Infertility & Reproductive News

AuguSt 2011

WWW.INFertIlItyreProNeWS.Com

Vol 3, No 4

AWHONN HIGHLIGHTS

CLINIC PROFILE

Combining High-tech research Keynote Speaker urges Nurses to expand their and Clinical Practice: leadership role Pacific Fertility Center

By Caroline Helwick

Interview with Carl M. Herbert, MD Fertility Specialist, Pacific Fertility Center, San Francisco, CA

Denver, CO—Beverly Malone, RN, PhD, FAAN, Chief Executive Officer of the National League for Nursing, delivered the keynote address at the 2011 Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN) annual convention, calling on nurses to help implement the recommendations issued earlier this year by the Institute of Medicine (IOM), urging all nursing professionals to return to nursing’s “core values.”

Dr Malone shared her “Reflections on

Challenges to the State of Nursing.” She has served as a surgical staff nurse, clinical nurse specialist, Director of Nursing, and Professor and Dean, North Carolina Agricultural and Technical State University School of Nursing, Greensboro.

President Bill Clinton appointed her to the US Delegation to the World Health Assembly, and she also participated in his roundtable discussion on the Patients’ Bill of Rights.

Dr Malone spoke about the nursing experience with tremendous depth and Continued on page 16

ADA HIGHLIGHTS

From left, top to bottom: Joe Conaghan, PhD, HCLD; Carl M. Herbert, MD; Eldon Schriock, MD; Philip Chenette, MD; Isabelle Ryan, MD; and Carolyn Givens, MD

T

he award-winning physicians and their entire team at Pacific Fertility Center offer full-service care to women and men throughout the San Francisco Bay area, while pursuing scientific advances in fertility treatment. In a recent interview, Carl

M. Herbert, MD, spotlighted some of the key features of the center.

What was the impetus to launch the clinic?

Our group of 5 physicians began Pacific Fertility Center in 1999. It was Continued on page 5

New Federal Standards to Cover Preventive Services for Women, Including Birth Control

By Caroline Helwick

T

he Obama administration followed the recommendations issued in July 2011 by the Institute of Medicine (IOM), paving the way for women to receive better preventive care by adding insurance coverage for preventive services, including birth control.

The IOM panel recommended that health plans will cover 8 preventive services for women at no cost to consumers under the Patient Protection and Affordable Care Act (ACA) of 2010.

The new healthcare bill requires health plans to cover services currently recomContinued on page 23

gestational Diabetes, Impaired glucose during Pregnancy a risk for Developing type 2 Diabetes

By Alice Goodman

San Diego, CA—Women with gestational diabetes are at very high risk for developing type 2 diabetes, and the risk is greater in black women than in white women, according to a study presented at the 2011 American Diabetes Association (ADA) annual meeting. A higher degree of glucose elevation was associated with increased risk, and impaired fasting glucose level during pregnancy was the stronger predictor for incident diabetes.

Continued on page 14

INS IDE 27 ASK THE EXPERT . . . . . . . . . . . . . . . . . . 6 COMPLIMENTARY CE

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

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Fetal cardiac activity in pregnancy CLINICAL NEWS

The Publicationof of The Official Offical Publication

“The risk of developing type 2 diabetes was decreased over time after delivery, suggesting that interventions among women with a history of gestational diabetes should be introduced as early as possible postpartum to be costeffective,” said investigator Yujie Wang, MD, Pennington Biomedical Research Center, Baton Rouge, LA. It is generally accepted that a history of gestational diabetes predicts incident

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High-dose fluconazole in early pregnancy linked to birth defects ACOG now recommends starting annual mammography at 40 INFERTILITY UPDATES

10

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Genetic mutation in sperm Preoperative chemotherapy precludes fertility preservation

CORRECTIONS

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WOMEN’S HEALTH

Cesarean rate climbs despite safety of vaginal birth NUTRITION . . . . . . . . . . . . . . . . . . . . . .

High-dose vitamin E relieves dysmenorrhea

24

MEETING HIGHLIGHTS

ADA Annual Meeting . . . . . . . . . . . .14 AWHONN Annual Conference . .15 ACOG Annual Meeting . . . . . . . . . 25

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

Rx only

BRIEF SUMMARY For full prescribing information, see package insert.

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

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

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

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

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

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

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

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

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

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

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

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

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

Drug Interactions No drug interactions have been assessed with Crinone.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Each applicator is wrapped and sealed in a foil overwrap.

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

Rx only

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

In This Issue WWW.INFERTILITYREPRONEWS.COM PUBLISHING STAFF

Publisher Jack Iannaccone jack@infertilitynurse.org 732-992-1537 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 Director, Client Services Russell Hennessy russell@novellushc.com 732-992-1888 Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Editorial Contact: Telephone: 732-992-1892 Fax: 732-656-7938 MISSION STATEMENT Infertility & Reproductive News is the official publication of the American Academy of OB/GYN and Infertility Nurses. Infertility & Reproductive News provides practical, authoritative, cutting-edge information on the physiologic, medical, and psychological aspects of women’s health, focusing on the role of the infertility practitioner, including nurses, MDs, PhDs, NPs, and PAs, in patient care. Our journal offers a forum for nurses, nurse practitioners, physician assistants, physicians, administrators, researchers, and all others involved in infertility and women’s health to discuss the entire scope of current and emerging diagnostic and therapeutic options, as well as counseling and patient followup for women throughout their reproductive years and beyond. Infertility & Reproductive News promotes peer-to-peer collaboration among all infertility professionals toward the advancement of integrated services for optimal delivery of patient care and offers continuing education for all clinicians involved in these interrelated fields of women’s reproduction.

Infertility & Reproductive News, 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.

Infertility & Reproductive News 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 Infertility & Reproductive News do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in Infertility & Reproductive News 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.

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CLINICAL NEWS Prenatal SSRI exposure may relate to autism

AWHONN ANNUAL CONFERENCE Refrain from social networking on the job

National group addresses impact of reproductive disorders on overall health

Smoking in pregnancy: it’s never too late to quit and improve outcomes

CDC updates guidelines for postpartum hormonal contraceptives

A new model for advanced practice nursing More…

More…

ADA ANNUAL MEETING Preexisting diabetes increases risk for abnormalities in the offspring

ACOG ANNUAL MEETING Novel scanning device for rapid detection of cervical cancer

Neuroprotection of preterm infants

Breastfeeding may protect against development of type 2 diabetes

More…

More…

COMPLIMENTARY CE Stem cells overview: the growing importance of fetal tissue

Clinic Profile

Combining High-Tech Research... the amalgamation of 2 groups of infertility physicians—one group from the University of California, San Francisco, and 2 physicians from private practice.

The goal was to bring together a large group of reproductive endocrinologists doing high-technology infertility work to provide a clinic that would have a high volume and give us an opportunity to do research and have quality control, while implementing new ideas.

Coming from academic medicine, we all brought an academic approach to infertility, but we wanted to do it in the context of a private practice. Because we have the background—we have all received funding, and we have all done academic research—we have been able to continue to do research within our center, while still having a very active clinical program, which provides us the best of the clinical world and clinical research projects.

What type of infertility research do you do?

We have just finished new research looking at a new form of follicle-stimulating hormone, which involves the use of 1 shot that lasts 5 to 7 days. We are just beginning a new research protocol looking at a particular microscope system with a computer attached that does time-lapsed photography of embryos as they grow.

This is a very new technology called the Eeva System, created by Auxogyn.

This technology takes very low-light photographs of individual embryos in culture and assesses their rate of cleavage while these embryos grow from a single cell or a fertilized egg to a day 3, 8-cell embryo. The rate at which the embryos cleave from day 1 to day 3, and the synchrony with which they cleave, predicts their ability to become a viable

blastocyst at day 5. Current research is looking at the degree of the genetic normality of these embryos as well. We are one of the first programs to have this microscope system put into our incubators, and we are currently enrolling patients in that research project.

The other critically important research project for in vitro fertilization (IVF) is documenting the genetic makeup of the embryos. We work fairly closely with a company called Gene Security Network, and we will be enrolling patients in their new program that does a biopsy of the embryos on day 3 to look at their genetic makeup. We hope that by selecting and transferring those that have the correct genetic makeup, we will produce a higher pregnancy rate and perhaps reduce the number of embryos needed for transfer.

With a similar goal in mind, we have been part of a research project based at Michigan State University, which involves biopsying and evaluating oocyte cumulus cells attempting to predict egg and embryo quality. Unlike at a university setting, we are not attempting to perform bench research, and we are not rubbing shoulders with the biochemistry or the genetics department at a basic science level. However, being immersed in clinical research, we are taking bench research to the next step to apply it to the clinical world of infertility. We keep a high volume of patients so that we are able to find answers to clinical issues in a reasonably short period of time.

Have you published any of this research?

Yes, our clinic physicians and laboratory staff appear as first authors in some, and as secondary contributors in other papers. We also participate in profession-

Continued from page 1

al group meetings, presenting oral papers, postgraduate courses, and poster exhibits.

At the recent 2011 meeting of the Pacific Coast Reproductive Society, we received a prize for our paper on the vitrification of blastocyst stage embryos.

We have instituted a technique we adopted of not only vitrifying embryos but also collapsing them.

Collapsing means that just before we freeze these embryos to store them, we collapse the blastocele cavity to remove as much fluid as possible. This diminishes the risk for ice-crystal formation and damage to the stored embryo. We presented our findings about these embryos and the successful increase in pregnancy rates that resulted by doing so. This study will be published at some point.

Are there other unique features of your clinic?

What separates us, I believe, is quality. We do everything related to infertility, and we do it well. If a patient comes to our clinic, she can freeze her eggs or her embryos. We treat single women, single men, and gay and lesbian couples.

We do genetic testing, as well as fertility preservation.

We do about 850 IVF cycles annually, of which 180 involve donors. We have one of the largest donor-egg programs in the United States. We have our own egg-donor agency, which facilitates patients’ ability to choose egg donors safely and rapidly. However, patients do not have to use our agency; they can use any reputable egg-donor agency that fulfills our criteria for egg donors to be part of our program. Our agency has between 60 and 80 donors at any one time. We are in the process of creating an egg bank so that instead of paying for an entire egg-donor cycle, patients can potentially contract with us to create Continued on page 9

june 2011 I VOLUME 3, NUMBER 3

5

Ask the Expert

Fetal Cardiac Activity in Early Pregnancy Question: I am 5 weeks pregnant and have undergone ultrasound. Although the fetal pole can be seen, there is still no cardiac activity. Is it too soon to know if it is a normal pregnancy? Should I wait another week to get cardiac activity?

Answer: By Debra Moynihan, WHNP-BC, MSN, Co-Editor-in-Chief Early transvaginal ultrasound is one of the most reliable tools that we have today to determine the gestational age of the fetus. By 5 weeks of pregnancy, a gestational sac can be seen in most cases. This aids the physician in ruling out ectopic pregnancy when in question.

Next, a yolk sac should be visible by approximately 5.5 to 6 weeks of gestation. The yolk sac is a membranous sac that is

attached to the embryo that provides early nourishment. It is a critical landmark in the diagnosis of pregnancy. Immediately after the appearance of the yolk sac, a fetal pole should appear.

This is the first visible sign of a developing embryo.

A fetal heart is visible by 6 weeks of gestation in the majority of cases, and then is clearly seen by 7 weeks. If the embryo measures <5 mm at 5 to 6 weeks of gestation, it may be too soon to visualize a fetal heart, and the ultrasound should be repeated in 1 week to confirm viability.

The fetal heart rate at 6 weeks is generally between 90 and 110 beats per minute. By 9 weeks of gestation, it increases to 140 to 170 beats per minute. After a fetal heartbeat has been established, the chances of the pregnancy continuing are very good. ■

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CO-EDITOR-IN-CHIEF

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

CO-EDITOR-IN-CHIEF

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

6

AUGUST 2011 l VOLUME 3, NUMBER 4

Clinical News long-term, high-Dose Fluconazole in early Pregnancy Associated with Birth Defects The US Food and Drug Administration (FDA) warned healthcare providers that the use of long-term, high-dose (400-800 mg/day) fluconazole (Diflucan) during the first trimester of pregnancy carries a risk for a â&#x20AC;&#x153;rare and distinctâ&#x20AC;? set of birth defects. This antifungal drug is still considered safe in a single low dose (150 mg) for the treatment of vaginal yeast infections. The publication of several case reports of congenital anomalies in infants has led the FDA to change the drugâ&#x20AC;&#x2122;s pregnancy category from category C to category D.

ning at age 40 rather than age 50 (Obstet Gynecol. 2011;118:372-382). The reasons cited include the high incidence of breast cancer, the potential for reduced breast cancer deaths for women aged 40 to 49 years, and the short period in that age-group from the time the small tumor is detected with mammography and the point at which it has grown large enough to become symptomatic.

That period is shortest in women aged 40 to 49 years.

The 5-year survival rate is 98% in women whose tumors are detected in the earliest stage. Annual mammography can increase the rate of early diagnosis of breast cancer in women in that age-group, which should lead to reducing the overall death toll from this disease.

ACOGâ&#x20AC;&#x2122;s previous guidelines recommended mammography screening either annually or every 2 years for women aged â&#x2030;Ľ40 years, with annual

ACog Now recommends Starting Annual mammography at Age 40 The American College of Obstetricians and Gynecologists (ACOG) has updated its mammography guidelines to recommend annual screening begin-

New Drug regimens Cut mother-to-Child hIV transmission A new National Institutes of Health (NIH) study has shown conclusively that adding 1 or 2 drugs to zidovudine Continued on page 8

Help her look forward to lighter days

Prenatal SSrI exposure may Be linked to Autism Results of a new study may shed some light on the ongoing debate related to the causes of autism. This new study shows a possible link between the use of some antidepressants during pregnancy and the risk for autism in the offspring.

According to this study, the offspring of women who receive selective serotonin reuptake inhibitors (SSRIs) during pregnancy may be at increased risk for autism (Croen LA, et al. Arch Gen Psychiatry.

2011 July 4. Epub ahead of print).

For this population-based, case-control study, researchers compared the medical records of 298 children with autism spectrum disorders, and their mothers, and 1507 randomly selected children and their mothers (control group) from the Kaiser Permanente Medical Care Program in Northern California.

Among the children with autism, 20 (6.7%) were prenatally exposed to antidepressants. In the control group, 50 (3.3%) had been exposed to antidepressants in utero. The use of SSRIs was associated with a 2-fold increased risk for autism in the offspring of mothers who received SSRIs during the 1 year before giving birth. The strongest effect on autism risk in the offspring was related to maternal SSRI treatment during the first trimester of pregnancy.

