006; 83:993-1016. 9. Vollset S, et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr 2000; 71:962-8. 10. Molloy A, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations Lancet 1997; 349: 1591–93 11. Ulrich CM, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98: 231–234. 12. Kirke P, et al. Impact of the MTHFR C677T polymorphism on the risk of neural tube defects: case control study. BMJ 2004; 328:1535-1536. 13. Botto L, et al. 5, 10-methylenetetrahydrofolate Reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 2000; 151:862-77. 14. Gos M, et al. Genetic basis of neural tube defects. J Appl Genet 2002; 43(4):511-524. 15. Koury, Mark J., Ponka, Prem; New Insights into Erythropoiesis: The Roles of Folate, Vitamin B12, and Iron; Annu. Rev. Nutr. 2004. 24:105-31 16. Bentley, Susan; Hermes, Amy; Phillips, Diane; Daoud, Yahya; Hanna, Sylvia; Comparative Effectiveness of a Prenatal Medical Food(Neevo/NeevoDHA) to Prenatal Vitamins on Hemoglobin Levels and Adverse Outcomes: A Retrospective Analysis; Presented 67th Annual Meeting of the American Soceity of Reproductive Medicine in Denver, CO, October 23-27, 2010. 17. Menzies, Rosa C.; Crossen, Peter E.; Fitzgerald, Peter H.; Gunz, Frederick W.; Cytogenetic and Cytochemical Studies on Marrow Cells in B12 and Folate Deficiency; Blood 1966 28: 581-594 18. Tamura, Tsunenobu; Picciano, Mary Frances; Folate and Human Reproduction; Am J Clin Nutr; May 2006 993-1016 Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany. Distributed By PAMLAB, L.L.C. Covington, LA 70433 PC-0053 Revised 02/11

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14

DEcEMbER 2011 l VOLUME 3, NUMBER 6

in oil, according to Dr Beltsos, Medical Director of the IVF Chicago–River North Program, Fertility Centers of Illinois. She presented her study data at the 2011 annual meeting of the American Society for Reproductive Medicine. In the open-label study, 110 premenopausal, infertile women aged 18 to 42 years (average age, 31 years) with PCOS were randomized before stimulation with follitropin or menotropins for injection to receive vaginal progesterone inserts or IM injections for luteal support. A mean of 14.8 oocytes were retrieved from women receiving vaginal progesterone versus 14.0 from the women who received IM progesterone,






ASRM Annual Meeting

ovulation Induction, ongoing Pregnancy greater with 25-Iu weekly Increments of rFsH versus 50-Iu Increments By Wayne Kuznar

Orlando, FL—Weekly increments of 25 IU in the daily dose of recombinant follicle-stimulating hormone (rFSH) may result in higher ongoing pregnancy rates compared with 50-IU increments, according to study data presented by Arthur Leader, BSc, MD, at the 2011 annual meeting of the American Society for Reproductive Medicine. The finding comes from a retrospective analysis of an open-label prospective randomized study. In the same study population, it was previously reported that 25-IU increments resulted in a higher incidence of monofollicular growth and ovulation, a lower cumulative rFSH dose, and fewer cancellations due to hyperresponse. In the study, 158 anovulatory or oligo-ovulatory infertile women were randomized to 1 of 2 protocols of 1 cycle of rFSH, follitropin beta, self-administered using a pen device. In both

groups, the starting dose was 50 IU daily for 7 days.

Weekly increments of 25 IU in the daily dose of recombinant folliclestimulating hormone may result in higher ongoing pregnancy rates compared with 50-IU increments.

After the initial 7-day treatment, if there were no follicles with a mean diameter ≥12 mm, the daily dosage of rFSH was increased by either 25 IU or 50 IU per week. Treatment was contin-

ued until 1 follicle ≥18 mm was seen, after which human chorionic gonadotropin (hCG) was administered. Some 60.9% of women in the 25-IU increment group required a daily dose of 75 IU rFSH before hCG administration. In the group assigned to 50-IU increments, 59.6% required a daily dose of 100 IU of rFSH before hCG. The mean daily dose of follitropin beta administered was lower in the 25IU group versus the 50-IU group (71.7 IU vs 91.2 IU, respectively). Women in the 25-IU group had 5 cancellations because of hyperresponse, whereas the group assigned to 50 IU had 16 cancellations, said Dr Leader, cofounder of the Ottawa Fertility Centre and Professor of Obstetrics, Gynecology, and Medicine (endocrinology), University of Ottawa, Ontario, Canada. Among evaluable patients, 16 (23%)

Arthur Leader, BSc, MD

of 69 women in the 25-IU group achieved ongoing pregnancies compared with 10 (18%) of 57 women randomized to 50-IU increments. This difference did not achieve statistical significance, notes Dr Leader. ■

women Value effectiveness Most in Their Hormonal Fertility Treatment View Self-Injections Positively Orlando, FL—Patients who are taught to self-inject their fertility medication value hands-on training. Many report positive emotions about the practice of self-injection, saying that it allowed them to take control of their treatment, according to Eline Dancet, MSc, RN. At the 2011 annual meeting of the American Society for Reproductive Medicine, she presented insight gained from in-depth interviews with 15 fertility patients. Her findings indicate that medication characteristics besides effectiveness are valued by patients (although highest value is attached to effectiveness) and suggest that fertility clinics should tailor medications not only to patients’ medical characteristics but also to their perspectives on the medications’ characteristics. Part of the emotional burden with fertility problems and treatment is the use of hormonal medication, of which there are several with comparable effectiveness. The published literature on patients’ perspectives on hormonal fertility medications show no consistently preferred product, but all studies used different methodologies and had important limitations (eg, some used biased

questionnaires), Ms Dancet said, a midwife and doctoral candidate at Leuven University Fertility Center, Belgium. “We did identify from these studies that there were 6 concepts that were important to patients, but none of the studies examined all at once,” she said. In her study, interviews lasting as long as 80 minutes with the 15 female fertility patients (mean age, 25 years) were conducted by a midwife researcher, and the topics covered were those identified as important to patients in previous studies. All women had at least 1 intrauterine insemination cycle and 1 in vitro fertilization cycle. Some of the negative emotions expressed by the interviewees were a feeling of “living by the clock” and a fear of the self-injections, until using the medication became a habit. “Patients described a lot of positive experiences, such as ‘taking control’ and ‘contributing to conception,’” said Ms Dancet. “This is quite novel, because when we look at previous studies, the researchers described the patients’ experiences quite negatively.” The strong wish to conceive leads to compliance with self-administration

of fertility medication, as is evident from the fact that all patients were completely compliant, she said. Another effect of the strong wish to

“Patients described a lot of positive experiences….This is quite novel, because when we look at previous studies, the researchers described the patients’ experiences quite negatively.” —Eline Dancet, MSc, RN

conceive was the acceptance of inconvenience and adverse effects and the attachment of highest value to the effectiveness of a medication when the characteristics of hormonal fertility medications were considered. Patients attached minimal value to

price, adverse effects, adaptations to daily life (ie, how often a medication is administered), and minimal technical challenges for medication preparation, such as a preference for a pen device versus a syringe for injection. However, patients’ rankings of the medication characteristics that were most important differed, so that some preferred minimal adverse effects, whereas others preferred effectiveness and minimal adaptation to daily life. “There were different opinions on the optimal medication route, so it was not the case that all patients would prefer vaginal medication over injections, which is quite surprising,” Ms Dancet said. Patients also valued hands-on injection training that provided them with an opportunity to ask questions. “You can’t just provide written information or a DVD; you have to train patients so that they are comfortable with the first injection, because they are very scared at first. The interviews also revealed that interest in low-stimulation protocols was limited, because of the women’s fear of decreased effectiveness and also of an increased number of cycles.—WK ■

DEcEMbER 2011 l VOLUME 3, NUMBER 6

15


ASRM Annual Meeting

ART nurses’ Practices Fraught with Many Interruptions By Wayne Kuznar

Orlando, FL—Nurses who were working in an assisted reproductive technology (ART) setting in Australia claimed that interruptions were a significant problem in their practice. Because of the pivotal role that ART nurses play in the coordination of treatment cycles, “it is imperative that strategies are explored to facilitate minimization of interruption during critical phases in daily ART nursing practice,” said Judith Applegarth, PhD, lead investigator of a study of 15 nurses working in an ART setting, and Clinic Manager/ Patient Coordinator, Monash IVF Rockhampton, Queensland, Australia. She presented the findings from her published study at the 2011 annual meeting of the American Society for Reproductive Medicine. The study was conducted using a comparative approach in which ART practices were sampled until no new

have been found to be associated with medication errors, omissions, and nearmisses, according to Dr Applegarth. This is a potential area of risk for the nurse, ART unit, and patient as well. “I believe that there are critical times

“My recommendation is that ART units, managers, and nurses think about ways to minimize interruptions, whether it be that they have an interruption-free zone or interruption-free times.” —Judith Applegarth, PhD

information was obtained. The data saturation point was achieved after interviewing 15 ART nurses. One of the factors identified as having a significant impact on practice was the number of interruptions that occur during daily nursing practice. Those interruptions included telephone calls, e-mails, and doctors and patients dropping in. Some of the comments from nurses interviewed included the following: ➤ “Phones can make or break your day.” ➤ “You might be really busy with a cycle and planning and a patient will come in upset because you sit and give them the time, which they deserve, that means that everything else is an hour behind.” ➤ “You’re dealing with something and then you put that in the file there, take a phone call, and then you’re dealing with something…hang up that call and then—so you have 5 things on the go at once.” In the literature, repeated interruptions during medication administration

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DEcEMbER 2011 l VOLUME 3, NUMBER 6

in ART practice that we should not be interrupted—things like timing for patients’ treatment, such as egg collection,” she said. “My recommendation is that ART units, managers, and nurses think about

ways to minimize interruptions, whether it be that they have an interruption-free zone or interruption-free times, so if you’re calculating timings or giving timing information to patients, then you don’t take calls.” ■

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Our commitment to affordable patient access With our Patient Assistance Programs, clinically eligible patients can have affordable access to therapy.* Financial assistance is available for clinically eligible insured and uninsured patients upon request. The Makena Co-pay Assistance Program will reduce co-pay costs for insured patients whose health plan covers Makena. Patients with a household income of up to $120,000† will pay between $0 and $20 per injection for Makena. Since there are no income caps, patients with a household income greater than $120,000 are also eligible for co-pay assistance. The Makena Patient Assistance Program supports uninsured patients by offering the drug at no cost or reduced cost. Patients who are uninsured and have an annual household income less than $60,000 will receive Makena at no out-of-pocket cost.

