The OB/GYN Nurse-NP/PA

june 2011

www.theobgynnurse.com

Vol 3, no 3

ACOG HIGHLIGHTS

CLINIC PROFILE

Progesterone Gel Greatly In Vitro Maturation and Preterm Birth Rate Metabolic Health: Delaware Valley Reduces Short Cervix a Significant Risk Factor Institute of Fertility & Genetics

By Caroline Helwick

Interview with Elizabeth A. Shrader, MSN, APN-C, IVF Nurse Coordinator, Delaware Valley Institute of Fertility & Genetics, Marlton, NJ

A

ccording to the March of Dimes, 1 of 8 babies is born too early. New research promises to have a substantial effect on preterm births and the neonatal complications related to them.

At the 2011 meeting of the American College of Obstetricians and Gynecologists, Roberto J. Romero, MD, Program Director for Obstetrics and Perinatology at the National Institutes of Health (NIH), presented results from a new NIH study showing that vaginal

progesterone gel can prevent preterm birth by as much as 50%.

“Preterm birth is the most challenging problem in obstetrics,” Dr Romero said. “Its frequency is unchanged in 20 years. It occurs in about 12% of live births.” Dr Romero delivered the Anna Marie D’Amico Lecture at the meeting and received a standing ovation for his presentation.

Short cervix (Figure) and progesterone deficiency play key roles in preterm birth, according to Dr Romero.

Continued on page 8

Left to right: Akas Jain, MD; Marie Reilly, LPN; Kim Rossi, MA; George Taliadouros, MD; Elizabeth A. Shrader, MSN, APN-C.

I

n the early 1990s, George Taliadouros, MD, started the Delaware Valley Institute of Fertility & Genetics. He had originally come to the United States from Greece to work at the National Institutes of Health (NIH).

When starting his own practice, he wanted to bring some of the knowledge he obtained in his home country and at

the NIH to be able to provide a more holistic approach to infertility care, not just in vitro fertilization (IVF). He developed different programs for the Delaware Valley Institute of Fertility & Genetics that address not only fertility per se but also metabolic health, pregnancy, and endocrinology. Our program has 3 clinic locations in Southern Continued on page 7

NAMS HIGHLIGHTS

Characteristics of Women with Hypoactive Sexual Desire Disorder First National Registry Reveals an Unmet Medical Need

By Wayne Kuznar

L

ACOG HIGHLIGHTS

New Frontiers in Fertility Preservation for Women with Cancer

By Alice Goodman

W

omen of reproductive age who are diagnosed with cancer have several options for preserving fertility. Teresa Woodruff, PhD, Feinberg School of Medicine, Northwestern University in Chicago, discussed new and emerging options in oncofertility at the 2011 American College of Obstetricians and Gynecologists meeting.

Dr Woodruff had coined the term “oncofertility” and has been a driving force behind the Oncofertility Consortium.

In the United States, 1.7 million females are diagnosed with cancer at age ≤40 years. Aggressive treatments, includ-

ing chemotherapy, radiation, and surgery, often result in premature menopause.

Survivors of pediatric cancers have a 20% reduced chance of becoming pregnant, and young adult survivors have a 50% reduction in the ability to become pregnant. “About 40,000 women each year have childbearing interruptions,” Dr Woodruff noted.

Fertility preservation is an established option for men (including sperm banking, testis biopsy, donor sperm), but women have had fewer choices, although these are now expanding. Hormonal stimulation can achieve oocyte producContinued on page 6

ess than half of women diagnosed with hypoactive sexual desire disorder (HSDD) seek medical care, and of those who do, many are not being treated, said Jan Shifren, MD, Associate Professor of Obstetrics, Gynecology, and

Reproductive Biology, Harvard Medical School, at the 2010 North American Menopause Society annual meeting.

Reduced sexual desire occurs in younger and older women and is not limited to hormonal changes after

IN THIS ISS UE COMPLIMENTARY CE

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Sexually transmitted diseases: diagnosis and treatment

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The Publicationof of The Official Offical Publication

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Pain after endometrial ablation We thank Watson Pharmaceuticals, Inc., for their gold level support. ©2011 Novellus Healthcare Communications, LLC

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Weight gain between pregnancies and gestational diabetes ASK THE EXPERT

ACOG HIGHLIGHTS

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IUD placement postpartum Pregnancy coercion, sabotage

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Infertility drug shortage

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WOMEN’S HEALTH. . . . . . . . . . . . . .

Continued on page 13

CLINICAL NEWS

PHARMACY CORNER

Combined testing for cervical cancer Women and heart disease, part 3 INFERTILITY UPDATES

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Pre-ART stress and pregnancy Gamete donation: medical implications

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AUA HIGHLIGHTS

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Trigger point wand for refractory pelvic pain

Because she counts on you to know...

Only works with one daily dose It’s a fact. CRINONE is the only once-daily vaginal progesterone gel approved for ART through 12 weeks of pregnancy.1 The vaginal insert required three daily applications to achieve similar efficacy rates.2* When she asks about progesterone, give her the facts.

The only *Results based on a multicenter, randomized, open-label (assessor-blinded), non-inferiority study in 1,211 women aged 18 to 42 undergoing IVF to compare pregnancy rates using Endometrin® 100 mg BID, Endometrin® 100 mg TID, or CRINONE once daily.

CRINONE 8% (progesterone gel) is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (ART) treatment for infertile women with progesterone deficiency.

Important Safety Information The most common side effects of CRINONE (progesterone gel) 8% include breast enlargement, constipation, somnolence, nausea, headache, and perineal pain. CRINONE 8% is contraindicated in patients with active, or a history of, thrombophlebitis or thromboembolic disorders, patients who have known sensitivity to CRINONE 8%, missed abortion, undiagnosed vaginal bleeding, liver dysfunction or disease, and known or suspected malignancy of the breast or genital organs. Should any of the earliest manifestations of thrombotic disorders occur, the drug should be discontinued immediately. No evidence is available to show that progesterone and progestins are effective in preventing miscarriage in women with a history of recurrent spontaneous pregnancy losses. The pretreatment physical exam should include special reference to breast and pelvic organs as well as a Papanicolaou smear. Nonfunctional causes of breakthrough bleeding should be considered, and for undiagnosed vaginal bleeding, diagnostic measures should be undertaken. Special care should be taken with patients who have conditions that may be influenced by fluid retention, those who have a history of psychic depression, and those with diabetes.

Please see brief summary of full prescribing information on the adjacent page.

Toll-free support line: 1-888-PRO-GEL8 (1-888-776-4358) References: 1. CRINONE® prescribing information. Morristown, NJ: Watson Pharmaceuticals, Inc. June 2010. 2. Doody KJ, Schnell VL, Foulk RA, et al.

Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril. 2009;91:1012-1017. © 2010, Watson Laboratories, Inc.

Printed in USA

06968

Clinical News Weight Gain between Pregnancies a Risk for Gestational Diabetes Increases in body mass index (BMI) between pregnancies are associated with a heightened risk for gestational diabetes in a woman’s subsequent pregnancy, results of a new study show (Ehrlich SF, et al. Obstet Gynecol. 2011; 117:1323-1330).

A review of outcomes in 22,351

women showed that for those who had gestational diabetes during their first pregnancy, the age-adjusted risk for gestational diabetes in their second pregnancy was 38.19% compared with 3.52% for women who had a normal first pregnancy.

Increased risk for gestational diabetes linked with increased BMI between first and second pregnancies corresponded with the amount of BMI gained. A BMI

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increase of 1.0 to 1.9 units carried an odds ratio (OR) of 1.71 for developing gestational diabetes in the subsequent pregnancy; an increase of 2.0 to 2.9 units had an OR of 2.46; and â&#x2030;Ľ3.0 units gained translated to a 3.40 OR. In overweight or obese women who had gestational diabetes in their first pregnancy, a lower BMI increase did not result in diabetes in their second pregnancy. A reduction in BMI only low-

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ered gestational diabetes risk for women who were overweight or obese during their first pregnancy.

L-Arginine with Antioxidants Reduces Preeclampsia Risk A new study has demonstrated that supplementation with L-arginine and antioxidant vitamins during pregnancy reduced the incidence of preeclampsia in those at high risk (Vadillo-Ortega F, et al. BMJ.2011;342:d2901), suggesting that supplementation had a prophylactic effect.

A total of 672 women from a tertiary public hospital in Mexico City were randomized to receive L-arginine plus antioxidant vitamins (n = 228), antioxidant vitamins alone (n = 222), or placebo (n = 222). The women were evaluated from weeks 14 to 32 of gestation and were followed through delivery.

The researchers found a significantly (P <.001) lower preeclampsia incidence in women receiving L-arginine plus antioxidants compared with those who were taking placebo. The use of antioxidant vitamins alone showed some, but not significant, risk reduction compared with placebo.

Further research with L-arginine plus antioxidants is necessary to determine whether the results can be generalized to women at low risk for preeclampsia, the researchers observed.

FDA Approves First Toxoplasmosis Test for Pregnancy Use The US Food and Drug Administration (FDA) took a step toward alleviating the risks associated with toxoplasmosis in pregnant women by approving the first test designed to determine whether the infection was contracted within the previous 4 months.

Toxoplasmosis poses a sizable threat to persons with compromised immune systems, especially to pregnant women, who can transmit the parasite Toxoplasma gondii to their unborn children.

During pregnancy, the infection can lead to miscarriage, stillbirth, or abnormal head size, along with potential problems for the child later in life, such as loss of vision, mental disability, or seizures.

The VIDAS TOXO IgG (immunoglobin G) Avidity Assay is for use in persons with confirmed T gondii infection who are pregnant or have swollen lymph glands. The test works by determining how strongly IgG avidity antibodies bind to the antigens in the assayâ&#x20AC;&#x201D;IgG avidity antibodies bind tightly with the antigens in infections older than 4 months, whereas newer infections form weaker bonds. The test is not meant to be used alone as a basis for clinical decisions, and its efficacy in prenatal screening, immunocompromised patients, or Continued on page 21

jUNE 2011 l VOLUME 3, NUMBER 3

3

Editorial Board WWW.THEOBGYNNURSE.COM PUBLISHING STAFF

CO-EDITOR-IN-CHIEF

CO-EDITOR-IN-CHIEF

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

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

Publisher Russell Hennessy russell@novellushc.com 732-992-1888 Editorial Director Dalia Buffery dalia@novellushc.com 732-992-1889 Associate Editor Lara J. Reiman lara@novellushc.com 732-992-1892 Editorial Assistant Jessica A. Smith Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Business Manager Blanche Marchitto Editorial Contact: Telephone: 732-992-1892 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, nurse practitioners, physician assistants, 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 NurseNP/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.

4

jUNE 2011 l VOLUME 3, NUMBER 3

Ask the Expert

Pain after Endometrial Ablation Question: I work in an ambulatory setting where endometrial ablation is performed. The majority of our patients who undergo this procedure have very strong or severe cramping postoperatively. Is there anything that can be done to reduce their pain? We use Toradol intraoperatively. Could this medication be given preoperatively as well as postoperatively, or would it be appropriate to use ibuprofen postoperatively? To your knowledge, is the pain level related to the surgeonâ&#x20AC;&#x2122;s skill or technique?

Answer: By Debra Moynihan, WHNP-BC, MSN, Womenâ&#x20AC;&#x2122;s Health Nurse Practitioner, Carolina OB/GYN, Myrtle Beach, SC, and Editor-in-Chief, The OB/GYN Nurse-NP/PA

Submit Your Questions Online

Readers are invited to submit questions online at www.theobgynnurse.com.

Appropriate questions will be published with a response from one of the Editorial Board members of the journal. All questions are published anonymously.

Help her look forward to lighter days /<67('$ 7KH QRQ KRUPRQDO ILUVW OLQH WKHUDS\ IRU ZRPHQ ZLWK F\FOLF KHDY\ PHQVWUXDO EOHHGLQJ â&#x20AC;˘ Significant reduction in menstrual blood loss (MBL) by 38% (vs 12% for placebo) in a 6-cycle study â&#x20AC;˘ Consistent reduction in MBL across all cycles studied â&#x20AC;&#x201D;Reduced MBL as early as the first menstrual cycle â&#x20AC;˘ Dosed only during menstruation, for up to 5 days

Endometrial ablation, a procedure that treats the lining of the uterus to control or stop menstrual bleeding, can be done in an office setting with local anesthesia and sedation, or under general anesthesia in the operating room. It generally produces some cramping or mild pain.

These side effects are not dependent on the surgeonâ&#x20AC;&#x2122;s technique or skill level. They are solely related to the procedure itself. Whenever instrumentation is introduced into the uterus, mild-to-severe cramping is to be expected and will be dependent on the individualâ&#x20AC;&#x2122;s pain tolerance.

Endometrial ablation can be done in a number of different ways; the heated balloon method and the use of radiofrequency energy (NovaSure) are the 2 most common procedures. A patient may feel more discomfort with the heated balloon procedure, because it generally takes 10 minutes to complete, as opposed to 90 seconds with the NovaSure procedure. In addition, the pressure of inflating the balloon in the uterine cavity may cause more cramping than the use of mesh with the NovaSure procedure.

Of course, one of our primary concerns is the comfort of the patient. In our practice, the doctors all agree that Toradol, administered preoperatively, is beneficial. Depending on the procedure, 30 mg intravenously may be given. Postoperatively, the patient could be given a narcotic pain medication, such as Lortab 10 mg every 4 to 6 hours, along with Toradol 10 mg every 6 hours. â&#x2013;

LYSTEDATM (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 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.

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 beneďŹ t 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 eďŹ&#x20AC;ects 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 (â&#x2030;Ľ5%, 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.

Please see Brief Summary of Prescribing Information on adjacent page.

Š2011 Ferring Pharmaceuticals Inc.

Lysteda.com

01/11

LYS-04737B

Help her look forward to lighter days.

jUNE 2011 l VOLUME 3, NUMBER 3

5

ACOG Highlights

new Frontiers in Fertility Preservation... tion, and embryos and eggs can be cryopreserved for use when the cancer treatment is completed.

Other options include egg vitrification, ovarian cryopreservation, and adoption/surrogacy. “The frozen embryo is the most mature option we have, but it doesn’t always work,” she said. “Unlike

“The ultimate objective is to replace the transplant technique, because the tissue can harbor cancer cells.”

—Teresa Woodruff, PhD

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

©201 Ferring Pharmaceuticals Inc.

6

jUNE 2011 l VOLUME 3, NUMBER 3

Continued from page 1

1/11

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

ordinary couples seeking fertility counseling, cancer patients only have a small window of time to undergo fertility preservation procedures. This should be a discussion point with patients.” transplanting ovarian tissue Cryopreservation of ovarian tissue is one option for protecting biologic fertility in women. “Unlike men, we have to remove the tissue from the outer layer of the ovary and preserve it,” she explained.

This method preserves ovarian follicles at a peripheral storage site for later use, and patients pay a nominal fee for storage each year.

Thus far, 12 live births around the world have resulted from ovarian tissue transplantation in cancer survivors.

However, transplanted tissue could harbor some cancer cells, and reimplantation of the tissue could reintroduce the disease after the patient has had curative treatment. This has led to the search for additional methods of fertility preservation that do not entail transplanting the patient’s tissue back into the patient. “In our lab, we are trying to recapitulate folliculogenesis in vitro and eliminate the need for cryogenic storage,” she said.

Dr Woodruff and colleagues are working with a 3-dimensional supportive environment for the ovarian follicle, supported by a material called alginate (derived from algae). Alginate is a gentle jelly mechanism that does not interact with mammalian cells. The in vitro process has spawned live offspring in mice and produced eggs and embryos in nonhuman primates.

The next frontier is humans. They are currently studying in vitro follicle growth using 40 secondary follicles from 19 patients with cancer. “We have gotten good-quality eggs from humans, and we are still tweaking out the optimal physical environment for the human follicle. The next step is to activate the egg. We are not legally allowed to activate human eggs, so this work will need to move forward to a non–federally funded lab or abroad,” she said. “The ultimate objective is to replace the transplant technique, because the tissue can harbor cancer cells.” ■

The Oncofertility Consortium Oncofertility is a multidimensional problem involving religious, ethical, ethnic, insurance, and legal issues, as well as patients’ and families’ expectations. The Oncofertility Consortium (www.myoncofertility. com) is a multidisciplinary initiative for patients, clinicians, and researchers. Their hotline is 866708-FERT.

Clinic Profile

In Vitro maturation and metabolic health Program...

New Jersey, serving patients from the entire state and from the greater Philadelphia area and beyond.

Does your practice continue to follow women once they become pregnant?

Yes. We follow our patients for the first 12 weeks of pregnancy, and then we offer them the option to continue to meet with our 2 registered dieticians, who are accredited for gestational diabetes management, on a monthly basis for their entire pregnancies.

Patients who develop diabetes will see them more frequently.

Unlike many fertility centers that transfer women to their OB/GYN providers once they become pregnant, we continue to manage the women for the first 12 weeks, or as long as their insurance will allow us; we follow them very closely during that period. After that, we discharge them to their OB/GYN providers. However, those who wish to continue with our nutrition program will then be managed by our dieticians throughout their entire pregnancy. It is a unique feature of our practice that is welcomed by the patients and by the staff, because we get to see the fruit of our work.

Can you describe the metabolic health program you mentioned?

One of the biggest perks of our practice is our metabolic health program.

Many of our patients benefit from this program, considering that about 70% of Americans are overweight.

For any of our patients who have metabolic complications, such as polycystic ovarian syndrome, small follicles within the ovaries, hirsutism, or a family history of diabetes, we will administer a glucose tolerance test. We have found that many of these patients are also prediabetic.

If these women were not being treated for infertility, their primary care provider might not have discovered these metabolic links. Thanks to our focus on metabolic health, we are able to find and address such issues and help them to institute lifestyle changes— such as increased exercise, changing their diet, or even prescribing metformin if they need it—to address their metabolic problems and perhaps even prevent the development of type 2 diabetes later in life. If we help them to institute such lifestyle changes early on, it is possible to reverse this trend. That is definitely something that most fertility clinics are not doing, and it is going to help the patient in the long-term, not just the short-term.

However, this is clearly challenging,

because these patients are here to have a baby; they want a baby, not necessarily to lose weight. There is a fine balance in trying to convey the importance of preconceptual health that is going to impact their pregnancy once they are pregnant. Women who are metabolically in better shape before becoming preg-

women have polycystic ovaries) and a body mass index of less than 32 kg/m2.