The investigators noted that further research is needed to confirm these findings, and that clinicians must balance the possible SSRI exposure risk with the risks that may come with untreated mental health disorders, including during pregnancy.

screening starting at age 50. The recommendations for clinical breast examination remain the same.

/<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

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.

AUGUST 2011 l VOLUME 3, NUMBER 4

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Clinical News New Drug regimens...

Continued from page 7

(Retrovir) reduces mother-to-child HIV transmission (www.nih.gov/news/ health/mar2011/nichd-02.htm).

“Our results showed conclusively that the 2 and 3 drug regimens are superior to the standard treatment with zidovudine,” said lead investigator Karin Nielson-Saines, MD, Clinical Professor of Pediatrics, David Geffen School of

Medicine, University of California.

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.

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.

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This NIH study evaluated 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 rates were reduced by >50% with the 2- and 3- drug regimens: 4.9% with zidovudine alone; 2.2% with zidovudine plus nevirapine;

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

and 2.5% with zidovudine, nevirapine, and nelfinavir.

National group examines Impact of reproductive Disorders on Fertility and overall health “It is clear that reproduction affects health, and health affects reproduction,” said Kurt T. Barnhart, MD, MSCE, Professor, Department of Obstetrics and Gynecology, University of Pennsylvania, during a plenary session that opened a series of vision workshops by the National Institute of Child Health and Human Development (NICHD), a division of the National Institutes of Health, aimed at elucidating the interrelation between reproductive disorders and overall health (Barnhart KT. Fertil Steril.

2011;95:2200-2203).

Through a series of vision workshops, the NICHD has set a long-term research agenda that seeks to move beyond the scope of traditional research on disciplinary boundaries. The NICHD sought to explain the interrelation within the various aspects of a woman’s reproductive lifespan and its impact of reproduction. “We need an understanding of the clinical processes, the time course, the natural history, and disruptors of these processes,” said Dr Barnhart.

Titled “Epidemiology of male and female reproductive disorders and impact on fertility regulation and population growth,” Dr Barnhart’s discussion served as the launching forum for the 2 days of workshops, which assessed how the reproductive changes during a woman’s lifetime may affect overall health, and how overall health may affect reproduction; specifically, how a woman’s health and wellness may affect her desire for reproduction, fertility regulation, and reproductive behavior.

CDC updates guidelines for Postpartum hormonal Contraceptives New guidelines from the Centers for Disease Control and Prevention (CDC) place further limitations on the use of combined hormonal contraceptives during the postpartum period for women who are not breastfeeding (MMWR Morb Mortal Wkly Rep. 2011; 60:878-883).

According to the new guidelines, women should not use combined hormonal contraceptives—including combined oral contraceptives, combined hormonal patch, and combined vaginal ring—during the first 21 days postpartum, because of the high risk for venous thromboembolism (VTE). In addition, from 21 to 42 days postpartum, women Continued on page 17

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AUGUST 2011 l VOLUME 3, NUMBER 4

Clinic Profile

Combining high-tech research and Clinical... embryos from a limited number of eggs for less cost. We are hopeful that this option will be available to our patients in the very near future.

Indeed, if we are anything, we are everything. Anything important that a patient would need done, we do well here, and generally with reasonable frequency. It is important that every program we offer has high quality. We do not want to have a good fresh cycle and a terrible frozen cycle, so we have created an embryo-freezing program that is as good as our fresh embryo program in most cases.

We probably do more single-embryo transfers (SETs) than the majority of fertility centers. We are very keen on pushing SETs in as many situations as we can to try to avoid multiple gestations. This requires excellence in fresh and in frozen embryo transfers to ensure maintenance of high pregnancy rates.

When would you transfer more than 2 embryos?

In an older woman, the embryos are not going to be as viable. In a woman aged 42 to 44 years, if we do not transfer more than 2 embryos, we are not going to get her pregnant very often.

Defining women with decreased ovarian reserve is not always so simple.

It is not just about chronologic age, but it also depends on the number and quality of residual eggs and the quality of the resultant embryos. Both the biological age and the individual situation

What is your approach to SET? We are strong advocates of SET, and we have been practicing SET for the past 3 or 4 years, which enabled us to show that transferring a single embryo in a program where we can grow excellent embryos is the preferable way to do most implantations.

Some programs report an 80% pregnancy rate with their egg-donor program, but the mean number of embryos transferred per cycle is frequently 2 or more, and the twin rate could be 50% or 60%, and we can do that. Similarly, we have found that with our blastocyst transfers, if we transfer 2 embryos in our egg-donor population, the twin rate is between 40% and 50%.

We get between a 60% and 65% pregnancy rate with SET, and we get about a 75% pregnancy rate with 2 embryos transferred. We only have a 2% twin rate with SET, and those are obviously embryos that have split, but we get a 40% to 50% twin rate when we transfer 2 embryos. By transferring 2 embryos, we are not gaining very much relative to our overall pregnancy rate, but we are “gaining” a huge number of risk factors relative to the twin rate.

In addition, we try to educate our patients as well as our referring physicians, because we all strongly believe in this approach. We explain to our patients what the statistics are, and why we are advocates for SET. Some patients say that they understand the risks, but they still want twins.

We tell them that it is ultimately their choice—we will transfer 1 or 2 embryos, but we will not transfer 3 embryos. This is in the donor program, or in young women aged about ≤32 years.

Carl M. Herbert, MD

of the woman have to be considered, because even if a woman has what looks like good ovarian reserve at age 43, the number of good embryos is still going to be low.

A woman may be aged 43 years and still have a lot of eggs, but those eggs are still 43 years old, and the percentage of those with good quality is diminished.

When we transfer embryos into 43- or 44-year-old women and the embryos are from their own eggs, it is quite common to put back 3 or 4 embryos to ensure success. Similarly, we cannot just assume that everything is fine because a woman is 32 years old; we must consider her ovarian reserve.

We have 32-year-old women who are almost going through menopause, and their embryos are also not particularly good. This requires a constant assessment of individuals to determine the best way to help them to get pregnant.

It is not as simple as saying that one parameter tells you everything.

How are the responsibilities between nurses and physicians being shared?

We try to provide an individual physician type of care, so that patients know that there is a person whom they can call and talk to or be involved with on a direct basis, who helps them to make decisions without it being a shifting field. Each of our physicians has his/her own patients within our clinic, although patients can change their pri-

mary doctor at any time. We feel that it is better for the patients to identify with the individual physicians and not just attend a clinic.

The doctors here do our own ultrasounds and daily monitoring, so we can see our patients directly and talk to them each visit to tell them the next step.

Some clinics have an ultrasonographer do the ultrasounds, someone else draws blood, and at the end of the day a call doctor will get the data together and contact the patient. We feel that the one-on-one patient care that comes with the physician doing the monitoring is important to patients. We are looking them in the eye and telling them where things are going and what is going to happen.

We also do all our own transfers if possible. This is another important time to talk with patients about their embryos and what their expectations should be. One of the compromises we have made, however, is that egg retrieval is done on a rotating basis; patients may not have their own physicians doing the egg retrieval. Each day, one doctor does all the egg retrieval, which allows the other physicians to do the monitoring, transfers, and individualized care.

We have built nursing teams, and we have just begun a new program in which each doctor has a nursing team that is responsible, along with the doctor, to care for a given group of patients.

The team includes a registered nurse, medical assistants, and a nurse coordinator. All these form 1 team. We now have 5 working teams, although they can help cross-cover for one another.

No one has to work for their one team all the time, but the idea is to try to have as much continuity of care for the individual patient at all levels.

What do you find is the greatest challenge in infertility?

I do not know that I can say what is the greatest challenge other than to make everybody pregnant. We obviously cannot do that, but we do the best we can. Multiple challenges come with running a clinic of our size.

Medically, our challenge remains whether we can make better embryos and have higher pregnancy rates with fewer embryos transferred. The research that we have been involved with in the past 10 years is mostly aimed at how to grow the best embryo, how to freeze and thaw the best embryo, and how to determine which embryo is the best for embryo transfer. The challenge is to create an embryo with the least amount of stimulation, so that we do not have to

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overstimulate someone but still have a very high likelihood of implanting and creating a healthy child.

This will likely continue to be the challenge, not just for us, but for all IVF centers. We will continue to address this by testing and analyzing each new clinical development and implementing the successful ones as we prove their efficacy.

I started in IVF in 1981. I was in training at Vanderbilt University and ours was the third or fourth program to be established in this country. Our pregnancy rate at any one time might have been about 5%. Our current 65% pregnancy rate says that a lot has been done in the field of IVF. But we need to continue to address the questions and see where we can go.

The idea of fertility preservation is probably one of the newest challenges, but there are also a lot of unanswered questions. As a new challenge for a clinical program, this is one of the most exciting areas. We have done fertility preservation for quite some time for women with various cancers, such as leukemia, lymphoma, and breast cancer, who are going to lose ovarian function as a result of their treatment.

Some of these women are younger and some are older, but not many of them have come back to use their eggs.

Many eggs were frozen with an older technology, which is probably not as good as our current approach, and probably will not produce many pregnancies.

However, if a woman is going to lose her eggs, it at least provides some hope.

With the new techniques for freezing eggs, hope can more likely be realized.

The concept of offering the same options to someone who electively wants to preserve future fertility is a very new and exciting area. As women are able and desirous of undertaking professional careers, which often require extended periods of academic study or rigorous working schedules, they have less time for childbearing in the younger and more fertile years.

Having an option to freeze eggs at a younger age and preserve the higher pregnancy rate associated with that seems logical.

Although the data for freezing and thawing eggs from young women look very promising, we are still uncertain about the effects on frozen egg survival among women beyond their mid-30s.

We are hoping for more data in the near future to reassure us that we are not creating false hope for this group of women.

For now, we offer egg freezing to women who are faced with losing ovarian function, whether it is a result of aging or treatment of medical conditions. ■

AUGUST 2011 l VOLUME 3, NUMBER 4

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Infertility Updates

genetic mutation in Sperm may Contribute to male Infertility Findings may affect treatment in some couples

By Caroline Helwick

A

significant proportion of unexplained infertility may be the result of a genetic mutation in sperm, according to researchers investigating a male contraceptive vaccine, who observed the deletion polymorphism in nearly 25% of sperm samples (Tollner TL, et al. Sci Transl Med. 2011;3:92ra65). This report is based on a live discussion of the findings in a press briefing.

Infertility is unexplained in almost 20% of infertile couples. The new findings suggest that a variation in the gene that encodes a protein called betadefensin 126 (DEFB126) may be responsible for many of these cases.

“Our data suggest that the ability for couples to conceive within 12 months is reduced if men lack the normal gene for DEFB126. Together with low sperm count, poor motility, antisperm antibodies in the female, menstrual cycle irregularity, and so forth, pregnancy through natural means becomes improbable,” said Gary Cherr, PhD, Professor of Environmental Toxicity and Nutrition at the University of California, Davis (UC Davis) School of Medicine.

DEFB126 is a glycosylated polypeptide that is derived from the epididymis, where sperm are made, and absorbed onto the surface of the sperm. The protein helps sperm to move efficiently through the mucosal fluid of the female reproductive tract and helps to protect the sperm from immune attack.

The researchers identified the mutation in the DEFB126 gene while attempting to clone DEFB126 as a component for a male contraceptive. They confirmed the existence of the genetic deletion in close to 1000 sperm samples from the National Center for Biotechnology Information database, other researchers, and their subsequent study of Chinese infertile couples.

Across populations that included

“The ability for couples to conceive within 12 months is reduced if men lack the normal gene for DEFB126. Together with low sperm count, poor motility, antisperm antibodies in the female, menstrual cycle irregularity, and so forth, pregnancy through natural means becomes improbable.”

—Gary Cherr, PhD

the United States, United Kingdom, Japan, Africa, and China, approximately 50% of all men carried at least 1 mutated copy of the DEFB126 gene (wt/del), 25% had 2 copies of the mutant allele (del/del), and 25% had 2 normal copies (ie, were wild-type [wt/wt]). Men with 2 copies of the vari-

CORRECTIONS We regret the following errors that appeared in the June 2011 issue of this publication.

In the article titled “Are You Familiar with the Treatment Changes for Sexually Transmitted Infections?” (page 10), the section on pelvic inflammatory disease (PID) says, “Levofloxacin or ofloxacin is used only in cases of gonococcal-associated PID.” This is incorrect. Instead, it should read, “Levofloxacin or ofloxacin is used only in cases of non–gonococcal-associated PID.”

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ant (del/del) probably lack the protein completely, making it very difficult for sperm to join with an egg, explained Charles Bevins, PhD, Professor, Department of Medical Microbiology and Immunology, UC Davis School of Medicine. Men with 1 defective copy and 1 normal copy may have less protein to coat the sperm surface, but not a complete lack of it; therefore, their sperm have a better chance.

In the article titled “Infertility Drug Shortages a Threat, but Preparation Can Thwart Disaster” (page 14), the footnote for the Table stated, “Some products listed above may be on manufacturer backorder when this article is printed.” The correct statement is, “Some products listed above may or may not be on manufacturer backorder when this article is printed.”

AUGUST 2011 l VOLUME 3, NUMBER 4

The researchers discovered that sperm from men with the defective DEFB126 gene look normal microscopically and have normal motility but are far less able to swim through viscous hyaluronic acid gel, a surrogate for human cervical mucus. In samples from 21 semen donors, this was especially true for donors who were homozygous for the DEFB126 polymorphism.

“We wanted to see if changes in the surface composition of the sperm resulted in a change in sperm function in the mucus,” said lead author Theodore Tollner, PhD, Assistant Adjunct Professor, Department of Obstetrics and Gynecology, UC Davis. “We found that sperm from donors lacking the normal gene have difficulty penetrating the mucus surrogate. The rate of penetration was about 20% that of sperm with normal genes,” he said.

“Looking at these sperm in conventional ways, there is no reason to think there would be reduced sperm function,” he said. “This suggests that detection of the mutated gene or lower levels of the complex sugar on the sperm surface [related to the protein’s effect] are better predictors of fertility than sperm motility or swimming velocity.”

DEFB126 Variant linked to Infertility “The critical question then became, are our laboratory observations meaningful?” Dr Tollner added. “Does the mutation, and altered sperm function, have anything to do with fertility?”

They conducted a prospective study of 638 newly married couples in China who were trying to conceive by natural means. Couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence, which was the case in 19% of the couples.

