October 2011, Vol 3, No 5 by Novellus Healthcare Communications, LLC

OctOBer 2011

www.iNfertilityreprONews.cOm

VOl 3, NO 5

INFERTILITY UPDATES

CLINIC PROFILE

combining care and convenience with competitive costs:

secondary infertility: A common, Underrecognized condition

Interview with Joseph Hill, MD, Fertility Centers of New England

By Brian R. Kaplan, MD Fertility Centers of Illinois

fertility centers of New england

econdary infertility is generally defined as the inability of a couple to conceive a child after a year of unprotected intercourse, when one or both partners have previously conceived. A very common problem, secondary infertility can account for as much as 40% of infertility cases. The treatment for this phenomenon, however, is sporadic and often delayed by patients and physicians, mainly because

of the misbelief that if an individual has previously conceived, that person will always be fertile. The workup and treatment for secondary infertility should be the same as for primary infertility. The woman’s age is critical in infertility, yet it is rarely the rate-limiting step. The man’s age, although not as significant a factor, also plays a role in reduced pregnancy rates. Women are born with a set number of Continued on page 14

From left: Robert M. Weiss, MD; Joseph A. Hill, III, MD; Lynette A. Scott, PhD; Danielle Vitiello, PhD, MD; R. Ian Hardy, MD, PhD.

oseph Hill, MD, and his team at the Fertility Centers of New England operate under the philosophy of treating others the way they would like to be treated, a credo that has led to offering in vitro fertilization (IVF) at affordable rates that help to make patients’ dreams of having a family into realities. By focusing on 3 key areas—care, convenience, and cost—

the Fertility Centers of New England and its collaborative care teams have been providing patient-centered fertility care for patients in the Boston area and beyond for more than 15 years. When was the center founded, and how has it evolved over time? The center was founded as the Fertility Center of New England in Continued on page 25

AWHONN HIGHLIGHTS

Home and Hospital Births Need Not Be Opposed By Caroline Helwick

New techniques for preimplantation Genetic screening By Eve C. Feinberg, MD, FACOG Fertility Centers of Illinois

he use of assisted reproductive technology (ART) has revolutionized the treatment of male and female infertility. Since the first live birth of Louise Brown in 1979, millions of babies have been born using ART. The second major breakthrough in the field came with the discovery of intracytoplasmic sperm injection. This technology allowed couples with severe male-factor infertility to conceive. Next

came the technology for preimplantation genetic testing. This process allows for biopsy of the embryo and testing for either a single-gene disorder, such as cystic fibrosis or sickle-cell anemia, or aneuploidy screening. It is this arena of ART that is expanding rapidly and uses cutting-edge technology. Blastomere biopsy from a day-3 embryo is one option for preimplantation genetic screening (PGS). In most cases, Continued on page 15

Denver, CO—Published data suggest that home births can be as safe as in-hospital births, but many obstetric and neonatal nurses remain fairly resistant to the idea. At the Association of Women’s Health, Obstetric and Neonatal Nurses 2011 annual convention, Ellise D. Adams, MSN, CNM, of the University of Al-

abama at Huntsville, asserted that the 2 approaches do not have to be “diametrically opposed.” Regardless of the birth setting, there is a critical need to develop integrated systems of care that promote the best health for women and their newborns, Ms Adams said. Continued on page 8

The Publicationof of The Official Offical Publication

IN S ID E 20 CLINICAL NEWS . . . . . . . . . . . . . . . . . . . . 5 COMPLIMENTARY CE

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Once- and twice-frozen embryos show similar birth rates NSAID use during pregnancy may double miscarriage risk ASK THE EXPERT

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Nurse Practitioners versus Physician Assistants AWHONN HIGHLIGHTS

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MEN’S HEALTH

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INFERTILITY UPDATES

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Thrombophilia and recurrent pregnancy loss Progesterone supplementation in early pregnancy WOMEN’S HEALTH

Program is proactive about perinatal mood disorders Helping babies to breathe wherever they are born

Pelvic floor muscle training provides no benefit for incontinence

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No evidence for routine pelvic examination BREAST CANCER AWARENESS