Our commitment to product quality and patient safety We believe that there is a need for a quality FDA-approved treatment. FDA-approved Makena—a sterile injectable—is manufactured in a facility compliant with current Good Manufacturing Practices (cGMPs). These FDA-enforced regulations help ensure the identity, strength, quality, and purity of the medication by requiring control and monitoring of the manufacturing process and facilities. This also helps ensure consistency from dose to dose and accurate potency according to the amount declared on the label.1 Adherence to these quality-management systems means your patients will receive the FDA-approved formulation for this indication.2 Makena is the only product for this indication that has been studied in clinical trials conducted by the NICHD and subsequently reviewed and approved by the FDA. As an FDA-approved medication, Makena is also subject to ongoing safety monitoring for adverse effects.

Our commitment to ongoing support In addition to access to FDA-approved Makena, your patients will have access to educational materials and compliance reminders throughout therapy. We established the Makena Care Connection™ to help facilitate the prescription process via a standardized distribution system. As part of this effort, dedicated specialists are available to support you, your staff, and your patients throughout the prescription process. Our commitment goes beyond simply bringing Makena to market. We are conducting large follow-up trials on Makena, designed in collaboration with the FDA. These studies will help provide enhanced medical knowledge to patients, families, and society as a whole. *Each patient’s eligibility is evaluated on an individual basis. Program eligibility criteria are subject to change. Financial assistance programs are administered by the Makena Cares Foundation, which is managed by the Chronic Disease Fund. †This encompasses 85% of US household incomes. Source: 2009 US census data. References: 1. Facts About Current Good Manufacturing Practices (cGMPs). Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm169105.htm. Accessed July 22, 2011. 2. CFR - Code of Federal Regulations Title 21. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1&subpart Node=21:4.0.1.1.11.6. Accessed July 22, 2011.

Visit www.makena.com for additional information about Makena. Please see next page for important safety information.


ASRM Annual Meeting

gaps in Fertility Knowledge of women of childbearing Age By Wayne Kuznar

Orlando, FL—Fertility knowledge among American women of childbearing age is generally on target, but most women surveyed in the 2011 fertility survey underestimate the magnitude of fertility decline with increasing age.

These were some of the findings from the Fertility IQ 2011 Survey, presented at the 2011 annual meeting of the American Society for Reproductive Medicine by Fulton F. Velez, MD, and colleagues at EMD Serono. This nation-

al survey was an online self-administered questionnaire completed by 1010 women aged 25 to 35 years who had not given birth and who were currently using birth control or not actively trying to conceive.

The mean age of the respondents was 29.1 years; 59% completed college education; 66% were non-Hispanic Caucasians, 17% Hispanic, 11% African American, and 4% Asian. “We found that women are generally Continued on page 18

ADVERTISEMENT Makena™ is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The effectiveness of Makena is based on improvement in the proportion of women who delivered <37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity. Limitation of use: While there are many risk factors for preterm birth, safety and efficacy of Makena has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.

Important safety information for Makena t Makena should not be used in women with any of the following conditions: – Currentorhistoryofthrombosisorthromboembolicdisorders – Known or suspected breast cancer, other hormone-sensitive cancer or history of these conditions – Undiagnosed abnormal vaginal bleeding unrelated to pregnancy – Cholestaticjaundiceofpregnancy – Liver tumors, benign or malignant, or active liver disease – Uncontrolledhypertension t Makena should be discontinued if thrombosis or thromboembolism occurs t Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or with other products containing castor oil t Women receiving Makena should be monitored if they: –Are prediabetic or diabetic – Have conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction –Have a history of clinical depression; Makena should be discontinued if depression recurs –Develop jaundice; consider whether benefit of use warrants continuation –Develop hypertension t Certain pregnancy-related fetal and maternal complications or events were numerically increased in Makena-treated subjects as compared to placebo subjects, including miscarriage (2.4% vs. 0%) and stillbirth (2% vs. 1.3%), admission for preterm labor (16% vs. 13.8%), preeclampsia or gestational hypertension (8.8% vs. 4.6%), gestational diabetes (5.6% vs. 4.6%), and oligohydramnios (3.6% vs. 1.3%) t The most common adverse reactions reported in ≥2% of subjects and at a higher rate in the Makena group than in the control group were injection site reactions (pain [35% vs. 33%], swelling [17% vs. 8%], pruritus [6% vs. 3%], and nodule [5% vs. 2%]), urticaria (12% vs. 11%), pruritus (8% vs. 6%), nausea (6% vs. 5%), and diarrhea (2% vs. 1%)

Please see next page for brief summary of prescribing information.

Marketed by Ther-Rx Corporation, St. Louis, MO 63044 © 2011 Ther-Rx Corporation 17-154-1 8/11

DEcEMbER 2011 l VOLUME 3, NUMBER 6

17


ASRM Annual Meeting

gaps in Fertility Knowledge of women... well informed about general aspects of infertility and reproductive health, such as mentioning age as the strongest risk factor for infertility. However, when we look more closely at their knowledge about the specific impact of age on infertility, we found that

women overestimate the chances of pregnancy at the different ages and underestimate the time to pregnancy,â&#x20AC;? said Dr Velez, Associate Director of Health Outcomes and Market Access, EMD Serono. â&#x20AC;&#x153;When women were asked about the

Continued from page 17

time to conception of a 20-year-old versus a 30-year-old versus a 40-yearold, they were saying it was a few months, but from what we know from the literature, itâ&#x20AC;&#x2122;s actually several months or more. The same was true for the likelihood of achieving pregnancy;

Table 2 Selected Maternal Complications Makena N=310 %

Pregnancy Complication BRIEF SUMMARY OF PRESCRIBING INFORMATION Please consult full prescribing information.

Admission for preterm labor1

INDICATIONS AND USAGE Makena is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The effectiveness of Makena is based on improvement in the proportion of women who delivered <37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity. Limitation of use: While there are many risk factors for preterm birth, safety and efficacy of Makena has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.

Gestational diabetes Oligohydramnios

13.8 















1.3

Other than delivery admission.

1

$PNNPO"EWFSTF3FBDUJPOT 5IFNPTUDPNNPOBEWFSTFSFBDUJPOXBTJOKFDUJPOTJUFQBJO XIJDIXBTSFQPSUFEBGUFSBUMFBTU POFJOKFDUJPOCZPGUIF.BLFOBHSPVQBOEPGUIFDPOUSPMHSPVQ5BCMFMJTUT BEWFSTFSFBDUJPOTUIBUPDDVSSFEJOĂśPGTVCKFDUTBOEBUBIJHIFSSBUFJOUIF.BLFOBHSPVQ than in the control group. Table 3 Adverse Reactions Occurring in â&#x2030;Ľ2% of Makena-Treated Subjects and at a Higher Rate than Control Subjects Preferred Term *OKFDUJPOTJUFQBJO

WARNINGS AND PRECAUTIONS Thromboembolic Disorders Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs. Allergic Reactions Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use PG.BLFOBPSXJUIPUIFSQSPEVDUTDPOUBJOJOHDBTUPSPJM$POTJEFSEJTDPOUJOVJOHUIFESVHJG such reactions occur. Decrease in Glucose Tolerance A decrease in glucose tolerance has been observed in some patients on progestin treatment. 5IFNFDIBOJTNPGUIJTEFDSFBTFJTOPULOPXO$BSFGVMMZNPOJUPSQSFEJBCFUJDBOEEJBCFUJD women while they are receiving Makena. Fluid Retention Because progestational drugs may cause some degree of fluid retention, carefully monitor women with conditions that might be influenced by this effect (e.g., preeclampsia, epilepsy, migraine, asthma, cardiac or renal dysfunction). Depression Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs. Jaundice $BSFGVMMZNPOJUPSXPNFOXIPEFWFMPQKBVOEJDFXIJMFSFDFJWJOH.BLFOBBOEDPOTJEFSXIFUIFS the benefit of use warrants continuation. Hypertension $BSFGVMMZNPOJUPSXPNFOXIPEFWFMPQIZQFSUFOTJPOXIJMFSFDFJWJOH.BLFOBBOEDPOTJEFS whether the benefit of use warrants continuation. ADVERSE REACTIONS For the most serious adverse reactions to the use of progestins, see Warnings and Precautions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. *OBWFIJDMF QMBDFCP DPOUSPMMFEDMJOJDBMUSJBMPGQSFHOBOUXPNFOBUSJTLGPSTQPOUBOFPVT preterm delivery based on obstetrical history, 310 received 250 mg of Makena and 153 received BWFIJDMFGPSNVMBUJPODPOUBJOJOHOPESVHCZBXFFLMZJOUSBNVTDVMBSJOKFDUJPOCFHJOOJOHBU UPXFFLTPGHFTUBUJPOBOEDPOUJOVJOHVOUJMXFFLTPGHFTUBUJPOPSEFMJWFSZ XIJDIFWFS occurred first. [See Clinical Studies.] $FSUBJOQSFHOBODZSFMBUFEGFUBMBOENBUFSOBMDPNQMJDBUJPOTPSFWFOUTXFSFOVNFSJDBMMZ JODSFBTFEJOUIF.BLFOBUSFBUFETVCKFDUTBTDPNQBSFEUPDPOUSPMTVCKFDUT JODMVEJOH miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables 1 and 2). Table 1 Selected Fetal Complications Makena n/N