These patients receive follicle-stimulating hormone for 3 days, and then their eggs are retrieved by the time the lead follicle reaches 12. And these women do not receive human chorionic gonadotropin themselves; the eggs do.

If patients are metabolically in better shape before becoming pregnant, they are going to decrease their overall risk factors when they become pregnant.

—Elizabeth A. Shrader, MSN, APN-C

nant are going to decrease their overall risk factors when they become pregnant.

We offer extensive patient education.

Our patients meet with the physicians, they meet with me as the Nurse Coordinator, and they meet with our accredited dieticians. We are available to see them as frequently as they want.

This education is individualized, and it is based on the patient’s medical history, family history, and present status.

Not everybody needs to have the metabolic education, but some thin patients are also included in this education program, and some obese patients do not go through it, depending on their individual and family history.

In addition, many of our returning patients are past their childbearing years, but they want to keep on top of their metabolic health. Many of the patients we had treated for infertility who know that they are at risk for developing type 2 diabetes want to continue to have that care from our expert providers.

As of December 31, 2010, 1406 babies were born by IVM worldwide, with most babies born in: • South Korea—455 • China—292 • Italy—157 • Canada—132 • Japan—69 • Vietnam—59 • Finland—52.

Delaware Valley Institute of Fertility & Genetics is the only center in the United States that was registered for IVM by 2010; we had the first live birth in 2006—overall, we have had a total of 6 births, including 1 set of twins. I believe there is one center in the Chicago area that is using IVM at this point.

IVM reduces some of the risks associated with IVF, especially hyperstimulation.

What is the main difference between IVM and IVF?

Is age related to eligibility for IVM?

With in vitro maturation (IVM), the egg is being developed and is maturing outside the body, in a dish, rather than in the body as in IVF, which may cause hyperstimulation. IVM reduces some of the risks associated with IVF, especially hyperstimulation, by removing the main cause for hyperstimulation— maturing the egg in the body.

IVM is used in a very specific population, that is, in women who have a history of ovarian hyperstimulation syndrome. Women who have gone through IVF cycles before and had to be hospitalized, or those who did not get an embryo transfer because their ovaries overresponded to their IVF medication, these are criteria for IVM eligibility.

Other criteria for IVM eligibility include women with more than 20 antral follicles within each ovary (certain

Yes. Women who are at the highest risk for ovarian hyperstimulation are those younger than age 35 and who have at least 20 antral follicles within each ovary. Thin women aged 25 to 35 years are at the highest risk for hyperstimulation syndrome, so they are candidates for IVM. This procedure is not usually done in women older than age 35, because their egg quality and their response are not going to be appropriate for IVM, and they are going to need more medication for a longer period to get a favorable response. For these women, even if they have 20 antral follicles in each ovary, the number of good ones is not quite as good as in younger women; they are also not at high risk for hyperstimulation. It can happen, but the chances for this are considerably lower than at a younger age.

Continued from page 1

Is IVM safer or less expensive than conventional IVF? The cost is probably about the same, although for different reasons. Patients undergoing IVM save some money on medications, but if patients who require IVM were to go through IVF, they would not be receiving many medications anyway, because we worry that they would hyperrespond. Overall cost is probably not that much different, because with IVM there is a slightly greater laboratory cost.

In terms of outcomes, IVM is safer for women who fall into the criteria that make them eligible for this procedure, and their risk for hyperstimulation is virtually zero. IVM is a safe and a good alternative to IVF. However, it requires a special medium in the laboratory for the process to work, which may be the reason why most centers are not doing this at this point. Once the correct medium is found, it can be used safely on the appropriate patients, with a good success rate.

Because we advertise our IVM program, some women think that they fit that category, but in reality, only about 1% or 2% in the entire reproductive endocrinology field would benefit from undergoing IVM.

Do you offer other unique features?

One other special feature at our clinic is our SEEDS (semen, embryo, and egg depository and storage) program for patients with cancer. We see a significant number of patients with cancer.

We have a relationship with several oncologists in the area, and we treat women and men who are diagnosed with some type of cancer for which they need chemotherapy, which would affect their fertility in the future.

For men, we have them freeze several samples of sperm so that they can use them at a later date to try to conceive a child. For women, after chemotherapy it is almost impossible to become pregnant and maintain a healthy pregnancy.

Chemotherapy damages the DNA of the cells and damages the eggs.

Dr Taliadouros has developed a program for such women who can undergo IVF. We have also done IVM on some women with cancer, because of time sensitivity, or traditional IVF, as long as their oncologist agrees that they are able to receive high doses of hormones.

They go through egg retrieval, and if they have a male partner, they create embryos and freeze them until their cancer is resolved. If they do not have a male partner, then we use donor sperm (if the patient desires) or freeze the eggs to thaw out later and inseminate.

We have had a couple of babies born through this program. ■

jUNE 2011 l VOLUME 3, NUMBER 3

7

ACOG Highlights

Progesterone gel greatly reduces...

Cervical length ≤15 mm is associated with a 50% risk for preterm delivery, and progesterone is essential for pregnancy maintenance. “A short cervix represents an untimely decline in cervical ripening that responds to treatment,” he said (see article, this page).

This multicenter study (Hassan SS, et al. Ultrasound Obstet Gynecol. 2011 Apr 6. Epub ahead of print) showed that daily vaginal progesterone gel use in women with a short cervix was associated with

“60% of all preterm infants are born to mothers in their first pregnancy, so we cannot depend on previous history.”

—Roberto J. Romero, MD rate of respiratory distress syndrome.

A total of 458 women with short cervix (10-20 mm) received daily treat-

Table Preterm Birth Rates: Progesterone versus Placebo Gestational age at delivery

Progesterone, %

Placebo, %

Risk reduction, %

<28 wks

5.1

10.3

50.0

<33 wks

8.9

16.1

45.0

<35 wks

14.8

23.3

38.0

Postpartum IUD Placement Safely Done in 1 Visit

By Caroline Helwick

W

omen who desire an intrasubstantial reductions in preterm uterine device (IUD) (<33 after weeks gestation) ratenot andmake the givingdelivery birth need an office visit to be assessed for pelvic inflammatory disease (PID) risk, according to a study presented at the 2011 American College of Obstetricians and Gynecologists (ACOG) meeting.

“Two postpartum visits for IUD insertion are unnecessary,” said David R. Kattan, MD, MPH, of the University of Colorado, Aurora. “Our study found that PID rates in the postpartum population seeking IUDs were low, consistent with previous studies.

We should adopt what ACOG already supports: a single-visit protocol for postpartum IUD insertion.”

Currently, the standard IUD placement protocol at many clinics includes a separate clinic visit to perform chlamydia and gonorrhea testing, with the placement visit 2 weeks later. The intent is to prevent IUD-associated PID, he noted.

“One possible solution to increasing successful follow-up and placement of IUDs is to eliminate this first visit and instead perform cervical sexually transmitted infection testing immediately prior to placement,” Dr Kattan observed.

Dr Kattan and colleagues reviewed the medical records of 1417 patients who received IUDs at his center in 2008 and identified 629 patients (average age, 25; average parity, 2.3) who had delivered babies up to 3 months before IUD placement.

8

Continued from page 1

“We should adopt what ACOG already supports: a single-visit protocol for postpartum IUD insertion.”

—David R. Kattan, MD, MPH

A total of 98 women had positive chlamydia culture at any time before delivery and 37 patients had a positive culture during their pregnancy; 5 women had positive gonorrhea cultures before delivery, none of which occurred during the antepartum period. Postpartum testing revealed 5 cases of chlamydia and 1 case of gonorrhea.

Clinical examination showed PID in 3 women, none of whom had positive cervical cultures during the postpartum period or at the time of PID diagnosis. No women required hospital admission for treatment of PID or removal of their IUDs, Dr Kattan reported.

“Chlamydia and gonorrhea rates postpartum were both under 1% and were not predictive of IUD-associated PID,” he noted. “Our results support the elimination of an additional clinic visit prior to IUD placement, which may increase the delivery of IUDs to postpartum women seeking a reliable contraceptive.” ■

jUNE 2011 l VOLUME 3, NUMBER 3

ment with vaginal progesterone gel or placebo initiated at 20 0/7 and 23 6/7 weeks gestation through 36 6/7 weeks.

The rate of premature delivery was reduced significantly with progesterone.

The Table lists the rate for deliveries at gestational age <35 weeks, <33 weeks, and <28 weeks. In addition, progesterone gel reduced the rate of respiratory distress by 61%—7.6% with placebo versus 3.0% with progesterone gel.

Several other infant outcomes were also significantly improved with progesterone gel; adverse event rates were similar in the 2 groups.

“The implications of the study are 2fold,” Dr Romero said. “One, we can screen for risk with cervical ultrasound.

Remember, 60% of all preterm infants are born to mothers in their first pregnancy, so we cannot depend on previous history. And two, a single intervention can make a big difference.”

Normal-length cervix

Short cervix

Although some experts have expressed concerns that this treatment will be expensive, Dr Romero said that screening and intervention will be cost-effective if the cost of the scans can be limited to ≤$184. ■

Cervical Length, Smoking Increase Spontaneous Preterm Delivery Risk

S

hortened cervical length in the second trimester and cigarette smoking independently increase the risk for spontaneous preterm delivery, according to Joseph Findley, MD, Charleston Area Medical Center Women and Children’s Hospital, WV. He presented the results of his study in a large cohort of women at the 2011 ACOG meeting.

Cervical length and smoking can identify women at risk for preterm delivery who may otherwise be overlooked, Dr Findley said. “We asked whether we could measure cervical length as a screening test for spontaneous preterm delivery. ACOG does not recommend this, based on the lack of an effective intervention, except for in women with a previous spontaneous preterm delivery. But progesterone gel is now being evaluated, so a treatment could become available,” Dr Findley told the OB/GYN Nurse-NP/PA. “We found that the risk of spontaneous preterm delivery can be seen in patients who were previously thought to have normal cervical lengths.”

Of the 1116 patients studied, 1 was a

current smoker. Cervical length was measured by transvaginal ultrasound in the second trimester (15-26 gestational weeks). Mean cervical length was 4.1 cm.

“We looked for the optimal cutoff point—that is, the length that maximized the sensitivity and specificity of screening, and we determined the valid cut-off value for short cervical length to be ≤3.71 cm,” he said.

Of the women with a short cervix, 6.7% had a spontaneous preterm delivery compared with <1% among those with cervix >3.71 cm. The short cervix group had a 5-fold increased risk for preterm delivery compared with women with a normal-length cervix.

Women with a cervical length ≤3.0 cm had a 17-fold increased risk. In addition, heavy smoking (>10 cigarettes daily) was an independent risk factor for preterm delivery, associated with a doubling in risk compared with nonsmokers.

“Smoking is not only an independent risk factor for spontaneous preterm delivery, regardless of cervical length, it also has an additive effect in the patient with shortened cervix,” said Dr Findley.—CH ■

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ACOG Highlights

Are You Familiar with the Treatment Changes for Sexually Transmitted Infections?

By Caroline Helwick

T

he Centers for Disease Control and Prevention revised its recommendations for the treatment of sexually transmitted infections (STIs) late last year. At a seminar at the 2011 American College of Obstetricians and Gynecologists meeting, Linda O. Eckert, MD, Associate Professor, Department of Obstetrics and Gynecology, University of Washington, Seattle, discussed what clinicians most need to know about the current guidelines. Key revisions to the guidelines include: • Change in dosage for gonorrhea • Change in outpatient regimen for pelvic inflammatory disease (PID) • Change in testing recommendations for cervicitis • More discussion of rapid test use • Emphasis on screening pregnant women for STIs • Less importance on screening for asymptomatic bacterial vaginitis (BV).

chlamydia Dr Eckert emphasized the need to routinely screen for Chlamydia trachomatis, because 80% of chlamydial infection is asymptomatic, no pelvic examination is required, the nucleic acid diagnostic tests are highly sensitive and specific, and uncomplicated infection is easily treated with 1 dose of azithromycin 1 g.

“If you screen all your patients, you will prevent PID,” she noted.

Screening is recommended for women with cervicitis, for sexually active females aged ≤25 years, and for women aged ≥25 years with inconsistent use of barrier contraception, at least 1 sexual partner, or a new partner in the past 3 months.

“Women should also be offered a treatment pack to take home to their partner. Not all states allow this, but it prevents reinfection,” she added. gonorrhea In the 2010 guidelines, fluoroquinolones are no longer recommended for the treatment of gonococcal infections. The recommended treatment is 1 dose of oral cefixime 400 mg or, preferably, one 250-mg intramuscular (IM) injection of ceftriaxone (a better treatment for pharyngeal gonorrhea), plus 1 dose of oral azithromycin 1 g or oral doxycycline 100 mg twice daily for 7 days.

“When specific test results are not available, if the patient has gonorrhea, you empirically treat for chlamydia as well,” she noted. “If the patient has

10

days, with or without metronidazole 500 mg twice daily for 14 days.

“What is a good change is that ceftriaxone 250 mg IM is now used for both cervicitis and PID. You just have to remember this 1 dose,” Dr Eckert said.

Hospitalization is necessary under a variety of circumstances, but the hospitalization of nulliparous women is no longer recommended, because it has not been shown to enhance pregnancy and pain outcomes.

“When specific test results are not available, if the patient has gonorrhea, you empirically treat for chlamydia as well. If the patient has chlamydia, you should treat for gonorrhea as well if the local prevalence rate is 5% or higher.”

—Linda O. Eckert, MD

chlamydia, you should treat for gonorrhea as well if the local prevalence rate is 5% or higher.” cervicitis Cervicitis remains a clinical diagnosis. Women who test negative for gonorrhea and chlamydia should be evaluated for BV and Trichomonas vaginalis.

If the wet mount is negative, patients should be further tested with culture or another US Food and Drug Administration (FDA)-cleared method, “because studies have associated these 2 conditions with cervicitis,” she said.

Mycoplasma genitalium can also cause cervical inflammation and should be considered as an etiologic agent, although there is no FDA-approved test. Therapy is with doxycycline or azithromycin.

Pelvic Inflammatory Disease In earlier guidelines, levofloxacin was a single-agent treatment for PID, but this has changed. Levofloxacin or ofloxacin is used only in cases of gonococcal-associated PID. Outpatient treatment is now with a single IM dose of 250-mg ceftriaxone, cefoxitin 2 g IM plus oral probenecid 1 g, or another third-generation cephalosporin. These are given with oral doxycycline 100 mg twice daily for 14

jUNE 2011 l VOLUME 3, NUMBER 3

Vaginitis testing and treatment Diagnosing vaginitis is still challenging. “Microscopy remains important, but there is no place for bacterial cultures,” Dr Eckert stressed. “They do not give relative quantitative amounts, and all women have many types of bacteria.

It’s like opening Pandora’s box to use cultures to diagnose bacterial vaginitis.”

Diagnostic tests discussed in the 2010 updates include the Affirm VPIII DNA probe for high concentrations of Gardnerella vaginalis, proline-iminopeptidase (Pip) test card (rarely used), and Gram stain (a research tool).

“Don’t spend a lot of money on molecular diagnostics for specific vaginal bacteria,” she emphasized. The presence of clinical criteria is more important.

Collection of vaginal pH (best done on the vaginal side wall) is underutilized, she added, although it is a “cheap, immediate, and useful triage tool.” A pH of 4.0 essentially rules out vaginitis and points to yeast.

No major changes were made in the treatment of acute and recurrent vaginitis, she said. trichomoniasis Molecular testing, including the use of newer rapid tests, is useful only in the diagnosis of trichomoniasis. FDAcleared tests for trichomoniasis include the OSOM Trichomonas Rapid Test (10 minutes) and the Affirm VPIII, a nucleic acid probe test that evaluates for T vaginalis, G vaginalis, and Candida albicans (45 minutes). Each of these tests, which are performed on vaginal secretions, have a sensitivity of >83% and a specificity of >97%.

Treatment of trichomoniasis is with oral metronidazole or tinidazole 2 g as a single dose or with oral metronidazole 500 mg twice daily for 7 days as an alternative. yeast Infections Treatment of vulvovaginal candidiasis is based on whether it is uncompli-

cated (ie, mild-to-moderate symptoms, sporadic, C albicans) or complicated (ie, severe symptoms, recurrent [≥4 episodes/year], non–C albicans, abnormal host immunology). The recommended treatment for uncomplicated infection is oral fluconazole 150 mg as a single dose; any 3- to 7-day intravaginal imidazole; a single dose of intravaginal butoconazole, miconazole, or tioconazole sustained-release cream; or nystatin 100,000-U vaginal tablet daily for 14 days.

Treatment failure is predicted by a history of recurrent severe infection and symptoms. Severe cases should be treated initially with 7 to 14 days of topical azole, or oral fluconazole, 150 to 200 mg in 2 doses, 72 hours apart. recurrent bacterial Vaginitis and yeast Infections “The management of recurrent BV and yeast infections follows the same strategy,” Dr Eckert said. “You control for risk factors, if possible, and treat for a prolonged period initially. Suppressive therapy can be given for 4 to 6 months.

Treatment of the partner is usually not helpful.”

Unfortunately, there is no way to clinically alter the vaginal lactobacilli or pH level clinically, and symptom recurrence is not unusual. Cultures can be taken for recurrent yeast infections to look for sensitivities to treatment.

Several regimens that may reduce the recurrence of yeast infections include: • Induction therapy: vaginal imidazole daily for 14 days or fluconazole 100 to 200 mg on days 1, 4, and 7 • Maintenance therapy: oral fluconazole 100 to 200 mg weekly for 6 months or clotrimazole 500 mg intravaginally weekly or 200 mg twice weekly • Symptom relief: low-potency topical steroids, nystatin cream, and sitz baths.

Non–C albicans infections that are refractory to azoles may respond to topical boric acid (intravaginal capsules), nystatin, or flucytosine. Recurrence may be controlled by alternate-day, then twice-weekly, boric acid.

For recurrent BV, longer therapy with antibiotics may be helpful, and the addition of boric acid to suppressive metronidazole treatment has been shown to be helpful. ■

See also CE article, page 24

What patients want in the treatment of external genital warts (EGW)...