22 29

Knowledge of fertility lacking in young women with breast cancer

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

Rx only

BRIEF SUMMARY For full prescribing information, see package insert. INDICATIONS AND USAGE Assisted Reproductive Technology Crinone 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (“ART”) treatment for infertile women with progesterone deficiency. Secondary Amenorrhea Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%. CONTRAINDICATIONS Crinone should not be used in individuals with any of the following conditions: known sensitivity to Crinone (progesterone or any of the other ingredients); undiagnosed vaginal bleeding; liver dysfunction or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders. WARNINGS The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately. Progesterone and progestins have been used to prevent miscarriage in women with a history of recurrent spontaneous pregnancy losses. No adequate evidence is available to show that they are effective for this purpose. PRECAUTIONS General 1. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear. 2. In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken. 3. Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation. 4. The pathologist should be advised of progesterone therapy when relevant specimens are submitted. 5. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. 6. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy. Information for Patients The product should not be used concurrently with other local intravaginal therapy. If other local intravaginal therapy is to be used concurrently, there should be at least a 6-hour period before or after Crinone administration. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage. Drug Interactions No drug interactions have been assessed with Crinone. Carcinogenesis, Mutagenesis, Impairment of Fertility Nonclinical toxicity studies to determine the potential of Crinone to cause carcinogenicity or mutagenicity have not been performed. The effect of Crinone on fertility has not been evaluated in animals. Pregnancy Crinone 8% has been used to support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens in two clinical studies (studies COL1620-007US and COL1620-F01). In the first study (COL1620-007US), 54 Crinonetreated women had donor oocyte transfer procedures, and clinical pregnancies occurred in 26 women (48%). The outcomes of these 26 pregnancies were as follows: one woman had an elective termination of pregnancy at 19 weeks due to congenital malformations (omphalocele) associated with a chromosomal abnormality; one woman pregnant with triplets had an elective termination of her pregnancy; seven women had spontaneous abortions; and 17 women delivered 25 apparently normal newborns. In the second study (COL1620-F01), Crinone 8% was used in the luteal phase support of women undergoing in vitro fertilization (“IVF”) procedures. In this multi-center, openlabel study, 139 women received Crinone 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer. Clinical pregnancies assessed at Day 90 post-transfer were seen in 36 (26%) of women. Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. Of the 47 newborns delivered, one had a teratoma associated with a cleft palate; one had respiratory distress syndrome; 44 were apparently normal and one was lost to follow-up. Geriatric Use The safety and effectiveness in geriatric patients (over age 65) have not been established. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Nursing Mothers Detectable amounts of progestins have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.