Control n/N

Miscarriage (<20 weeks)1

5/209

0/107

Stillbirth (â&#x2030;Ľ20 weeks)2



2/153

/5PUBMOVNCFSPGTVCKFDUTFOSPMMFEQSJPSUPXFFLTEBZT 2 /5PUBMOVNCFSPGTVCKFDUTBUSJTLĂśXFFLT



Makena N=310 %

Control N=153 %



32.7

*OKFDUJPOTJUFTXFMMJOH

17.1

7.8

6SUJDBSJB

12.3

11.1

Pruritus

7.7

5.9

*OKFDUJPOTJUFQSVSJUVT

5.8

3.3

Nausea *OKFDUJPOTJUFOPEVMF Diarrhea

5.8 

DEcEMbER 2011 l VOLUME 3, NUMBER 6







2.0

2.3

0.7

*OUIFDMJOJDBMUSJBM PGTVCKFDUTSFDFJWJOH.BLFOBXFSFSFQPSUFEBTEJTDPOUJOVJOH UIFSBQZEVFUPBEWFSTFSFBDUJPOTDPNQBSFEUPPGDPOUSPMTVCKFDUT5IFNPTUDPNNPO BEWFSTFSFBDUJPOTUIBUMFEUPEJTDPOUJOVBUJPOJOCPUIHSPVQTXFSFVSUJDBSJBBOEJOKFDUJPOTJUF QBJOTXFMMJOH FBDI  1VMNPOBSZFNCPMVTJOPOFTVCKFDUBOEJOKFDUJPOTJUFDFMMVMJUJTJOBOPUIFSTVCKFDUXFSFSFQPSUFE BTTFSJPVTBEWFSTFSFBDUJPOTJO.BLFOBUSFBUFETVCKFDUT DRUG INTERACTIONS /PESVHESVHJOUFSBDUJPOTUVEJFTXFSFDPOEVDUFEXJUI.BLFOB Drugs Metabolized by CYP1A2, CYP2A6 and CYP2B6 5IFNFUBCPMJTNPGESVHTNFUBCPMJ[FECZ$:1" TVDIBTUIFPQIZMMJOF UJ[BEJOF  DMP[BQJOF $:1" TVDIBTBDFUBNJOPQIFO IBMPUIBOF OJDPUJOF BOE$:1# TVDIBT efavirenz, bupropion, methadone) may be increased during treatment with Makena [see Clinical Pharmacology]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B:5IFSFBSFOPBEFRVBUFBOEXFMMDPOUSPMMFETUVEJFTPG.BLFOBVTF in women during the first trimesterPGQSFHOBODZ%BUBGSPNBWFIJDMF QMBDFCP DPOUSPMMFE clinical trial of 310 pregnant women who received Makena at weekly doses of 250 mg by JOUSBNVTDVMBSJOKFDUJPOJOUIFJSTFDPOEBOEUIJSEUSJNFTUFST BTXFMMBTMPOHUFSN ZFBST  GPMMPXVQTBGFUZEBUBPOPGUIFJSJOGBOUT EJEOPUEFNPOTUSBUFBOZUFSBUPHFOJDSJTLTUP infants from in utero exposure to Makena. 3FQSPEVDUJPOTUVEJFTIBWFCFFOQFSGPSNFEJONJDFBOESBUTBUEPTFTVQUPBOE  respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Makena. Makena administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days BOEPGHFTUBUJPO5IFSFXFSFOPUFSBUPHFOJDFGGFDUTJOFJUIFSTQFDJFT Labor and Delivery Makena is not intended for use to stop active preterm labor. The effect of Makena in active labor is unknown. Nursing Mothers Discontinue Makena at 37 weeks of gestation or upon delivery. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breastfeeding performance, or on the health, growth, or development of the infant. Pediatric Use Makena is not indicated for use in children. Safety and effectiveness in pediatric patients less UIBOZFBSTPGBHFIBWFOPUCFFOFTUBCMJTIFE"TNBMMOVNCFSPGXPNFOVOEFSBHFZFBST XFSFTUVEJFETBGFUZBOEFGGJDBDZBSFFYQFDUFEUPCFUIFTBNFJOXPNFOBHFEZFBSTBOE above as for users 18 years and older. [See Clinical Studies.]

1

18

 8.8

Preeclampsia or gestational hypertension

CONTRAINDICATIONS Do not use Makena in women with any of the following conditions: t$VSSFOUPSIJTUPSZPGUISPNCPTJTPSUISPNCPFNCPMJDEJTPSEFST t,OPXOPSTVTQFDUFECSFBTUDBODFS PUIFSIPSNPOFTFOTJUJWFDBODFS  or history of these conditions t6OEJBHOPTFEBCOPSNBMWBHJOBMCMFFEJOHVOSFMBUFEUPQSFHOBODZ t$IPMFTUBUJDKBVOEJDFPGQSFHOBODZ t-JWFSUVNPST CFOJHOPSNBMJHOBOU PSBDUJWFMJWFSEJTFBTF t6ODPOUSPMMFEIZQFSUFOTJPO

Pregnancy Complication



Control N=153 %

.BSLFUFECZ5IFS3Y$PSQPSBUJPO4U-PVJT .0

most women believe that the likelihood of becoming pregnant at different ages is a lot higher than it actually is.â&#x20AC;? On average, the women had a fertility IQ of 3.3 on a scale of 1 to 10. Among the respondents, 78% of the women answered correctly that fertility drops off more than a decade prior to menopause, 70% identified a correct trend for the average time to conception after unprotected sex, and 89% identified a correct trend for the likelihood of conception after 1 month among different age-groups.

â&#x20AC;&#x153;Womenâ&#x20AC;Śoverestimate the chances of pregnancy at the different ages and underestimate the time to pregnancy.â&#x20AC;? â&#x20AC;&#x201D;Fulton F. Velez, MD

Nine of every 10 respondents, however, overestimated the likelihood of pregnancy among women of various ages who have unprotected sex and most underestimated the time to conception among women having unprotected sex. For example, only 10% answered correctly that the chance of a 40-year-old woman achieving pregnancy after 1 month of regular unprotected intercourse is less than 10%. Most of the women correctly disagreed with false statements regarding fertility, such as that oral contraceptives protect future fertility (78%) and that a low difficulty in achieving pregnancy is predicted by a healthy appearance in women (72%) or in men (69%). Furthermore, 27% agreed and 52% neither agreed nor disagreed with the statement that â&#x20AC;&#x153;movie actresses over the age of 35 do not seem to have problems becoming pregnant using assisted reproductive technologies using their own eggs,â&#x20AC;? and 17% agreed and 47% neither agreed nor disagreed that â&#x20AC;&#x153;movie actresses over the age of 35 do not seem to have problems becoming pregnant naturally.â&#x20AC;? These results indicate important gaps in womenâ&#x20AC;&#x2122;s knowledge about fertility and the need for education, said Dr Velez. â&#x20AC;&#x153;More can be done to educate women around age as a risk factor, and how they can preserve their fertility at increasing age, such as preserving their eggs if they havenâ&#x20AC;&#x2122;t found a partner to start a family with by a certain age.â&#x20AC;? â&#x2013;


ASRM Annual Meeting

web-Based IVF Teaching Tool Frees up nurses’ Time By Wayne Kuznar

Orlando, FL—For women who are about to undergo in vitro fertilization (IVF), Web-based learning about the procedure is as effective as didactic learning in a classroom format, according to Tannys Vause, MD. Furthermore, women using a Web-based teaching tool were more satisfied with this method of teaching than those undergoing nurse-led traditional didactic learning. Findings from her randomized controlled trial were presented at the 2011 annual meeting of the American Society for Reproductive Medicine. “We felt that the nurse didactic group sessions were not very cost-effective, as it required a lot of nursing time and because it required patients to take time off of work to spend an afternoon at our clinic learning the information,” said Dr Vause, physician at the Ottawa Fertility Center, Ottawa, Ontario, Canada. “Once they had the information they weren’t able to go back and review it.” To this end, an interactive Webbased teaching tool was developed as a teaching alternative. “We developed it

“For infertility nurses, the benefit is that they don’t have to take time out of their day to run these sessions every week, so it’s cost-effective because nursing time can be spent elsewhere.” —Tannys Vause, MD

so that patients could choose their specific IVF protocol, be it the long ago-

nist, antagonist, or luteal estradiol patch protocol,” she said. Before undergoing their first IVF cycle, 50 women completed a baseline knowledge questionnaire and then were randomized to the interactive Webbased teaching tool or nurse-led didactic teaching. The women completed the same knowledge questionnaire after their interventions, in addition to a perceived stress scale and a satisfaction questionnaire, which was also completed after embryo transfer. Education levels attained were similar between the 2 groups, and more than 80% in each group reported annual incomes exceeding $50,000. The average age was 34.3 years in the group assigned to the Web-based intervention and 32.9 years in the group assigned to the classroom teaching. More than 75% in each group reported having advanced Internet skills. There was no significant difference in the knowledge demonstrated between the 2 groups, both before and after the teaching session. There was a statistically nonsignificant trend toward less stress in the Web-based teaching tool.

“We found that patients who had been randomized to the Web-based teaching group were significantly more satisfied with their teaching tool,” said Dr Vause. On the satisfaction questionnaire, the patients were asked whether they found the teaching tool effective and easy to follow, and effective and whether they had questions afterward that they believed had not been answered appropriately. The same group is in the process of developing a Web-based teaching tool for patients undergoing superovulation interuterine insemination, according to Dr Vause. “For infertility nurses, the benefit is that they don’t have to take time out of their day to run these sessions every week, so it’s cost-effective because nursing time can be spent elsewhere. We’ve also found that patients have had fewer questions when they come in to meet with the nurses for scheduling visits, as well as fewer questions they call in with after hours; we haven’t done a formal study but have noticed a subjective decrease in those questions,” said Dr Vause. ■

Is Arcuate-shaped uterus a Risk Factor for Miscarriage? New Data Suggest So, but More Evidence Needed By Rosemary Frei

Toronto, Canada—A study presented at the 2011 Canadian Fertility and Andrology Society annual meeting suggests there is a relationship between mullerian duct abnormalities (MDAs) and miscarriages. The analysis of 1329 consecutive patients showed a 48.3% miscarriage rate among those without an MDA and a 64.7% to 66.7% rate among those with MDAs. The son-and-father team of Michael Hartman, MD, and Alex Hartman, MD, included women who were being investigated for secondary infertility at the True North Imaging in Thornhill, Ontario, between October and March 2011. All of them had previous pregnancies that were not electively terminated. The women were categorized into 4 groups: 887 (66%) had no MDA; 29.6% had an arcuate deformity; 2.6%

had a septate uterus; and 1.1% had a unicornuate, didelphys, or bicornuate uterus. The miscarriage rates in these 4 groups were 48.3%, 66.7%, 64.7%, and 66.7%, respectively, representing a significant difference between those with and without MDAs. The physicians also analyzed the characteristics of patients with and without MDAs, including age, body mass index, presence of polycystic ovaries, and tubal patency. The only differences found were younger ages among women with unicornuate/didelphys/bicornuate uteruses, as well as significantly lower tubal patency rates in this group. “Radiologists have ignored the importance of arcuate uteruses as a possible cause of miscarriage but it could be important,” Dr Alex Hartman said. “This is because, as our studies

show, approximately 30% of infertility clinic patients have an arcuate uterus.” Drs Michael and Alex Hartman studied separately the effects of large versus

“Approximately 30% of infertility clinic patients have an arcuate uterus.” —Alex Hartman, MD

small arcuate uteruses and determined there was no difference between the 2 categories in terms of miscarriage rate. Jessica B. Spencer, MD, MSc, Assistant Professor of Reproductive

Endocrinology and Infertility, Emory University School of Medicine, Atlanta, said that although uterine septae have been clearly shown to increase the risk for miscarriage, additional studies are needed before she would agree that an arcuate-shaped uterus increases the risk of miscarriage or other complications. “Although age alone is the single best predictor of a woman’s risk for miscarriage, multiple miscarriages in any woman should never be attributed to age alone, until a thorough evaluation has been performed. Women with any uterine anomaly should be seen by a reproductive endocrinologist prior to pregnancy if possible, and ideally followed by a maternal fetal medicine specialist in pregnancy if the anomaly is associated with an increased preterm delivery risk,” Dr Spencer said. ■

DEcEMbER 2011 l VOLUME 3, NUMBER 6

19


Legal Update

Mississippi Initiative 26: The “Personhood” Amendment By Melissa B. Brisman, Esq, and Nancy M. Hartzband, Esq Ms Brisman is a reproductive attorney at Melissa B. Brisman, Esq, LLC, and is sole owner of Reproductive Possibilities, LLC, Montvale, NJ. Ms Hartzband is an associate attorney at Melissa B. Brisman, Esq, LLC.