Effectively clears genital warts and keeps patients clear Short treatment, daily dosing s Applied once daily for up to 8 weeks

Significant clearance in females s 37% complete clearance, 48% partial clearance _75% reduction in â&#x20AC;&#x201C; Partial clearance defined as > EGW count from baseline

Patients who clear with Zyclara can expect to remain clear s Only 15% of patients had a recurrence at 12 weeks posttreatment1

Tough on warts, easy on patients s Low incidence of treatment-related adverse events at the application site: itching (3%), irritation (6%), or pain (7%)1 s Local skin reactions, most of which were mild to moderate, included severe erythema (9%) and severe erosion/ulceration (11%)1

Zyclara Cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years or older.

In clinical studies, the most frequently reported adverse reactions were local skin and application site reactions. These reactions included erythema, edema, erosion or ulceration, and exudate at the genital wart site. Most local skin reactions were rated as mild to moderate. Intense local inflammatory reactions and/or flu-like systemic signs and symptoms can occur. Dosing interruptions may be required.

Avoid concomitant use of Zyclara Cream and any other imiquimod cream because of increased risk for adverse reactions.

Zyclara Cream is not recommended for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease as it has not been studied.

The effect of Zyclara Cream on the transmission of genital warts is unknown. Zyclara Cream may weaken condoms and diaphragms.

Sexual contact should be avoided while the cream is on the skin.

Please see Brief Summary of Prescribing Information on adjacent page.

Reference: 1. Data on file. Graceway Pharmaceuticals, LLC.

Š2011 Graceway Pharmaceuticals, LLC, Bristol, TN

www.gracewaypharma.com

ZYC031143

www.ZyclaraCream.com

1

ACOG Highlights

Pregnancy Coercion and Birth Control Sabotage

by Partner Are Common

By Caroline Helwick

B

irth control sabotage and pregnancy coercion are experienced by 1 in 3 women in western North Carolina, according to survey results presented at the 2011 American College of

Obstetricians and Gynecologists meeting. â&#x20AC;&#x153;Reproductive control is a new concept that is a component of intimate partner violence. The vast majority of women had never realized that this kind

[zi-clar-a]

of behavior was a type of control found in such relationships,â&#x20AC;? said lead investigator Jessica L. Versage, MD, Mountain Area Health Education Center, Asheville, NC.

The frequency and severity of local skin reactions were similar in both genders, with the following exceptions: a) flaking/scaling occurred in 40% of men and in 26% of women and b) scabbing/crusting occurred in 34% of men and in 18% of women.

In the clinical trials, 32% (126/400) of subjects who used ZYCLARA Cream and 2% (4/202) of subjects who used vehicle cream discontinued treatment temporarily (required rest periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used ZYCLARA Cream discontinued treatment permanently due to local skin/application site reactions.

INDICATIONS AND USAGE

Other adverse reactions reported in subjects treated with ZYCLARA Cream include: rash, back pain, application site rash, application site cellulitis, application site excoriation, application site bleeding, scrotal pain, scrotal erythema, scrotal ulcer, scrotal edema, sinusitis, nausea, pyrexia, and influenza-like symptoms.

External Genital Warts

Postmarketing Experience

ZYCLARA Cream is indicated for the treatment of external genital and perianal warts (EGW)/condyloma acuminata in patients 12 years or older.

The following adverse reactions have been identified during post-approval use of imiquimod. 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.

BRIEF SUMMARY OF PRESCRIBING INFORMATION SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

Limitations of Use Treatment with ZYCLARA has not been studied for prevention or transmission of HPV. Unevaluated Populations The safety and efficacy of ZYCLARA Cream have not been established in the treatment of: D >;.=1;*5 27=;* ?*027*5 ,.;?2,*5 ;.,=*5 8; 27=;* *7*5 1>6*7 9*925586* ?2;*5 -2<.*<.

D *,=272, 4.;*=8<2< @1.7 =;.*=.- @2=1 68;. =1*7 87. ,B,5. =;.*=6.7= ,8>;<. 27 =1. <*6. *;.* D 9*=2.7=< @2=1 A.;8-.;6* 9206.7=8<>6.

D <>9.;ficial basal cell carcinoma.

D 266>78<>99;.<<.- 9*=2.7=<

â&#x20AC;&#x201D;Jessica L. Versage, MD

Application Site Disorders: tingling at the application site.

Body as a Whole: angioedema.

Cardiovascular: capillary leak syndrome, cardiac failure, cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, supraventricular tachycardia, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope.

Endocrine: thyroiditis.

Gastro-Intestinal System Disorders: abdominal pain.

CONTRAINDICATIONS None.

Hematological: decreases in red cell, white cell and platelet counts (including idiopathic thrombocytopenic purpura), lymphoma.

WARNINGS AND PRECAUTIONS

Hepatic: abnormal liver function.

Local Skin Reactions

Infections and Infestations: herpes simplex.

7=.7<. 58,*5 <427 ;.*,=287< 27,5>-270 <427 @..9270 8; .;8<287 ,*7 8,,>; */=.; * /.@ *9952,*=287< 8/ ZYCLARA Cream and may require an interruption of dosing. ZYCLARA Cream has the potential to exacerbate inflammatory ,87-2=287< 8/ =1. <427 27,5>-270 ,1;872, 0;*/= ?.;<>< 18<= -2<.*<.

Musculo-Skeletal System Disorders: arthralgia.

-6272<=;*=287 8/ )( # ;.*6 2< 78= ;.,866.7-.- >7=25 =1. <427 2< 1.*5.- /;86 *7B 9;.?28>< -;>0 8; surgical treatment.

Systemic Reactions

Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide.

Respiratory: dyspnea.

Urinary System Disorders: proteinuria, urinary retention, dysuria.

5> 524. <207< *7- <B69=86< 6*B *,,869*7B 8; .?.7 9;.,.-. 58,*5 <427 ;.*,=287< *7- 6*B 27,5>-. /*=20>. 7*><.* /.?.; 6B*502*< *;=1;*502*< 6*5*2<. *7- ,1255< 7 27=.;;>9=287 8/ -8<270 *7- *<<.<<6.7= of the patient should be considered.

Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar, hypopigmentation.

Ly691*-.789*=1B 8,,>;;.- 27 8/ <>+3.,=< @2=1 *,=272, 4.;*=8<2< =;.*=.- @2=1 )( # ;.*6 %12< ;.*,=287 ;.<85?.- 27 *55 <>+3.,=< +B @..4< */=.; ,8695.=287 8/ =;.*=6.7=.

USE IN SPECIFIC POPULATIONS

Ultraviolet Light Exposure Risks

There are no adequate and well-controlled studies in pregnant women. ZYCLARA Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of ZYCLARA Cream. "*=2.7=< <18>5- +. @*;7.- =8 ><. 9;8=.,=2?. ,58=1270 . 0 * 1*= @1.7 ><270 )( # ;.*6 "*=2.7=< @2=h sunburn should be advised not to use ZYCLARA Cream until fully recovered. Patients who may have ,87<2-.;*+5. <>7 .A98<>;. . 0 ->. =8 =1.2; 8,,>9*=287 *7- =18<. 9*=2.7=< @2=1 271.;.7= <.7<2=2?2=B =8 sunlight should exercise caution when using ZYCLARA Cream.

7 *7 *726*5 918=8 ,*;cinogenicity study 262:>268- ,;.*6 <18;=.7.- =1. =26. =8 <427 =>68; /8;6*=287 The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. %1.;./8;. 9*=2.7=< <18>5- 627262C. 8; *?82- 7*=>;*5 8; *;=2/2,2*5 <>75201= .A98<>;.

Increased Risk of Adverse Reactions with Concomitant Imiquimod Use C87,862=*7= ><. 8/ )( # *7- *7B 8=1.; 262:>268- 9;8->,=< 27 =1. <*6. =;.*=6.7= *;.* <18>5- +. *?82-.- <27,. =1.B ,87=*27 =1. <*6. *,=2?. 270;.-2.7= 262:>268- *7- 6*B 27,;.*<. =1. ;2<4 /8; *7- <.?.;2=y 8/ 58,*5 <427 ;.*,=287< The safety of concomitant use of ZYCLARA Cream and any other imiquimod products has not been established and should be avoided since they contain the same active ingredient (imiquimod) and may increase t1. ;2<4 /8; *7- <.?.;2=B 8/ <B<=.62, ;.*,=287< Immune Cell Activation in Autoimmune Disease Z( # ;.*6 <18>5- +. ><.- @2=1 ,*>=287 27 9*=2.7=< @2=1 9;. .A2<=270 *>=8266>7. ,87-2=287< +.,*><. imiquimod activates immune cells.

ADVERSE REACTIONS Because clinical trials are conducted under widely varB270 ,87-2=287< *-?.;<. ;.*,=287 ;*=.< 8+<.;ved 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 practice.

Clinical Trials Experience: External Genital Warts 7 =@8 -8>+5. +527- 95*,.+8 ,87=;855.- <=>-2.<

<>+3.,=< *9952.- >9 =8 87. 9*,4.= 8/ )( # ;.*6 8; ?.12,5. -*25B /8; >9 =8 @..4< %1. 68<= /;.:>.7=5B ;.98;=.- *-?.;<. ;.*,=287< @.;. *9952,*=287 <2=. ;.*,=287< *7- 58,*5 <427 ;.*,=287< Selected adverse reactions are listed in Table 1.

Table 1: Selected Adverse Reactions Occurring in â&#x2030;Ľ2% of ZYCLARA Treated Subjects and at a Greater Frequency than with Vehicle in the Combined Trials (EGW) ZYCLARA Cream 3.75% Vehicle Cream Preferred Term (N=400) (N=202) Application site pain 28 (7%) 1 (<1%) Application site irritation

2 (1%) Application site pruritus 11 (3%) 2 (1%) Vaginitis bacterial*

2 (2%) Headache

1 (<1%) *Per,.7=*0. +*<.- 87 /.6*5. 989>5*=287 8/ /8; )( # ;.*6 *7-

/8; ?.12,5. ,;.*6 8,*5 <427 ;.*,=287< @.;. ;.,8;-.- *< *-?.;<. ;.*,=287< 875B 2/ =1.B .A=.7-.- +.B87- =1. =;.*=6.7= *;.* if they required any medical intervention, or they resulted in patient discontinuation from the study. The incidence and severity of selected local skin reactions are shown in Table 2.

Table 2: Selected Local Skin Reactions in the Treatment Area Assessed by the Investigator (EGW) All grades*, (%) ZYCLARA Cream 3.75% Vehicle Cream Severe, (%) (N=400) (N=202) Erythema* 70% 27% Severe erythema 9% <1% Edema* 41% 8% Severe edema 2% 0% Erosion/ulceration* 36% 4% Severe erosion/ulceration 11% <1% Exudate* 34% 2% Severe exudate 2% 0% *Mild, Moderate, or Severe

Vascular: Henoch-Schonlein purpura syndrome.

Pregnancy Pregnancy Category C:

The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this label. The animal multiples of human exposure were based on weekly dose comparisons for the carcinogenicity studies described in this label. For the animal multiple of human exposure ratios presented in this label, the Maximum Recommended Human Dose (MRHD) was set at 2 packets (500 mg cream) per treatment of actinic keratosis with ZYCLARA Cream (imiquimod 3.75%, 18.75 mg imiquimod) for BSA comparison. The maximum human AUC value obtained in the treatment of external genital and perianal warts was higher than that obtained in the treatment of actinic keratosis and was used in the calculation of animal multiples of MRHD that were based on AUC comparison.

Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5 and 20 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 â&#x20AC;&#x201C; 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (163X MRHD based on AUC comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (28X MRHD based on AUC comparisons).

Intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 â&#x20AC;&#x201C; 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (2.1X MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (115X MRHD based on AUC comparisons).

A combined fertility and peri- and post-natal development study was conducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day imiquimod were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (25X MRHD based on AUC comparisons), the highest dose evaluated in this study.

In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (25X MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment related effects on teratogenicity were noted at 3 mg/kg/day (12X MRHD based on AUC comparisons).

Nursing Mothers It is not known whether imiquimod is excreted in human milk following use of ZYCLARA Cream.

Because many drugs are excreted in human milk, caution should be exercised when ZYCLARA Cream is administered to nursing women.

Pediatric Use Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established.

Geriatric Use Clinical studies of ZYCLARA Cream for EGW did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 400 subjects treated with ZYCLARA Cream in the EGW clinical studies, 5 subjects (1%) were 65 years or older.

OVERDOSAGE Topical overdosing of ZYCLARA Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions.

Hypotension was reported in a clinical trial following multiple oral imiquimod doses of >200 mg (equivalent to ingestion of the imiquimod content of more than 21 packets of ZYCLARA). The hypotension resolved following oral or intravenous fluid administration.

Rx Only

Manufactured by 3M Health Care Limited Loughborough LE11 1EP England Distributed by Graceway Pharmaceuticals, LLC Bristol, TN 37620

â&#x20AC;&#x153;Examples of reproductive control include refusing to pay for birth control pills, flushing pills, poking holes in condoms, not withdrawing, or forcing sex without birth control.â&#x20AC;?

Issued: March 2011 ZYC031137

â&#x20AC;&#x153;Reproductive controlâ&#x20AC;? is used when a womanâ&#x20AC;&#x2122;s partner demands or enforces a certain reproductive outcome that is in conflict with a womanâ&#x20AC;&#x2122;s interests. It involves pregnancy promotion, contraceptive sabotage, or the controlling of pregnancy outcomes by economic, physical, emotional, or sexual violence or threats, Dr Versage said. â&#x20AC;&#x153;Examples include refusing to pay for birth control pills, flushing pills, poking holes in condoms, not withdrawing, or forcing sex without birth control with the intent of pregnancy,â&#x20AC;? she said. This leads to unsafe sex, unintended pregnancy, and poor pregnancy outcomes.

According to Dr Versage, only 1 study conducted in California has examined the issue (Miller E, et al.

Contraception. 2010;81:316-322). â&#x20AC;&#x153;We became curious about this situation in our population, which is much more conservative and less educated than the California population, and we found even higher rates,â&#x20AC;? she said. â&#x20AC;&#x153;We believe that this behavior is probably more prevalent than we have realized.â&#x20AC;?

Dr Versage included patients (aged â&#x2030;¤45 years) seen in the past year for gynecologic or postpartum visits at her center; 328 patients responded to the survey. Patients were mostly white (69%) or black (21%); 38% were single, 22% were married, 30% had a partner, and 10% classified their status as â&#x20AC;&#x153;other.â&#x20AC;? Educational status was high school or beyond for the majority; 20% did not complete high school. More than 33% reported having a previous unwanted pregnancy. male sabotage Survey responses indicated that 37% of the women experienced some type of coercion or sabotage; 15% reported both types of reproductive control, 19% reported sabotage, and 3% reported coercion.

Continued on next page

12

jUNE 2011 l VOLUME 3, NUMBER 3

ACOG Highlights NAMS HIGHLIGHTS

Characteristics of Women with Hypoactive... menopause. Data from the first-ever registry of women with HSDD aged ≥40 years was conceived to chart the natural history of HSDD, which had not previously been attempted. The registry indicates that clinicians are often not considering effective therapy for HSDD. The characteristics and treatmentseeking behaviors of the first 377 women enrolled in the registry were presented at the meeting. Enrollment has now reached approximately 1500 women, Dr Shifren said.

Most of the women had experienced moderate to severe HSDD for at least 5 years; women generally reported distress over their HSDD, with 60.5% of them reporting being happy or very happy in their relationship. “This is probably one reason why HSDD is so distressing to them,” Dr Shifren said.

When asked what might be contributing to the problem, menopausal symptoms were mentioned by 51.1% of the women, “which tells us that we do need to intervene with treating hot flashes and vaginal dryness,” Dr Shifren said. “If we’re not asking about sexual problems and looking for the causes, we’re missing a lot.”

As many as 50% of the women reported that pain during intercourse was a contributing factor to their HSDD, and 47.2% cited stress or fatigue as a cause. “Stress and fatigue are common predictors of sexual problems, and we should be helping these women be less stressed and less fatigued; there are good interventions for both. There are also very good studies that overweight

“If we’re not asking about sexual problems and looking for the causes, we’re missing a lot. Stress and fatigue are common predictors of sexual problems, and…there are good interventions for both.” —Jan Shifren, MD women who lose weight feel better about their sex lives. These are all things that lend themselves to effective interventions, but if we don’t identify these women and ask these questions, we won’t be able to help them.” many women Are not seeking treatment Formal treatment-seeking behavior was defined as discussion with a healthcare provider and/or use of offlabel prescription drugs for HSDD. Informal treatment-seeking behavior was defined as the use of over-thecounter products or information-seeking research of HSDD online or via other anonymous media.

“These are women who have distress associated with their low desire, and it’s amazing that only 44% of the premenopausal women sought formal healthcare,” Dr Shifren said. Of the postmenopausal women, 64% sought formal healthcare.

“If you think of it the other way, 50% of premenopausal women with low desire associated with distress didn’t do anything; they didn’t even go online to

Pregnancy Coercion...

In one case, a patient indicated that her partner had yanked out the string of her intrauterine device (IUD).

“Things like this have happened,” Dr Table Questions Indicating Coercion

Question

“Yes” N (%)

Told you NOT to use birth control?

36 (11)

Said he wanted you to have a baby so you would be tied to him forever?

Said he would leave you unless you got pregnant?

28 (8.5) 9 (2.7)

7 Told you he would have a baby with someone else unless (2.1) you got pregnant?

6 Hurt you physically because (1.8) you would not get pregnant?

Accused you of unfaithfulness if you did not get pregnant?

9 (2.7)

Continued from page 12

Versage said. “I have read that some gynecologists will cut the IUD string very short if they know this kind of behavior exists in the relationship.”

Sabotage related to male birth control (eg, failure to withdraw, condom failure) was 3 times more common than sabotage of female birth control.

Sabotage was least likely with long-acting reversible contraceptives. “This was, hands down, much less than we saw with pills and patches,” she said.

Responses to questions regarding coercion are shown in the Table. Many of the respondents said that this was the first time they had heard of the concepts of reproductive sabotage or coercion, adding that this helps them in their relationships.

“Taking this survey seemed to raise their awareness,” Dr Versage added. “In the long run, we hope to take advantage of this information to change how we counsel women about birth control.” ■

address their concern,” she said. “And 30% of the postmenopausal women didn’t do anything. Women who are distressed by this problem aren’t looking for help.”