ADVERSE REACTIONS Assisted Reproductive Technology In a study of 61 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Crinone 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women were: bloating (7%), cramps not otherwise specified (15%), pain (8%), dizziness (5%), headache (13%), nausea (7%), breast pain (13%), moniliasis genital (5%), vaginal discharge (7%), pruritus genital (5%). In a second clinical study of 139 women using Crinone 8% once daily for luteal phase support while undergoing an IVF procedure, treatment-emergent adverse events reported in 5% or greater of the women were: abdominal pain (12%), perineal pain female (17%), headache (17%), constipation (27%), diarrhea (8%), nausea (22%), vomiting (5%), arthralgia (8%), depression (11%), libido decreased (10%), nervousness (16%), somnolence (27%), breast enlargement (40%), dyspareunia (6%), nocturia (13%). Secondary Amenorrhea In three studies, 127 women with secondary amenorrhea received estrogen replacement therapy and Crinone 4% or 8% every other day for six doses. Treatment-emergent adverse events during estrogen and Crinone treatment that occurred in 5% or more of women treated with Crinone 4% or Crinone 8% respectively were: abdominal pain (5%, 9%), appetite increased (5%, 8%), bloating (13%, 12%), cramps not otherwise specified (19%, 26%), fatigue (21%, 22%), headache (19%, 15%), nausea (8%, 6%), back pain (8%, 3%), myalgia (8%, 0%), depression (19%, 15%), emotional lability (23%, 22%), sleep disorder (18%, 18%), vaginal discharge (11%, 3%), upper respiratory tract infection (5%, 8%), and pruritus genital (2%, 6%). Additional adverse events reported in women at a frequency of less than 5% in Crinone ART and secondary amenorrhea studies and not listed above include: autonomic nervous system–mouth dry, sweating increased; body as a whole–abnormal crying, allergic reaction, allergy, appetite decreased, asthenia, edema, face edema, fever, hot flushes, influenza-like symptoms, water retention, xerophthalmia; cardiovascular, general–syncope; central and peripheral nervous system–migraine, tremor; gastro-intestinal–dyspepsia, eructation, flatulence, gastritis, toothache; metabolic and nutritional–thirst; musculo-skeletal system– cramps legs, leg pain, skeletal pain; neoplasm–benign cyst; platelet, bleeding & clotting– purpura; psychiatric–aggressive reactions, forgetfulness, insomnia; red blood cell– anemia; reproductive, female–dysmenorrhea, premenstrual tension, vaginal dryness; resistance mechanism–infection, pharyngitis, sinusitis, urinary tract infection; respiratory system–asthma, dyspnea, hyperventilation, rhinitis; skin and appendages–acne, pruritus, rash, seborrhea, skin discoloration, skin disorder, urticaria; urinary system–cystitis, dysuria, micturition frequency; vision disorders–conjunctivitis. OVERDOSAGE There have been no reports of overdosage with Crinone. In the case of overdosage, however, discontinue Crinone, treat the patient symptomatically, and institute supportive measures. As with all prescription drugs, this medicine should be kept out of the reach of children. DOSAGE AND ADMINISTRATION Assisted Reproductive Technology Crinone 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Crinone 8% is administered vaginally at a dose of 90 mg twice daily in women with partial or complete ovarian failure who require progesterone replacement. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10-12 weeks. Secondary Amenorrhea Crinone 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Crinone 8% every other day up to a total of six doses may be instituted. It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed. HOW SUPPLIED Crinone is available in the following strengths: 4% gel (45 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel. NDC 52544-283-24 - 6 Single-use prefilled applicators. 8% gel (90 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel. NDC 52544-284-12 - 15 Single-use prefilled applicators. Each applicator is wrapped and sealed in a foil overwrap. Store at 20-25°C (68-77°F). [See USP controlled room temperature.] Rx only

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

In This Issue WWW.INFERTILITYREPRONEWS.COM PUBLISHING STAFF

Publisher Russell Hennessy russell@novellushc.com 732-992-1888 Editorial Director Dalia Buffery dalia@novellushc.com 732-992-1889 Associate Editor Dawn Lagrosa 732-992-1891 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. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issue, $17.00. Orders will be billed at individual rates unless proof of status is confirmed. SUBSCRIPTIONS/CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Infertility & Reproductive News, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831; Fax: 732-656-7938.

AsK tHe eXpert Nurse Practitioners versus Physician Assistants

iNfertility UpDAtes Thrombophilia and recurrent pregnancy loss

AwHONN HiGHliGHts Program is proactive about perinatal mood disorders

Progesterone supplementation in early pregnancy

Helping babies to breathe wherever they are born

Varicocele and infertility

Perinatal depression: still overlooked, undertreated

Assisted reproductive technologies and birth defects

meN’s HeAltH Pelvic floor muscle training provides no benefit for incontinence

wOmeN’s HeAltH Lifestyle intervention does not appreciably improve obstetric and neonatal outcomes in obese women

Ovarian preservation effect of GnRH agonists

No evidence for routine pelvic examination BreAst cANcer AwAreNess Knowledge of fertility lacking in young women with breast cancer

CHEK2 screening with family history of breast cancer?