O

n Election Day, November 8, 2011, residents of Mississippi voted on Initiative 26, a socalled “personhood” amendment that, if enacted, would have changed how a “person” is defined in the Mississippi Constitution. The Mississippi Supreme Court ruled that the personhood amendment qualified for the November ballot after a petition with more than 100,000 signatures from Mississippi residents was submitted. Mississippi is now the second state, after failed votes in 2008 and 2010 in Colorado, to consider a personhood amendment.1-3 If the measure had passed, language would have been added to the Mississippi Constitution declaring that life begins “from the moment of fertilization, cloning or the functional equivalent thereof.” As a result, undeveloped embryos would have been entitled to a series of protections under the Mississippi Constitution, including the right to life, liberty, and the pursuit of happiness.1-3 Simply stated, abortion in the state of Mississippi would not be permitted for any reason, including rape or incest. If “person” were defined as proposed, a woman choosing to have an abortion could be prosecuted and charged with the crime of murder. Women’s bodies, rights, and health would be subordinated to the protection of the embryo. In addition, certain forms of birth control, such as the “morning after” pill, would no longer be available, and stemcell treatments for patients with Parkinson’s disease, Lou Gehrig’s disease, and cancers such as leukemia would likely be discontinued. To support their stance, supporters of the Mississippi personhood amendment pointed to language in the majority opinion written by Justice Harry Blackmun in the landmark 1973 case of Roe v Wade (410 U.S. 113). Many of us can recall, and others have since learned, the facts of this case, which involved a single, pregnant Texas woman, under the fictional name of Jane Roe, who challenged antiabortion laws by stating that they violated her rights under the Constitution. Ultimately, the case was presented before the Supreme Court, which decided that a fetus is not a person but a “potential life” and therefore does not have constitutional rights of its own. Roe’s claim was upheld, and her right to privacy entitled her to an abortion. Although the Supreme Court ruling provided for abortion rights, Justice Blackmun, who wrote the majority

20

opinion, noted, “The appellee (State of Texas) and certain amici [prolife advocates] argue that the fetus is a ‘person’ within the language and meaning of the Fourteenth Amendment. In support of this, they outline at length and in detail the well-known facts of fetal development. If this suggestion of personhood is established, the appellant’s case, of course, collapses, for the fetus’ right to life would then be guaranteed specifically by the Amendment.”4-6 Supporters of Mississippi’s personhood amendment rely on this language to contend that during Blackmun’s time, the “well-known facts of fetal development” were a far cry from what is known today. Ultrasound and DNA testing were not yet invented. In 1973, it was commonly believed that “life” began at “quickening,” or when a woman first felt movement of the baby in the womb, somewhere between 18 and 24 weeks. Supporters argue that in 1973, technology was unable to prove that a fully human and unique individual existed at the moment of fertilization and continued to grow through various stages of development until natural death from old age. Their position is that scientific evidence has advanced tremendously and can now establish the humanity of the preborn child. As a result, legal protections of personhood should be restored to the preborn child. Although the personhood amendment would have on obvious effect on abortion and a woman’s right to choose, there are other potential and perhaps unintended effects that could be far reaching and could tremendously impact the services performed at in vitro fertilization (IVF) clinics in Mississippi. Since more than one egg is harvested and fertilized to achieve a successful IVF pregnancy, making all the embryos “persons” under Mississippi law would make it difficult, if not impossible, to continue offering IVF treatment within the state. When embryos are created and frozen as a part of reproductive fertility treatments, these embryos would legally be persons if this initiative passes and, consequently, will have all the rights due persons. The problems resulting from this change would not only be many but illogical as well. For example, if embryos are to be defined as persons, would the freezing of embryos be considered child abuse? If one of these embryos “dies” in some part of the IVF process, will a criminal inves-

DEcEMbER 2011 l VOLUME 3, NUMBER 6

tigation be conducted? Would physicians, if faced with the choice of saving a woman’s life or refusing to harm an embryo, be sued for malpractice no matter what choice was made? Would stored embryos be given names (nonbirth certificates)?

You do not have to necessarily like abortion to respect the right of a woman’s choice. As so aptly stated by Margaret Sanger, who founded what later became the Planned Parenthood Federation of America, “No woman can call herself free, who does not own her own body.”

What about the several references to “person” currently found in Mississippi laws that are inconsistent or incompatible with the personhood amendment? If the amendment had passed, would that have meant that embryos would have property or inheritance rights? Are Termination of Parental Rights laws applied to these embryos or to adoption laws? If more than 5 unrelated embryos are housed in a single building, will that building have to be licensed as a child residential care home? It’s ludicrous, yet the list could go on and on. It seems that Mississippi Initiative 26 was drafted and proposed in an attempt to revisit and challenge Mississippi’s abortion laws. These efforts have been successful in that the personhood amendment during the past few months has been passionately debated, spurring on prolife speeches and challenges to women’s rights. The personhood amendment has called into question not only a woman’s right to choose but also stem-cell research and treatment and accepted infertility treatments designed to assist couples in creating and sustaining birth, which, ironically, is the stated goal of its proponents. The concept that a person exists from the moment of “fertilization, cloning or the functional equivalent thereof” stems from religious beliefs. People have many different ideas and

theories about when human life begins. Mississippi’s personhood amendment was an attempt to impose one particular theory, that life begins at fertilization. But what about those who believe otherwise? Why should they be forced to accept and live by this one theory? Religious ideology is not an appropriate foundation for the law in this country. Clearly, it is possible to be personally opposed to abortion for moral or religious reasons yet believe it is wrong to impose these values on others via legislation. If this amendment had passed, legal challenges from entities such as Planned Parenthood and the American Civil Liberties Union would likely have followed and, in all probability, been successful. The reason is that if enacted, Mississippi’s personhood amendment would have affected the state’s constitution and laws that would be in direct contradiction to the United States Supreme Court’s ruling in Roe v Wade. Paragraph 2 of the United States Constitution, commonly referred to as the Supremacy Clause, establishes that the federal constitution and federal law generally trumps state laws and state constitutions.7 You do not have to necessarily like abortion to respect the right of a woman’s choice. As so aptly stated by Margaret Sanger, who founded the American Birth Control League, which later became the Planned Parenthood Federation of America, “No woman can call herself free, who does not own her own body.”8 It’s a fundamental concept. ■ References 1. Barber R. Personhood could have unintended effects. Bolivar Commercial. September 20, 2011. www.bolivarcom.com/printer_friendly/15593832. Accessed October 10, 2011. 2. Erfelt S. Mississippi abortion-personhood amendment gets November vote. September 9, 2011. Life News.com. www.lifenews.com/2011/09/09/mississippiabortion-personhood-amendment-gets-november-vote. Accessed October 10, 2011. 3. Coleman LR. Christian medical groups weigh in on Mississippi personhood measure. Christian Post. September 24, 2011. www.christianpost.com/news/christianmedical-groups-weigh-in-on-mississippi-personhoodmeasure-56443. Accessed December 15, 2011. 4. 10 Arguments in favor of pro-choice policy. amplify yourvoice.org. January 26, 2009. www.amplifyyour voice.org/u/Pheo152/2009/1/26/10-Arguments-inFavor-of-ProChoice-Policy. Accessed October 10, 2011. 5. Johansen J. A summary of pro choice arguments. Pregnant Pause. September 4, 2000. www.pregnantpause. org/abort/choicarg.htm. Accessed October 10, 2011. 6. Future Choices. Legal abortion: arguments pro & con. Westchester Coalition for Legal Abortion, Inc. Updated April 7, 2008. http://futurechoices.net/articles/abortion/ abortionprocon.html. Accessed December 15, 2011. 7. The United States Constitution. Article VI. Updated September 20, 2004. http://www.house.gov/house/ Constitution/Constitution.html. Accessed December 15, 2011. 8. Gale Cengage Learning. Women’s history. Margaret Sanger. www.gale.cengage.com/free_resources/whm/ bio/sanger_m.htm. Accessed October 10, 2011.


Infertility Update

Primary ovarian Insufficiency still often neglected Despite serious Health Implications Poor Quality of Care for a Misunderstood Condition By Rosemary Frei, MSc

Toronto, Canada—The healthcare community must do much more to help women with primary ovarian insufficiency, experts suggested during a presentation on the latest evidence surrounding this underdiagnosed condition during the 2011 Canadian Fertility and Andrology Society meeting. Bart C.J.M. Fauser, MD, PhD, Chair, Division of Woman & Baby, University Medical Center Utrecht, the Netherlands, told Infertility & Reproductive News that these women are often given advice, such as to try hormone replacement therapy (HRT), even when the choice of appropriate therapy is not clear. “We first need to counsel them, to help them come to terms with their condition. Only then should we discuss HRT, to show them it may provide a benefit,” said Dr Fauser. “And what is truly needed is a standardized approach, involving both physicians and nurse practitioners, to thoroughly assess the patients—including their bone density, cardiovascular risk markers, and sexual health—and also to conduct regular follow-up.”

“The quality of clinical care for women with primary ovarian insufficiency is generally poor.…We need to develop a truly patientcentered, multidisciplinary approach.” —Bart C.J.M. Fauser, MD, PhD

Jessica B. Spencer, MD, MSc, Assistant Professor of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, agreed, stating that it often takes years for women to be correctly diagnosed. “They are often started on oral contraceptives to fix their amenorrhea or irregular cycles, without ever having a thorough evaluation, including genetic testing, autoimmunity screening, and so on, or a clear understanding of what their diagnosis is,” said Dr Spencer. “These patients need careful, empathetic counseling, and a complete evaluation and review of their options for hormone therapy and fertility treatment such as egg donation.”