Of the women who sought medical care, the most common treatments reported were nonprescription lubricants or arousal creams—by 34% of premenopausal and 66% of postmenopausal women. Off-label prescription medications were used by 19% of premenopausal and 22% of postmenopausal women.

There are currently no treatments approved by the US Food and Drug Administration for HSDD. “It is good to see that about 20% of those women

Continued from page 1

TAKEAWAY qUICK POINTS ➤ The first national registry for women aged ≥40 years shows that 50% of premenopausal and 30% of postmenopausal women do not seek medical help for HSDD. ➤ Of those who seek medical help, many are not offered any treatment, although beneficial treatments are available. ➤ Nonprescription lubricants or arousal creams are used by 34% of premenopausal and 66% of postmenopausal women. ➤ Off-label prescription medications are used by 19% of premenopausal women and 22% of postmenopausal women. were referred for counseling, individuals or in groups, and I think it’s a shame that that number is not even higher.

These are effective interventions, and they’re safe,” Dr Shifren said. ■

Younger Women Still Want Mammography Screening

T

he new mammogram screening guidelines have drawn strong skepticism, which is increased by exposure to media that criticize the guidelines, according to AuTumn Davidson, MD, an obstetrician/gynecologist at the University of Massachusetts Memorial Hospital, Worcester, who presented her study at the 2011 American College of Obstetricians and Gynecologists meeting.

In its 2009 updated recommendations, the US Preventive Services Task Force stated that mammography screening should commence at age 50, not age 40, based in part on the psychological stress associated with falsepositive results, unnecessary imaging and radiation exposure, unnecessary biopsies, and morbidity associated with diagnosis and treatment of cancer that is not clinically relevant.

“These changes sparked intense debate within the popular media,” Dr Davidson said. “Little is known about American women’s attitudes toward these changes and the effect the popular media has played on shaping them.”

To study this issue, Dr Davidson and colleagues surveyed all women aged 39 to 49 years who presented at 1 of 4 OB/GYN practices in Worcester for annual examinations. Patients were

randomized to read 1 of 2 articles selected from the lay press—either an article supporting the 2009 guideline changes or opposing them. After reading these, participants answered questions reflecting their opinion of the guideline changes. The attitudes of the 2 groups were compared.

From 244 survey responses, the investigators determined that 78% of women overestimated their lifetime breast cancer risk, and 89% reported feeling that they should have yearly mammograms in their 40s despite the guideline changes. Women who read the article that was favorable toward the guidelines were less likely to desire early screening (85% vs 92% of those reading the more critical article; P = .05).

The guidelines were considered unsafe by 86% of respondents, and those with a close friend or family member with breast cancer were especially likely to reject the guideline changes. Women with a previous falsepositive mammogram were also less likely to adhere to the new guidelines, even if their physicians supported the guidelines.

“It seems the media play an important role in shaping public opinion regarding evidence-based medicine,” Dr Davidson said.—CH ■

jUNE 2011 l VOLUME 3, NUMBER 3

13

Pharmacy Corner

Infertility Drug Shortages a Threat, but Preparation Can Thwart Disaster

By Sandra Fernandez, PharmD Pharmacist, Mandell’s Clinical Pharmacy, Somerset, NJ

N

ow more than ever, drug shortages are posing challenges to the healthcare community, because they typically appear with little or no warning, and significant resources are needed to manage patients affected by therapies in short supply. A drug shortage is defined as a supply issue that may compromise patient care, because a prescriber must use alternative therapy.1 Shortages of a specific product from all manufacturers/distributors of that product have more than tripled in the past 5 years. In 2010, more than 240 drugs were either in short supply or were unavailable, according to a Premier Healthcare Improvement Alliance analysis.2 For the majority of these shortages, the drugs have remained in short supply in 2011, and research suggests that the numbers keep increasing. The majority of drugs affected are injectable medications needed for sedation and emergency care, chemotherapeutics, and, most recently, infertility drugs.

Because drug shortages are multifactorial, understanding barriers in the medication supply chain is essential for

healthcare professionals to more effectively manage these shortages and ensure proper care for patients. The supply chain includes the availability of raw materials, manufacturers, regulators, wholesalers, vendors, buying groups, and healthcare organizations.

Factors that can cause disruptions in the supply chain, ultimately resulting in a drug shortage, include1: • Raw material unavailability. Raw and bulk material shortages are especially problematic when several manufacturers produce a drug product from raw material available from a single source that discontinues production • Manufacturing difficulties. Good manufacturing practice (GMP) guidelines are a set of regulations set forth by the US Food and Drug Administration (FDA) enabling companies to minimize or eliminate contamination and errors, ultimately protecting consumers from purchasing a product that is not effective or is even hazardous to their health.

Noncompliance with current GMPs can result in very serious conse-

•

•

•

•

quences, including recalls and halted production of products Natural disasters. Manufacturing facilities may encounter unexpected damage from natural disasters, leaving plants inoperable and therefore causing shortages, especially in the case of those involved in the sole production of a product Production decisions. Production of drug products is often discontinued because of a lack of financial return, poor demand, or safety concerns; production may also be temporarily or permanently reduced by manufacturers to shift production or reallocate resources to another product Industry consolidations. Mergers of manufacturers may result in decisions to discontinue products and change product labeling Market shifts. The launch and addition of generics to the market leads to a decrease in the production of brand medications, causing a reduction in availability. Military action may cause shifts, as large quantities of medications are diverted to aid our armed forces

Table Infertility Drug Shortages and Available Alternatives Affected product

Strengths affected

Important information

Available alternatives

Cetrotide

250-µg injection

Diprivan 1% injectable emulsion

10 mg/mL 20-, 50-, 100-mL vials

Confirm whether alternative product contains sulfa

Propofol 1% injectable emulsion

Estraderm patch

0.05 mg/day 0.1 mg/day

Verify equivalent dosing information and product availability with physician and pharmacy

Vivelle-Dot patch Climara patch

Follistim AQ

75-IU, 150-IU vials 300-IU, 600-IU, 900-IU cartridges

Bravelle, Menopur, Repronex 75-IU vials, Gonal-f 75-IU vials, 300-IU pen, 450-IU MDV/pen, 900-IU pen, 1050-IU MDV

Ganirelix acetate

250-µg injection

Cetrotide 250-µg injection

Leuprolide acetate 2-wk kit

1 mg/0.2 mL

Ensure that the leuprolide is being compounded from raw material according to FDA regulations

Synarel nasal spray Ganirelix acetate 250-µg injection Cetrotide 250-µg injection Compounded leuprolide 1 mg/0.2 mL

Medrol tablets Methylprednisolone tablets

2-mg, 4-mg, 8-mg, 16-mg, 32-mg tablets 4-mg dose pack

Some products are available only in brand or generic; ask supplying pharmacy for availability information 16-mg tablets are scored, allowing for various dosing capabilities

Medrol tablets Methylprednisolone tablets

Ganirelix acetate 250-µg injection

NOTE: Table only includes the most recent drug shortages that have affected the infertility market. Some products listed above may be on manufacturer backorder when this article is printed. Please verify with the dispensing pharmacy for up-todate drug shortage information, because information changes daily.

FDA indicates Food and Drug Administration; MDV, multiple-dose vial.

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jUNE 2011 l VOLUME 3, NUMBER 3

• Unexpected demand. Increases in demand sometimes exceed existing supplies and production capacities; reasons for this are new off-label uses, disease outbreaks, or changes in product formulations.

Providers and pharmacists should develop strategies to prepare all staff members for drug shortages, should they occur. The process should begin with determining the cause of the shortage from the manufacturer and/or wholesaler, because this will provide clues about the duration of the shortage. This is important, because some wholesalers will report short supplies, but the problem may actually be a temporary outage at the wholesaler, not the manufacturer.

Once the shortage is confirmed, providers should be contacted to evaluate alternative therapies available, so as to not interrupt patient care. Providers should be presented with all available alternatives, if any.

Recent infertility drug shortages, as well as available alternatives that may be considered so that patient care is not interrupted, are listed in the Table.

Some pharmacies are able to provide medications that are in short supply by compounding them from the raw ingredients. Although compounding is not a process approved by the FDA, physicians and patients should verify with the compounding pharmacy that they are properly equipped to execute the desired drug in a safe and effective manner.

Such pharmacies must follow all state regulations set by their governing board of pharmacy with regard to compounding medications, for example, adhering to formulas created by FDA- and Drug Enforcement Administration (DEA)registered compounding firms and sending all compounded products to an FDA- and DEA-registered analytic laboratory for potency and sterility testing.1 Whether a result of a natural disaster or of unexpected increases in demand, drug shortages are becoming more frequent. Proper planning and communication are key components in the management of drug shortages. Information about drug shortages and limited distribution can be found on the FDA’s website (www.fda.gov/Drugs/DrugSafety/ DrugShortages/ucm050792.htm). ■ references 1. American Society of Health-System Pharmacists.

ASHP guidelines on managing drug product shortages.

Am J Health Syst Pharm. 2001;58:1445-1450.

2. Bowman L. Drug shortages hit hospitals hard. April 20, 2011. www.commercialappeal.com/news/2011/apr/20/ drug-shortages-hit-hospitals-hard/. Accessed June 2, 2011.

Women’s Health

Combined Testing Can Reduce Cervical Cancer Screening Frequency

By Caroline Helwick

C

ervical cancer screening that involves a Pap test and screening for human papillomavirus (HPV) infection at the same visit allows most women to extend their screening intervals by 1 to 3 years, according to a large study highlighted at the 2011 American Society of Clinical Oncology meeting.

The study also showed that HPV testing may be more accurate than a Pap test in determining cervical cancer risk, said lead investigator Hormuzd Katki, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD. “Our results are a formal confirmation that the 3-year follow-up is appropriate and safe for women who have a negative HPV test and normal Pap result,” he said. “These results also suggest that an HPV-negative test result alone could be enough to give a high level of security for extending the testing interval to every 3 years.”

“The Pap test can show immediate disease, while HPV testing can predict who is most likely to get cancer in the future.”

—Hormuzd Katki, PhD

The American College of Obstetricians and Gynecologists and the American Cancer Society have already endorsed the use of concurrent HPV testing with Pap tests for women aged ≥30 years, with cotesting recommended every 3 years when the results of both tests are normal. However, cotesting has not been widely adopted by physicians and women who are unsure about the safety of extending testing intervals beyond 1 year, Dr Katki pointed out.

The study involved 331,818 women aged ≥30 years who were enrolled in the Kaiser Permanente Northern California cotesting program. The 5-year cumulative incidence of cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3+) was determined.

“In routine clinical practice, a single HPV test was clearly superior to a single Pap smear for predicting who would develop CIN3+ within 5 years,” Dr Katki reported. “Cytology strongly modified risks only for HPV-positive women.”

The cancer risk for women who tested negative for HPV and had normal cytology was very low—3.2 per 100,000 women annually. Looking at the test results individually, women who tested negative for HPV had half the risk of women with a normal Pap test—3.8 compared with 7.5 per 100,000 women

annually. This suggests that HPV testing alone is more accurate than Pap testing alone and is almost as good as concurrent testing, he said. “When you combine testing, you get the best results,” he said Women who tested positive for HPV at enrollment had a higher risk of developing cervical cancer than those with an

abnormal Pap test, but cancer risk was highest when both tests were abnormal.

“The Pap test can show immediate disease, while HPV testing can predict who is most likely to get cancer in the future,” Dr Katki said. Pap tests, therefore, help in triaging patients for treatment.

Based on these findings, Kaiser

Permanente Northern California initially screens women for HPV, and if the results are negative, they are asked to return in 3 years. Pap tests are reserved for women who are HPV-positive.

“This reduces the number of Pap tests by 95% while retaining the safety of cotesting,” Dr Katki said. ■

1st & Only Only FDA FD F Cleared Blood Blood Test Te T ffo Pre -Surgical Evaluation Evaluation of of Ovarian Ovarian Masses M a s ses The The 1st DA Cleared est for or Pre-Surgical

A sensitive test for a sensitive subject. t OVA1® is the most clinically sensitive FDA cleared* blood test

to evaluate an ovarian mass for malignancy before surgery. t OVA1 improved overall Sensitivity (95.7%) and NPV (94.6%)

when combined with a physician’s Clinical Impression. (Overall data included patients [n=516] evaluated by either gynecologic oncologists or non-gynecologic oncologists.)1 t A clinical trial demonstrated that OVA1 would have helped to

identify 70% of women whose malignancies were missed when only clinical or radiological assessments were used to evaluate a mass. 2 t OVA1 is available nationwide exclusively through Quest Diagnostics.

ova-1.com clearance does not denote official approval.

OVA1 VA1 p product roduc t insert. inser t. 2D Data ata ffrom rom O OVA1 VA1 C Clinical linical T Trial. rial. O OVA1 VA1® is a q qualitative ualitative sserum erum test **FDA FDA c le a r a n c e d oes n ot d e n o te o f ficial a pproval. 1O te s t combines off fi five numerical or w women om en w who ho m meet eet tthe he ffollowing ollowing c criteria: riteria: o over tthat hat c ombines tthe he rresults esult s o ve iimmunoassays mmunoassays iinto nto a ssingle ingle n umerical rresult. esult. IItt is iindicated ndicated ffor ver an na aid id tto o ffurther ur t h e r a assess ss e ss age 18, ovarian adnexal mass present which planned, and not yet oa an no oncologist. ncologist. O OVA1 VA1® is a a ge 1 8, o varian a dnexal m a ss p resent ffor or w hich ssurgery urger y iiss p lanned, a nd n ot y et rreferred eferred tto tthe he llikelihood ikelihood tthat hat m malignancy alignancy is p present r e s e nt w when hen tthe he p physician’s hysician’s iindependent n d e p e n d e nt c clinical linical a and nd rradiological adiological e evaluation valuation d does oes n not ot iindicate ndicate m malignancy. alignancy.

T The he ttest est is n not ot iintended nt e n d e d a ass a sscreening creening o orr sstand-alone tand-alone d diagnostic iagnostic a assay. ssay. V Vermillion ermillion a and nd O OVA1 VA1 a are re rregistered egistered ttrademarks r ad e ma r k s o off V Vermillion, ermillion, IInc. n c.

jUNE 2011 l VOLUME 3, NUMBER 3

15

Meetings JUNE Midwest Reproductive Symposium 6/10-6/11 Chicago, IL Contact: (888) MBM-MTGS www.mwrs.org Cancer Survivorship and Sexual Health Symposium 6/17-6/19 Washington, DC Contact: (847) 517-7225 info@smsna.org www.cancersurvivorsandsex.org

Association of Reproductive Health Professionals 9/15-9/17 Las Vegas, NV

AWHONN Convention 6/25-6/29 Denver, CO Contact: (800) 673-8499 customerservice@awhonn.org www.awhonn.org JULY Controversies in Women’s Health 7/14-7/16 Wisconsin Dells, WI Contact: (800) 323-2688 cme@mayo.edu www.mayo.edu/cme Gynecologic Oncology Group 2011 7/15-7/17 Philadelphia, PA Contact: (215) 854-0770 meeting_reg@gog.org www.gog.org Office Gynecology 7/17-7/20 Jackson Hole, WY Contact: (925) 828-7100 hheath@cforums.com www.contemporaryforums.com AUGUST Infectious Diseases Society for Obstetrics and Gynecology 8/11-8/13 Chicago, IL Contact: (604) 875-5101 cpd.info@ubc.ca www.idsog.org Pathways to Clinical Excellence in OB/GYN 8/12-8/14 Orlando, FL Contact: (904) 674-0751 cfilbert@flobgyn.org www.obgpathways.com SEPTEMBER Birth World Congress 9/9-9/11 Chicago, IL Contact: +39 02 34 93 44 04 info@mcaevents.org www.mcaevents.org Oncofertility Consortium Conference 2011 9/12-9/14 Chicago, IL Contact: (312) 503-2506 a-krausfeldt@northwestern.edu http://oncofertility.northwestern.edu American Urogynecologic Society 9/14-9/17 Providence, RI Contact: (202) 367-1167 info@augs.org www.augs.org

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Contact: (202) 466-3825 ARHP@arhp.org www.reproductivehealth2011.org

American Gynecological & Obstetrical Society 9/15-9/17 Chicago, IL Contact: (804) 924-9937 www.agosonline.org

jUNE 2011 l VOLUME 3, NUMBER 3

NAMS Annual Meeting 9/21-9/24 Washington, DC Contact: (440) 442-7550 info@menopause.org www.menopause.org

Ambulatory OB/GYN Nursing 9/25-9/28 Orlando, FL Contact: (925) 828-7100 hheath@cforums.com www.contemporaryforums.com OCTOBER American College of Osteopathic Obstetricians & Gynecologists 10/12-10/16 Philadelphia, PA

Vagifem® is an estrogen (estradiol) indicated for the treatment of atrophic vaginitis due to menopause.

Important Safety Information WARNING: CARDIOVASCULAR DISORDERS, ENDOMETRIAL CANCER, BREAST CANCER and PROBABLE DEMENTIA Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.

Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia.

The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg], relative to placebo.

The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.

The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo.

The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

The use of Vagifem® is contraindicated in women who exhibit one or more of the following: undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogendependent neoplasia; active deep vein thrombosis, pulmonary embolism or history of these conditions; active arterial thromboembolic disease or a history of these conditions; known liver dysfunction or disease, or known or suspected pregnancy.

Vagifem® is intended only for vaginal administration. Systemic absorption occurs with the use of Vagifem®.

The warnings, precautions, and adverse reactions associated with the use of systemic estrogen therapy should be taken into account.

The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer.

Other warnings include: gallbladder disease, severe hypercalcemia, loss of vision, severe hypertriglyceridemia, cholestatic jaundice, and vaginal abrasion caused by the Vagifem® applicator. Women on thyroid replacement therapy should have their thyroid function monitored.

In a randomized, double-blind, parallel group, placebo-controlled study for Vagifem® 10 mcg, adverse events with an incidence of ≥5% included vulvovaginal mycotic infection, vulvovaginal pruritus, back pain and diarrhea.

Please see Brief Summary of the Prescribing Information on adjacent pages.

Reference: 1. Vagifem® (estradiol vaginal tablets) prescribing information.