The odds of pregnancy among couples in which males had the del/del genotype were 60% lower than for couples in which the males had wt/wt or del/wt genotypes. These couples also had a longer time (17.4 months) from study enrollment to live birth compared with 15.7 months for the other 2 genotypes. This translated to a probability of live births per month that was 70% lower than in couples without 2 variants of DEFB126.

Findings Could Change Clinical Practice The researchers suggest that these findings could alter the clinical management of infertility. Should the DEFB126 deletion the polymorphism be established early in the evaluation process, couples could be more promptly referred for interventions, such as intrauterine insemination or in vitro fertilization.

“The development of a relatively inexpensive diagnostic, even a ‘home kit’ for determining genotype, would enable couples to bypass extended clinical workups,” Dr Cherr said. “We also envision a treatment where recombinant DEFB126 is added to sperm to allow beta-defensin coating, either during insemination or in a vaginally applied gel or cream.”

The author of an accompanying editorial (Rozen S. Sci Transl Med. 2011;3: 92ps31) supports these findings. “If it is known that time to pregnancy is likely to be long because the man has the del/del genotype, then resorting immediately to assisted reproduction may be attractive,” Dr Rozen wrote. “It is clear that this genetic information could lead to more informed assisted reproduction, in addition to possible new methods of treating sperm.” ■

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Infertility Updates

Preoperative Chemotherapy for Breast Cancer Precludes Fertility Preservation Leaner, wealthier women more likely to undergo fertility preservation?

By Caroline Helwick

Chicago, IL—Young women with breast cancer who receive preoperative (neoadjuvant) chemotherapy to shrink the tumor are significantly less likely to undergo fertility preservation procedures, according to a multicenter study reported at the 2011 American Society of Clinical Oncology annual meeting.

“Except in cases where neoadjuvant chemotherapy clearly improves survival, oncologists may consider offering adjuvant [postsurgical] chemotherapy, rather than neoadjuvant, in women who are interested in fertility preservation,” said lead investigator Jayeon Kim, MD, Division of Reproductive Endocrinology and Infertility, University of North Carolina at Chapel Hill.

Many academic centers are now equipped with fertility preservation programs, where oncologists team up with fertility specialists to allow for prompt referrals and treatments. However, in a 2010 study of more than 1000 patients

with breast cancer, <8% who were referred to fertility specialists before starting chemotherapy actually underwent fertility preservation (Lawrenz B, et al. Arch Gynecol Obstet. 2011;283: 651-656).

Dr Kim and colleagues analyzed women undergoing fertility preservation consultation at 3 large academic hospitals in 3 different states, specifically looking for variables that predict who does or does not pursue fertility preservation treatment.

This retrospective study included 185 patients aged ≤42 years with early- to advanced-stage breast cancer and no previous chemotherapy.

The 3 centers had different patient profiles in terms of age, body mass index [BMI], parity, and income, as well as in patients’ lymph node involvement and use of neoadjuvant chemotherapy.

Center 2 (N = 116) tended to have an older, leaner, higher-income popu-

lation. Patients in this center were also significantly less likely to have neoadjuvant chemotherapy than those in center 1 (N = 36)—3% versus 48%—

“This is the first multicenter study that shows administration of neoadjuvant chemotherapy is an independent negative predictor of fertility preservation treatment.”

—Jayeon Kim, MD

but only slightly less so than those in center 3 (N = 33), among whom the rate was 6%.

Center 2 patients also were signifi-

cantly more likely to undergo fertility preservation treatment (71%) than center 1 patients (28%) or center 3 patients (48%).

The group undergoing fertility preservation was significantly more underweight and wealthier, and had a less advanced cancer stage than the group that did not undergo fertility preservation treatments.

The rate of neoadjuvant chemotherapy was also significantly lower in the fertility preservation group.

“This is the first multicenter study that shows administration of neoadjuvant chemotherapy is an independent negative predictor of fertility preservation treatment,” Dr Kim said.

“While age, BMI, income, cancer stage, and neoadjuvant chemotherapy appear to predict the likelihood of undergoing fertility preservation, neoadjuvant chemotherapy is the only variable that may be modified, in appropriate patients, said Dr Kim.” ■

Continuing Success of the Annual midwest reproductive Symposium Judith R. Farrar, PhD Executive Director, Midwest Reproductive Symposium

Chicago, IL—This year’s Midwest Reproductive Symposium (MRS) was the largest in the 7-year history of the program. The Organizing Committee, under the direction of Angeline Beltsos, MD, Executive Chairperson, and the host organization, Fertility Centers of Illinois, welcomed more than 300 attendees and more than 30 exhibitors.

“The MRS is an excellent meeting that offers relevant and informative topics, and the Nurse Practicum Day is an especially good program for in vitro fertilization [IVF] nurses. Keep it going!” That was the consensus of the feedback received from attendees at the 2011 MRS and Nurse Practicum Day held June 9-11.

The MRS grew out of a discussion in 2004 among Dr Beltsos and colleagues at the Fertility Centers of Illinois who were looking for closer-to-home quality continuing education for health professionals and scientists in reproductive medicine in the midwestern United States.

12

The first MRS, a 2.5-day session in June 2005, was attended by 80 registrants. Today, the MRS includes 3 times that number, and current programming

The Practicum is a program developed by nurses for nurses. In 2011, it incorporated a double track in the morning session—one for nurses who are new to the field, and another for more experienced practitioners.

reflects changes recommended by attendees and faculty. The program was shortened to 2 days; exhibitors were invited and granted support of the academic

AUGUST 2011 l VOLUME 3, NUMBER 4

program; reproductive endocrinology and infertility fellows were invited to present posters; and, most recently, the MRS Nurse Practicum was added.

The Nurse Practicum is a program developed by nurses for nurses. In 2011, it incorporated a double track in the morning session—one for nurses who are new to the field and another for more experienced practitioners. The nurses were polled and unanimously voted to keep the tracked programming for future MRS meetings. Attendees agreed that the best part was the panel discussion, which explored various protocols used in different clinics and included polling the audience.

Also new in 2011 was a half-day session for IVF clinic business managers.

Today, the MRS is recognized as a relevant and innovative meeting of excellence that attracts attendees from around the world, while keeping its closer-to-home focus for continuing education in the United States. Its outcomes are impactful.

Practice Changes Attendees were asked to be specific about what changes they planned to make when returning to their practices after the meeting. The top 5 responses were: • Explore preconceptual genetic screening of patients in the clinical setting • Optimize/improve male infertility assessment/counseling • Use anti-Mullerian hormone to check ovarian reserve • Consider a more detailed post–recurrent pregnancy loss investigation • Reevaluate thyroid-stimulating hormone testing for patients.

The organizing committee is currently busy developing the 2012 program, gathering noted authorities to present the most current aspects of their research and discuss their findings in relation to the issues that you encounter daily in your practice. Your feedback is invited at info@mwrs.org, and we look forward to seeing you in Chicago, May 17-19, 2012. ■

Infertility Updates

Novel Vaginal Progesterone ring Shows good efficacy for IVF

By Caroline Helwick

Washington, DC—A vaginal ring that is currently in clinical trials may become the new mode of progesterone delivery associated with in vitro fertilization (IVF), according to a study presented at the American Congress of Obstetricians and Gynecologists (ACOG) 2011.

In a late-phase trial, patients undergoing IVF procedures using weekly progesterone vaginal rings for lutealphase supplementation had pregnancy rates similar to women using the daily 8% progesterone vaginal gel, reported Kaylen M. Silverberg, MD, of Texas Fertility Center, Austin.

Oral, intramuscular, and vaginal progesterone preparations are all effec-

tive in priming the uterus for embryo implantation and in sustaining the pregnancy. Vaginal progesterone gel is a convenient alternative to conventional intramuscular injections.

The vaginal progesterone ring—a flexible silicone product containing the active ingredient is formulated for once-weekly insertion—may be an equal or even more convenient option, according to Dr Silverberg.

In a previous study of 511 patients, the investigators showed vaginal gel to be superior to intramuscular injections.

They are currently comparing the vaginal ring, vaginal gel, and intramuscular injections. The findings presented at

Table Clinical Pregnancy Rate per Retrieval by Duration of Infertility Infertility

Gestational age, Vaginal progesterone wks ring, %

Progesterone gel, %

<1 yr

12

53.1

47.6

1 yr to <2 yrs

12

49.3

43.5

2 yrs to <3 yrs

12

51.8

41.8

>3 yrs

12

41.5

47.9

ACOG were a comparison of the ring with the vaginal gel, but emerging data are showing that the ring is also superior to injections, Dr Silverberg said.

“The ring is definitely easier for the patient,” he said. “It avoids the painful injections, and compared to the everyday gel, it is only inserted once a week.”

This prospective, randomized, multicenter noninferiority study of 1297 women undergoing IVF compared the qualitative efficacy of the novel weekly progesterone vaginal ring with the daily 8% progesterone vaginal gel (90 mg/day) for luteal-phase supplementation. Patients were stimulated with a standard protocol and oocytes were retrieved. Clinical pregnancy rates per retrieval were determined for each treatment group after stratification based on self-reported duration and diagnosis of infertility.

Pregnancy rates Comparable Pregnancy rates were comparable between treatment groups and appeared to favor the vaginal ring for women with fewer than 3 years of infertility.

Numerically, rates were higher for the

gel among women who were infertile for 3 or more years, Dr Silverberg reported (Table). The pregnancy rates

“The ring is definitely easier for the patient.

It avoids the painful injections, and compared to the everyday gel, it is only inserted once a week.”

—Kaylen M. Silverberg, MD

in this study were similar to national rates across diagnoses, he added.

A total of 42% of patients reported >1 infertility diagnosis, including male factor (39%), ovulatory dysfunction (29%), and tubal factors (26%). When grouped by infertility diagnosis, clinical pregnancy rates ranged from 31.1% to 53.4% and were similar between treatment groups for the 2 modes of progesterone delivery. ■

ADA Highlights

Preexisting Diabetes Increases risk for Congenital Anomalies in the offspring

By Alice Goodman

San Diego, CA—The risk for structural congenital anomalies is nearly 4-fold greater in offspring of women with pregestational diabetes compared with women who do not have preexisting diabetes, according to a study presented at the 2011 meeting of the American Diabetes Association. Strong independent predictors of congenital anomalies in this study included poor periconception glycemic control and prepregnancy nephropathy.

“This study suggests that glucose control should be optimized before conception, as this could reduce the risk of congenital anomalies in offspring of women with diabetes,” said Svetlana Glinianaia, MD, Institute of Health & Society, Newcastle University, Newcastle upon Tyne, United Kingdom.

“There is good evidence that improving preconception glycemic control

should reduce the risk of adverse pregnancy outcome,” noted senior investigator Ruth Bell, MD, also of Newcastle University.

“The association between prepregnancy nephropathy and congenital anomalies has not been previously described,” Dr Bell continued. “The reason for the association is not clear, but it merits further research, which we plan to do. It may be that women with diabetic neuropathy have poor glucose control.”

The study was based on data from regional population-based registries for the years 1996-2008. The aim was to examine the influence of a range of clinical and sociodemographic factors for congenital anomalies in offspring of women with pregestational type 1 and type 2 diabetes.

Among 1677 pregnancies in women with pregestational diabetes, 120 off-

spring had structural congenital anomalies. The risk for congenital anomaly was nearly 4-fold greater for women

“Glucose control should be optimized before conception, as this could reduce the risk of congenital anomalies in offspring of women with diabetes.”

—Svetlana Glinianaia, MD

with pregestational diabetes: 71.6 per 1000 in women with pregestational diabetes compared with 19.1 per 1000 in

women without diabetes. The risk for offspring of women with pregestational diabetes was increased across all types of anomalies, including those of the nervous, cardiovascular, digestive, and urinary systems, as well as syndromes and multiple anomalies.

Univariate analysis identified the following factors as significant predictors of anomalies: lack of preconception folic acid, poor periconception glycemic control, nephropathy diagnosed prepregnancy, and more deprived socioeconomic status. Type or duration of diabetes, fetal sex, body mass index, and prepregnancy retinopathy or neuropathy were not associated with increased risk for a congenital anomaly.

Poor periconception glycemic control, nephropathy, and multiparity were independently associated with increased risk for congenital anomaly. ■

AUGUST 2011 l VOLUME 3, NUMBER 4

13

ADA Highlights

Preliminary evidence Suggests Breastfeeding may Protect against Progressing from gestational Diabetes to type 2 Diabetes

By Alice Goodman

San Diego, CA—In addition to being good for infants, breastfeeding may have important benefits for women with a history of gestational diabetes, according to interim results of companion studies presented at the 2011 meeting of the American Diabetes Association.

In one study, intensive lactation promoted greater weight loss for mothers than formula feeding, and the second study suggested that intensive lactation may reduce the incidence of diabetes in women with a history of gestational diabetes.

Both studies are part of the Study of Women, Infant Feeding and Type 2 Diabetes (SWIFT) Longitudinal Cohort, an ongoing follow-up study of mothers with gestational diabetes conducted by Kaiser Permanente Northern California.

“These are preliminary findings, but if confirmed, show yet another benefit of breastfeeding in a diverse cohort of women with a history of gestational diabetes,” stated lead investigator Erica P. Gunderson, PhD, an epidemiologist and research scientist, Division of Research, Kaiser Permanente Northern California, Oakland.

The observational study includes a prospective cohort of postpartum women with recent gestational diabetes who are members of Kaiser Permanente

1 year after a pregnancy with gestational diabetes. Approximately 68% were minority women (30% Hispanic, 28% Asian, and 10% black).

“These are preliminary findings, but if confirmed, show yet another benefit of breastfeeding in a diverse cohort of women with a history of gestational diabetes.”

—Erica P. Gunderson, PhD

Northern California. The target sample is 1100 women, and 805 women are currently enrolled.

In the present companion studies, women were divided into 2 groups based on infant-feeding characteristics: intensive breastfeeding (<6 oz of formula daily) or all or mostly formula feeding (>14 oz of formula daily).

The first study included 316 women and focused on weight changes related to prediabetes and incident diabetes at

Approximately 40% of the women gained weight by 1 year after giving birth. Mean weight change was significantly different: the breastfeeding group lost a mean of 0.06% of body weight, whereas the formula feeders gained a mean of 2.4% of body weight.