Diagnostic criteria not evidence-Based The mechanisms underlying primary

ovarian insufficiency—also known by a cluster of other terms, such as premature ovarian failure and gonadal dysgenesis

—are poorly understood. The diagnostic criteria are not evidence-based, said Dr Fauser, and come from a decades-old Continued on page 22

The 1st FDA Cleared Blood Test for Pre-Surgical Evaluation of Ovarian Masses

The Power of

Five Apolipoprotein A1

ơ2 microglobulin

Transthyretin

CA125-II

Transferrin

Five Markers, One Result t

OVA1® is a simple blood test to help evaluate ovarian masses for malignancy before a planned surgery.

t

Combined with a physician’s preoperative assessment, OVA1 achieved a sensitivity of 99% for Epithelial Ovarian Cancers and 94% for early stage ovarian cancers.1

t

OVA1 uses the FDA cleared OvaCalc® software* to produce a single score with improved diagnostic accuracy. 1

Effectiveness of a Multivariate Index Assay in the Preoperative Assessment of Ovarian Tumors, Ueland, FR, et al. Obstet Gynecol 2011;117:1289–97

Helping Guide Surgical Decisions

t

ova-1.com

*FDA clearance does not denote official approval. FDA evaluated OvaCalc as part of its OVA1 clearance. Vermillion, OVA1 and OvaCalc are registered trademarks of Vermillion, Inc. OVA1® is a qualitative serum test that combines the results of five immunoassays into a single numerical result. It is indicated for women who meet the following criteria: over age 18, ovarian adnexal mass present for which surgery is planned, and not yet referred to an oncologist. OVA1® is an aid to further assess the likelihood that malignancy is present when the physician’s independent clinical and radiological evaluation does not indicate malignancy. PRECAUTION: OVA1 is not intended as a screening or stand-alone diagnostic assay. Incorrect use of OVA1 carries the risk of unnecessary testing, surgery, and/or delayed diagnosis.

DEcEMbER 2011 l VOLUME 3, NUMBER 6

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Infertility Update

competing PgD Technologies showcased at Fertility Meeting By Rosemary Frei, MSc

Toronto, Canada—Preimplantation genetic diagnosis (PGD) has become a competitive field, with a great deal of money and credibility at stake. A session at the 2011 Canadian Fertility and Andrology Society meeting was dedicated to this topic. “The challenge in this field is ensuring that technologies have been fully and independently validated before they are widely implemented,” said session chair Jon Havelock, MD, Principal, Pacific Centre for Reproductive Medicine, Vancouver, BC. “As clinicians, our obligation is not necessarily to use the latest technology but to do what’s best for our patients.” Focus on Array comparative genomic Hybridization Santiago Munné, PhD, head of Reprogenetics, Livingston, NJ, had helped to develop the first PGD test in the early 1990s. In 2001 he created Reprogenetics, the first laboratory in the United States to be accredited to perform PGD. The work performed by Dr Munné and his team these days focuses on array comparative genomic hybridization (aCGH). This technique highlights the presence of defects such as microdeletions and duplications in the DNA and uses a standard control rather than parental DNA in the analysis. “The advantages of aCGH are that all of the chromosomes are analyzed. It can analyze mutations, translocations, and many other types of genetic abnormalities, and you can get results in 12 to 23 hours, allowing for day 5 biopsy and day 6 transfer,” said Dr Munné. “In

addition, parental DNA is not required, while it is for single nucleotide polymorphism [SNP], and the latter also requires data cleaning to arrive at the diagnosis.”

from women as old as 42 years and a pregnancy rate of 82.2% in a 2010 study of 45 couples, including women whose average age was 37.7 years. Responding to a question from the

“The advantages of aCGH are that all the chromosomes are analyzed. It can analyze mutations, translocations, and many other types of genetic abnormalities, and you can get results in 12 to 23 hours, allowing for day 5 biopsy and day 6 transfer.” —Santiago Munné, PhD The use of aCGH covers a larger part of the genome than SNP analysis, at approximately 600 MB versus 1.5 MB for aCGH and SNP, respectively, said Dr Munné. He noted that analysis of the parental DNA is unnecessary in many cases, because 90% of cases of an abnormal genetic complement have maternal origin, and because mitotic abnormalities do not have parental origin. In addition, aCGH can be used to analyze the genetic complement of the polar bodies, the chromosomal remains that are expelled from the oocyte after meiosis. Dr Munné said that a recent study indicated that using aCGH with polar bodies results in only a 6% error rate (Geraedts J, et al. Hum Reprod. 2011;26: 3173-3180). Day 5 aCGH has been used to produce a 100% rate of normal embryos

audience, Dr Munné noted that the average survival rate with aCGH analysis of day 5 blastomeres is 90%. strength Is in single nucleotide Polymorphism Analysis Matthew Rabinowitz, PhD, Principal, Gene Security Network, Redwood City, CA, described his transition from rocket scientist to expert in PGD after his sister had lost a child as a result of a severe genetic defect. In 2003, the consulting associate professor of aeronautics and astronautics at Stanford University dove into PGD and formed Gene Security Network in 2004. The “Parental Support” technology developed by Dr Rabinowitz and others at his company analyzes genetic information from the fetus 3 days after fertilization, as well as from both parents. A blastomere is removed from each day-3

Primary ovarian Insufficiency still often neglected... article. These criteria are: • Amenorrhea lasting more than 6 months • Follicle-stimulating hormone serum levels >40 IU/L on repeated testing • Age over 40 years. “The most controversial issue is the age criterion—why on earth is age 40 the threshold for diagnosis, rather than, say, 39 or 41?” queried Dr Fauser. “The accepted criteria suggest that at a certain, clear-cut time, function moves from being normal to being abnormal. But this is not the case. Several studies have shown that you can have intermediate function in the age range of 35 to 45 years, unless there are 2 completely different patient cate-

22

gories with 2 completely different sets of genes involved, but that is extremely unlikely,” he said. The possible causes for primary ovarian insufficiency include genetics, chemotherapy or radiation treatment, surgery, infection, and autoimmune disease. However, in “the great majority of cases we don’t have a clue what the etiology is,” stated Dr Fauser. “This is unsatisfactory for us, but it is also very unsatisfactory for the patients. There’s a lot with respect to empathy that we have to learn when working with these women.” Two competing Hypotheses The 2 competing hypotheses for the

DEcEMbER 2011 l VOLUME 3, NUMBER 6

embryo and used for DNA screening using a microarray to detect SNPs. The results are available within 24 hours; hence, the healthiest embryos can be implanted in the mother 5 days after fertilization. Citing a previous study that indicates that this method in blastocysts is as accurate as the “gold standard” of metaphase karyotyping, Dr Rabinowitz also said that his method has produced a 44.3% implantation rate and a 60.6% clinical pregnancy rate (Johnson DS, et al. Hum Reprod. 2010;25:1066-1075). These rates are slightly better than those they had achieved with day-3 embryos (at 48.6% vs 56.4%, respectively). He cited a study he and his colleagues presented at the 2010 American Society for Reproductive Medicine annual meeting, which involved embryos from mothers aged >40 years being implanted after going through Parental Support screening and resulted in a 60.9% clinical implantation rate compared with a 47.7% rate among screened embryos from mothers aged 35 to 39 years. Therefore, the system “abrogates the effects of advanced maternal age,” Dr Rabinowitz said. In April 2011 the company received a $2-million grant from the National Institutes of Health for a clinical trial of the Parental Support technology. The principal investigator is Ron Wapner, MD, Columbia University, and 20 centers are participating. “It’s a unique moment in medicine, and PGD is absolutely going to grow in prevalence,” concluded Dr Rabinowitz. “I think we’re heading for a very interesting 5 years.” ■

Continued from page 21

cause of this condition are ovarian follicle depletion and ovarian follicle dysfunction. Dr Fauser and his team believe that the underlying problem is accelerated follicle loss rather than a low initial follicle number. “That’s why we can preserve these women’s ovarian function if we cryopreserve their ovarian tissue very early on,” said Dr Fauser. In a review article by Dr Fauser and 2 of his collaborators (De Vos M, et al. Lancet. 2010;376:911-921), they noted that although genetics may only play a small part in the development of ovarian insufficiency, the FOX03a gene— which is implicated in early follicle exhaustion—is a promising candidate.

Antimüllerian hormone has also been shown to be a useful marker for primary ovarian insufficiency. Dr Fauser and his coauthors also noted in the review that ovarian insufficiency increases the risk not only for infertility but also for osteoporosis, dementia, cardiovascular disease, and other chronic conditions. “The quality of clinical care for women with primary ovarian insufficiency is generally poor,” concluded Dr Fauser. “We need to do more follow-up studies regarding women’s health implications that test various possible interventions.…The time is now for a new approach to primary ovarian insufficiency. We need to develop a truly patientcentered, multidisciplinary approach.” ■


Infertility Update

should obesity Be a Barrier to Accessing Fertility Treatment? A Controversial Topic with Legal Implications By Rosemary Frei, MSc

Toronto, Canada—Should a high body mass index (BMI) be enough to bar a woman from an infertility program? The pros and cons of such a policy were discussed at the 2011 Canadian Fertility and Andrology Society annual meeting. obesity a High Risk for Fertility Treatment Arya Sharma, MD, PhD, Professor of Medicine and Chair in Obesity Research and Management, University of Alberta, Edmonton, defended the case for the argument that excess weight is a barrier and therefore obese women should not have access to fertility treatment. The position is controversial, but in reality, several countries have already made this the official policy. For example, in New Zealand, women with a BMI ≥32 kg/m2 are barred from fertility treatment, and in British Columbia, egg retrieval under sedation is not allowed in women with a BMI >32 kg/m2. Analyses have shown that obesity is a “major causal contributor to female infertility, there are poorer success rates of fertility treatment in overweight and obese women, and it increases risks of fertility treatment” and produces other deleterious reproductive effects, said Dr Sharma. He cited a review article showing that although many obese women have had successful pregnancies, obesity has been associated with an impaired ability to conceive, primarily because of hormonal disturbances (Brewer CJ, et al. Reproduction. 2010;140:347-364). The authors note that women with abdominal adiposity are less likely to conceive during each treatment cycle. Furthermore, obesity impairs the response of women to assisted reproductive technologies by impairing ultrasound imaging—and, therefore, egg retrieval; it also provokes a poor response to superovulation, leading to overall lower pregnancy rates and higher miscarriage rates. Dr Sharma said that research also links obesity to complications during pregnancy, such as hypertension, gestational diabetes, prolonged labor, increased blood loss, unexplained stillbirth, and increased neonatal admissions. “We consider obese women to be high risk right off the bat, because of these potential complications,” Dr Sharma said regarding the protocol at his institution, the Royal Alexandra