Princeton, NJ: Novo Nordisk Inc; 2009.

Vagifem® is a registered trademark of Novo Nordisk FemCare AG. © 2011 Novo Nordisk. Printed in the U.S.A. 0111-00001636-1 February 2011

Meetings Contact: (817) 377-0421 info.acoog.org www.acoog.org

National Association of Nurse Practitioners in Women’s Health 10/12-10/15 Austin, TX Contact: (202) 543-9693 info@npwh.org www.npwh.org

International Society for the Study of Women’s Sexual Health 10/14-10/16 Scottsdale, AZ Contact: (847) 517-7225 info@isswsh.org orgwww.isswsh.org ASRM Annual Meeting 10/15-10/19 Orlando, FL

Contact: (866) 471-7224 asrmregistration@jspargo.com www.asrm.org

North American Forum on Family Planning 10/22-10/24 Washington, DC Contact: info@societyfp.org www.societyfp.org

Low-dose Vagifem® 10 mcg The lowest dose* of local vaginal estrogen commercially available

Minimal systemic absorption There is minimal systemic absorption with Vagifem® 10 mcg,† and systemic estrogen levels remain low throughout treatment.1 Average Daily Serum Concentration (arithmetic mean, Cave(0-24)) of Estradiol During Vagifem® 10 mcg Treatmenta (uncorrected for baseline, N=29)1

a

Day 1

10.09 pg/mL

Day 14

7.35 pg/mL

Day 83

5.50 pg/mL

A 12-week, single-center, randomized, open-label, multiple-dose, parallel group study of 58 patients treated with Vagifem® 10 mcg and 25 mcg.1 Patients received vaginal tablets as a once daily intravaginal treatment for the first 2 weeks and a twice weekly intravaginal maintenance for the following 10 weeks.

Estrone and estrone sulfate parameters were also measured but not shown.

*Based on a 12-week dosing schedule according to Vagifem® Prescribing Information1 †

Clinical relevance of these pharmacokinetic data is unknown.

Call 1-855-NOVO-V10 (668-6810) to order samples and copay cards today.

Please see important safety information and Brief Summary of the Prescribing Information on adjacent pages.

jUNE 2011 l VOLUME 3, NUMBER 3

17

Infertility Updates

Pre-Art Distress not linked to Failure to become Pregnant, new Analysis shows Will This Study Resolve or Reignite the Debate?

By Rosemary Frei, MSc

S

tress has often been suggested as a potential cause for infertility or for negative outcomes for in vitro fertilization. New evidence from a comprehensive review of previous studies now

suggests that pretreatment emotional distress does not result in a negative outcome after a cycle of assisted reproductive technology (ART).

This new meta-analysis included

studies conducted in the United States, Canada, Australia, Turkey, Israel, and Europe (Boivin J, et al. BMJ. 2011;342:d223), showing that emotional distress neither reduces nor increases the likelihood of pregnancy after ART or after other forms of assisted reproduction.

Vagifem® (estradiol vaginal tablets) Rx only BRIEF SUMMARY. Please consult package insert for full prescribing information.

WARNING: CARDIOVASCULAR DISORDERS, ENDOMETRIAL CANCER, BREAST CANCER and PROBABLE DEMENTIA: Estrogen-Alone Therapy: Endometrial Cancer: There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions]. Cardiovascular Disorders and Probable Dementia: Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions]. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg], relative to placebo [see Warnings and Precautions]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Estrogen Plus Progestin Therapy: Cardiovascular Disorders and Probable Dementia: Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions]. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions]. The WHIMS estrogen plus progestin ancillary study of the WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions]. Breast Cancer: The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

INDICATIONS AND USAGE: Treatment of Atrophic Vaginitis due to Menopause CONTRAINDICATIONS: Vagifem® should not be used in women with any of the following conditions: Undiagnosed abnormal genital bleeding; Known, suspected, or history of breast cancer; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism or history of these conditions; Active arterial thromboembolic disease (for example, stroke, and myocardial infarction), or a history of these conditions; Known liver dysfunction or disease; Known or suspected pregnancy WARNINGS AND PRECAUTIONS: Risks From Systemic Absorption: Vagifem® is intended only for vaginal administration. Systemic absorption occurs with the use of Vagifem®.

The warnings, precautions, and adverse reactions associated with the use of systemic estrogen therapy should be taken into account. Cardiovascular Disorders: An increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen-alone therapy. An increased risk of pulmonary embolism, DVT, stroke, and myocardial infarction has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogens with or without progestins should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of venous thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately. Stroke: In the Women’s Health Initiative (WHI) estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted.

Should a stroke occur or be suspected, estrogens should be discontinued immediately. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in all women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (33 versus 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Coronary Heart Disease: In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen alone compared to placebo. Subgroup analysis of women 50 to 59 years of age suggests a statistically non-significant reduction in CHD events (CE 0.625 mg compared to placebo) in women with

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jUNE 2011 l VOLUME 3, NUMBER 3

“The debate over whether emotional distress impacts fertility treatment outcome started in the 1940s, with psychosomatic medicine to explain ‘unexplained’ infertility,” lead author Jacky Boivin, PhD, Professor of Health Psychology, Cardiff Fertility Studies Research Group, School of Psychology, Cardiff

less than 10 years since menopause (8 versus 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n=2,763), average age 66.7 years, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/ Progestin Replacement Study [HERS]) treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of the original HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE (0.625 mg) plus MPA (2.5 mg) group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism (VTE): In the WHI estrogen-alone substudy, the risk of VTE (DVT and pulmonary embolism [PE]) was increased for women receiving daily CE (0.625 mg) compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years. Should a VTE occur or be suspected, estrogens should be discontinued immediately. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted. Should a VTE occur or be suspected, estrogens should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms: Endometrial Cancer: An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with an increased risk of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer: The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg). In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg) was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] . The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Ovarian Cancer: The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for 5 or more years, has been associated

Infertility Updates

University, Wales, United Kingdom, told Infertility & Reproductive News. “We’ve been making steady progress, but questions answered generate new ideas about how best to address the debate, and starts a new flow of studies with new strengths and weaknesses. I expect the meta-analysis will do the same.”

Dr Boivin added that this study has received a lot of attention, noting that some experts believe that the study’s focus was too narrow—that is, it should have covered more than emotional distress of a particular type, measured at a particular point, and associated with a specific outcome—whereas others wel-

with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. Probable Dementia: In the estrogen-alone Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to daily CE (0.625 mg) or placebo. In the WHIMS estrogen-alone ancillary study, after an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent nCI, 0.83-2.66). The absolute risk of probable dementia for CE alone versus placebo was 37 versus 25 cases per 10,000 women-years. In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent nCI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent nCI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. Gallbladder Disease: A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Hypercalcemia: Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. Visual Abnormalities: Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. Addition of a Progestin When a Woman Has Not Had a Hysterectomy: Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. Elevated Blood Pressure: In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Hypertriglyceridemia: In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs. Hepatic Impairment and/or Past History of Cholestatic Jaundice: Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued. Hypothyroidism: Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.

Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range.

Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. Fluid Retention: Estrogens may cause some degree of fluid retention.

Women with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed. Hypocalcemia: Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Exacerbation of Endometriosis: A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. Exacerbation of Other Conditions: Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. Local Abrasion: A few cases of local abrasion induced by the Vagifem® applicator have been reported, especially in women with severely atrophic vaginal mucosa. Laboratory Tests: Serum follicle stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy. Drug-Laboratory Test Interactions: Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay.

T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.

Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin

come the clear-cut research question and ensuing results.

Pamela Berens, MD, Professor of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, is in the latter group.

“The fact that this was a meta-analysis gives us a bit more backing when we

substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels. Impaired glucose tolerance.

ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions]; Endometrial Cancer [see Boxed Warning, Warnings and Precautions]. Clinical Study Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a 12-month randomized, double-blind, parallel group, placebo-controlled study, a total of 309 postmenopausal women were randomized to receive either placebo or Vagifem® 10 mcg tablets. Adverse events with an incidence of ≥5% in the Vagifem® 10 mcg group and greater than those reported in the placebo group are listed in Table 1.

Table 1: Treatment-Emergent Adverse Events Reported at a Frequency of ≥5% and More Frequent in Women Receiving Vagifem® 10 mcg Body System Adverse Event

Treatment Number (%) of Women Placebo N = 103 Vagifem® N = 205 n (%) n (%)

Body As A Whole Back Pain 2 (2) 14 (7) Digestive System Diarrhea 0 11 (5) Urogenital System Vulvovaginal Mycotic Infection 3 (3) 17 (8) Vulvovaginal Pruritis 2 (2) 16 (8) N = Total number of women in study. n = Number of women who experienced adverse event.

In a 12-week, randomized, double-blind, placebo-controlled study, 138 postmenopausal women were randomized to receive either placebo or Vagifem® 25 mcg tablets. Adverse events with an incidence of ≥5% in the Vagifem® 25 mcg group and greater than those reported in the placebo group are listed in Table 2.

Table 2: Treatment-Emergent Adverse Events Reported at a Frequency of ≥5% and More Frequent in Women Receiving Vagifem® 25 mcg Body System Adverse Event

Treatment Number (%) of Women Placebo N = 47 Vagifem® N = 91 n (%) n (%)

Body As A Whole Headache 3 (6) 8 (9) Abdominal Pain 2 (4) 6 (7) Back Pain 3 (6) 6 (7) Respiratory System Upper Respiratory Tract Infection 2 (4) 5 (5) Urogenital System Moniliasis Genital 1 (2) 5 (5) N = Total number of women in study. n = Number of women who experienced adverse event.

Postmarketing Experience: The following adverse reactions have been reported during post approval use of Vagifem® 25 mcg. 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. Genitourinary System: Endometrial cancer, endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration Breast: Breast cancer Cardiovascular: Deep vein thrombosis Gastrointestinal: Diarrhea Skin: Urticaria, erythematous/pruritic rash, genital pruritus Central Nervous System: Aggravated migraine, depression, insomnia Miscellaneous: Fluid retention, weight increase, drug ineffectiveness, hypersensitivity, blood estrogen increase. Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

OVERDOSAGE: Overdosage of estrogen may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding in women. Treatment of overdose consists of discontinuation of Vagifem® together with institution of appropriate symptomatic care.

More detailed information is available upon request.

Date of Issue: November 25, 2009 Version: 6 For information contact: Novo Nordisk Inc., 100 College Road West, Princeton, NJ 08540, USA 1-888-824-4336 Manufactured by: Novo Nordisk A/S, 2880 Bagsvaerd, Denmark Vagifem® is a registered trademark owned by Novo Nordisk FemCare AG. © 2003-2010 Novo Nordisk A/S 140373 1/10

tell women that they don’t have to feel guilty, that their stress is not contributing to their infertility,” commented Dr Berens. “Women often do feel very

“The fact that this was a meta-analysis gives us a bit more backing when we tell women that they don’t have to feel guilty, that their stress is not contributing to their infertility.”—Pamela Berens, MD guilty when they’re having trouble conceiving, so this article is very useful to help us reassure them.”

Dr Boivin and colleagues searched the literature for articles published between 1985 and March 2010. They were looking for studies that prospectively tested the association between pretreatment anxiety or depression and pregnancy in women undergoing a single cycle of ART. This search yielded 14 studies that included a total of 3583 women. Of the studies, 2 were conference abstracts and 12 were published in a peer-reviewed journal. Dr Boivin’s team rated 6 of the studies as being high quality, 3 were rated average quality, and 5 were low quality.

The meta-analysis revealed that there was not a significant difference in pretreatment emotional distress between women who became pregnant after treatment and those who did not. The team also did not find any significant differences between a number of subgroups, such as women who had previously used ART and those who had not.

They did, however, find that among women who were in the 4 studies that used a positive pregnancy test as proof of pregnancy rather than a positive fetal scan or live birth, those who did not become pregnant after treatment were more likely to have higher pretreatment distress than those who did become pregnant. The investigators noted that these 4 studies were the smallest of the 14. Dr Boivin said that the result is likely a result of “‘small study bias,’ where positive associations are caused by the unreliability of estimates produced by small sample sizes rather than caused by genuine effects.”

She and her colleagues also noted that the study results do not preclude the possibility that emotional distress may lower the overall chance of ART success by making couples less willing to stay in treatment for the optimal number of cycles. ■

jUNE 2011 l VOLUME 3, NUMBER 3

19

Infertility Updates

gamete Donation: medical and genetic Implications Wendy Kramer, Co-founder and Director of the Donor Sibling Registry

T

he US fertility industry is one of the least regulated among developed nations. No records exist for the number of children born from sperm donation or for the number of children born from each donor. In April, we discussed the emotional implications on the offspring. This article focuses on both potential and reported medical implications.

The mission of the Donor Sibling Registry (DSR) is to educate, connect, and support all persons associated with gamete donation. The DSR has >30,000 members and has facilitated mutual consent contact between >8500 donor-conceived persons and their halfsiblings and/or their genetic parents.

Since its establishment in 2000, the DSR has counseled many donor recipients whose children have an inherited and previously undisclosed disease.

Some parents find that their donor did not disclose a hereditary disorder or that their sperm bank did not disclose that offspring of the donor they used had been diagnosed with a hereditary disorder. Others have even found out that their sperm bank has amended information on the donor’s medical form (Johnson v California Cryobank).1 medical Implications The consequences of nondisclosure can be devastating. Over the years, many cases were publicly discussed in professional and lay publications.

Between 2009 and 2011 alone the following cases were reported: • London Women’s Clinic used chromosomally abnormal donor sperm to treat 11 women, including a couple who had to destroy 22 embryos created over a year of treatment • A child conceived using gametes from anonymous sperm and ova donors was diagnosed with spinal muscular atrophy type 1 • New England Cryogenic was sued by a woman claiming that her children inherited genetic disorders. Other families who used this donor also reported issues • A Pacific Reproductive Services donor passed along hypertrophic cardiomyopathy, a fatal heart disease, to 9 of his 22 known offspring. One child consequently died • At least 9 children (California Cryobank/Nordic Cryobank) that have been conceived via an anonymous donor have been born with the inheritable disease neurofibromatosis type 1.

The frequency and severity of these health issues are of significant concern because donors can father in excess of

50 to 100 children. The largest known half-sibling group in the DSR is approaching 130 children.

Sperm banks have estimated that only 20% to 40% of women report their live births to them, meaning there is no accurate accounting of all children born from any one donor.

When a donor illness is reported, it is impossible to notify all relevant fami-

suffer from depression” [former sperm donor] 4. “My husband was a medical student and was an occasional sperm donor….He died of pancreatic cancer in 2002” 5. “I would like to contact other offspring. Both my children have autism, and we have no history in my family of any disabilities.”

Donors can father in excess of 50 or even 100 children. Therefore, a donor with an undisclosed hereditary disorder can easily pass on a disease to many children.

lies, because for the most part they are not known. To complicate matters, 21% to 27% of our surveyed donors reported donating to >1 fertility clinic.2 Some sperm banks refuse to give donors their donor numbers, making it practically impossible for them to make mutual consent contact and share important medical information with biologic offspring.

Many US clinics and sperm banks refuse to update donor or offspring medical information. Of those who accept updates, some refuse to share the information with families.

Our research on 164 sperm donors revealed that 84% of them have never been contacted by their clinics or sperm banks for medical updates, although 23% reported feeling that they or close family members had medical/genetic issues that would be important to share with recipient families.2 In addition, 94% of surveyed sperm donors said that they would have accepted an offer for genetic testing had it been offered by their sperm bank.2 The few following quotes from parents of donor-conceived children or from donors illustrate the impact of the lack of regulation in the industry: 1. “Our daughter is 6 years old and has been diagnosed with a hereditary bone disease called MHE [multiple hereditary exostoses]. There is no history in our family” 2. “At the age of 3, my daughter developed a very rare disease, Rasmussen’s encephalitis, which caused seizures and significant brain damage” 3. “My father and grandmother both died of multiple myeloma, a nasty cancer. Many members of my family

Our own research on 155 egg donors showed that only 2.6% of them had been contacted by their fertility clinics after donation to update information that might impact the donor-conceived offspring, although 31% of them reported that they or close family members had medical/genetic issues that would be important to share with recipient families.3 Survey respondents reported developing breast cancer, being diagnosed with hemochromatosis, or giving birth to a child who was a carrier for cystic fibrosis. Even more surprising, >33% of the egg donors who reported a new medical problem in themselves or a close family member did not attempt to contact their fertility clinic.3 Overwhelmingly, the reason reported was lack of education about the value of providing such information, and a lack of encouragement by the fertility clinic to do so.

Two of our most recent reports on donors and offspring experiences have just been published.4,5 Donor screening in the united states Oversight from the US Food and Drug Administration has so far been directed at the prevention of infectious diseases, including sexually transmitted diseases (STDs). Little attention has been paid to genetic disease transmission. Genetic testing varies significantly by clinic.

Donor screening for STDs includes HIV, human T-lymphotropic virus, hepatitis B and C, syphilis, gonorrhea, chlamydia, and cytomegalovirus. Some fertility clinics and sperm banks also test

for cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Canavan disease, Gaucher disease, Niemann-Pick disease, and beta thalassemia.

The DSR recommends that all donors be tested for a larger scope of tests, possibly including karyotyping, cystic fibrosis, Tay-Sachs disease, fragile X syndrome, hemochromatosis (for HFE mutation), BRCA1 and 2 mutations, celiac disease, polyposis conditions caused by APC gene mutations, hereditary nonpolyposis colorectal cancer, glycogen-storage diseases, such as Fabry disease and Niemann-Pick disease, polycystic disease, Huntington disease, melanoma (CDKN2A mutation), myopia, and Marfan syndrome (for donors taller than 6 ft 2 in).

In addition, the DSR recommends more thorough physical examinations, face-to-face medical history intakes, and full psychologic screening. Among our surveyed donor offspring who wished to make contact with their donors, 74% listed learning more about their medical background as a reason for the desired contact.6 recommendations for Fertility clinics • Adequately counsel prospective donors before they begin donation, including the legal, ethical, moral, and mental health implications for themselves, recipients, and offspring.