Weight loss of ≥5% was associated with a lower prevalence of prediabetes and the development of postpartum diabetes compared with weight loss of <5%. In this preliminary analysis,

gestational Diabetes, Impaired glucose... diabetes. This study explored whether racial differences predicted the risk for developing type 2 diabetes, and the link to specific factors such as fasting glucose levels.

Using a database from Louisiana State University Hospital, researchers followed 20,096 women (aged 13-50 years) with a first pregnancy. Of these, 1190 women developed gestational diabetes. At a mean follow-up of 8.6 years, 1117 women without gestational diabetes and 374 with gestational diabetes developed type 2 diabetes after their pregnancy.

Women with gestational diabetes had an almost 7 times greater risk for developing diabetes than women who did not have gestational diabetes. In addition, the relative risk for developing type 2 diabetes was higher in black women than in white women with a history of gestational diabetes compared with those without a history of gestational diabetes.

Abnormal glucose levels during

14

pregnancy were associated with increased risk for type 2 diabetes, with impaired fasting glucose being the strongest predictor.

Dr Wang advises that during pregnancy, women with gestational diabetes should be given individualized advice

TAKEAWAY qUICK POINTS ➤ Gestational diabetes increases the risk for developing type 2 diabetes by approximately 7-fold. ➤ This risk is greater for black women than for white women. ➤ After delivery, monitor glucose levels of women with gestational diabetes or glucose abnormalities for at least 6 weeks. ➤ Perform an annual oral glucose tolerance test for all women with a history of gestational diabetes or glucose abnormalities in pregnancy.

AUGUST 2011 l VOLUME 3, NUMBER 4

intensive breastfeeding was twice as likely as formula feeding to be associated with weight loss of ≥5%.

Follow-up is under way to examine the relationship between lactation and longterm glucose tolerance in women with gestational diabetes, including the role of weight change, Dr Gunderson said.

The second study included 323 women. Both feeding groups had a similar severity of prenatal glucose intolerance. Women who breastfed intensively had a numerically lower mean 2-hour plasma glucose reading 1 year postpartum compared with formula feeders; the prevalence of prediabetes was approximately 12% lower and the prevalence of new diabetes was approximately 35% lower in breastfeeders versus formula feeders.

“These preliminary findings are promising for intensive lactation in this large, diverse cohort of women with gestational diabetes,” Dr Gunderson said. She added that a longer follow-up for a larger number of women is needed to determine whether intensive breastfeeding reduces the future risk of type 2 diabetes in women with a history of gestational diabetes. ■

Continued from page 1

“Interventions among women with a history of gestational diabetes should be introduced as early as possible postpartum.”

—Yujie Wang, MD

by trained dietitians and obstetricians on dietary modification, physical activity, and blood glucose monitoring.

If glycemic control targets are not achieved, insulin therapy should be initiated, with education on how to use insulin, she said.

“Women with gestational diabetes should be reclassified 6 weeks after delivery to detect persistent glucose abnormalities,” Dr Wang said. “For women who maintain impaired fasting glucose or glucose intolerance after the

pregnancy, annual oral glucose tolerance testing should be performed.

Furthermore, women with previous gestational diabetes who have normal results at the first evaluation after delivery should have an oral glucose tolerance test with regular intervals, beginning 1 year after pregnancy.”

Women with a history of gestational diabetes should follow recommendations to control/reduce body weight, eat a healthy diet, and increase breastfeeding for weight control. ■

AWHONN Highlights

refrain from Social Networking on the Job

By Caroline Helwick

Denver, CO—In using social media, healthcare professionals should exercise caution, understand privacy issues, and always err on the side of a conservative approach, said Lisa Miller, CNM, JD, an attorney and a certified midwife.

At the 2011 Association of Women’s Health, Obstetric and Neonatal Nurses annual meeting, Ms Miller entertained a packed room with stories of nurses who failed to realize the new reality that nothing is private once it has been “tweeted” on Twitter or posted on Facebook. “If you tweet it, type it, or post it, consider it public,” Ms Miller warned.

“Social media is expanding exponentially on a daily basis,” she said. Facebook claims an estimated 550 million unique visitors monthly. Twitter now has nearly 96 million unique visitors, MySpace claims 80 million, and even LinkedIn now has 50 million monthly users. The average user has 130 friends, and on a given day, 50% of active Facebook users log on to the site (www.facebook.com/ pressinfo.php?statistics).

“This case bordered on silly, and it is the instructor, not the nurse, who should be reprimanded,” she maintained. “But the message is that those things for which we give permission could well end up on Facebook.”

Some cases are more serious. In 2009,

2 nurses in Wisconsin were fired because they took pictures of an x-ray image of a sexual device lodged in a patient’s rectum. In 2010, a California nurse and other staff took pictures of a 60-year-old stabbing victim, posted them on Facebook, and texted them to other hos-

pital employees; 4 staff members were fired and 3 more were disciplined.

Equally risky and probably a lot more common are such postings as, “I hate my job,” and, “We had a bad outcome last night.” Ms Miller described one nurse who attended a party at a neonaContinued on page 16

for your postmenopausal patients experiencing vaginal atrophy

Get the Conversation Started Introducing the Conversation Starter Kit Novo Nordisk has created a tool kit to help you talk to postmenopausal patients about vaginal atrophy. It includes a variety of educational resources and support materials both for use in the office and to be sent home with patients.

“But the message is that those things for which we give permission could well end up on Facebook.”

In-office materials

—Lisa Miller, CNM, JD

t Symptom Worksheet Tear Pad t Vaginal Symptom Diary t Educational Ring Cards

“Sounds like fun for everyone, right?

Clearly, the reach of social media is wonderful and the ability to connect with nearly anyone in the world is amazing, but like everything else, there are pros and cons,” Ms Miller said. examples of What to Avoid A picture of a placenta, posted on Facebook with the permission of a nursing instructor, nearly ended the nursing career of one student who merely intended to boast about her first delivery. She was expelled from school, but sued and was reinstated.

“The judge ruled in her favor, and his opinion included some interesting comments on expectations,” Ms Miller said.

She quoted him, saying, “Photos are taken to be viewed. When granted permission to take the photos, it was unreasonable to assume that they would not be viewed….By giving the student permission to take the photos, which [the nursing supervisor] admitted, it was reasonable to anticipate that the photos would be shown to others.”

For your patients t Vaginal Atrophy Brochure t Copay Cards

To order the Conversation Starter Kit or other materials for your office please call 1-855-NOVOV10 or visit novomedlink.com/HT

© 2011 Novo Nordisk. 0511-00002628-1 June 2011

AUGUST 2011 l VOLUME 3, NUMBER 4

15

AWHONN Highlights

Keynote Speaker urges Nurses to expand... breadth and was rewarded with a standing ovation. She began by noting that the AWHONN convention was “coming at the right moment,” that is, at a time of change and challenge as the role of nursing rapidly expands.

Nurses “can lead and work with colleagues in a way that is professional and collaborative,” she said, especially if they keep core values in mind. These core values, which are the formal goals of the National League for Nursing, are: • Caring • Integrity • Diversity • Excellence.

Caring involves promoting health and healing, and fostering hope in response to the human condition, she said. “We can’t wait until the patient encounter, and then ask if anyone has brought some hope,” she said. “Nurses carry the hope. Hope flows through us.

We bring hope to the encounter.”

Integrity, she continued, is demanded of nurses “without conditions or limitations.” Diversity is not just about skin color, but about “ideals” as well.

Excellence means creating and implementing transformative strategies “with daring ingenuity,” she said. Such transformation is represented by the following example: “If I give you $1 and you give me 4 quarters, you have given me ‘change.’ But if I give you $1 and

you give me $5 back, we have transformed the situation. We are not just going for change, but transformation,” Dr Malone told the audience. “We are looking for added value.”

And “real excellence” is a moving target that slips away before it is secured. “The pursuit of excellence is really what we want,” she emphasized.

The IOM report marks “the first time someone outside of nursing affirmed what we know inside to be true. The glue holding the system together is nursing, but we have been the invisible glue. It’s now time for us to become visible.”

—Beverly Malone, RN, PhD, FAAN

A Blueprint for Change The Future of Nursing report is an action-oriented blueprint for change, urging nurses to take a greater leadership role to meet the increasing demands of healthcare. The report marks “the first time someone outside of nursing affirmed what we know inside to be true,” Dr Malone said.

The IOM report validates the critical role of nurses and gives credence to the expanding role of nursing, she said. It essentially affirms that “the glue holding the system together is nursing, but we have been the invisible glue,” she said.

“It’s now time for us to become visible.”

The future of nursing lies in satisfying 5 key areas highlighted in the IOM report: • Scope of practice • Academic progression • Data collection • Leadership • Education.

Dr Malone emphasized that all nurses—not just advanced practice

refrain from Social Networking... tologist’s home, and posted the following day, “What a great party! I’m surprised how drunk everyone got. I’m still hungover and have to go to work in 4 hours!”

“Imagine what this does to the nursing reputation, when families see this,” she said. “Don’t type it and don’t text it.

It can come back to haunt you.” employers use Social media too Also beware that your Facebook profile may not paint a flattering picture of you, and is available for current or prospective employers to view. “When you are interviewing for a new job, do you really want an inappropriate Facebook post or tweet to make a difference in your getting it?” Ms Miller asked.

Do not think that it will not, she said. Pharmacy residency program directors were recently surveyed about their attitudes toward social media in residency recruitment and selection (Cain J, et al. Am J Health Syst Pharm.

2010;67:1635-1639). Of the 454 program directors who responded, 20%

16

revealed that they had viewed an applicant’s social media information; >50% had encountered “e-professionalism issues,” including questionable photos and posts revealing unprofessional atti-

tion from social media sites to support their cases—specifically in medical malpractice cases. “They can easily get an idea of your personality and perhaps your work relationships,” Ms Miller

—Lisa Miller, CNM, JD

Social media and medical malpractice Lawyers are also obtaining informa-

AUGUST 2011 l VOLUME 3, NUMBER 4

nurses—should “practice to their full scope,” because “the United States will need this.” She urged nurses to continue their education and not to pause for so many “deep breaths” between degrees.

Nurses must also strive for leadership positions, she added. “Gallup polls show nurses to be the most trusted professionals, but we aren’t at the decision-making tables. Committees at your hospital need nurses,” she said.

Advice for Nurses Dr Malone advised her nursing colleagues to: • Create a vision and share it. “The beauty of this is that someone will buy into it, and take it in a new direction.”

• Create and maintain boundaries.

“Sometimes we lose sight of where our boundaries end and begin.”

• Develop resilience. “We all get knocked down. The point is to keep getting up.”

• Maintain mastery. “Nursing is a lifelong learning endeavor. We need the best prepared nursing work force possible.”

• Be a mentor. “Mentoring helps distinguish between a wall and a door; it helps us figure things out.”

• Show joy for what you do. “We talk about the pain. We need to show our joy as well and not let others take it away, including our colleagues.” ■

Continued from page 15

“If you tweet it, type it, or post it, consider it public.”

tudes; and 89% agreed that information voluntarily published online was fair game for judgments on character, attitudes, and professionalism.

Continued from page 1

said. “And in some cases, the information has been used to provide the appearance of possible collusion.”

One malpractice suit involved an emergency situation in which the timing was questionable. Contact was documented among nursing staff, some of whom had not kept in touch for years

before the suit. “Call me—having my deposition—let’s talk!” read one Facebook message. “How will it look to the jury, that after 5 years of no contact, they are talking now?” Ms Miller pointed out.

“You don’t need to prove collusion, you just need to give the appearance of it, and this case was settled when this information was brought to light,” she continued. “When you choose to use social media, you are choosing to make information public.” She urged nurses to: • Think twice about whatever they post, especially pictures and information referring to patients • Kindly refuse patients’ requests to take their photos • Avoid using Google to look for their patients (“don’t create a trail”) • Decline any “friend” requests from patients.

“I have become friends with many of my patients,” she said, “but once they have accessed my Facebook page, they may view me differently.” ■

Clinical News CDC updates...

Continued from page 8

at risk for VTE (such as previous VTE or recent cesarean delivery) generally should not use a combined hormonal contraception product.

For other women, the advantages of combined hormonal contraceptives usually outweigh the risks. Although these restrictions apply to the first 42 days postpartum, the CDC points out that all other medical conditions or risk factors should always be taken into account when prescribing combined hormonal contraception postpartum.

The guidelines for other contraceptive methods used postpartum, many of which can be used safely during that period, have not been changed.

The incidence of ectopic pregnancy has increased 6-fold in the past 25 years.

The use of methotrexate therapy has been shown beneficial in early cases of unruptured, tubal pregnancy. However, in cases of live tubal pregnancy, a 20.5% failure rate has been reported with the use of methotrexate therapy alone.

In this small study of 13 asymptomatic women (average age, 22-37 years) with singleton, live, unruptured tubal

ectopic pregnancies, the women underwent transvaginal ultrasoundâ&#x20AC;&#x201C;guided aspiration of the pregnancy (a novel treatment for live, unruptured ectopic pregnancies) followed by methotrexate (a single dose of 25 mg/m2 divided in half) administered into the gestational sac and intramuscularly.

A total of 12 of the pregnancies were successfully aborted, without the need for salpingectomy or salpingostomy.

Although methotrexate treatment is widely used in ectopic pregnancies, the single-dose regimen used in this study resulted in fewer adverse effects than in cases where it is used excessively.

The novel use of fetal aspiration, in concert with single-dose methotrexate, can help to avert further surgical interventions, along with repeated high doses of methotrexate, the researchers suggested. â&#x2013;

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

FDA Strengthens Warning for transvaginal Surgical mesh for Pelvic Prolapse Transvaginal surgical mesh for the treatment of pelvic organ prolapse (POP) carries more risks than was previously thought. Almost 3 years after its original warning, the FDA has issued an updated warning that the â&#x20AC;&#x153;serious complications associated with surgical mesh for transvaginal repair of POP are not rare,â&#x20AC;? and that POP can usually be successfully treated without mesh (www. fda.gov/MedicalDevices/Safety/Alertsand Notices/ucm262435.htm).

From 2005 to 2007, >1000 adverse events with surgical mesh devices used for POP and stress urinary incontinence (SUI) had been reported to the FDA. Between 2008 and 2010, the FDA received an additional 2874 reports, 1503 associated with POP and 1371 associated with SUI. The FDA says that the most frequently reported complication of surgical mesh for POP is mesh erosion, which can require multiple surgeries to correct, if it can be corrected at all.

A recently identified risk with this treatment is contraction or shrinkage of the mesh, which is associated with vaginal shortening, tightening, and pain.