Hospital in Edmonton. He added that “costs associated with assisted reproductive technologies are not a little bit more expensive—they’re far more expensive as BMI goes up,” because of the technical difficulties and lower success rate. Dr Sharma advised that the best approach is to offer obese women who are seeking fertility treatment “structured, evidence-based obesity treatments including surgery, rather than… commercial weight-loss programs.” Even modest weight loss, or a 5% to 10% drop in the person’s mass, is associated with “resumption of ovulation, better response to gonadotropin, and spontaneous pregnancies leading to live births,” he said. Studies have shown that such weight losses are easy to achieve by patients who are motivated, and even if the patients do not keep the weight off, “you only need short-term weight loss for increased fertility,” Dr Sharma said. He suggests using BMI rather than waist circumference as a criterion for acceptance into a fertility program, or a

Analyses have shown that obesity is a “major causal contributor to female infertility, there are poorer success rates of fertility treatment in overweight and obese women, and it increases risks of fertility treatment.” —Arya Sharma, MD, PhD

system that he and another colleague designed—called the Edmonton Obesity Staging System—which takes into account morbidity associated with excess weight (Sharma AM, et al. Int J Obes. 2009;33:289-295). The evidence Is Inconclusive Presenting the other side of the issue, Anthony Cheung, MD, MPH, MBA, argued that the evidence linking obesity to reduced fertility is not conclusive. Dr Cheung, founder and Medical Director, Grace Fertility Centre, and

Assistant Professor of Reproductive Endocrinology and Infertility, University of British Columbia, Vancouver, said that study results are often confounded by the presence of type 2 diabetes in obese women.

“I agree that obesity is a problem and has inherent risks, but we cannot use BMI alone to determine access to fertility treatment.” —Anthony Cheung, MD, MPH, MBA

“Let’s look at the studies critically. When you do that, it’s not as clear-cut as you think,” he said. In support of his view that BMI is not an impediment to fertility or to fertility treatment, Dr Cheung cited the following studies. Study 1: One study showed that BMI does not affect overall outcome of ovulation induction in women with polycystic ovary syndrome (PCOS) and a BMI as high as 35 kg/m2 (Balen AH, et al. BJOG. 2006;113:1195-1202. Epub 2006 Aug 10). Study 2: Another study showed that significantly poorer in vitro fertilization (IVF) outcomes do not occur in women with a BMI <40 and that even among morbidly obese (BMI ≥40 kg/m2) women, there is not a significant negative effect on pregnancy, miscarriage, or live-birth rates; there is only an increase in the rates of gestational diabetes and preeclampsia (Dokras A, et al. Obstet Gynecol. 2006;108:61-69). However, Dr Cheung did not mention that the IVF cycle cancellation rate in the morbidly obese group was 25.3% compared with 10.9% in women with a normal BMI, that morbidly obese women without PCOS had an even higher cancellation rate of 33%, that obese women required significantly more days of gonadotropin stimulation, and that obese women also had a significantly higher rate of cesarean delivery—findings that prompted the investigators to recommend that morbidly obese women “should be aggressively counseled regarding their increased obstetric risk and offered treatment options for weight reduction before the initiation of fertility therapy.”

TAkEAWAY qUIck POINTS ➤ Obesity is a known contributor to infertility in women ➤ It leads to poor success rates of fertility treatment in addition to other health conditions ➤ Obese women who seek fertility treatment should be advised on weight loss before beginning treatment ➤ Even modest (5%) weight loss is associated with a resumption of ovulation and improves the response to gonadotropin therapy ➤ Some experts suggest that excess weight is a barrier to reproduction and therefore obese women should not have access to fertility treatment ➤ Others argue that the evidence is inconclusive and is not sufficient to withhold fertility treatment

Study 3: Yet another study showed no differences between women with a normal BMI and those with a high BMI in terms of associated costs: the cost per IVF cycle, cost of prenatal care, cost per positive pregnancy test, or cost per ongoing pregnancy (Maheshwari A, et al. Hum Reprod. 2009;24:633-639). However, Dr Cheung did not discuss the study’s conclusion, which included a recommendation for overweight or obese women to lose weight before starting IVF, because of “increased obstetric complications” with excess weight, the authors write. “I look at the results as a clinician, a patient advocate, and an epidemiologist,” said Dr Cheung. “If we set the BMI cut-off at the same level to access treatment as they do in New Zealand— 32 kg/m2—are you really being fair, is any discrimination being used? Are we applying our own biases or are there really truly some problems?” He noted that if we apply such a cut-off, “we may further stigmatize women who are already suffering,” because of difficulty conceiving. “I agree that obesity is a problem and has inherent risks, but we cannot use BMI alone to determine access to fertility treatment. I fully endorse Dr Sharma’s system, which incorporates many factors, and not just BMI,” Dr Cheung concluded. ■

DEcEMbER 2011 l VOLUME 3, NUMBER 6

23


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


Women’s Health

Breastfeeding May Be compromised but Important in survivors of childhood cancer By Rosemary Frei, MSc

A

lthough breastfeeding may be impaired in some survivors of childhood cancers as a result of treatments, such women who are able to successfully breastfeed should do so, because of the protective effects it can impart, according to research led by Susan W. Ogg, RN, MSN, a research nurse at the Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN (Ogg SW, et al. J Cancer Surviv. 2011;5:175-181). “Some nurses work with women and assess their lactation potential throughout pregnancy, labor, delivery, and postpartum,” Ms Ogg told the Infertility & Reproductive News. “When working with a mother who has survived childhood cancer, we recommend that nurses or other medical professionals conduct more frequent breast exams to monitor the survivor’s lactation potential. [That way], if it appears that the survivor may be unable to lactate, she can be better prepared to employ other nutritional options in the postpartum context.” Ms Ogg, James Klosky, PhD, a clinical psychologist at the St. Jude Children’s Research Hospital, and colleagues also strongly advocate for breastfeeding whenever possible among childhood cancer survivors. “It is one more health behavior that survivors can engage in to promote their

own health and their children’s health,” Dr Klosky said. “Furthermore, breastfeeding may alleviate some of the potential late effects of childhood cancer therapy experienced by these mothers.” In the study, the researchers reviewed the scant amount of literature addressing lactation outcomes in patients with cancer, as well as the evidence for benefits of lactation to cancer survivors.

“When working with a mother who has survived childhood cancer, we recommend that nurses or other medical professionals conduct more frequent breast exams to monitor the survivor’s lactation potential.” —Susan W. Ogg, RN, MSN

“This is the first paper to provide an overview of the whole topic,” commented Pamela Berens, MD, professor of obstetrics and gynecology at the University of Texas Health Science

2007 Percent of Children Exclusively Breastfed Through 3 Months

Center at Houston, who was not one of the researchers. “We need better longterm research, and the time is ripe for both retrospective and prospective studies, as the authors point out, since quite a number of women have survived childhood cancer.” The small number of studies on lactation and breastfeeding in cancer survivors all point to lower rates of lactation, and not only among breast cancer survivors. For example, a study of longterm survivors of Hodgkin lymphoma showed that only 61% of women’s breastfeeding attempts were successful compared with 79% of attempts in a sibling control group (McCullough L, et al. Cancer. 2010;116:4866-4871). Another team reviewed the lactation experiences of 12 survivors of childhood acute lymphoblastic leukemia (Johnston K, et al. Pediatr Blood Cancer. 2008;50:721-722). Every woman had received 24 to 25 Gy of cranial radiation therapy and chemotherapy as part of treatment, and only 17% were able to breastfeed. One mechanism for the lactation difficulties appears to be a growth hormone deficiency; cranial radiation is linked to a high risk for such a deficiency, the researchers point out. They also outline the salubrious effects of breastfeeding, including: • Well-established benefits to infants, such as lower infectious disease and malignancy rates, and benefits to mothers, such as lowered risk for postpartum hemorrhage and decreased rates of breast, ovarian, and uterine cancers

• The potential to reduce the severity and risks associated with late effects of childhood cancer, such as low bone mineral density, metabolic syndrome, obesity, diabetes, cardiovascular disease, and second malignant neoplasms. “We propose that education of childbearing cancer survivors about the health benefits of breastfeeding should be added to the list of interventions that are commonly recommended to cancer survivors,” the researchers concluded. They also stressed that healthcare professionals who have patients with childhood cancer should be aware of the potential deleterious effects of the cancer treatment on lactation, as well as the likely benefits of breastfeeding for infants and mothers. ■

Maternal Drug exposure Declining, at least at one large center Less Cocaine Abuse Noted By Caroline Helwick

Breastfed Percentage 15.2-26.0 26.1-32.0 32.1-40.0 40.1-46.1 46.2-50.8

Source: Centers for Disease Control and Prevention National Immunization Survey (NIS), for the cohort of children born in the years 2005-2007; Data are provisional for 2007; HP2020 Target: 46.2%.

Washington, DC—Maternal substance abuse has decreased over the past decade, in particular cocaine use, at the University of Maryland Medical Center in Baltimore. At 2011 American College of Obstetricians and Gynecologists annual meeting, Mishka Terplan, MD, MPH, described the trends in drug-exposed deliveries at her center for the period 2001-2009. She and her colleagues reviewed maternal

and newborn administrative data, which included urine toxicology and International Classification of Diseases, Ninth Revision, codes for substance abuse and birth outcomes. The population included 15,150 women, 10% of whom had drugexposed deliveries. But drug use peaked in 2004 to nearly 12%, and has since declined to approximately 6%, Dr Terplan reported. Continued on page 28

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Women’s Health

Advantages shown for collaborative Physician/Midwifery oB Program By Caroline Helwick

Washington, DC—A model of obstetric collaboration between certified nurse midwives and physicians at the University of Texas Medical Branch (UTMB) at Galveston showed that obstetric responsibilities can be amicably shared and patient outcomes optimized, according to a study presented at the 2011 American College of Obstetricians and Gynecologists (ACOG) annual meeting. “This ongoing study has emphatically demonstrated that the collaboration of certified nurse midwives and physicians in an intrapartum setting has maintained the percentage of safe deliveries for uncomplicated cases and has facilitated cost-savings measures,” said Tony Wen, MD, chief, Education Division, and residency director, UTMB, who presented the study. Susan Nilsen, CNM, and Ruth Soulsby-Monroy, CNM, were coinvestigators. Collaborative practice is becoming increasingly important given the current emphasis on healthcare reform and cost-containment, but there is a gap in understanding how collaboration between obstetricians and certified nurse midwives brings about high-quality, cost-effective labor and delivery services, the researchers noted. “The ultimate goal of collaborative obstetric practice is to provide comprehensive quality healthcare services while offering patients a choice of providers

wives also conduct postpartum rounds for 90% of vaginal deliveries. Patients with medical or obstetric complications are managed by the physician team. They are responsible for antepartum services, intrapartum care, triage, obstetric surgical procedures, and postpartum care.