They must also be educated about their legal and ethical responsibilities to be honest as a donor • Require donors to regularly update their family medical history and have this information available to all families who have used this donor • Track all recipients, donors, and births, and report all live births from each donor • Limit the number of births conceived from any one donor; the DSR lists 32 sibling groups of between 15 and 129 children, and 91 groups of >10 half siblings • Counsel parents on openness, full disclosure, and the importance of using open donors; emphasize the importance of having information about genetic, ancestral, and medical backgrounds • Encourage all donors and recipient parents to register with the DSR to be able to share and update medical information with one another.

As we hear more frequently from families who have been formed using donor conception, we think that the industry should respond accordingly as it moves forward, and consider updating Continued on next page

20

jUNE 2011 l VOLUME 3, NUMBER 3

Clinical News FDA Approves...

Continued from page 3

cases of toxoplasmosis reinfection or relapse has not been established.

The T gondii parasite is largely associated with cats, but it can be found in a wide array of animal and bird species worldwide. combination therapy cuts motherto-child hIV transmission A new study from the National Institutes of Health (NIH) has shown conclusively that adding 1 or 2 drugs to zidovudine (Retrovir) reduces mother-tochild HIV transmission (www.nih.gov/ news/health/mar2011/nichd-02.htm). â&#x20AC;&#x153;Our results showed conclusively that the 2- and 3-drug regimens are superior to the standard treatment with zidovudine,â&#x20AC;? said lead investigator Karin NielsonSaines, MD, Clinical Professor of Pediatrics, University of California, LA. According to the NIH, approximately 20% of Americans with HIV are unaware that they carry the virus, and many of the women delivering the 100 to 200 neonates born with HIV annually are not tested early in pregnancy or are not treated during pregnancy. When HIV is not diagnosed until a woman is in labor, the infant is given prophylactic zidovudine therapy.

The investigators reviewed 1684 infants born to mothers whose HIV infection was not diagnosed until they went into labor. The infants were randomized to standard 6-week therapy with zidovudine, 6 weeks of zidovudine

plus 3 doses of nevirapine (Viramune) during the first week of life, or 6 weeks of zidovudine plus 2 weeks of lamivudine (Epivir) and nelfinavir (Viracept). HIV transmission was reduced by more than 50% with the 2- and 3-drug regimens: the proportions of infants infected with HIV at 3 months were 4.9% with zidovudine alone; 2.2% with zidovudine plus nevirapine; and 2.5% with zidovudine, nevirapine, and nelfinavir.

IVF yields Poorer obstetric outcomes than spontaneous conception Babies born through in vitro fertilization (IVF) have inferior obstetric outcomes compared with their non-IVF counterparts, regardless of whether they are born through IVF with single embryo transfer (SET), elective SET (eSET), nonelective SET (non-eSET), or double embryo transfer (DET), a

Swedish study showed (Sazonova A, et al. Hum Reprod. 2011;26:442-450).

The researchers compared outcomes for all IVF (N = 13,544) and non-IVF (N = 587,009) children born in Sweden between 2002 and 2006, examining the main outcomes of preterm birth (born <28 weeks, <32 weeks, or <37 weeks of gestation), low birth weight (LBW), and very low birth weight (VLBW).

Continued on page 28

Not all pre-natalâ&#x20AC;&#x2122;s are created equal!

gamete Donation...

Continued from page 20

and reevaluating the methodologies that are now known to be insufficient in safeguarding the health of all involved. â&#x2013;

Make the connection at www.neevodha.com

references 1. Johnson v Superior Court (California Cryobank). (2000) 80 Cal. App. 4th 1050 [95 Cal.Rptr.2d 864].

2. Kramer W, Daniels K, Perez y Perez M. Semen donors who are open to contact with their offspring. Presented at the American Society for Reproductive Medicine 66th Annual Meeting; October 23-27, 2010, Denver, CO; Fertility 2011, the 7th biennial conference of the UK Fertility Societies, January 5-7, 2011, Dublin, Ireland; 2nd International Congress on Controversies in Cryopreservation of Stem Cells, Reproductive Cells, Tissue & Organs and Cryo Surgery, April 7-9, 2011, Valencia, Spain.

3. Kramer W, Schneider J, Schultz N. US oocyte donors: a retrospective study of medical and psychosocial issues. Hum Reprod. 2009;24:3144-3149.

4. Jadva V, Freeman T, Kramer W, Golombok S. Sperm and oocyte donorsâ&#x20AC;&#x2122; experiences of anonymous donation and of being contacted by their donor offspring. Hum Reprod. 2011;26:638-645.

5. Jadva V, Freeman T, Kramer W, Golombok S. Experiences of offspring searching for and contacting their donor siblings and donor. Reprod Biomed Online.

2010;20:523-532.

6. Kramer W, Jennings P, Beeson D. Anonymity, disclosure and contact with donors: how experiences of donor conceived offspring vary by family type. Hum Reprod [In press]. Presented at the American Society for Reproductive Medicine 66th Annual Meeting, October 2327, 2010, Denver, CO; Fertility 2011, the 7th biennial conference of the UK Fertility Societies, January 5-7, 2011, Dublin, Ireland.

Prenatal vitamins containing synthetic folic acid have limitations.

See if the benefits of NeevoDHAÂŽ are for you.

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jUNE 2011 l VOLUME 3, NUMBER 3

21

Women’s Health

Imaging in Pregnant Women Can Be Safe, Helpful When Indicated

By Rosemary Frei, MSc

S

hould an ill or injured pregnant woman undergo magnetic resonance imaging (MRI) or computed tomography (CT) if required to help the diagnosis? An expert presenting at

the 2011 Canadian Association of Radiologists meeting said that the answer depends on how important the imaging is for ensuring the survival of the patient and the fetus.

“In practice, it is unlikely that any single diagnostic study would deliver a sufficient radiation dose to justify not carrying out the study; however, the effects are cumulative,” said Phyllis

radiation risk Ultrasound and MRI do not result in ionizing radiation and therefore are preferred over CT in almost all cases.

In experienced hands, ultrasound can yield valuable information, Dr Glanc said, such as accurate confirmation of acute cholecystitis, bile duct stones, hydronephrosis caused by stones, appendicitis, and traumatic internal injury. Ultrasound is less useful for confirming pyelonephritis or most hepatic diseases specific to pregnancy.

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.

“It is unlikely that any single diagnostic study would deliver a sufficient radiation dose to justify not carrying out the study; however, the effects are cumulative.”

Commercial Product (30 capsules) 0525-0621-30* Use under medical/physician supervision.

Sample Product (4 capsules) 0525-0621-04* Professional samples-not for sale * 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.

—Phyllis Glanc, MD

Patents Some or all of the following patents may apply: U.S. Patent No. 6,207,651 U.S. Patent No. 6,011,040 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. 5,997,915 U.S. Patent No. 6,528,496 and other pending patent applications.

Radiation exposure from chest xrays, limb x-rays, or head or chest CT is well below the estimated levels that would cause damage to fetuses; however, a CT of the abdomen or pelvis delivers an approximate 3.5-rad dose to the fetus, an amount that is approximately 500,000-fold higher than the radiation exposure from a chest x-ray, Dr Glanc said.

Radiation exposure at this level may be teratogenic and can increase by 1.4 to 1.8 times the resultant offspring’s risk of developing childhood cancer, she said. The embryo is most sensitive to ionizing radiation during embryogenesis, which occurs during the first 2 to 15 weeks of gestation.

Ultrasound has not been shown to have any biologic effects on the fetus; however, it is recommended to avoid pulsed-Doppler ultrasound during the early first trimester, she said.

MRI also does not involve radiation and has not been shown to produce deleterious effects in fetuses. MRI can be considered when ultrasound will not help to provide a diagnosis and when it is the appropriate test to answer the clinical question at hand.

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

3DPODE

1$785$/ 3(5621$/,=(' 0(',&,1(

22

jUNE 2011 l VOLUME 3, NUMBER 3

Glanc, MD, Associate Professor, Department of Medical Imaging, University of Toronto. “It’s important to…do the clinically appropriate examination with minimal radiation exposure, without compromising patient care, and in a timely fashion.”

Continued on page 23

Women’s Health

First national survey uncovers Disparities in out-of-Pocket mammography expenditures Across the country

By Rosemary Frei, MSc

T

he first national study of average out-of-pocket (OOP) and overall mammography expenditures indicates that in 2007 and 2008, women living in the midwestern United States had an OOP expenditure that was nearly double that of those living in the Northeast or the West, at $47, $24, and $25, respectively, based on data presented at the 2011 International Society for Pharmacoeconomics and Outcomes Research meeting.

Women using office-based facilities had far higher OOP expenditures than those receiving mammograms at outpatient hospitals ($35 vs $28, respectively). However, overall mammography costs were higher at the outpatient hospitals ($310 vs $243, respectively).

The good news is that the average OOP mammography cost for all

TAKEAWAY qUICK POINTS ➤ Women living in the midwestern United States had nearly double the OOP expenditure of those living in the Northeast or the West. ➤ Among women with insurance, those with private insurance paid the highest OOP amount and the largest proportion of total mammography expenditures. ➤ Women who were uninsured had the greatest OOP and paid the highest proportion of the total mammography cost.

“This study highlights where disparities and variations exist among OOP and total expenditures for mammography, but also informs women what they can expect to pay OOP.” —Traci LeMasters, BS, MA

women was only $32.90, with average total mammography expenditures of $266.49. “This study highlights where disparities and variations exist among OOP and total expenditures for mammography, but also informs women what they can expect to pay OOP,” said principal investigator Traci LeMasters, BS, MA, research assistant, School of Pharmacy, West Virginia University, Morgantown.

“However, these are just averages for these subgroups from this particular data set.…And this also is not representative of all women aged 18 to 64, because we included women with only 1 mammogram in a year,” she added.

The investigators analyzed 20072008 data from a nationally representative survey known as the Medical Expenditure Panel Survey, conducted by the Agency for Healthcare Research and Quality.

Data in the current analysis included 2020 women who received only 1 mammogram in 2007 or in 2008; of

Imaging in Pregnant Women... Continued from page 22 choosing ultrasound, mrI, or ct Ultrasound is particularly useful for rapidly triaging potential maternal abdominal trauma, because of its high specificity for this condition. Ultrasound is the first-line examination for maternal abdominal trauma, followed

by MRI as appropriate.

MRI may take too long in the case of trauma or a potentially unstable patient; therefore, the second-line procedure is typically a radiologic examination, Dr Glanc noted.

CT is the first-line examination when it is indicated and when there is concern for serious injury or a potentially unstable patient.

“Two of the main principles for maternal trauma are that no fetus survives without maternal survival and that even minor maternal trauma may

cause fetal death, typically due to placental abruption,” she said.

Ultrasound also provides high specificity for gallstones that are >2 mm in diameter or acute appendicitis. If an ultrasound examination for appendicitis is inconclusive or negative, MRI is usually the next choice, particularly if the woman is in the first trimester.

MRI and CT are both acceptable in the second and third trimesters, because organogenesis is completed in the first trimester, she noted. Furthermore, ultrasound is the first-line imaging modality for renal colic in pregnant women, with low-dose CT and MRI as the second- and third-line modalities.

Ultrasound can rule out alternative hepatic or bile-duct pathology when a hepatic disease specific to pregnancy is suspected, Dr Glanc said. ■

these women, 80% were white, 85.1% were not poor, and 86.8% had private insurance.

Not surprising, women who were uninsured had the greatest OOP expenditures ($60) of any of the women and paid the highest proportion of the total mammography cost (31%). In addition, OOP costs varied by region and by facility type.

Among women with insurance, those with private insurance paid $33 OOP—

the highest amount and the largest proportion of total mammography expenditures (14%). Those with Medicaid coverage paid the lowest OOP, which was also the smallest proportion of total mammography expenditures.

Ms LeMasters is now analyzing survey data collected from women attending Bonnie’s Bus, a mobile mammography program. The bus crisscrosses West Virginia, with medical professionals on board providing mammography services to women in areas where low rates of mammography utilization and high rates of late-stage breast cancer have been historically observed. Although it does not provide free mammograms, 38.6% and 34.2% of the mammograms received by women from Bonnie’s Bus in 2009 and 2010, respectively, were paid for by the West Virginia Breast and Cervical Cancer Screening Program. Such services help remove the disparities highlighted in the study, observed Ms LeMasters. ■

Screening for Cervical Cancer Saves Lives

E

arly detection of cervical cancer with a Pap smear pays off, according to a new study presented at the 2011 International Society for Pharmacoeconomics and Outcomes Research meeting.

More than 10,000 life-years were added and more than 300 deaths averted among the more than 1.8 million women screened with Pap smears between 1991 and 1997 through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). Furthermore, the program saved approximately 2 days of life per woman screened compared with if the NBCCEDP were not in place, according to an analysis led by Donatus U. Ekwueme, PhD, Senior Health Economist, Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, US Centers for Disease Control and Prevention, Atlanta, GA. The NBCCEDP, authorized by Congress in 1990, provides free breast cancer and cervical cancer screening and diagnostic services to low-income, uninsured, and underinsured women across the United States.

Approximately 50% of the 2.6 million women screened for cervical cancer are white, 27% are Hispanic, and 13% are black. At the time of screen-

ing, 42.8% were aged 50 to 64 years, and 37% were aged 40 to 49 years.

The researchers estimated that there would be a benefit of approximately 2 days per woman screened with the NBCCEDP compared with if there were no such program in place, and roughly 21 days gained per woman if no cervical cancer screening were conducted in this population. These estimates translate into a total of >10,000 life-years gained compared with if there were no similar program in place, and >101,000 life-years gained compared with no screening at all. The investigators estimated that >300 deaths were prevented with the institution of the program and >3500 deaths were prevented compared with no screening at all.

Paul Blumenthal, MD, MPH, Professor of Obstetrics and Gynecology, and Director, Stanford Program for International Reproductive Education and Services, Stanford University School of Medicine, Stanford, CA, said that “in essence the results are a reasonable look backwards at what appears to be a successful program in some response.”

Referring to the use of the Pap test as a cervical-screening tool, he added that the analysis “is perhaps most noteworthy for demonstrating what is possible with a very mediocre test.”—RF ■

jUNE 2011 l VOLUME 3, NUMBER 3

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CONTINUING EDUCATION

WWW.INFERTILITYREPRONEWS.COM

PROGRAM CE14 • RELEASE DATE: JUNE 20, 2011 • EXPIRATION DATE: JUNE 20, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Diagnosis, treatment, and Prevention of common sexually transmitted Diseases in the united states Carolyn R. Jones, MSN, FNP-C Ms Jones is a Family Planning Nurse Practitioner and Program Manager, Family Planning/STD/HIV/MCH, South Carolina Department of Health & Environmental Control, Region 6 STATEMENT OF NEED Many healthcare providers have little or no experience with the diagnosis and treatment of, or prevention strategies relating to, sexually transmitted diseases (STDs). More than 19 million new STD diagnoses are made in the United States annually, with an overall cost of >$16 billion. In women, clinical sequelae of STDs may include pelvic inflammatory disease, ectopic pregnancy, and infertility. HIV transmission is a problem in men and women. The risk factors for STDs are many, including adolescent age, black race, drug or alcohol abuse, exchanging sex for drugs/money, inconsistent condom use, low socioeconomic status, men having sex with men, and multiple sex partners or having a new partner. Among the most common STDs are trichomoniasis, human papillomavirus, chlamydia, and herpes simplex virus. It is therefore vitally important that providers involved in women’s health become more active in the prevention and control of STDs than is currently the case. This can be done effectively through education and counseling.

TARGET AUDIENCE Nurses whose primary interest is women’s health and infertility.

LEARNING OBjECTIVES After completing this activity, the reader should be able to: • Discuss the impact of STDs in the United States • Identify the pathogenesis of STDs • Describe the clinical manifestations of STDs • Review the diagnoses and treatment of common STDs CONTINUING NURSING EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT Science Care is approved by the California Board of Registered Nursing, Provider number 15559, for 1.0 contact hour.

METHOD OF PARTICIPATION 1. Read the article in its entirety 2. Go to www.infertilityrepronews.com 3. Select “Continuing Education” 4. Click on this article’s title from the list shown 5. Select “Click here to complete the posttest and obtain a CE certificate online” 6. Complete and submit the CE posttest and CE activity evaluation

24

M

any healthcare providers have little or no experience with the diagnosis and treatment of, or prevention strategies relating to, sexually transmitted diseases (STDs).

More than 19 million new STD diagnoses are made in the United States annually. Healthcare costs for STDs have sky-rocketed to more than $16 billion annually.1 In women, clinical sequelae of STDs can include pelvic inflammatory disease, ectopic pregnancy, and infertility. Men may have epididymitis, urethritis, proctitis, and pharyngitis. HIV transmission is a problem in men and women.1 Infant morbidity and mortality are other issues of concern. Infants may have herpes simplex virus (HSV) infection, congenital syphilis, neonatal HIV, conjunctivitis with resultant blindness, perihepatitis, or neonatal amniotic infection syndrome.1 Populations at greatest risk for STDs are adolescents, racial or ethnic minorities, and men having sex with men (MSM).1 STDs are transmitted in women in several ways: vaginally, orally, rectally, and perinatally, through genital contact and contact with infected blood.

Some STDs infect only sexual and reproductive organs, whereas others (ie, HIV, syphilis, and hepatitis B and C) cause secondary infections (eg, pneumonia, cirrhosis) in other organs, such as skin, the cardiovascular system, and the central nervous system.1

risk Factors The risk factors for STDs are many, varying by age and race. They include2: • Adolescent age • Black race • Blood transfusion/blood products/ organ transplant before 1992 • Drug or alcohol abuse • Exchanging sex for drugs or for money • Having received clotting factors before 1987 • Incarceration • Inconsistent condom use • Long-term hemodialysis • Low socioeconomic status • MSM • Multiple sex partners or a new partner. stD Prevalence Reported gonorrhea cases have declined by 17% since 2006. Although gonorrhea rates are declining in all races and ethnicities, the drop has been smaller for blacks, who accounted for 71% of all gonorrhea cases in 2009.1 Chlamydia diagnoses are up by 19% from 2006, which is most likely a result of expanded screening. Between 2000 and 2009, the chlamydia screening rates among young women nearly doubled, from 25% to 47%.1 Reported syphilis cases have increased 39% since 2006, with the largest increase among MSM. In 2009, MSM accounted for 62% of syphilis cases.1 The most common STDs (Table 1) are discussed below.

trichomoniasis Trichomoniasis is a protozoan disease of the genitourinary tract, which may be characterized in women by vaginitis and a profuse, frothy, malodorous, greenishyellow discharge. Some men may be asymptomatic; others may experience nongonococcal urethritis. Trichomoniasis often coexists with gonorrhea, and the majority of women also have bacterial vaginosis.2-4 Diagnosis is done by the identification of the motile protozoa through culture or microscopy of vaginal discharges. Microscopy has a sensitivity of only about 60% to 70% and requires immediate wet preparation slide evaluation for best results. Other diagnostic tests include the OSOM Rapid Test and the Affirm VPIII Microbial Identification Test. These test vaginal secretions and have a sensitivity of more than 83% and a specificity of more than 97%.