These latter 2 adverse effects may cause severe pelvic pain, painful sexual intercourse, or an inability to have sex.

Other complications include pain, infection, bleeding, dyspareunia, organ perforation, and urinary problems.

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live tubal ectopic Pregnancies effectively treated with Aspiration of the embryo plus SingleDose methotrexate Embryo aspiration combined with single-dose methotrexate administration provides a safe option for treating live, unruptured ectopic pregnancies, Turkish researchers have found (Ă&#x2021;epni I, et al. Fertil Steril. 2011;96:79-83).

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AUGUST 2011 l VOLUME 3, NUMBER 4

17

AWHONN Highlights

Prenatal Smoking: It’s Never too late to Quit and Improve outcomes

By Caroline Helwick

Denver, CO—It is never too late for pregnant women to quit smoking to improve neonatal outcomes, according to research presented at the 2011 meeting of the Association of Women’s

Health, Obstetric and Neonatal Nurses.

“Even if women quit smoking during the second trimester in our study, they had significantly improved outcomes compared with women who continued

to smoke,” said Beth A. Bailey, PhD, Associate Professor, Department of Family Medicine, East Tennessee State University, Johnson City.

“Obviously, those who quit earlier

“Those who quit earlier had the best outcomes, but we found big gains in outcomes up to 27 weeks.” —Beth A. Bailey, PhD

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.

had the best outcomes, but we found big gains in outcomes up to 27 weeks,” she said in an interview.

Dr Bailey and colleagues recruited 1040 women entering prenatal care at 6 prenatal practices. Of these, 707 continued to smoke during pregnancy, 103 entered prenatal care as smokers but quit smoking by 27 weeks of gestation, and 230 were nonsmokers.

Compared with women who continued to smoke, those who quit by the third trimester gave birth to babies who were significantly heavier (mean difference, 190 g), of longer length (mean difference, 2 cm), and had greater head circumferences (mean difference, 0.8 cm).

“In fact, babies born to women who quit were virtually identical in size to babies born to women who did not smoke at all,” she reported.

For the intervention, women who expressed a desire to stop smoking (or even to diminish exposure to secondhand smoke) met with a case manager 4 times during prenatal care.

The “5 As” used in the intervention included Asking about smoking behavior, Assessing willingness to quit, Advising against smoking, Assisting with treatment and referrals, and Arranging follow-up.

“The findings are encouraging, as they suggest that efforts to intervene with pregnant smokers can lead to direct improvements in birth outcomes, and that quitting even later in pregnancy can be beneficial,” she said.

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.

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

Professional samples-not for sale Sample Product (4 capsules) 0525-0621-04* * Pamlab, LLC does not represent this product code to be a National Drug Code (NDC) number. Instead, Pamlab has assigned a product code formatted according to standard industry practice to meet the formatting requirements of pharmacy and health insurance computer systems.

Storage Store at controlled room temperature 15oC to 30oC (59oF to 86oF) (See USP). Protect from light and moisture. Dispense commercial product in original container. Dispense sample product in original container.

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

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

Nurses may Need SmokingCessation education A second study targeted 41 neonatal nurses with a program aimed at enhancing their ability to deliver a smoking prevention intervention.

Because most women who quit smoking during pregnancy relapse within weeks of giving birth, smoking prevention services should be integrated along the continuum of care.

Postpartum and neonatal hospitalization provides a window of opportunity for nurses to coordinate services and bridge the gap between the obstetric

Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany.

Distributed By PAMLAB, L.L.C. Covington, LA 70433 PC-0053 Revised 02/11

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Continued on page 19

18

AUGUST 2011 l VOLUME 3, NUMBER 4

AWHONN Highlights

New model for Advanced Practice Nursing: A Promising Change in Direction

By Caroline Helwick

roles, Populations, and Specialties All APRNs must satisfy the core concepts of advanced physical or health assessment, advanced pathophysiology, advanced pharmacology, and a minimum of 500 clinical hours in their chosen role and population.

Licensure occurs at the level of the “role” and “population” foci (Figure).

All APRNs must choose 1 role and 1 population. Roles include clinical nurse specialist, nurse anesthetist, nurse midwife, or nurse practitioner. The populations are shown in the Figure.

Above these levels is specialization, which is a focus of practice beyond role and population foci, linked to healthcare needs. Examples include oncology, older adult, orthopedics, nephrology, and palliative care. Specialties will not be regulated. “You can switch around without a change in license,”

program, and is educated in at least 1 of the 6 populations • All APRN programs preapproved by the accrediting body: An individual starting a new program will not be at risk for not obtaining licensure • Consistency in APRN titles, mobility across states: Across all states, all APRNs will be considered independent practitioners with no need for collaborative agreements. “There will be no need to worry about which state you are in, especially if you are in a border state, with regard to the scope of your practice. There is no more, ‘I can do it here, but not there,’” Ms Thompkins said • Uniformity of education, certification, and licensure: The requirements now vary state by state, but with new regulations will come greater consistency.

Figure APRN Regulatory Model

APRN specialties Focus of practice beyond role and population focus linked to healthcare needs Examples include, but are not limited to, oncology, older adults, orthopedics, nephrology, palliative care

Population foci Licensure occurs at levels of role and population foci

Denver, CO—The new model for advanced practice registered nurses (APRNs) has the potential to change the field for the better, according to Diane L. Thompkins, MS, RN, Assistant Director, Certification, the American Nurses Credentialing Center, who described the coming changes and their impact at the 2011 meeting of the Association of Women’s Health, Obstetric and Neonatal Nurses.

“I view the consensus model as my gift from those of us in the profession to those coming behind us. Your future should be brighter because of this,” Ms Thompkins told attendees during her update on new directions and regulations in advanced practice nursing.

The Consensus Model for APRN Regulation was developed by stakeholders representing licensure, accreditation, certification, and education of APRNs and has been endorsed by 48 organizations. It will be fully implemented in 2015.

“Often, documents are created and then nothing happens. Not here—this will occur,” Ms Thompkins assured the attending nurses.

The consensus model addresses vexing issues, such as regulations being set by each state, scope of practice, the lack of common definitions and titles for APRNs, increasing specialization without regulation, uniformity in education, and the lack of requirement for certification in some states. These barriers compromised patient access to care, she said.

The full document can be found at www.aacn.nche.edu/education/apn.htm.

Key points include: • APRN defined: An APRN is a registered nurse who has obtained the advanced knowledge and skills to provide direct patient care, completed a graduate degree or postgraduate

Family/ individual across lifespan

Adultgerontology

Neonatal

Pediatrics

Women’s health/genderrelated

Psychiatricmental health

APRN roles Nurse anesthetist

Nurse-midwife

Clinical nurse specialist

Nurse practitioner

APRN indicates advanced practice registered nurse. © 2011 American Nurses Credentialing Center. Reprinted with permission.

“I view the consensus model as my gift from those of us in the profession to those coming behind us. Your future should be brighter because of this.”

—Diane L. Thompkins, MS, RN

Ms Thompkins pointed out.

Regarding the fear that the requirements would only become stricter, and that a Doctorate of Nursing Practice (DNP) will eventually be required for certification, she said that this may eventually be the case. But even if this should happen, APRNs who are already certified, licensed, and in practice will be grandfathered in and not required to obtain a higher degree. A number of schools are already converting to DNP programs.

Some of the positive outcomes anticipated with the new APRN regulation are: • Recognition of independent practice for all roles • Congruent scope of education, certification, and practice • Set criteria for a population versus a specialty, for purposes of regulation • Role and title to reflect educational preparation and certification • APRNs practicing to the full extent of their education and training.

“When we started with the model, we saw huge barriers,” Ms Thompkins acknowledged. “We have gone over the rocky shore, and we are all now in the same boat, working in harmony. This ship will get us to the future.” ■

Prenatal Smoking... Continued from page 18 and outpatient pediatric settings, explained Sharron R. Forest, APRN, NNP-BC, DNP, Neonatal Intensive Care Unit, Women & Children’s Hospital, Lake Charles, LA. The educational program she used was the state’s “Fax-to-Quit” program (also used by Dr Bailey). Patients desiring help to quit smoking provide consent to healthcare providers to allow a tobacco quit line counselor to contact them; the referrals are made via fax, and the healthcare providers receive periodic status reports.

“Participation with smoking prevention interventions is now a required competency for neonatal nurses.”

—Sharron R. Forest, APRN,

NNP-BC, DNP After 4 live training classes, the instructional program was ultimately converted to interactive computer-

based training to increase staff participation. The module was modified to incorporate videos of mock conversations between nurses and mothers to simulate the role-play experience of the live training.

Pre- and posttraining testing showed a substantial improvement in the nurses’ knowledge about smoking risks and smoking-cessation strategies. Overall, knowledge scores improved by 66%, and overall self-efficacy scores improved by 32%.

“Computer-based training is cost-

effective and eliminates the need for us to pay for speakers and to reimburse expenses related to nurses’ attendance.

Most of the nurses received this instruction during their scheduled breaks,” Ms Forest said. Once the computer-based training was instituted, nurses’ participation rates increased by 128%.

“Participation with smoking prevention interventions is now a required competency for neonatal nurses,” she said.

The greatest effect of the training was increasing the nurses’ confidence in broaching the topic with new mothers. ■

AUGUST 2011 l VOLUME 3, NUMBER 4

19

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

Rx only

BRIEF SUMMARY For full prescribing information, see package insert.

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

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

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

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

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

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

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

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

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

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

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

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

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

Drug Interactions No drug interactions have been assessed with Crinone.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Each applicator is wrapped and sealed in a foil overwrap.

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

Rx only

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

Women’s Health

New Federal Standards to Cover Preventive Services... mended by the US Department of Health & Human Services (HHS), but there remained critical gaps in preventive services for women.

At the HHS’s request, an IOM committee proposed measures that should ensure better coverage of essential services for women. “This report provides a road map for improving the health and well-being of women,” said committee chair Linda Rosenstock, MD, MPH, Dean of Public Health, University of California, Los Angeles.

On August 1, 2011, the US government endorsed these recommendations by issuing new standards that guarantee free coverage (ie, without copayments) for many preventive services for women.

Coverage for Birth Control a Key recommendation To reduce the rate of unintended pregnancies, the report advocated, and the government now mandates, that the full range of contraceptive methods currently approved by the US Food and Drug Administration, as well as patient education and counseling, be covered by health insurance companies.

“Unintended pregnancies carry health consequences for the mother

and also consequences for the newborn,” Dr Rosenstock said. “The overwhelming evidence is strongly supportive of the health benefit” of contraception use.

traceptives. The US Conference of Catholic Bishops and some conservative groups, including the Family Research Council, had strenuously opposed any requirement for coverage of contraceptives.

“This report provides a road map for improving the health and well-being of women.”

New Preventive Services to Be Covered Coverage of preventive health services, as recommended by the IOM panel, was also mandated. The services include: • At least 1 “well-woman” preventive care visit annually • Annual HIV counseling and screening for sexually active women • Screening for and counseling about domestic violence • Annual counseling on sexually transmitted infections for sexually active women • Support for breastfeeding mothers, including the cost of renting pumps • Screening for human papillomavirus starting at age 30, then every 3 years • Screening for gestational diabetes.

Although many women already had coverage of preventive services under private insurance or Medicare, researchers have found that they use them much less than recommended.

—Linda Rosenstock, MD, MPH Although birth control is virtually universal in this country, and generic versions of oral contraceptives cost as little as $9 a month, about 50% of all pregnancies are unplanned. Experts say that a shift to longer-acting forms of contraception would help. Greater use of birth control could also help women to space their pregnancies at 18 to 24 months apart or longer, which would optimize health.

Sterilization procedures will also be covered, along with emergency con-

Continued from page 1

Federal officials said that they would try to promote their use by publicizing their being universally cost-free.

Insurers can still, however, use “reasonable medical management techniques” to control costs and promote the efficient delivery of care. For example, an insurer can charge copays for brand-name drugs if a lower-cost generic version is available.

“Profound Shift” in Care “As a centerpiece of the ACA of 2010, the focus on preventive services is a profound shift from a reactive system that primarily responds to acute problems and urgent needs to one that helps foster optimal health and well-being,” a news release from the IOM noted.

“Women stand to benefit from this shift, given their longer life expectancies, reproductive and gender-specific conditions, and historically greater burden of chronic disease and disability.

And, for the same reasons, they will benefit economically, since the ACA removes cost-sharing requirements for specified preventive services—eliminating out-of-pocket costs that often put screenings, counseling, and procedures supporting health out of reach for moderate- and lower-income women.” ■

Cesarean rate Climbs despite Safety of Vaginal Birth Higher reimbursement encourages overuse of surgical procedures

By Rosemary Frei, MSc

F

or more than 20 years, experts have called for changes in physician and hospital payments to curtail the rapidly rising rates of cesarean sections. However, the average physician reimbursement rate in the United States is still higher for performing a cesarean section than a vaginal delivery.

James R. Scott, MD, Editor-in-Chief of Obstetrics & Gynecology, addressed this topic in a clinical expert series article just published in the journal (Scott JR. Obstet Gynecol. 2011;118:342-350), focusing on the importance of reducing the escalating rate of cesarean deliveries, and why the fee structure still favors cesarean section.

In an interview with Dr Scott, he observed, “This is one of many examples of wrong incentives in our healthcare system. In my view, the physician fee should be the same for a vaginal delivery as it is for a cesarean, and it should be higher for vaginal birth after cesarean delivery [VBAC]….Whether third-party payers are receptive to a more fair and rational fee schedule is a question I can’t answer.”

Dr Scott discusses the benefits of vaginal delivery in the article and provides detailed information on the safety of vaginal birth, as well as practical instructions on how to assess patients for a potential trial of labor after cesarean and how to deal with emergencies arising during vaginal birth.

However, the elephant in the room is the fact that the time/payment equation for physicians still tilts in favor of cesarean sections—and appears likely to stay that way for the near future.

“It would be very complicated to change the fee schedule and would require a concerted effort on the part of third-party payers, hospitals, and physicians,” Dr Scott pointed out.

“And another factor weighing against VBAC is the medicolegal difficulties associated with a bad outcome from vaginal delivery.”

One of the main reasons for first delivery by cesarean is nonreassuring fetal heart rate, says Dr Scott. According to one study, this constituted 32% of the increase in primary cesarean sections in the United States between

2003 and 2009 (Barber EL, et al. Obstet Gynecol. 2011;118:29-38). Dr Scott noted that although continuous fetal heart rate monitoring is “entrenched” in American obstetrics, it is associated

“In my view, the physician fee should be the same for a vaginal delivery as it is for a cesarean, and it should be higher for vaginal birth after cesarean delivery.”