Tony Wen, MD, and Susan Nilsen, CNM

who embrace compatible healthcare philosophies. UTMB has been one model of success,” Dr Wen said. Division of labor The inpatient collaborative team at UTMB consists of 17 certified nurse midwives, 10 maternal-fetal medicine physicians, 13 obstetric residents, 7 maternal-fetal medicine fellows, and 3 generalists. The certified nurse midwives provide intrapartum management of low-risk pregnancies between 35 and 42 weeks gestation under a collaboratively established protocol. Services include management of labor, induction of labor, delivery, and the immediate postpartum period. In general, low-risk pregnancies do not involve preeclampsia, diabetes, fetal anomalies, or known intrauterine growth restriction. Certified nurse mid-

Maternal Drug exposure... For individual drug classes, rates of abuse have varied across the time period, but a trend is evidence for the decline in cocaine abuse: • In 2004, cocaine exposure was 3.25%, which dropped to 0.8% in 2009 • Opiate exposure peaked in 2005 to 4.43% and fell to 2.62% in 2009 • Marijuana exposure at delivery has ranged from 2.23% to 4.51% in 2001 and fell again to 2.25% in 2009. By total use at the time of delivery: • 435 women were exposed to marijuana (69% aged, 20-30 years) • 413 exposed to opiates (46% aged 20-30, 42%, >30 years) • 141 exposed to cocaine (57% aged ≥30 years). Risk Factors for Drug exposure at Delivery Significant demographic differences

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Continued from page 27

were noted among drug-exposed women. Drug exposure was documented for 11% of black women, 13% of white women, and 6% of women of other races. Only 7% of mothers younger than age 20 years were drugexposed compared with 10% of those aged 20 to 30 years and 14% of women aged ≥30 years. Drug exposure was more common among: • Women with public, versus private, insurance coverage • Unemployed women • Those living within the city of Baltimore • Smokers. Drug exposure at the time of delivery was associated with increased length of stay for the baby: 11.2 days versus 7.8 days. All these differences were statistically significant, Dr Terplan noted. ■

DEcEMbER 2011 l VOLUME 3, NUMBER 6

“The collaboration of certified nurse midwives and physicians in an intrapartum setting has maintained the percentage of safe deliveries for uncomplicated cases and has facilitated costsavings measures.” —Tony Wen, MD

certified nurse Midwives Handle 33% of Births In 2009, UTMB’s collaborative obstetric practice involved 11,956 triage encounters and 6220 deliveries. The certified nurse midwives service attended 2014 births, accounting for 32.4% of all deliveries. Of those pregnancies, more than 33% were nulliparous patients between 35 and 42 weeks gestation, whereas less than 2% were at 35 to 37 weeks gestation. Approximately 25% of the patients attended by certified nurse midwives were induced, 74% of which were after the due date. On average, the midwives transferred less than 16% of their patients to the physician service. Of these, 65% required a primary cesarean section. “Of particular note is the difference in the population for which the physicians provided care,” Dr Wen said. Physicians provided high-risk care for 1086 deliveries, which translates to approximately 26% of their population, in sharp contrast to the certified nurse midwives population of low-risk patients. The model “frees each specialty to work with the patient population appropriate to their knowledge and training,” he said. “At our university, maternal-fetal medicine physicians need not attend normal spontaneous vaginal deliveries. They are instead available to work with our highly complicated patients.” The delegation of high-risk patients

to the physician service is a primary contributing factor to the success of our collaborative effort.” In addition, the model encourages research and teaching in areas in which the certified nurse midwives are actively involved. some Preferences Are Different The collaborative care is evidencebased and congruent with ACOG guidelines, but the providers do not always practice identically, he said. For example, for low-risk patients receiving induction, the certified nurse midwives service prefers oxytocin and intracervical Foley bulb induction, and misoprostol (Cytotec) as the agent for cervical ripening. In contrast, the physician service uses the same methods and agents when attending high-risk patients, but usually prefers dinoprostone (Cervidil) over misoprostol. Amniotomy, intrauterine pressure catheters, and fetal scalp electrodes are used by both certified nurse midwives and physicians, he noted. collaboration will Provide cost-savings Although the investigators did not conduct a formal cost analysis, Dr Wen pointed out that the collaborative model will emerge as cost-saving. On average, institutions pay the certified midwives less than half the salary of a physician, although before 2011, institutions were reimbursed by the Centers for Medicare & Medicaid Services (CMS) for midwifery services at 65% of the physicians’ rate for the same work, he noted. This disparate reimbursement rate would not seem to incentivize an institution to use cost-saving certified nurse midwives, he suggested. However, in anticipation of a shortage of primary care providers, Congress has set forth measures to reimburse for midwifery care at 100% of the physicians’ rate. Additional congressional provisions to be implemented by 2015 include a 10% bonus payment to institutions that employ certified nurse midwives whose primary services account for 60% of CMS-allowed charges. “This increased reimbursement rate will significantly draw attention to resultant cost-savings in the use of certified nurse midwives in collaborative practice,” Dr Wen predicted. “Collectively, these changes will make abundantly obvious the financial advantages of establishing or enhancing an institution’s collaborative OB services.” ■


Women’s Health

chemotherapy generally safe in Pregnancy All Outcomes Appear Normal, Although Prematurity Is a Risk By Audrey Andrews

Stockholm, Sweden—The diagnosis of cancer in a pregnant patient is always unsettling, with fears for both the mother’s and the baby’s health. But a recent study found that fetal exposure to common chemotherapy regimens after the first trimester was generally safe. “Fear of chemotherapy is not an indication to terminate pregnancy and not a reason to delay maternal treatment for cancer,” said Frederic Amant, MD, University Hospitals Leuven, Belgium. Results of the large prospective study, which involved centers in Belgium, the Netherlands, and the Czech Republic, were presented at the 2011 European Multidisciplinary Cancer Congress. “What adds to the complexity of the treatment of cancer during pregnancy is the unknown effect of chemotherapy on the children,” Dr Amant said. Cancer is diagnosed in about 1 per 1000 to 2000 pregnancies (0.05%-0.1%), yielding up to 5000 cases of fetal exposure in Europe each year, mainly for breast cancer (42%) followed by hematologic malignancy (16%), according to Dr Amant. The study prospectively followed children who were prenatally exposed to chemotherapy, which was an anthracycline-based regimen in 78% of cases. The children were examined at age 18 months, then from age 5 to 6 years, and every 3 years thereafter until age 18. “The children’s behavior, general health, hearing, and growth were in the range of the general population. Most of the children have age-adequate neurological development and cardiac function,” Dr Amant reported. “But prematurity was frequently encountered, and this was associated with some impairment in cognitive development.”

“We have to take care to reduce iatrogenic prematurity,” he added.

ongoing, and the average child has been followed for 22 months at this point.

comprehensive Testing Done Testing comprised a clinical neurologic examination, testing of cognitive function (Bayley and IQ tests), electro/echocardiography and questionnaire for general health and development. Beginning at age 5, the children were also evaluated with audiometry and the Auditory Verbal Learning Test, subtasks of the Children’s Memory Scale, Test of Everyday Attention for Children, and the Child Behavior Checklist.

neonatal outcomes Dr Amant said that the 70 children who were exposed to chemotherapy before birth were born at a median gestational age of 35.7 weeks. Specifically: • 23% of them were born at ≥37 weeks gestation • 31% were born at 34 to 37 weeks of gestational age • 9% were born between 32 and 34 weeks • 7% were born between 28 and 32 weeks. The median birth weight was 2612 g (range, 720-3970 g). Intrauterine growth retardation was observed in 14 children (20.6%). Neonatal neurologic examination was normal in 64 infants (91.4%). Transient hypotonia was observed in 5 (7.1%), and benign sleep myoclonus and contracture of the right elbow in 1 infant each (1.4%). There were no excess congenital malformations or health problems, compared with the general population. The Bayley test at 18 months and the IQ test between 5 and 18 years were normal although there was a tendency for worse outcomes in children born prematurely, he said. There was a correlation between pregnancy duration and IQ score, with IQ scores increasing by an average of 2.5 points for each additional week of gestation. “While 2.5 points doesn’t sound like much, if you induce delivery at 32 weeks you may be risking 20 IQ points,” Dr Amant pointed out. “This is a significant clinical message.” Hearing was tested in 21 children, and 18 were normal though 3 had some hearing loss (1 had infection as a con-

“Fear of chemotherapy is not an indication to terminate pregnancy and not a reason to delay maternal treatment for cancer. What adds to the complexity of the treatment of cancer during pregnancy is the unknown effect of chemotherapy on the children.” —Frederic Amant, MD

Altogether, 236 cycles of chemotherapy were administered during 68 pregnancies, involving 70 children whose median gestational age at maternal cancer diagnosis was 18 weeks. The study is

TAkEAWAY qUIck POINTS ➤ New data suggest that fetal exposure to common chemotherapy regimens after the first trimester is generally safe. ➤ Fear of chemotherapy is not an indication to terminate pregnancy. ➤ It is also not a reason to delay maternal treatment for cancer. ➤ The main finding in the group of 70 who had been exposed to chemotherapy before birth was prematurity, which was associated with some cognitive impairment development. ➤ The majority of other outcomes were normal.

founder). Cardiac testing revealed no congenital heart malformation and normal functional parameters. In children exposed to anthracyclines, echocardiography showed some shortening fraction and decreased ejection fraction, compared with matched controls, but this was “modest,” he said. Whereas the vast majority of outcomes were normal, there were 2 “outliers,” twins who were born prematurely with birth weights of 1630 g and 1390 g. One had autistic disorder, and mental and motor retardation; the other had delayed neurologic development. “We are most likely observing a genetic syndrome, not a chemotherapyinduced one, although we could not diagnose it. All other neuropsychological results were within normal ranges, so this was reassuring,” he said. ■

“Back to sleep” okay for Moms, Too By Caroline Helwick

Washington, DC—Pregnant women have traditionally been advised to avoid the supine position, because of the potential for adverse maternal and fetal effects. However, a study presented at the 2011 American Congress of Obstetricians and Gynecologists annual meeting found no basis for this recommendation. “While further investigation is needed, our findings suggest that asymptomatic pregnant women may

safely sleep in the supine position in the second and third trimesters,” said Jennifer Wong, MD, Mount Sinai School of Medicine, New York. In her study of 29 women, the supine position was not associated with any adverse effect on fetal testing, compared with the lateral position, and no significant changes in maternal hemodynamic parameters. While in the supine position, up to 8% of pregnant women in the second

and third trimesters may develop subjective symptoms, such as dizziness, nausea, and shortness of breath, as well as decreased blood pressure (BP) and increased heart rate. Additional studies demonstrated abnormalities of Doppler velocimetry of the uterine and umbilical arteries, suggesting a potential risk to the fetus as a result of impaired placental perfusion. Other studies have not observed these effects, nevertheless, women are often coun-

seled to avoid the supine position while sleeping, she noted. “We set out to evaluate the effects of the supine position on fetal testing over a prolonged period of time in order to best simulate sleep. Our primary outcome was the number of fetal accelerations over a 4-hour testing period in the supine versus lateral position,” she said. The study included 29 women of 24 to 37 weeks of gestational age, who underwent continuous fetal monitorContinued on page 30

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“Back to sleep” okay for Moms... Continued from page 29

ing for 4 hours in the lateral position, followed by 4 hours in the supine position. During each testing period, investigators measured the uterine artery pulsatility index, umbilical artery systolic/diastolic BP ratio and maternal and fetal heart rate (hourly). Three independent examiners interpreted the fetal tracings.