Clinical News twice-frozen embryos show pregnancy, live-Birth rates similar to Once-frozen embryos Although twice-frozen embryos have a lower survival rate after thawing than once-frozen embryos, they have similar pregnancy and equivalent live-birth rates, according to new research from Australia (Koch J, et al. Fertil Steril. 2011;96:58-62). Researchers compared live-birth rates in twice-frozen embryo transfers and once-frozen embryo transfers generated from the same in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment cycle, using data acquired retrospectively from the IVF Australia patient database. They identified infertile women who underwent IVF/ICSI and had embryos twice frozen between January 2003 and May 2009. In total, 21,877 stimulation cycles resulted in a pregnancy rate of 32.2% per fresh transfer and 11,377 thaw cycles resulted in a pregnancy rate of 26.4% per embryo transfer. Of these, the twice-frozen embryos of 54 women achieved an 82% survival rate (55 embryos) and resulted in 52 embryo transfers in 44 women. The researchers found that from the 40 once-frozen embryos transferred, there were 11 pregnancies, 6 live births, and 5 miscarriages. From the 52 twicefrozen embryos, there were 13 pregnancies, 7 live births, and 6 miscarriages. The survival rate of twice-frozen embryos was lower than that of those frozen once (82% vs 89%; P = .012). The clinical pregnancy rates (25% vs 27.5%, respectively; P = .78) and livebirth rates (13% vs 15%, respectively; P = .83) were similar among twicefrozen and once-frozen embryo transfers. NsAiD Use During pregnancy may Double miscarriage risk Women taking nonaspirin nonsteroidal anti-inflammatory drugs

(NSAIDs) during early pregnancy may face more than double the risk for spontaneous abortion, a recent study showed (Nakhai-Pour HR, et al. CMAJ. 2011 Sept 6. Epub ahead of print). This risk was associated with all NSAIDs studied, although at varying levels, suggesting a class effect. In addition, the risk was not dose-dependent. The researchers enrolled 4705 women who had experienced spontaneous abortion, along with 47,050 controls matched according to date of the spontaneous abortion and gestational age. Of the women who had spontaneous abortions, 352 (7.5%) had filled 1 or more nonaspirin NSAID prescriptions during their pregnancies. Among women who did not have spontaneous abortions, 1213 (2.6%) had filled prescriptions for nonaspirin NSAIDs during pregnancy. Naproxen was used with the most prevalence among all the women— 2.8% among women who experienced spontaneous abortion and 0.9% among those who did not. The next most often used nonaspirin NSAID was ibuprofen—used by 1.3% of women with spontaneous abortions and 0.6% of those without—followed by rofecoxib (0.8% vs 0.3%, respectively), diclofenac (0.7% vs 0.2%, respectively), and celecoxib (0.6% vs 0.2%, respectively.) Use of 2 or more nonaspirin NSAIDs during pregnancy was reported in 0.6% of women with spontaneous abortions and in 0.2% of the control group. After adjustment for potential confounders, results showed a 2.4-fold increase in the risk for spontaneous abortion in women who used any type of nonaspirin NSAID during pregnancy. Although all nonaspirin NSAIDs imparted this risk, it was found to be highest among women who used diclofenac alone and lowest in women who used rofecoxib alone.

AcOG releases contraceptive Guide for OB/GyNs Determining the safety of the many available contraceptive options for patients has just become easier, thanks to a new guide for OB/GYNs released by the American College of Obstetricians and Gynecologists (ACOG. Obstet Gynecol. 2011;118:754-760). “Nearly half of all pregnancies in the US are unplanned,” said Eve Esprey, MD, MPH, chair of ACOG’s LongActing Reversible Contraception Work Group, who helped develop the guide. “Women with certain medical conditions are at higher risk for adverse outcomes with an unintended pregnancy, and these recommendations can assist clinicians in helping patients choose the most appropriate contraceptive method.” Based on the Centers for Disease Control and Prevention’s US Medical Eligibility Criteria for Contraceptive Use, 2010, the guide rates the safety of different contraceptives on a scale of 1 to 4 according to a woman’s age, health status, and preexisting medical conditions. Category 1 indicates no restrictions for use of a contraceptive method, whereas category 4 denotes that a method could pose an unacceptable health risk. Featuring more than 65 medical conditions and characteristics listed alphabetically and paired with appropriate contraceptive methods, the guide includes the revised guidelines for the use of contraceptives during the postpartum period issued in July 2011. Oral contraceptive Adherence improved with Greater supply at initiation Women receiving a larger supply of oral contraceptives at the time of initiation may show greater adherence to the pill after 6 months, especially those aged younger than 18 years, a recent study showed (White KO, et al. Obstet Gynecol. 2011;118:615-622). Continued on page 30

OCTOBER 2011 l VOLUME 3, NUMBER 5

Ask the Expert

Nurse Practitioners versus Physician Assistants Question: Can you tell me whether nurse practitioners (NPs) or physician assistants (PAs) are preferred in OB/GYN practice? Also, can either deliver babies or assist in the operating room?