—James R. Scott, MD

with false-positives and has not improved perinatal outcomes or lowered the rate of cerebral palsy.

In 2010, the American Congress of Obstetricians and Gynecologists (ACOG) issued updated guidelines for VBAC (ACOG. Obstet Gynecol. 2010; 116:450-463). The guidelines state that VBAC should be offered to most women with 1 previous cesarean deliv-

ery with low transverse incision, and that it should also be considered in those with 2 previous low-transverse cesarean deliveries.

Dr Scott added that vaginal delivery is associated with fewer complications than cesarean section, is less expensive, has a shorter recovery, and “for many women, is more satisfying than cesarean delivery.” He lays out factors that physicians and patients should consider when deciding whether to do a trial of labor after a cesarean, and how to safely manage labor and delivery.

In an accompanying editorial on the topic, Deputy Editor John Queenan, MD, agreed with Dr Scott (Queenan JT. Obstet Gynecol. 2011;118:199-200). Dr Queenan writes that the current estimated 50% rate of cesarean deliveries “seems too high and would draw commonsense criticism from many areas. As of now, the problem is ours to solve. If cesarean delivery rates spiral upward, our profession will lose both credibility and the opportunity to determine our direction as third-party payers and the government will become involved.” ■

AUGUST 2011 l VOLUME 3, NUMBER 4

23

Nutrition

high-Dose Vitamin e may relieve Dysmenorrhea The use of 800 IU, but not 400 IU, appears therapeutic

By Caroline Helwick

Washington, DC—High-dose vitamin E was effective in treating primary dysmenorrhea in young women participating in a controlled study presented at the 2011 meeting of the American College of Obstetricians and Gynecologists.

The use of vitamin E 800 IU/day significantly decreased the pain of primary dysmenorrhea compared with the control group, but 400 IU did not, according to researchers from the West Indies.

“This indicates that a higher dose of

vitamin E was needed to obtain significant reduction in menstrual cramps for the population studied,” said Gregory Lewis, MD, University of the West Indies, Kingston, Jamaica.

Vitamin E is a known inhibitor of

The T he 1st 1st & Only Only FFD FDA DA C Cleared le a r ed B Blood loo d T Te Test est ffo for or P Pre-Surgical re -Surgical Evaluation Evaluation of of Ovarian Ovarian Masses M a s ses

Pain Scores among Women Table with Dysmenorrhea Managed with Vitamin E Mean pain Group score P comparison difference value –.332 .855 Vitamin E 400 IU vs control –1.80 .009 Vitamin E 800 IU vs control –1.47 .038 Vitamin E 400 IU vs vitamin E 800 IU protein kinase C, which prevents the release of arachidonic acid from cellmembrane phospholipids and inhibits prostaglandin biosynthesis. Based on its mode of action, therefore, vitamin E may be an effective treatment for primary dysmenorrhea, the investigators hypothesized.

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 *FDA official OVA1 VA1 p product roduct insert. inser t. 2Data Data from from O OVA1 VA1 C Clinical linical T Trial. rial. O OVA1 VA1® is a q qualitative ualitative serum serum test te s t *FDA clearance clearance does does not not denote d e n o te o f ficial aapproval. pproval. 1O off fi five for women women who who meet meet the the following following criteria: criteria: over over into a single single numerical numerical result. result. It It is indicated indicated for tthat hat ccombines ombines tthe he rresults esult s o ve iimmunoassays mmunoassays into n aaid id tto o ffurther ur ther aassess ss e ss 18, ovarian mass present which to an an oncologist. oncologist. O OVA1 VA1® is aan hich surgery surger y is is planned, planned, and and not not yet yet referred referred to aage ge 1 8, o varian aadnexal dnexal m a ss p resent ffor or w the the likelihood likelihood that that malignancy malignancy is p present r e s e nt w when hen the the physician’s physician’s independent independent clinical clinical aand nd rradiological adiological eevaluation valuation d does oes n not ot iindicate ndicate m malignancy. alignancy.

The The test test is not not intended intended as as a screening screening o orr sstand-alone tand-alone d diagnostic iagnostic aassay. ssay. V Vermillion ermillion and and OVA1 OVA1 are are registered registered trademarks trademark s of of Vermillion, Vermillion, Inc. In c.

24

AUGUST 2011 l VOLUME 3, NUMBER 4

“This indicates that a higher dose of vitamin E was needed to obtain significant reduction in menstrual cramps for the population studied.”

—Gregory Lewis, MD

This prospective, randomized, controlled trial included 115 women aged 18 to 25 years who reported primary dysmenorrhea and regular menstrual cycles. After having a pelvic ultrasound to rule out pathology, the women were randomly assigned to receive vitamin E 400 IU daily, vitamin E 800 IU daily, or no vitamin E (control group).

The women began taking the supplement at least 2 days before the start of their periods and continued through the first 3 days of bleeding, for a minimum of 5 days for 1 cycle. Ibuprofen could be taken as needed.

Data relating to pain and blood loss were collected for 2 period cycles.

Severity of pain was established by use of a visual analog pain scale (0-10). Blood loss was assessed via a standardized pictorial blood loss assessment chart.

Vitamin E 800 IU was associated with significant reductions in pain scores compared with the control group, whereas 400 IU had no significant treatment effect. The efficacy of vitamin E 800 IU was significantly greater than was seen with 400 IU (Table).

Although differences in blood loss were observed between the controls and those receiving vitamin E 400 IU (–6.48 mL) and 800 IU (–17.5 mL), the differences were not significant. ■

ACOG Highlights

Novel Scanning Device offers rapid Detection of Cervical Cancer and Precursors

By Caroline Helwick

Washington, DC—A novel scanning device for detecting cervical dysplasia in patients with abnormal Pap tests was described at the 2011 meeting of the American College of Obstetricians and Gynecologists, and is now under review by the US Food and Drug Administration.

The LuViva Advanced Cervical Scan is a noninvasive and painless test that identifies precursors to invasive cervical cancer by measuring fluorescence and reflectance spectra (changes in light relative to depth). The cervix is viewed via a live video feed that is inserted through the speculum.

Unlike the Pap test and tests for human papillomavirus (HPV), the LuViva Scan does not require a tissue sample or a laboratory analysis, and the results are available within minutes.

Leo Twiggs, MD, of the University of Miami Miller School of Medicine, FL, noted that cervical cancer rates

“Cervical spectroscopy improves the detection of high-grade dysplasia and eliminates unnecessary colposcopy and biopsy.

The test is relatively simple and not uncomfortable.”

—Leo Twiggs, MD

have increased by 26% within the past 5 years. He said that the standard tests

(ie, Pap smear, HPV testing, and colposcopy) are inadequate for identifying all cervical cancer cases. Colposcopy misses up to 40% of cervical cancers, and Pap smears detect only 5% to 10% of cases.

Dr Twiggs and colleagues enrolled 1607 women at 7 clinical centers for their study with the LuViva Scan.

These women were referred after abnormal Pap smears or other abnormal endometrial findings. All the women underwent a second Pap smear, colposcopy, and biopsy in addition to the LuViva Scan.

At the meeting, Dr Twiggs presented the 2-year follow-up data of 801 women who underwent colposcopy within the past 2 years; each subject served as her own control.

Cervical spectroscopy by the LuViva

Scan detected cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in 91% of the women compared with 76% with standard tests. This translated to a 20% improvement in the detection of CIN2+, he noted.

Based on these outcomes, the use of the LuViva Scan would reduce the number of false-positive test results by 39% in women with normal histology and by 30% in women with low-grade cervical dysplasia.

“This would translate into significant cost-savings to patients and the healthcare system,” Dr Twiggs said.

“Cervical spectroscopy improves the detection of high-grade dysplasia and eliminates unnecessary colposcopy and biopsy. The test is relatively simple and not uncomfortable, and it is well accepted by patients.” ■

hope for the Future: Neuroprotection of Preterm Infants Washington, DC—The use of nanodevices to deliver anti-inflammatory agents to the neonatal, and perhaps the newborn, brain may alter the risk for cerebral palsy in preterm infants, according to cutting-edge research presented at the 2011 meeting of the American College of Obstetricians and Gynecologists.

Roberto J. Romero, MD, Chief, Perinatal Research Branch, National Institutes of Health, and Professor of Molecular Obstetrics and Genetics, Wayne State University, Detroit, MI, presented recent findings on the topic.

Dr Romero described the protective effects of magnesium sulfate, which have been recognized for some time.

The 3 randomized, controlled trials that have studied this effect have arrived at different conclusions, he said. “The evidence from these was not clear, so our group looked carefully at the studies in a meta-analysis and found a persuasive trend,” he explained.

In a 2009 meta-analysis by Dr Romero and colleagues, the use of magnesium sulfate reduced the risk for cerebral palsy by 31%, including risk for severe cerebral palsy, without increasing pediatric mortality. The

number of mothers needed to treat to prevent 1 case of cerebral palsy was 52, and the cost of prevention was just $197 per patient, he said.

Infection a Cause of Preterm Birth and Cerebral Palsy The evidence is “compelling” that intrauterine infection and inflammation play a role in preterm labor and, therefore, in the development of cerebral palsy, Dr Romero said. In utero infection or inflammation accounts for about 20% of cases of cerebral palsy.

Bacterial infections are implicated in cerebral palsy. Specifically, infection or inflammation leads to periventricular leukomalacia, which leads to cerebral palsy, he said.

“The presence of funisitis at birth suggests the neonate was exposed to infection in utero, and this can be useful in the medicolegal setting,” he added. In other words, this condition suggests that cerebral palsy is not a result of birth injury.

Cerebral palsy appears to be associated with intra-amniotic infection and inflammation can be prevented. In neonatal animals, infusion of dendrimers (nanodevices) containing the anti-inflammatory agent N-acetyl -

“By using nanodevices, we can deliver anti-inflammatory agents to neonatal, and maybe newborn, brains, thus changing the development of cerebral palsy.”

—Roberto J. Romero, MD

cysteine ameliorated neural inflammation, he said.

“Dendrimers preferentially localize in activated microglia and astrocytes (key cells in cerebral palsy),” Dr Romero said. “They behave like stem cells. You give them intravenously and they find their way to the neuroinflammation.”

An experiment in pregnant rabbits with endotoxin-induced neuroinflammation produced a dramatic effect. At birth, littermates either remained untreated or were injected with dendrimers that release N-acetylcysteine.

The untreated endotoxin-exposed rabbits exhibited motor symptoms of cerebral palsy, but animals who received the experimental treatment showed substantial improvement in motor coordination, demonstrated by a video accompanying Dr Romero’s presentation.

“I believe these experiments show that neuroinflammation can cause cerebral palsy, that molecular techniques can detect neuroinflammation at birth, and that using nanodevices, we can deliver anti-inflammatory agents to neonatal, and maybe newborn, brains, thus changing the development of cerebral palsy,” Dr Romero acknowledged.—CH ■

AUGUST 2011 l VOLUME 3, NUMBER 4

25

ACOG Highlights

Few Women Can Accurately Predict Day of ovulation

By Caroline Helwick

Washington, DC—Only 1 in 8 women trying to conceive accurately identified their day of ovulation in a study presented at the 2011 meeting of the American College of Obstetricians and Gynecologists.

Jayne Ellis, PhD, of SPD Swiss Precision Diagnostics GmbH in Geneva, which makes the Clearblue Easy Fertility Monitor, presented the study.

“Women tend to think they ovulate around day 14, but there is a lot of variability in the menstrual cycle, and we found that many women ovulate much later,” she said in an interview. “Women who had previously used home ovulation tests were more likely to provide an answer to the question ‘When do you think you ovulate?,’ indicating that their use had provided some degree of education and awareness regarding their menstrual cycle. However, many women’s estimates were wrong for the cycle in which they conceived.”

The prospective conception study examined the accuracy of women’s estimation of the days they ovulate by comparing their estimated fertile days

against an accurate analysis using urinary hormone monitoring. Only 56% of the women estimated correctly their ovulation time within a margin of ±2

“Women who are aware of their real fertile periods have much better chances of conceiving than those who just guess.”

—Jayne Ellis, PhD

days. This was likely a result of lack of awareness of their menstrual cycle characteristics and intracycle variability, according to Dr Ellis. During the study, women provided daily urine samples and used the Clearblue Fertility Monitor to aid in conception.

For each woman who became pregnant, a laboratory measurement of luteinizing hormone (LH) was used to

verify LH surge in the cycle during which they conceived. Their ovulation day was calculated as the day after the confirmed LH surge.

Of the 130 women who became pregnant, 102 reported at recruitment that they knew their day of ovulation, including most of those who previously used an ovulation test.

For women who reported a (perceived) day of ovulation, 51% believed that they ovulated on day 14 or 15; however, laboratory analysis showed that ovulation occurred on these 2 days in only 20% of the cycles that led to conception. The actual ovulation day ranged from day 9 to day 44.

The women’s perceptions and laboratory tests were an exact match in <13% of cases; they matched within 1 day in 38% of cases, and within 2 days in 56% of cases. The median difference in agreement was 2 days (ie, the calculated ovulation day was typically 2 days later than expected by the women); the range of inaccuracy spanned from –10 to +27 days.

For 22% of women, ovulation

occurred earlier than predicted, and 44% were >2 days too late or 2 days too early in their predictions.

“If this latter group had been relying on calendar ovulation methods alone to predict peak fertility, they would have missed their opportunity to conceive,” Dr Ellis noted. “It would be expected that previous ovulation test users would have better awareness of their own cycle characteristics, but in our study, the numbers were too low to test this hypothesis. However, even if women are able to correctly cite their ‘average day of ovulation,’ since the typical menstrual cycle length variability is 6.7 days, it is not likely to be correct in any given cycle.”

“The study reinforces what is known —that women who are aware of their real fertile periods have much better chances of conceiving than those who just guess,” Dr Ellis commented.

She added that a prospective method for correctly identifying the fertile phase, which identifies the LH surge, is useful for couples who wish to time intercourse. ■

labor Progresses Differently for Induced Versus Spontaneous Delivery in Nulliparous Women Washington, DC—Is there a difference in the labor progression of nulliparous women in induced versus spontaneous labor? Investigators from St Luke’s Roosevelt Hospital in New York say that there is.

In a study presented by Hasra K. Philip, MD, MPH, at the 2011 meeting of the American College of Obstetricians and Gynecologists, this question was evaluated in a prospective study of 195 women presenting for delivery over a 4-month period.