Culture is the most sensitive and specific commercially available method of diagnosis. For men, wet preparation is insensitive, but urethral, urine, and semen cultures have optimal sensitivity.

The incubation period is 4 to 20 days, and many patients are symptom-free carriers for years.2-4 Treatment consists of metronidazole 2 g, taken in a single dose; metronidazole 500 mg, twice daily for 7 days; or tinidazole 2 g, taken in a single dose. Patients should avoid alcohol use during treatment and for 24 hours after treatment Continued on page 25

7. Print your Certificate of Credit This activity is provided free of charge to participants.

FACULTY DISCLOSURES As a provider accredited by the California Board of Registered Nursing, Science Care must ensure balance, independence, objectivity, and scientific rigor in all its activities. All course directors, faculty, planners, and any other individual in a position to control the content of this educational activity are required to disclose to the audience any relevant financial relationships with any commercial interest.

Science Care must determine if the faculty’s relationships may influence the educational content with regard to

jUNE 2011 l VOLUME 3, NUMBER 3

exposition or conclusion and resolve any conflicts of interest prior to the commencement of the educational activity. Disclosures are as follows: • Carolyn R. Jones, MSN, FNP-C, has nothing to disclose.

• Dalia Buffery, MA, ABD, has nothing to disclose.

• The staff members of Science Care have nothing to disclose.

DISCLAIMER The opinions and recommendations expressed by faculty, authors, and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of Science Care or Novellus Healthcare Communications, LLC.

COPYRIGHT STATEMENT Copyright © 2011 Science Care. All rights reserved.

EDITORIAL BOARD Carolyn R. Jones, MSN, FNP-C Family Planning Nurse Practitioner and Program Manager Family Planning/STD/HIV/MCH South Carolina Department of Health & Environmental Control, Region 6 927 Shine Avenue Myrtle Beach, SC 29577-3580 Debra Moynihan, WHNP-BC, MSN Nurse Practitioner, Women’s Health Clinical Director, Carolina OB/GYN 242 Willow Bay Drive, Murrells Inlet, SC 29576

CONTINUING EDUCATION

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Diagnosis, treatment, and Prevention... Continued from page 24 with metronidazole, and for 72 hours after treatment with tinidazole.2-4 gonorrhea Gonorrhea is caused by the gonococcus, Neisseria gonorrhoeae, which infects columnar and transitional epithelium.

Symptoms may include an acute purulent discharge of the penis or cervix, dysuria, tenesmus, and septicemia.

Diagnosis is made by Gram stain, bacteriologic culture on selective media, or tests that detect gonococcal nucleic acid.

The incubation period is usually 2 to 7 days, and communicability may extend for months in untreated individuals.

Quinolone-resistant N gonorrhoeae continues to spread in the United States.1,2 Treatment of uncomplicated gonorrhea includes ceftriaxone 250 mg intramuscularly (IM) in a single dose, cefixime 400 mg orally in a single dose, ciprofloxacin 500 mg orally in a single dose, floxacin 400 mg orally in a single dose, or levofloxacin 250 mg orally in a single dose. Patients who cannot take cephalosporins or quinolones may be treated with spectinomycin 2 g IM in a single dose.

If chlamydial infection is not ruled out, patients must also be treated with azithromycin 1 g orally in a single dose or with doxycycline 100 mg orally twice daily for 7 days. Gonococcal infections of the pharynx are more difficult to eliminate than urogenital and anal/rectal infections. Recommended regimens include ceftriaxone 250 mg IM in a single dose or ciprofloxacin 500 mg orally in a single dose. Quinolones and tetracyclines may not be used during pregnancy. chlamydia Chlamydia trachomatis is the most frequently reported infectious disease, and the prevalence is greatest among young persons aged ≤25 years. Chlamydial organisms are obligate intracellular bacteria that are sensitive to broad-spectrum antimicrobials. Genital infection in men is primarily manifested as urethritis. In women, chlamydial manifestations (eg, mucopurulent cerricitis, arrhythmia, edema) are primarily cervical and endocervical; however, many patients may be asymptomatic.5 Infection during pregnancy may result in premature rupture of membranes, preterm delivery, or conjunctival and pneumonic infections of the newborn.5 Endocervical chlamydia infection has been associated with an increased risk for HIV infection. The incubation period is poorly defined but is a minimum of 7 to 14 days.5 Diagnosis is done by smear and culture, as well as nonculture methods, such as endocervical swab by direct

reduce the frequency of recurrences by 70% to 80% or eliminate symptomatic outbreaks. Recommended regimens are acyclovir 400 mg twice daily, famciclovir 250 mg twice daily, valacyclovir 500 mg daily, or valacyclovir 1.0 g daily.6

Table 1 Common STDs: Incidence and Prevalence STD

Incidence

Prevalence

Trichomoniasis

7.4 million

No data

HPV

6.2 million

20 million

Chlamydia

2.8 million

No data

HSV-2

1.6 million

16.2% of US population

Gonorrhea

718,000

No data

Syphilis

37.000

No data

Hepatitis B

38,000

800,000 to 1.4 million

Hepatitis C

18,000

2.7 million-3.9 million

NOTE: These data were published in 2009 but reflect the years that data were last available for some of the most common STDs. Source: Centers for Disease Control and Prevention National Prevention Information Network. STDs today. www.cdcnpin.org/scripts/std/std.asp.

Accessed May 24, 2011.

immunofluorescence test with monoclonal antibody, enzyme immunoassay, DNA probe, and nucleic acid amplification tests (NAATs). NAATs may be used with urine specimens.2 The recommended treatment is azithromycin 1 g in a single dose or doxycycline 100 mg twice daily for 7 days.1,2 During pregnancy, doxycycline may be substituted with amoxicillin 500 mg 3 times daily for 7 days.

recurrent genital herpes are caused by HSV-2 infection. Although HSV-1 infection is usually associated with oral lesions, it is becoming a more common cause of first-episode genital herpes.

Either serotype may infect the genital tract or the oral mucosa.2,6 In women, the principal sites of primary HSV infection are the cervix and the vulva. Recurrent disease may involve the vulva, buttocks, perineum,

Chlamydia trachomatis is the most frequently reported infectious disease, and the prevalence is greatest among young persons aged ≤25 years.

Infection during pregnancy may result in premature rupture of membranes, preterm delivery, or conjunctival and pneumonic infections of the newborn. herpes simplex Virus HSV infection is a chronic, lifelong viral infection characterized by a localized primary lesion, latency, and a tendency to localized recurrence. The majority of HSV infections are undiagnosed, are transmitted by people unaware that they have the infection, or are transmitted by those who are asymptomatic when the transmission occurs.2,6 With an initial genital episode of HSV infection, symptoms often include multiple lesions that progress from painful vesicles to ulcer formation, to crusting and healing. Lesions usually appear as small, grouped vesicles on an erythematous base. Recurrent episodes are characterized by tender, superficial lesions that usually recur at the same site. Recurrent prodromal symptoms are tingling and/or tenderness.2,6 The 2 serotypes are HSV-1 and HSV2. In the United States, the majority of

and legs. In men, lesions appear on the glans penis or the prepuce. For men engaging in anal sex, lesions may appear in the rectum and anus.2,6 Neonatal infections may be disseminated infections involving the liver, encephalitides, and other infections limited to the skin, eyes, or mouth.

Maternal excretion at the time of delivery is the main risk to the newborn, with the exception of intrauterine infections.2,6 Diagnosis is made with viral cultures; however, the sensitivity of culture is low, especially for recurrent lesions.2,6 Treatment is recommended for 7 to 10 days with acyclovir 400 mg 3 times daily, acyclovir 200 mg 5 times daily, famciclovir 250 mg 3 times daily, or valacyclovir 1 g twice daily. Patients with frequent recurrent episodes (ie, 6 in a 12-month period) should be considered for suppressive therapy, which can

syphilis Syphilis is a systemic treponemal disease characterized clinically by overlapping stages—primary, secondary, early latent, syphilis of unknown duration, and tertiary disease. A primary, painless lesion (ulcer or chancre at the infection site) appears about 3 weeks after exposure. After 4 to 6 weeks, a secondary eruption involving skin and mucous membranes appears (maculopapular rash of palm and soles with lymphadenopathy).1,7 The early latent stage is characterized by seroconversion or unequivocal symptoms of the primary or secondary stages within the previous 12 months.1,7 Syphilis of unknown duration (ie, late latent) is characterized by a positive syphilis serology in the absence of clinical manifestations in the previous 12 months, with no history of previous serologic tests in that same time period.1,7 One third of patients with the disease will exhibit tertiary syphilis signs and symptoms, such as cardiac, neurologic, ophthalmic, and lesions of the skin, bone, and viscera. Latent infections (those lacking clinical symptoms) are detected by serologic testing.1,7 Fetal infection with syphilis occurs with high frequency in untreated early infections of pregnant women and causes abortion, stillbirth, and infant death through preterm delivery of lowbirth-weight infants, or from generalized systemic disease.2,7 A serologic diagnosis is made through 2 types of tests—FTA-ABS (fluorescent antibody absorbed) and TP-PA (Treponema pallidum passive particle agglutination). False-positive serologic tests are associated with medical conditions unrelated to syphilis; therefore, the use of 1 serologic test is insufficient for diagnosis. Dark field microscopy and direct fluorescent antibody tests of lesion exudate or tissue sample are the definitive methods for diagnosing early syphilis.2,7 Adult primary, secondary, and early latent syphilis are treated with benzathine penicillin G 2.4 million units IM in a single dose. Late latent syphilis, latent syphilis of unknown duration, and tertiary syphilis are treated with benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals. Neurosyphilis is treated with aqueous crystalline penicillin G 18 million to 24 million units daily, adminisContinued on page 26

jUNE 2011 l VOLUME 3, NUMBER 3

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CONTINUING EDUCATION

WWW.INFERTILITYREPRONEWS.COM

Diagnosis, treatment, and Prevention of sexually... Continued from page 25 tered as 3 million to 4 million units intravenously every 4 hours or continuous infusion for 10 to 14 days.2,7 Pregnant patients should be desensitized and treated with penicillin. All patients with syphilis should be tested for HIV, and all patients should be examined clinically and serologically 6 months and 12 months after treatment.2,7 human Papillomavirus Human papillomavirus (HPV) infection is one of the most common STDs, with the cost of treatment reaching $1.6 billion annually in the United States. It is estimated that 80% of women will become infected with genital HPV infection by age 50, and that 9.2 million sexually active youth aged 15 to 24 years are currently infected. More than 100 types of HPV infections exist, and at least 30 to 40 types can infect the genital tract.2,8-11 Genital HPV infection types are divided into 2 groups—low risk and high risk. Low-risk types can cause genital warts and benign or low-grade cervical changes that are not associated with cervical cancer. High-risk types can cause low- and high-grade cervical changes that are precursors to cancer of the cervix, vulva, anus, and penis.2,8-11 Most infections are undiagnosed, because they are asymptomatic. Transmission is predominantly associated with viable HPV infection and tissue microtrauma during sexual activity.

Genital warts are usually associated with HPV type 6 or 11.2,8-11 Although rare, genital HPV infection may be transmitted from mother to

baby during delivery, causing respiratory tract warts known as recurrent respiratory papillomatosis.2,8-11 Diagnosis is based on detection of viral nucleic acid or capsid protein.

Several types of tests are available to detect HPV DNA in cervical cells.

Treatment for abnormal Pap smears is based on risk factors and degree of severity of the lesions. Please see the American College of Obstetricians and Gynecologists’ cervical cancer screening guidelines for the management of women with abnormal Pap smears.8,9

Fetal infection with syphilis occurs with high frequency in untreated early infections of pregnant women and causes abortion, stillbirth, and infant death.

Currently, 2 vaccines are available to guard against HPV. A quadrivalent vaccine recombinant (Gardisil) has antigens for HPV types 6, 11, 16, and 18, and a bivalent vaccine recombinant (Cervarix) has antigens for HPV types 16 and 18. Existing data suggest that genital wart treatment may reduce, but will likely not eliminate, HPV infectivity. There is no evidence to support that the presence of genital warts is associated with the development of cervical cancer. Provider-applied treatments are cryotherapy, podophyllin resin 10% to

Table 2 Preventive Measures • Assess patients’ risk and test accordingly • Diagnose

and treat infected patients • Male circumcision • Prophylactic agents in the eyes of newborns • Provide or refer for partner management • Provide risk-reduction counseling • Report STD/HIV and AIDS cases in accordance with statutory requirements • Safer sexual practices Avoiding multiple sexual partners Consistent condom use Female nitrile condoms Mutual monogamy • Talk

to patients about pre-exposure vaccination Reference 2.

25%, trichloroacetic acid, bichloroacetic acid, and laser surgery. Patientapplied regimens are podofilox 0.5% solution and imiquimod 5% cream.2,8-11 Preventive measures Nurses managing women, and especially those treating women who are sexually active or those with multiple partners, should inquire about their and their partners’ sexual activity and provide information regarding the risks for STD transmission and the way to prevent the transmission of infections (Table 2). conclusion It is vitally important that healthcare providers who are involved in women’s

health become more active in the prevention and control of STDs than is currently the case. This can be done effectively through education and counseling, identification of asymptomatic infected persons and symptomatic persons unlikely to seek care, effective diagnosis and treatment of infected persons and their sex partners, and preexposure vaccination of those at risk for vaccine-preventable STDs. ■

references 1. Centers for Disease Control and Prevention. 2009 Sexually transmitted diseases surveillance, trends in sexually transmitted diseases in the United States: 2009 national data for gonorrhea, chlamydia and syphilis.

2010. www.cdc.gov/std/stats09/trends.htm. Accessed May 24, 2011.

2. Workowski KA, Berman S; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1-110.

3. Centers for Disease Control and Prevention.

Trichomoniasis—CDC fact sheet. 2007. www.cdc. gov/std/trichomonas/STDFact-Trichomoniasis.htm.

Accessed May 24, 2011.

4. Centers for Disease Control and Prevention. Selfstudy STD module—vaginitis:trichomoniasis:4-10. http://www2a.cdc.gov/stdtraining/Self-Study/vaginitis/ vaginitis4.asp. Accessed May 24, 2011.

5. Hayman DL, ed. Control of Communicable Disease Module. Washington, DC: American Public Health Association; 2004:100-102.

6. Centers for Disease Control and Prevention. Selfstudy STD module—genital herpes simplex (HSV) infection. http://www2a.cdc.gov/stdtraining/self-study /hsv.asp. Accessed May 24, 2011.

7. Centers for Disease Control and Prevention.

Syphilis—CDC fact sheet. 2008. www.cdc.gov/std/ syphilis/STDFact-Syphilis.htm. Accessed May 24, 2011.

8. Apgar BS, Kittendorf AL, Bettcher CM, et al.

Update on ASCCP consensus guidelines for abnormal cervical screening tests and cervical histology. Am Fam Physician. 2009;80:147-155.

9. ACOG Committee on Practice Bulletins— Gynecology. ACOG Practice Bulletin no 109: cervical cytology screening. Obstet Gynecol. 2009;114:1409-1420.

10. Centers for Disease Control and Prevention.

Genital HPV infection—fact sheet. 2009. www.cdc.gov/ std/HPV/STDFact-HPV.htm. Accessed May 24, 2011.

11. Hatcher RA, Trussell J, Nelson A, et al, eds. Contraceptive Technology. 19th revised edition. New York, NY: Ardent Media; 2007:559-581.

More Support for Mammography in Young Women

By Caroline Helwick

N

ew findings from a 10-year chart review presented at the 2011 American Society of Breast Surgeons meeting support mammography screening in women aged 40 to 49 years—a group that is currently excluded from screening under the 2009 revised guidelines of the US Preventive Services Task Force (USPSTF).

Another study of nearly 47,000 patients indicated that the USPSTF guidelines may have an especially negative impact on nonwhite women.

The revised guidelines encouraged individualized decision-making about mammography starting at age 50 years (see article, page 13).

In the first study, women aged <50 years whose breast cancer was diagnosed by clinical examination had tumors that were 50% larger and 3 times more likely to have lymph node involvement

26

compared with cancers detected by mammography, said Paul S. Dale, MD, Chief, Division of Surgical Oncology, University of Missouri, Columbia.

In addition, the risk for breast cancer recurrence was nearly 6 times greater and survival was significantly lower for women not diagnosed by mammography.

“Breast cancer has a better prognosis when treated before tumors become palpable and identifiable through a physician or self-breast exam,” Dr Dale said. “The study also found that tumors identified through mammography generally had better outcomes after treatment than those found through clinical exams.”

Dr Dale called attention to the widespread objections to the new guidelines, and noted that despite these objections, “few researchers have specifically looked at mammography and its long-

jUNE 2011 l VOLUME 3, NUMBER 3

term impact on outcomes in younger women. This study provides important new information.”

The study included 145 women with breast cancer and showed that mean tumor size for cancer detected by mammography was 20 mm compared with 30

“Tumors identified through mammography generally had better outcomes after treatment than those found through clinical exams.”

—Paul S. Dale, MD

mm with a clinical examination; in addition, lymph node–positive cancer was found in 25% of the women with mammography versus 56% by physical exam-

ination. “Excluding women in this agegroup from routine mammograms will potentially result in late-disease diagnosis and poorer survival rates for women ages 40 to 49,” Dr Dale concluded.

The second study analyzed data from 46,700 women with cancer, of whom 10,566 were aged 40 to 49 years.