“We set out to evaluate the effects of the supine position on fetal testing over a prolonged period of time in order to best simulate sleep….Our findings suggest that asymptomatic pregnant women may safely sleep in the supine position in the second and third trimesters.” —Jennifer Wong, MD

No significant differences were observed in the number of fetal accelerations, fetal decelerations, maternal heart rate, or maternal systolic BP. The umbilical artery systolic/diastolic BP ratio and uterine artery pulsatility index were also not significantly different. There were also no differences in fetal accelerations or decelerations in subgroup analyses based on gestational age. For the supine versus lateral positions, accelerations numbered 11.94 and 11.38; decelerations numbered 0.88 versus 0.80; maternal heart rate was 87 and 88; and systolic BP was 117 mm Hg and 110 mm Hg, respectively. No subjects reported symptoms of dizziness, nausea, or shortness of breath. The only difference was a higher systolic BP in the supine versus lateral position, with a mean difference of 6.43 mm Hg. ■

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GENERESS™ Fe (norethindrone and ethinyl estradiol chewable tablets and ferrous fumarate chewable tablets) 0.8 mg/25 mcg Brief Summary For full prescribing information, see package insert Rx only WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications (4).] 1 INDICATIONS AND USAGE GENERESS Fe is indicated for use by women to prevent pregnancy. The efficacy of GENERESS Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated. 4 CONTRAINDICATIONS Do not prescribe GENERESS Fe to women who are known to have the following: • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: - Smoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)] - Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)] - Have cerebrovascular disease [see Warnings and Precautions (5.1)] - Have coronary artery disease [see Warnings and Precautions (5.1)] - Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)] - Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] - Have uncontrolled hypertension [see Warnings and Precautions (5.4)] - Have diabetes with vascular disease [see Warnings and Precautions (5.6)] - Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.7)] • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.2)] • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3) in the full prescribing information] • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)] • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Thrombotic and Other Vascular Events Stop GENERESS Fe if an arterial or deep venous thrombotic (VTE) event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. If feasible, stop GENERESS Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

extent to which these findings may be due to differences in sexual behavior and other factors. 5.3 Liver Disease Discontinue GENERESS Fe if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop GENERESS Fe if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. 5.5 Gallbladder Disease Studies suggest the relative risk of developing gallbladder disease may be increased among COC users. 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking GENERESS Fe. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.7 Headache If a woman taking GENERESS Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue GENERESS Fe if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.8 Bleeding Irregularities Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Patient diaries from the clinical trial of GENERESS Fe showed that on the first cycle of use, 37% of subjects taking GENERESS Fe had unscheduled bleeding and/or spotting. From Cycle 2-13, the percent of women with unscheduled bleeding/ spotting ranged from 21-31% per cycle. For those women with unscheduled bleeding/spotting, the mean number of days of unscheduled bleeding/spotting was 5.2 in the first cycle of use and ranged from 3.6 – 4.2 in cycles 2-13. A total of 15 subjects out of 1,677 (0.9%) discontinued the study prematurely due to metrorrhagia or irregular menstruation.

Start GENERESS Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

Women who are not pregnant and use GENERESS Fe may not have scheduled (withdrawal) bleeding every cycle or may experience amenorrhea (absence of any bleeding and spotting). The incidence of amenorrhea in the clinical trial increased from 8.1% of the subjects in Cycle 2 to 18.4% by Cycle 13. For those women who had scheduled (withdrawal) bleeding, the average duration of bleeding per cycle in Cycles 2-13 was 3.7 days.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.

If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

Stop GENERESS Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

5.9 COC Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. GENERESS Fe use should be discontinued if pregnancy is confirmed.

5.2 Carcinoma of the Breasts and Reproductive Organs Women who currently have or have had breast cancer should not use GENERESS Fe because breast cancer is a hormonally-sensitive tumor. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the

DEcEMbER 2011 l VOLUME 3, NUMBER 6

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)]. 5.10 Depression Women with a history of depression should be carefully observed and GENERESS Fe discontinued if depression recurs to a serious degree.


5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs. 5.12 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.13 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. 6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and smoking [see Boxed Warning, and Warnings and Precautions (5.1)] • Vascular events [see Warnings and Precautions (5.1)] • Liver disease [see Warnings and Precautions (5.3)] Adverse reactions commonly reported by COC users are: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A phase 3 clinical trial evaluated the safety and efficacy of GENERESS Fe for pregnancy prevention. The study was a multicenter, non-comparative, open-label study with a treatment duration of 12 months (thirteen 28-day cycles). A total of 1,677 women aged 18-46 were enrolled and took at least one dose of GENERESS Fe. Adverse Reactions Leading to Study Discontinuation: 8.5% of the women discontinued from the clinical trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were nausea (1.0%), weight increase (0.8%), acne (0.8%), metrorrhagia (0.7%), altered mood (0.4%), hypertension (0.4%), irritability (0.3%), migraine (0.3%), decreased libido (0.3%) and mood swings (0.3%). Common Adverse Reactions (≥ 2% of all treated subjects): nausea/vomiting (8.8%), headaches/migraine (7.5%), depression/mood complaints (4.1%), dysmenorrhea (3.9%), acne (3.2%), anxiety symptoms (2.4%), breast pain/tenderness (2.4%), and increased weight (2.3%). Serious Adverse Reactions: Hypertension, depression, cholecystitis, and deep vein thrombosis. 7 DRUG INTERACTIONS No drug-drug interaction studies were conducted with GENERESS Fe. 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: • barbiturates • bosentan • carbamazepine • felbamate • griseofulvin • oxcarbazepine • phenytoin • rifampin • St. John’s wort • topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

7.2 Increase in Plasma Levels of Ethinyl Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain combination oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. 7.3 Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. Women who do not breastfeed may start COCs no earlier than four weeks postpartum. 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing OCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4 Pediatric Use Safety and efficacy of GENERESS Fe have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use GENERESS Fe has not been studied in postmenopausal women and is not indicated in this population. 8.6 Renal Impairment The pharmacokinetics of GENERESS Fe have not been studied in subjects with renal impairment. 8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of GENERESS Fe. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal [see Contraindications (4), and Warnings and Precautions (5.3)]. 8.8 Body Mass Index The safety and efficacy of GENERESS Fe in women with a BMI > 35 kg/m2 have not been evaluated. 10 OVERDOSAGE There have been no reports of serious ill effects from overdose of oral contraceptives including ingestion by children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. For all medical inquiries contact: WATSON Medical Communications Parsippany, NJ 07054 USA 800-272-5525 Manufactured By: Warner Chilcott Company, LLC Fajardo, PR 00738 Distributed By: Watson Pharma, Inc. Parsippany, NJ 07054 USA March 2011

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

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NEW

a unique side of birth control • Unique, low-dose combination of norethindrone and ethinyl estradiol (0.8 mg/25 mcg), hormones that you know and can trust 1 • 24/4 oral dosing for short, lighter, predictable periods1,2,* • A decreased incidence of breakthrough bleeding over time 2 • Highly effective at preventing pregnancy when taken as directed1

And, with every Generess Fe Rx that’s filled, a $5 donation is made to a women’s charity of the patient’s choice.

Patients pay no more than $25 for each monthly prescription with savings card *In women who experienced withdrawal bleeding, the mean median intensity of withdrawal bleeding decreased from Cycle 2 (1.83/3.0) to Cycle 13 (1.64/3.0). References: 1. GeneressTM Fe prescribing information. Morristown, NJ: Watson Pharma, Inc. December 2010. 2. Data on file. Watson Pharma, Inc.

GENERESS FE is an estrogen/progestin COC indicated for use by women to prevent pregnancy. Women who are over 35 years old and smoke should not use GENERESS FE. Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. GENERESS FE is contraindicated in pregnant patients, and those with a high risk of arterial or venous thrombotic disease, undiagnosed abnormal uterine bleeding, breast cancer or other estrogen- or progestin-sensitive cancer, liver tumors, or liver disease. Use of GENERESS FE should be stopped if a thrombotic event occurs, and at least 4 weeks before and through 2 weeks after major surgery. GENERESS FE should not be started any earlier than 4 weeks after delivery, in women who are not breastfeeding. If jaundice occurs, GENERESS FE treatment should be discontinued. GENERESS FE should not be prescribed for women with uncontrolled hypertension or hypertension with vascular disease. Women who are pre-diabetic or diabetic, should be monitored while using GENERESS FE. Alternate contraceptive methods should be considered for women with uncontrolled dyslipidemia. Patients using GENERESS FE who have a significant change in headaches or irregular bleeding or amenorrhea should be evaluated. The most commonly reported adverse events associated with the use of GENERESS FE included nausea/vomiting, headaches/migraine, depression/ mood complaints, dysmenorrhea, acne, increased weight, breast pain/tenderness and anxiety. GENERESS FE will not protect against HIV infection (AIDS) or other sexually transmitted diseases. Please see brief summary of Prescribing Information on next page.

©2011, Watson Pharma, Inc. Parsippany, NJ 07054. All rights reserved.

07569

06/11

Learn more at generess.com or call 855-GEN PILL (855-436-7455)

December 2011, Vol 3, No 6  

Infertility & Reproductive News

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