“Our findings suggested that the progression of an induced labor differs from spontaneous labor in nulliparous women,” Dr Philip said.

The researchers found absolute indications for induction in 25% of the women, and relative indications in 65%. Method of delivery for the spontaneous labor group (n = 71) was vaginal in 83%, operative vaginal in 22%, and cesarean section in 19%. For the induced labor group (n = 124), 27%

26

had vaginal delivery, 5% had operative vaginal delivery, and 29% underwent cesarean section. This yielded a signifi-

“Our findings suggested that the progression of an induced labor differs from spontaneous labor in nulliparous women.”

—Hasra K. Philip, MD, MPH

cant 2.66 increased risk for having a cesarean delivery among the induced group, Dr Philip reported.

Induced nulliparous women had a significantly shorter active phase of labor: 3.9 hours versus 5.4 hours. The second stage of labor in induced women was also significantly shorter: 1.3 hours versus 1.8 hours. No significant differ-

AUGUST 2011 l VOLUME 3, NUMBER 4

ence was seen in the duration of the latent phase of labor, which was 9.1 hours for the induced group and 10.2 hours in the spontaneous group.

“The traditional Friedman labor curve developed for nulliparous women may not apply, therefore, to induced patients,” Dr Philip concluded.—CH ■

updated Menopause Practice released The North American Menopause Society has released the updated and referenced fourth edition of Menopause Practice: A Clinician’s Guide.

Edited by dozens of experts in the field, this comprehensive clinical practice textbook is available in print and digital formats (www. menopause.org).

“This current, annotated resource is for all clinicians caring for menopausal women,” said contributing editor Risa Kagan, MD, FACOG, CCD, NCMP, University of California, San

Francisco. “It is also an invaluable tool for teaching medical students and staff.”

The book provides an overview of menopause and its physical effects, premature menopause and primary ovarian insufficiency, clinical issues and disease risks associated with menopause, clinical evaluation and counseling of midlife women, and treatment options for menopausal symptoms ranging from lifestyle interventions to nonprescription therapies to prescription hormonal therapies. ■

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CONTINUING EDUCATION

PROGRAM CE14 • RELEASE DATE: AUGUST 26, 2011 • EXPIRATION DATE: AUGUST 26, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Stem Cells overview: the growing Importance of Fetal tissue

By Kate Torchilin, MS, PhD, MBA Ms Torchilin is CEO of Biocell Center, Medford, MA STATEMENT OF NEED With more than 4 million women giving birth in the United States every year, approximately 3% or 120,000 babies are born each year with various birth defects. Many of these problems are detected prenatally, with the use of a variety of screening and diagnostic tests. As people age, they are at increased risk for chronic diseases, such as cardiovascular and neurodegenerative diseases, diabetes, or cancer. Researchers are now finding ways to potentially treat many such conditions with different types of stem cells. Knowing which stem cells can be preserved during pregnancy is therefore important for those treating expecting parents. It is also important that those who provide healthcare for women are aware of the increasing role of fetal tissue in regenerative medicine and the potential applications of stem cells collected during pregnancy.

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 definition and main characteristics of stem cells, including mesenchymal stem cells, such as pluripotency, proliferation, and genetic stability • Describe the difference between stem cells derived from embryonic cells, amniotic fluid, cord blood cells, and adult tissue • Review the role of stem cells in regenerative medicine • Understand the potential applications of stem cells collected during pregnancy 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.theobgynnurse.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”

W

ith more than 4 million women giving birth in the United States every year, approximately 3% or 120,000 babies are born each year with various birth defects.1 Many of these problems are detected prenatally, using a variety of screening and diagnostic tests. As people age, they are at increased risk for chronic diseases, such as cardiovascular and neurodegenerative diseases, diabetes, or cancer. Researchers are now finding ways to potentially treat many of these conditions with stem cells.

Stem cells hold enormous potential for medicine. A day does not go by without a new announcement about an exciting scientific discovery or a medical achievement with stem cells. The many achievements in the past year alone have ranged from the replacement of a cancerous trachea with a healthy one grown from a patient’s own stem cells2 to the first patient being treated with novel stem-cell therapy for spinal cord injury3 to mouse fetal kidneys being grown from amniotic-fluid stem cells.4 The potential to replace defective or damaged cells (resulting from a variety of disorders and injuries), leading to a range of new regenerative therapies, is the driving force behind the profound interest in stem cells.

It is critical that providers who are managing pregnant women or those who provide medical care for women in general are aware of the latest options available through stem-cell therapies.

regenerative Potential Stem cells are unique cells whose fate is not yet “decided,” meaning that they have the ability to eventually develop into various types of cells. When stem cells divide, the new cells can either remain as stem cells or become specialized cells, such as nerve, lung, blood, or muscle cells.3 In an embryo, stem cells differentiate into cells that form all the organs and tissues of the body. In an adult, stem cells generate replacement cells for those lost through normal wear and tear, or help to repair injured or diseased organs.5 Throughout one’s life, stem cells constantly carry out regenerative functions. For example, the outer layer of the skin (ie, epidermis) renews itself completely every 2 weeks. In some organs, such as the intestine, the tissues lining the interior walls are subject to a constant cell turnover. Another critical area where cells regenerate is bone marrow, which contains progenitor cells of blood: red cells, white cells, platelets, and immune cells. Thanks to stem cells in the bone marrow, blood is regenerated continuously at a rate of 100 billion cells daily and is totally renewed every 4 months.

The figure of Prometheus from Greek mythology helps to illustrate the basic concept of stem cells. When Prometheus transgressed the laws of the gods and gave man the gift of fire, his punishment was to be chained to Mount Caucasus, where his liver was

devoured by an eagle during the day and regenerated during the night. This strong imagery captures the extraordinary ability of the human body to renew itself. This ability is now being materialized by developments in biomedical research for many disease treatments. historical Background The history of stem-cell research started in the early 1900s, when stem cells were discovered as cells that had the ability to generate blood cells. The first prominent application of stem-cell research was bone marrow transplantation using adult stem cells. In 1963, Becker, McCulloch, and Till illustrated the presence of self-renewing cells in mouse bone marrow.6 This caused physicians to speculate whether it was feasible to transplant bone marrow from one human to another.

Early attempts included several transplants in France after a radiation accident in the late 1950s, and the bone marrow transplant between 2 siblings in 1968, which successfully treated severe combined immunodeficiency.

Since then, bone marrow transplants have been a common medical practice.

In one of the latest examples, Japanese authorities have proposed the precautionary measure of harvesting and banking stem cells from the bone marrow of workers at the Fukushima Nuclear Power Plant to transplant the cells back into those who may be exposed to dangerous levels of radiation.

Continued on page 28

6. Complete and submit the CE posttest and CE activity evaluation 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 exposition or conclusion and resolve any conflicts of interest prior to the commencement of the educational activity. Disclosures are as follows: • Kate Torchilin, PhD, MBA, 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 Kate Torchilin, PhD, MBA Chief Executive Officer Biocell Center Corp.

200 Boston Ave, Suite 1550 Medford, MA 02155 Debra Moynihan, WHNP-BC, MSN Nurse Practitioner, Women’s Health Clinical Director, Carolina OB/GYN 242 Willow Bay Drive Murrells Inlet, SC 29576

AUGUST 2011 l VOLUME 3, NUMBER 4

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CONTINUING EDUCATION

WWW.THEOBGYNNURSE.COM

Stem Cells overview... Continued from page 27 Ultimately, the biggest hope for stem cells is the development of stem-cell– based therapies that could offer promise for curing serious diseases for which limited or no treatment options are available (ie, Alzheimer’s disease, Parkinson’s disease, paralysis, spinal cord injury, heart failure, liver disease, or type 1 diabetes).

Key Definitions and Properties Stem cells are comprised of a large class of cells that form the basis for all human cells. These cells have different functions, depending on where they are found in the human body and when they are collected during the human organism’s lifetime.

The medical and scientific communities use several key characteristics to define and describe stem cells. All stem cells—regardless of their source—have 2 general properties5: 1. They are unspecialized and can give rise to specialized cell types (ie, differentiation) 2. They are capable of dividing and renewing themselves for long periods (ie, proliferation).

Differentiation Stem cells can be classified into several categories, based on their ability to differentiate: • Totipotent stem cells can develop into any other cell type and can form a complete organism; this cell type is found only in early embryos, is produced from the fusion of an egg and sperm cell, and exists through the first few divisions of a fertilized egg • Pluripotent stem cells can differentiate into nearly all cells (ie, cells derived from any of the 3 germ layers). For example, amniotic-fluid stem cells are pluripotent and can develop into skin, cartilage, bone, nerve, cardiac, and other types of cells • Multipotent stem cells can differentiate only into a closely related family of cells; for example, umbilical-cord blood cells can develop into several different types of blood cells but not into other types of tissue • Unipotent stem cells can produce only 1 cell type—their own—but have the ability to self-renew, which distinguishes them from non–stem cells (eg, muscle stem cells).

Proliferation Stem cells possess a high capacity to go through many cycles of cell division, or proliferation, while staying undifferentiated. The exact number of divisions that a stem cell can go through and remain unspecialized is different for different types of stem cells.

For example, amniotic-fluid stem

28

cells can go through several hundred cell divisions and remain undifferentiated, whereas some stem cells, such as those from cord blood and from adult tissues, can only go through 10 to 20 divisions.7,8 Proliferation is an important feature for clinical stem-cell uses, because it provides the ability to generate a large number of cells from few initial cells. the many types of Stem Cells Stem cells can be found in and obtained from several sources, and each source has important implications on the properties of cells. The Table lists characteristics of some of these different types of stem cells.

Embryonic Cells Embryonic stem cells are derived from the inner cell mass of an embryo at a very early stage of development, when it is comprised of a hollow sphere of dividing cells (ie, a blastocyst).9 Embryonic stem cells have the greatest ability of all cells to proliferate and differentiate into any cell type. However, the use of human embryonic stem cells remains a heavily disputed ethical issue, because these cells are collected from early-stage embryos.

Although the embryos from which embryonic stem cells have been obtained are produced from discarded embryos resulting from in vitro fertilization, many persons consider preimplantation human embryos to be human beings, and therefore consider anything that would terminate their potential to be born as morally wrong.

In addition, when embryonic stem cells proliferate, it often results in accumulation of DNA breakdown, and the cells ultimately become cancerous.

This is also known as the lack of genetic stability.10,11

Adult Cells Stem cells also can be found in a variety of adult tissue. However, these somatic cells are not as versatile and durable as embryonic stem cells, because most cannot produce all cell types. Adult stem cells typically only generate the cell types of the tissue in which they reside. For example, a blood-forming adult stem cell in the bone marrow normally gives rise to various types of blood cells.12,13 Umbilicalcord blood, although collected from the newborn baby, is an example of adult hematopoietic stem cells—and can only give rise to other blood cells.

The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Because adult stem cells are unable to produce all cell types, this

AUGUST 2011 l VOLUME 3, NUMBER 4

Table Characteristics of Various Types of Stem Cells Type of stem cell

Pluripotency

Proliferation

Genetic stability

Embryonic

Totipotent

Very high

Not stable Ethical consideration

Fetal

Pluripotent

High

Stable

Easily collected from amniotic fluid, placenta

Adult

Multipotent or Low unipotent

Stable

Often difficult to harvest (bone marrow, fat, muscle)

Induced pluripotent

Pluripotent

Varied

Reverse engineered from adult tissue

Varied

Comments

Sources: References 9, 11, 12, 16, 17, 22.

limits how they can be used to treat different diseases.

Furthermore, adult stem cells do not seem to have the same ability to multiply as embryonic stem cells, and are more likely to contain abnormalities as a result of environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, adult stem cells offer an advantage over embryonic stem cells in their freedom from ethical controversy.

Adult stem cells do not seem to have the same ability to multiply as embryonic stem cells, and are more likely to contain abnormalities as a result of environmental hazards.

Adult stem cells are rare in mature tissue; therefore, isolating these cells is challenging, and methods to expand their numbers in cell culture are limited.14 This is an important distinction, because large numbers of cells are needed for stem-cell replacement therapies.

Fetal Cells Fetal stem cells fit in the developmental continuum between embryonic and adult stem cells. They typically come from tissue that surrounds the fetus during pregnancy and not from the fetus directly. Fetal stem cells have distinct characteristics that combine the advantages and avoid the disadvantages of embryonic and adult stem cells.7,15 Their use does not present any ethical issues, because the embryo is not affected or harmed by the collection of these cells (eg, just a teaspoon of amniotic fluid taken from a prenatal

test contains enough potent stem cells to create tissues, such as heart valves, parts of a diaphragm, or trachea).16-18 Fetal stem cells have excellent biological characteristics, and can be derived from amniotic fluid, placenta, and chorionic villi.

Induced Pluripotent Cells Finally, the most recently discovered type of stem cell is the so-called induced pluripotent cell—cells that are generated via genetic engineering and manipulation of the fully developed adult cell (typically, the epithelial cell) to revert it to a stem-cell state.19 These cells may eventually offer the way to generate stem cells in the laboratory without relying on other sources, although the research is still early, and human applications are likely many years away.

Mesenchymal Stem Cells and Amniotic Fluid One specific type of stem cell that has moved to the forefront of stem-cell research and clinical development is the mesenchymal stem cell (MSC). This type of stem cell is defined by several characteristics.

First, MSCs have fibroblastic (ie, elongated) morphology under the microscope, they are pluripotent, and can differentiate into many other types of cells, including skin, muscle, neurons, cardiac tissue, kidney, liver, cartilage, and bone.

In addition, they are genetically stable upon proliferation, meaning that they can divide many times and do not form cancer. All these characteristics make MSCs potentially useful for a broad range of therapeutic applications and tissue engineering.20 Bone marrow, certain adult tissues, and fetal tissues, such as amniotic membranes and amniotic fluid, are all sources of human MSCs.21 Amniotic fluid is the nourishing and protective liquid that surrounds the

CONTINUING EDUCATION

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fetus during pregnancy. Most OB/GYN specialists are familiar with the use of this fluid for prenatal genetic diagnosis during the second trimester of pregnancy, when a small amount of fluid is collected via an amniocentesis procedure for the analysis of potential fetal chromosomal abnormalities, or for the confirmation of fetal lung maturing later in pregnancy.

Amniotic fluid is also one of the richest natural sources of stem cells.7,22 As the fetus grows inside the amniotic sac, it sheds various cells into the amniotic fluid, including the cells that are developing into various organs in its body.