Women with small tumors were significantly more likely to be of a minority racial/ethnic group, reported Sharon Lum, MD, Associate Professor of Surgery, Loma Linda University School of Medicine, CA. “By excluding these younger women from mammographic screening, you may be relatively diminishing the benefits of new targeted therapies. While younger women do have lower cancer rates, under the USPSTF guidelines, you miss tremendous opportunities to improve outcomes in specific racial and disease groups,” she said. ■

Pushing Your Limits Current activities at www.COEXM.com include:

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To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s web browser, and select “Download” • Visit the app store for your smartphone

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Clinical News IVF yields Poorer obstetric...

Continued from page 21

Comparison of all SET births (N = 7763) with all births in the general population showed a significantly higher rate of preterm (<28 weeks gestation) births among the IVF-based births. Significantly higher rates of preterm birth (<28 weeks and <37 weeks) and greater rates of LBW and VLBW babies were also seen for IVF singletons (regardless of number of embryos transferred) compared with non-IVF singletons.

For eSET singletons, a significantly higher rate of preterm birth at <37 weeks compared with non-IVF singletons was also observed; non-eSET singletons had significantly higher rates of preterm birth at <28 weeks and birth weight <2500 g.

Benefits of InsulinSensitizing Agents in PCOS Questioned Metformin is the only insulin-sensitizing agent on the market that does not involve major safety concerns for reproductive-aged women; however, new data suggest that its efficacy in treating polycystic ovarian syndrome (PCOS) remains questionable at best (Franks S. Clin Endocrinol [Oxf]. 2011; 74:148-151).

An abundance of evidence exists for the use of metformin to treat the symptoms of PCOS, including menstrual disturbances, infertility, and androgen excess, but precise indications for treatment remain unclear.

Metformin provides a small improvement for ovulation and menstrual frequency, but this may not be independent of weight loss. The medication has shown no benefit in pregnancy outcomes, except in cases of gestational diabetes, and has no proven benefit for treating hirsutism, acne, or alopecia.

In infertility, metformin increases ovulation and pregnancy rates when used in combination with clomiphene, but it does not increase the rate of live births. In super-ovulation procedures for in vitro fertilization and intracytoplasmic sperm injection, metformin may reduce the rate of ovarian hyperstimulation syndrome.

Metformin appears to benefit the endocrine and metabolic features of PCOS and may help to thwart its progression but the evidence is insufficient to reach a conclusion. Impaired glucose tolerance may be the only condition indicated for metformin in the treatment of PCOS.

FDA Approves First Qualified Health Claim in Infant Nutrition The FDA granted its first-ever qualified health claim for an infant nutri-

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tion product based on data suggesting that Gerber Good Start milk-based formulas may reduce the risk for atopic dermatitis in infants.

“For healthy infants who are not exclusively breastfed and who have a family history of allergy, feeding a 100% whey protein partially hydrolyzed infant formula from birth up to 4 months of age instead of a formula containing intact cow’s milk pro-

teins may reduce the risk of developing atopic dermatitis throughout the first year of life,” the FDA stated, adding that a lack of evidence on the relationship between 100% whey protein partially hydrolyzed infant formulas and atopic dermatitis makes the risk reduction uncertain.

Several pediatric and allergy organizations, however, have confirmed a positive association between such

infant formulas and a reduction in atopic dermatitis risk in infants, including the American Academy of Pediatrics, the American Academy of Allergy Asthma and Immunology, and the National Institute of Allergy and Infectious Diseases.

The FDA label claims that partially hydrolyzed formulas should not be fed to infants who are allergic to milk or have symptoms of milk allergy. ■

Women’s Health

Women and Heart Disease Across the Lifespan, Part 3 Recognizing Risk in Your Postmenopausal Patients

By Caroline Helwick

This is the last article in a 3-part series, based on a presentation at last year’s Association of Women’s Health, Obstetric and Neonatal Nurses meeting.

A

fter menopause (natural or surgical), women lose their protection against heart disease.

Before women reach this vulnerable period, they should already have cardiovascular risk factors under control, according to Carolyn Strimike, RN, MSN, CCRN, APN-C, Women’s Heart Center, St. Joseph’s Regional Medical Center, Paterson, NJ.

heart Failure: A major Problem Heart failure is a major cause of morbidity and mortality in older women, especially as the population ages, prevalence of hypertension increases, and more women survive myocardial infarctions (MIs), the most common cause; yet few data exist on heart failure in women, and there are no guidelines specific to its management in women.

Fewer than 15% of women with heart failure survive more than 8 years postdiagnosis, and 33% die within 1 year of initial hospitalization.

Although symptoms are similar between women and men, women have more symptoms, including dyspnea, tachypnea, tachycardia, chest pain, fatigue, confusion, pulmonary edema, and peripheral edema, and women are more likely to develop atrial fibrillation than men, Ms Strimike said.

The consequences of developing atrial fibrillation are clear. It renders women 4 times more likely to have a stroke and 30% more likely to die prematurely. It is associated with decreased quality of life and more adverse effects from medications. Although catheter ablation can be a good treatment, women are referred less frequently for this procedure.

jUNE 2011 l VOLUME 3, NUMBER 3

Major risk factors in women, in addition to previous MI, are advanced age and left ventricular hypertrophy caused by hypertension. Electrocardiography can detect this and should be done annually, according to Ms Strimike.

Other major causes are cardiomegaly and coronary artery disease (CAD), the most frequent cause in men. Additional risk factors include diabetes (especially

“Stress may be the straw that breaks the camel’s back. It is caused by an acute release of catecholamines that attack the heart muscle, and treatment is directed toward reversing this.”

—Carolyn Strimike, RN, MSN, CCRN, APN-C

in young women), valve disease, increased body mass index, malnutrition, doxorubicin exposure, “broken heart syndrome,” and peripartum cardiomyopathy.

“Women are more likely to develop heart failure after an MI, even with a higher ejection fraction, especially diabetic women,” she noted. A preserved ejection fraction is seen in 1 of every 2 women with heart failure. “broken heart syndrome” Is real One really can die of a broken heart, especially postmenopausal women, according to Ms Strimike, who described takotsubo cardiomyopathy, or broken heart syndrome, as a condition marked by abrupt-onset chest pain after psychological stress, mimicking MI. Other signs are ST-T wave changes

Table Easy, Heart-Healthy Actions for Your Patients • Limit caffeinated beverages to 3 per day to avoid palpitations • Consider having 1 alcoholic beverage per day but weigh risks/benefits • Exercise 30 minutes daily, 5-7 days per week (can be divided) • Eat 7-9 small servings of fruits and vegetables daily • Take plant sterols for lowering lipids; consider red yeast rice, but be sure of the product’s quality • Take omega-3 fatty acids (fish oil) to lower cardiovascular risk • Consider an ultrasound scan of the carotid arteries every 3 years to evaluate arterial health • Consume adequate calcium daily, but limit total amount (diet plus supplements) to 1200-1500 mg

and transient left ventricular hypokinesia without obstructive CAD. “Stress may be the straw that breaks the camel’s back,” she said. “It is caused by an acute release of catecholamines that attack the heart muscle, and treatment is directed toward reversing this.” sudden cardiac Death Approximately 120,000 women die of sudden cardiac death in the United States annually. Although sudden cardiac death has declined among men, it has increased among women. This is not a “massive” heart attack but generally death caused by arrhythmia. In survivors, CAD is common in men (80%) but less so in women (45%).

Only 35% of all eligible patients receive a potentially life-saving implantable cardiac defibrillator. “And who is getting these? Men,” she said.

“Women are 65% less likely to receive this device than men.” ■

Nutrition

Total Matrix of a Food More Important than Saturated Fat in Heart Disease Risk

By Jessica A. Smith

A

lthough intake of saturated fat has been named one of the culprits leading to coronary heart disease (CHD) in current dietary recommendations, recent evidence from Danish scientists shows that reducing CHD risk is more related to the total makeup of a food than its saturated fat content (Astrup A, et al. Am J Clin Nutr.

2011;93:684-688).

â&#x20AC;&#x153;There is increasing evidence to support that the total matrix of a food is more important than just its fatty acid content when predicting the effect of a food on CHD risk.â&#x20AC;?

is difficult to identify specific types of foods that will help to reduce CHD risk, epidemiologic studies have demonstrated a lowered risk for cardiovascular disease from reduced intake of full-fat dairy

products and fatty red meats, along with higher intake of polyunsaturated fatty acids from vegetable fats.

In addition, risk is reduced by using nonhydrogenated vegetable oils instead of consuming animal fats. Essentially, an overall healthy diet is largely plant-

Help her look forward to lighter days /<67('$ 7KH QRQ KRUPRQDO ILUVW OLQH WKHUDS\ IRU ZRPHQ ZLWK F\FOLF KHDY\ PHQVWUXDO EOHHGLQJ â&#x20AC;˘ Significant reduction in menstrual blood loss (MBL) by 38% (vs 12% for placebo) in a 6-cycle study â&#x20AC;˘ Consistent reduction in MBL across all cycles studied â&#x20AC;&#x201D;Reduced MBL as early as the first menstrual cycle â&#x20AC;˘ Dosed only during menstruation, for up to 5 days

â&#x20AC;&#x201D;Arne Astrup, MD, PhD

â&#x20AC;&#x153;There is increasing evidence to support that the total matrix of a food is more important than just its fatty acid content when predicting the effect of a food on CHD risk,â&#x20AC;? wrote lead investigator Arne Astrup, MD, PhD, head of the Department of Human Nutrition, University of Copenhagen, Denmark, and colleagues.

According to the authors, although previous studies show that the risk for CHD is reduced by replacing saturated fatty acids with polyunsaturated fatty acids, the issue is more complex than that. For example, some food sources of saturated fat may contain significant amounts of protein, calcium, and other nutrients that have an effect on CHD risk; therefore, it is not sufficient to evaluate a foodâ&#x20AC;&#x2122;s effect on CHD by its saturated fat content alone but rather by its entire nutrient combination.

Substituting carbohydrates for saturated fatty acids has not been proved as a way to reduce CHD risk, although unrefined carbohydrates with a low glycemic index may be beneficial. In attempts to avoid saturated fat, people may consume trans-saturated fats or highly processed, refined carbohydrates, which could impart little positive effect, or even an adverse effect, on their CHD risk.

Assessing CHD risk by examining the effect of diet on a single biomarker does not provide sufficient evidence to make a substantive evaluation, the researchers stated. Instead, â&#x20AC;&#x153;the combination of multiple biomarkers and the use of clinical end points could help substantiate the effects on CHD.â&#x20AC;?

The researchers note that although it

based, with minimal saturated fat; small-to-modest amounts of low-fat dairy products and lean meats can also be included. â&#x20AC;&#x153;A valuable way to communicate the message is to describe the broad dietary pattern that reduces [CHD] risk,â&#x20AC;? the researchers wrote. â&#x2013;

LYSTEDATM (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 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.

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 beneďŹ t 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 eďŹ&#x20AC;ects 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 (â&#x2030;Ľ5%, 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.

Please see Brief Summary of Prescribing Information on adjacent page.

Š2011 Ferring Pharmaceuticals Inc.

Lysteda.com

01/11

LYS-04737B

Help her look forward to lighter days.

jUNE 2011 l VOLUME 3, NUMBER 3

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AUA Highlights

Trigger Point Wand May Be Effective for Refractory Pelvic Pain

By Jill Stein

A

curved, plastic trigger point wand can help to relieve the pelvic muscle tenderness that is often reported by patients with urologic chronic pelvic pain syndrome (UCPPS), researchers reported at the 2011 American Urological Association meeting.

In this study, patients whose pain was refractory to conventional therapies had a dramatic improvement when they used the wand to self-treat painful internal trigger points in the pelvic floor. The wand is placed transrectally in men and either transrectally or transvaginally in women.

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

©201 Ferring Pharmaceuticals Inc.

30

jUNE 2011 l VOLUME 3, NUMBER 3

1/11

“The device we used was designed to serve as an extended finger to locate and release painful internal myofascial trigger points that are often unresponsive to standard pharmacologic or surgical therapy or physical therapy,” said Rodney U. Anderson, MD, Professor of

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 (mg/m2). 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

“Most of our patients were able to achieve a reduction or abatement of their pelvic pain after supervised instruction on how to use the wand.”

—Rodney U. Anderson, MD

Urology, Stanford University School of Medicine, Palo Alto. “Most of our patients were able to achieve a reduction or abatement of their pelvic pain after supervised instruction on how to use the wand, and there were no reports of serious adverse events.”

The wand is intended for patients with UCPPS, approximately two thirds of whom complain of pain associated with palpation of internal and external pelvic muscles, Dr Anderson noted. The pain frequently emanates from myofascial trigger points, which are tender on palpation and reproduce the specific anatomic location of pain described by the patient. Trigger points are defined as hyperirritable areas in skeletal muscles associated with palpable nodules in taut bands of muscle fiber.

All participants had failed traditional treatments for muscle-based pelvic pain.

After completing the 6-day immersion program, which also included physiotherapy and progressive relaxation training, patients were advised to continue wand massage at home 3 or 4 times weekly in 5- to 10-minute sessions to release the pelvic floor from active trigger points.

At the 6-month follow-up, 106 of 111 patients reported that the wand was very effective (n = 44) or moderately effective (n = 62) in alleviating pain. Approximately 40% of these patients had a ≥50% reduction in pelvic muscle sensitivity.

“The results show that proper training with professional supervision allows patients with refractory UCPPS to effectively and safely perform their own internal trigger point release using an internal therapeutic wand,” Dr Anderson said.

Because the study population was predominantly male, it is not possible to comment conclusively at this time about the benefit of the device in women, Dr Anderson added. He also noted that the study did not use standardized pain symptom scores, but added that it has been widely established that pain sensitivity “is an issue of individual patient perception that can be adequately assessed by self-rating.” ■

AUA Highlights

Silodosin Helps Men with Debilitating Pelvic Pain Condition

By Jill Stein

T

he highly selective alpha-blocker silodosin may reduce symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), investigators announced at the 2011 meeting of the American Urological Association.

The drug is approved for the treatment of benign prostatic hyperplasia (BPH) associated with lower urinary tract symptoms (LUTS).

New data from a phase 2 study show that once-daily silodosin 4 mg was associated with a modest but significant symptomatic improvement in men with moderate-to-severe abacterial CP/CPPS who had not been previously treated with an alpha-blocker. â&#x20AC;&#x153;Successful management of CP/CPPS is a difficult challenge, because of a lack of effective evidence-based, disease-specific treatment options,â&#x20AC;? said J. Curtis Nickel, MD, Professor of Urology, Queenâ&#x20AC;&#x2122;s University, and urologist at Kingston General Hospital, Canada.

â&#x20AC;&#x153;Successful management of CP/CPPS is a difficult challenge, because of a lack of effective evidencebased, disease-specific treatment options.â&#x20AC;? â&#x20AC;&#x201D;J. Curtis Nickel, MD

Prostatitis-like symptoms are fairly common in adult men, and at least 90% of all cases of chronic prostatitis are attributable to abacterial CP/CPPS, Dr Nickel pointed out. CP/CPPS, which is characterized by urogenital pain and variable LUTS in the absence of urinary tract infection, can be debilitating and has been found to worsen disease-specific and general quality of life.

Alpha-blockers with proven efficacy in BPH-associated LUTS are often used to treat CP/CPPS, but studies have provided inconsistent results.

A total of 151 men were randomized to daily treatment with silodosin 4 mg, silodosin 8 mg, or placebo for 12 weeks. The study included men aged â&#x2030;Ľ18 years with a total National Institutes of HealthChronic Prostatitis Symptom Index (NIH-CPSI) score â&#x2030;Ľ15 and an NIHCPSI pain score â&#x2030;Ľ8. All patients had complained of pain in the pelvic region for â&#x2030;Ľ3 months.

Silodosin 4 mg significantly decreased the total NIH-CPSI score versus placebo.

The 4-mg dose also resulted in significant reductions in NIH-CPSI total symptom scores and quality-of-life impact scores, and significant increases in physical component scores on the Medical Outcomes 12-Item Short Form Health Survey, which is an established tool for assessing functional health and well-being.

Overall, 56% of patients receiving silodosin 4 mg reported moderate or marked global improvement versus 29% of placebo-receiving patients.

The 8-mg daily silodosin dose provided no added benefit. Silodosin 4 mg was well tolerated. The most common adverse event was retrograde ejaculation.

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jUNE 2011 l VOLUME 3, NUMBER 3

31

Because she counts on you to know...

Only works with one daily dose It’s a fact. CRINONE is the only once-daily vaginal progesterone gel approved for ART through 12 weeks of pregnancy.1 The vaginal insert required three daily applications to achieve similar efficacy rates.2* When she asks about progesterone, give her the facts.

The only *Results based on a multicenter, randomized, open-label (assessor-blinded), non-inferiority study in 1,211 women aged 18 to 42 undergoing IVF to compare pregnancy rates using Endometrin® 100 mg BID, Endometrin® 100 mg TID, or CRINONE once daily.

CRINONE 8% (progesterone gel) is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (ART) treatment for infertile women with progesterone deficiency.

Important Safety Information The most common side effects of CRINONE (progesterone gel) 8% include breast enlargement, constipation, somnolence, nausea, headache, and perineal pain. CRINONE 8% is contraindicated in patients with active, or a history of, thrombophlebitis or thromboembolic disorders, patients who have known sensitivity to CRINONE 8%, missed abortion, undiagnosed vaginal bleeding, liver dysfunction or disease, and known or suspected malignancy of the breast or genital organs. Should any of the earliest manifestations of thrombotic disorders occur, the drug should be discontinued immediately. No evidence is available to show that progesterone and progestins are effective in preventing miscarriage in women with a history of recurrent spontaneous pregnancy losses. The pretreatment physical exam should include special reference to breast and pelvic organs as well as a Papanicolaou smear. Nonfunctional causes of breakthrough bleeding should be considered, and for undiagnosed vaginal bleeding, diagnostic measures should be undertaken. Special care should be taken with patients who have conditions that may be influenced by fluid retention, those who have a history of psychic depression, and those with diabetes.

Please see brief summary of full prescribing information on the adjacent page.

Toll-free support line: 1-888-PRO-GEL8 (1-888-776-4358) References: 1. CRINONE® prescribing information. Morristown, NJ: Watson Pharmaceuticals, Inc. June 2010. 2. Doody KJ, Schnell VL, Foulk RA, et al.

Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril. 2009;91:1012-1017. © 2010, Watson Laboratories, Inc.

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