Many of these cells are MSCs that can be used for future clinical applications.

Conclusion: Potential Applications of Stem Cells Collected during Pregnancy Experimental data show a great potential for stem cells to revolutionize regenerative medicine. In July 2011, doctors in the United Kingdom performed ground-breaking surgery to replace a cancer-damaged trachea in a patient with a new, fully functioning trachea grown out of the patient’s own stem cells, and the patient is already released home as cancer free.

In animal models, stem cells can

engraft and repair damaged areas of bone, kidney, gut, and the central nervous system. Stem cells could potentially be used for the treatment of currently incurable diseases, such as neurodegenerative and cardiovascular diseases, autoimmune disorders, traumatic injuries, cirrhosis, and cancer.

Genetically “corrected” stem cells could potentially replace cells with genetic mutations, such as monogenetic recessive mutations of CFTR in cystic fibrosis patients.23,24 Tissues that develop during a woman’s pregnancy, such as placenta, Wharton’s jelly, and amniotic fluid, are becoming more and more important sources of stem cells for therapeutic applications. This is reasonable, considering that they combine the best features of embryonic and adult cells but lack the disadvantages of these sources.

Compared with embryonic cells, fetal cells can be obtained without interfering with the normal development of the unborn baby, they are more genetically stable, and they are easier to handle and process. And they are more pluripotent and have higher rates of proliferation compared with adult stem cells.25 Educating patients has always been a critical role of nurses. Now, expecting parents and their healthcare providers

are faced with more options of which stem cells can be preserved during pregnancy, as well as more education on stem cells and their increasing role in regenerative medicine. It is critical that providers who are managing pregnant women or those who provide medical care for women in general are aware of the latest options available through stem-cell therapies. ■ references 1. Centers for Disease Control and Prevention. Birth defects data and statistics. www.cdc.gov/ncbddd/birth defects/data.html. Accessed June 14, 2011.

2. Naik G. Lab-made trachea saves man. Wall Street Journal. July 8, 2011. http://online.wsj.com/article/ SB10001424052702304793504576432093996469056. html. Accessed July 8, 2011.

3. Winslow R, Mundy A. First embryonic stem-cell trial gets approval from the FDA. Wall Street Journal. January 23, 2009. http://online.wsj.com/article/SB123268485 825709415.html. Accessed June 14, 2011.

4. Perin L, Giuliani S, Jin D, et al. Renal differentiation of amniotic fluid stem cells. Cell Prolif. 2007;40:936-948.

5. National Institutes of Health. Stem cell basics. 2009. http://stemcells.nih.gov/info/basics/defaultpage.

Accessed May 20, 2011.

6. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature.

1963;197:452-454.

7. De Coppi P, Bartsch G Jr, Siddiqui MM, et al.

Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol. 2007;25:100-106.

8. Sessarego N, Parodi A, Podestà M, et al. Multipotent mesenchymal stromal cells from amniotic fluid: solid perspectives for clinical application. Haematologica.

2008;93:339-346.

9. Evans MJ, Kaufman MH. Establishment in culture of pluripotent cells from mouse embryos. Nature. 1981;292: 154-156.

10. Blum B, Benvenisty N. The tumorigenicity of

human embryonic stem cells. Adv Cancer Res. 2008;100: 133-158.

11. Hanson C, Caisander G. Human embryonic stem cells and chromosome stability. APMIS. 2005;113:751-755.

12. Seita J, Weissman IL. Hematopoietic stem cell: selfrenewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med. 2010;2:640-653.

13. National Institutes of Health. Hematopoietic stem cells. 2001. http://stemcells.nih.gov/info/scireport/ chapter5. Accessed May 20, 2011.

14. National Institutes of Health. What are adult stem cells? 2010. http://stemcells.nih.gov/info/basics/basics4.

Accessed May 20, 2011.

15. Gucciardo L, Lories R, Ochsenbein-Kölble N, et al.

Fetal mesenchymal stem cells: isolation, properties and potential use in perinatology and regenerative medicine. BJOG. 2009;116:166-172.

16. Schmidt D, Achermann J, Odermatt B, et al.

Cryopreserved amniotic fluid-derived cells: a lifelong autologous fetal stem cell source for heart valve tissue engineering. J Heart Valve Dis. 2008;17:446-455.

17. Fuchs JR, Kaviani A, Oh JT, et al. Diaphragmatic reconstruction with autologous tendon engineered from mesenchymal amniocytes. J Pediatr Surg. 2004;39: 834-838.

18. Kunisaki SM, Freedman DA, Fauza DO. Fetal tracheal reconstruction with cartilaginous grafts engineered from mesenchymal amniocytes. J Pediatr Surg.

2006;41:675-682.

19. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676.

20. Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217:318-324.

21. Edwards RG, Hollands P. Will stem cells in cord blood, amniotic fluid, bone marrow and peripheral blood soon be unnecessary in transplantation? Reprod Biomed Online. 2007;14:396-401.

22. In ‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, et al. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation.

Blood. 2003;102:1548-1549.

23. Atala A. Advances in tissue and organ replacement.

Curr Stem Cell Res Ther. 2008;3:21-31.

24. Sueblinvong V, Suratt BT, Weiss DJ. Novel therapies for the treatment of cystic fibrosis: new developments in gene and stem cell therapy. Clin Chest Med. 2007;28:361-379.

25. Pappa KI, Anagnou NP. Novel sources of fetal stem cells: where do they fit on the developmental continuum? Regen Med. 2009;4:423-433.

COMMENTARY

Implications of Stem-Cell research

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

S

tem-cell research has been one of the most controversial topics of the past 2 decades. If executed in a responsible manner, the use of stem cells in medicine may prove to be of great benefit to many people in the future. Stem cells may provide ways to treat conditions such as Alzheimer’s disease, spinal-cord injuries, heart disease, diabetes, and rheumatoid arthritis. The list of possibilities continues to grow as research moves forward.

Stem cells can also be used to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects. The current dilemma lies in how the cells are obtained.

In 2005, Research!America conducted a poll to determine Americans’ opin-

ions on stem-cell research.1 Suprisingly, 58% of respondents indicated that they were in favor of using embryonic stem cells in medical research. A total of 29% were opposed to it, and of that 29%, 57% were opposed because of religious reasons.1 Having grown up in a Catholic household, I recognize the teachings of the church and why some people are so opposed to embryonic stem-cell research. After working in the field of infertility for 13 years, however, my views have changed drastically.

For years, clinicians have been freezing embryos for future use by patients, but inevitably, many of those embryos are abandoned or discarded. If a patient has conceived in a previous in vitro fertilization cycle, she may no longer need

the frozen embryos. Some couples have issues with donating their frozen embryos to other infertile couples. In other cases, embryos never get used, because their owners move and cannot be found. As a result, embryos nest in tanks all over the world. If more people were aware of this, maybe they would understand that using embryos for research is a much better option than the ultimate destruction of these embryos as a result of abandonment.

I believe that donating embryos for medical research is the same as donating an organ. This may someday enable us to recreate needed organs with stem cells instead of persons in need being placed on a waiting list for those organs.

The option of obtaining cells through amniotic fluid seems like a

wonderful opportunity, because it does not require the destruction of embryos, and cells are easier to obtain. Also, the benefit of these cells being coaxed into developing a wide range of cell types appears promising.

Let us hope that the OB/GYN population will develop a convenient way to collect amniotic fluid for this purpose in the near future. In the meantime, the public, as well as medical professionals, need to be educated and updated on the growing progress of stem-cell research to reduce some of the prevalent resistance. ■ reference 1. Research!America. Taking our pulse: the PARADE/ Research!America health poll. Charlton Research Company. 2005. www.researchamerica.org/uploads/poll stemcellparade.pdf. Accessed August 7, 2011.

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Meetings 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 Pacific Coast Obstetrical and Gynecological Society 9/14-9/18 Sunriver, OR Contact: www.pcogs.org/contact.cfm www.pcogs.org American Gynecological & Obstetrical Society 9/15-9/17 Chicago, IL Contact: (804) 924-9937 www.agosonline.org Association of Reproductive Health Professionals 9/15-9/17 Las Vegas, NV Contact: (202) 466-3825 ARHP@arhp.org www.reproductivehealth2011.org 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 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

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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

GENERESS™ Fe (norethindrone and ethinyl estradiol chewable tablets and ferrous fumarate chewable tablets) 0.8 mg/25 mcg Brief Summary For full prescribing information, see package insert Rx only WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications (4).]

1 INDICATIONS AND USAGE GENERESS Fe is indicated for use by women to prevent pregnancy.

The efficacy of GENERESS Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated.

4 CONTRAINDICATIONS Do not prescribe GENERESS Fe to women who are known to have the following: • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: - Smoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)] - Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)] - Have cerebrovascular disease [see Warnings and Precautions (5.1)] - Have coronary artery disease [see Warnings and Precautions (5.1)] - Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)] - Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] - Have uncontrolled hypertension [see Warnings and Precautions (5.4)] - Have diabetes with vascular disease [see Warnings and Precautions (5.6)] - Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.7)] • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.2)] • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3) in the full prescribing information] • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)] • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Thrombotic and Other Vascular Events Stop GENERESS Fe if an arterial or deep venous thrombotic (VTE) event occurs.

Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

If feasible, stop GENERESS Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

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

extent to which these findings may be due to differences in sexual behavior and other factors.

5.3 Liver Disease Discontinue GENERESS Fe if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop GENERESS Fe if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

5.5 Gallbladder Disease Studies suggest the relative risk of developing gallbladder disease may be increased among COC users.

5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking GENERESS Fe. COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.7 Headache If a woman taking GENERESS Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue GENERESS Fe if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.8 Bleeding Irregularities Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Patient diaries from the clinical trial of GENERESS Fe showed that on the first cycle of use, 37% of subjects taking GENERESS Fe had unscheduled bleeding and/or spotting. From Cycle 2-13, the percent of women with unscheduled bleeding/ spotting ranged from 21-31% per cycle. For those women with unscheduled bleeding/spotting, the mean number of days of unscheduled bleeding/spotting was 5.2 in the first cycle of use and ranged from 3.6 – 4.2 in cycles 2-13. A total of 15 subjects out of 1,677 (0.9%) discontinued the study prematurely due to metrorrhagia or irregular menstruation.

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

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

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

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

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

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

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

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

5.2 Carcinoma of the Breasts and Reproductive Organs Women who currently have or have had breast cancer should not use GENERESS Fe because breast cancer is a hormonally-sensitive tumor.

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the

AUGUST 2011 l VOLUME 3, NUMBER 4

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.10 Depression Women with a history of depression should be carefully observed and GENERESS Fe discontinued if depression recurs to a serious degree.

NOVEMBER Contraceptive Technology: Quest for Excellence 11/3-11/5 Atlanta, GA Contact: (800) 377-7707 info@cforums.com http://contemporaryforums.com

University of North Carolina Women’s Mental Health Conference 11/5 Chapel Hill, NC Contact: (919) 972-7442 douglas_hudson@med.unc.edu www.med.unc.edu/psych

5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs. 5.12 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.13 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. 6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and smoking [see Boxed Warning, and Warnings and Precautions (5.1)] • Vascular events [see Warnings and Precautions (5.1)] • Liver disease [see Warnings and Precautions (5.3)] Adverse reactions commonly reported by COC users are: • Irregular uterine bleeding • Nausea • Breast tenderness • Headache 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A phase 3 clinical trial evaluated the safety and efficacy of GENERESS Fe for pregnancy prevention. The study was a multicenter, non-comparative, open-label study with a treatment duration of 12 months (thirteen 28-day cycles). A total of 1,677 women aged 18-46 were enrolled and took at least one dose of GENERESS Fe. Adverse Reactions Leading to Study Discontinuation: 8.5% of the women discontinued from the clinical trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were nausea (1.0%), weight increase (0.8%), acne (0.8%), metrorrhagia (0.7%), altered mood (0.4%), hypertension (0.4%), irritability (0.3%), migraine (0.3%), decreased libido (0.3%) and mood swings (0.3%).

Common Adverse Reactions (≥ 2% of all treated subjects): nausea/vomiting (8.8%), headaches/migraine (7.5%), depression/mood complaints (4.1%), dysmenorrhea (3.9%), acne (3.2%), anxiety symptoms (2.4%), breast pain/tenderness (2.4%), and increased weight (2.3%).

Serious Adverse Reactions: Hypertension, depression, cholecystitis, and deep vein thrombosis.

7 DRUG INTERACTIONS No drug-drug interaction studies were conducted with GENERESS Fe. 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: • barbiturates • bosentan • carbamazepine • felbamate • griseofulvin • oxcarbazepine • phenytoin • rifampin • St. John’s wort • topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

DECEMBER World Congress on Pediatrics & Gynecology 12/6-12/8 Philadelphia, PA Contact: (800) 216-6499 pediatrics2011@omicsonline.org http://omicsonline.org/pediatrics2011/

7.2 Increase in Plasma Levels of Ethinyl Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain combination oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

7.3 Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed may start COCs no earlier than four weeks postpartum.

8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing OCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use Safety and efficacy of GENERESS Fe have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use GENERESS Fe has not been studied in postmenopausal women and is not indicated in this population.

8.6 Renal Impairment The pharmacokinetics of GENERESS Fe have not been studied in subjects with renal impairment.

8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of GENERESS Fe. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal [see Contraindications (4), and Warnings and Precautions (5.3)].

8.8 Body Mass Index The safety and efficacy of GENERESS Fe in women with a BMI > 35 kg/m2 have not been evaluated.

10 OVERDOSAGE There have been no reports of serious ill effects from overdose of oral contraceptives including ingestion by children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

For all medical inquiries contact: WATSON Medical Communications Parsippany, NJ 07054 USA 800-272-5525 Manufactured By: Warner Chilcott Company, LLC Fajardo, PR 00738 Distributed By: Watson Pharma, Inc. Parsippany, NJ 07054 USA March 2011

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

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NEW

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

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

Patients pay no more than $25 for each monthly prescription with savings card *In women who experienced withdrawal bleeding, the mean median intensity of withdrawal bleeding decreased from Cycle 2 (1.83/3.0) to Cycle 13 (1.64/3.0).

References: 1. GeneressTM Fe prescribing information. Morristown, NJ: Watson Pharma, Inc. December 2010. 2. Data on file. Watson Pharma, Inc.

GENERESS FE is an estrogen/progestin COC indicated for use by women to prevent pregnancy.

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

Please see brief summary of Prescribing Information on next page.

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

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