Answer: By Debra Moynihan, WHNP-BC, MSN, Co-Editor-in-Chief I do not believe that there is any preference between NPs and PAs in OB/GYN practices. Many similarities exist within the 2 disciplines. Many times when practices are recruiting, they may advertise for an NP and a PA simultaneously. After the interview process, a practice may decide which is the best fit. It may depend on what the practice is looking for—both OB and GYN experience, or just one or the other. For example, most of my patients are OB patients. The doctors believe that the mid-level practitioners are willing and able to spend more

time on education with the OB patients. Geographic location also may be a factor. Sometimes different services may be needed in certain rural areas in the country. Neither of these professional roles is trained to deliver babies. Only nurses who have been trained and certified as midwives are licensed to perform deliveries. Working as a “first assist” in the operating room usually requires extra training and certification and comes under the PA’s scope of practice. Depending on geographic location, NPs may perform or assist in minor surgical procedures, such as dermatologic biopsies, suturing, and casting. NPs or PAs who desire to work in an OB/GYN practice should not hesitate to send a resume, no matter which discipline is being advertised. If you have the experience and enthusiasm for the position, let the interview process determine your fate. n

submit your Questions Online Readers are invited to submit questions online at www.theobgynnurse.com. Appropriate questions will be published with a response from an Editorial Board member 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, New York Medical College; Director, Institute for Fertility Preservation, NY

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

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

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

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

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

CO-EDITOR-IN-CHIEF

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

CO-EDITOR-IN-CHIEF

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

OCTOBER 2011 l VOLUME 3, NUMBER 5

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11SP0146-0911

AWHONN Highlights

Home and Hospital Births... Approximately 1% of all births in the United States occur outside of the hospital. Most are attended by a certified professional midwife (CPM) or direct-entry midwife (DEM), with the remainder attended by physicians (probably not by choice) or a relative. The typical patient is aged 35 years or older, married, and multigravida. These are “not women making uninformed choices,” noted Ms Adams. “I have seen intelligent women making the choice to not go to the hospital. They feel a hospital birth is not as safe, and no one listens to them there.” Boucher and colleagues concluded that American women choose home birth to have a safe environment with better outcomes and fewer interventions, to avoid a negative hospital experience, to control their birth experience, and to ensure a comfortable and peaceful environment (J Midwifery Womens Health. 2009;54:119-126). Of planned home births, 88% actually occur in the home, and 12% are transferred to the hospital setting. The litera-

Table Elements for a Soothing Environment • Bed placement not central • Doors lock to ensure privacy • Furniture soft, with curved lines • Necessary equipment screened from view • Natural light provided • Bath and shower available • Nutritious food available

ture indicates that most transfers are a result of failure to progress, need for pain medication, or maternal exhaustion; only 3% to 4% are for emergency reasons. “But most of what we nurses see are train wrecks, so we may have a skewed view of home births,” she acknowledged. “In reality, most home births are successful.”

Continued from page 1

legality and safety of Home Births Laws vary by state allowing certified nurse midwives to assist in home birth. Currently, 27 states license or regulate CPMs or DEMs; 23 have no regulation, and consider it illegal for CPMs or DEMs to assist in birth. The American College of Obstetricians and Gynecologists does not support planned home births, but emphasizes

BA. BMJ. 2005;330:1416); however, the neonatal mortality analysis has been criticized. In contrast, the recent meta-analysis by Wax and colleagues (Am J Obstet Gynecol. July 2, 2010. Epub ahead of print) was “a real kicker,” Ms Adams added. Although multiple superior outcomes were found for home births, neonatal mortality was increased 3-fold

“Until we all give up the need to be in charge, we won’t be able to collaborate.” —Ellise D. Adams, MSN, CNM

that women who choose this option should work with a certified nurse midwife or a physician within an integrated health system, have ready access to consultation, and have a plan for safe and quick transportation to a nearby hospital. Contrary to conventional belief, home births attended by certified providers actually appear safe, Ms Adams said. A 2009 analysis of the data from 5331 Canadian women showed very low and comparable rates of perinatal death, less need for medical interventions, and fewer adverse perinatal outcomes for planned home births versus hospital births (Janssen PA, et al. CMAJ. 2009;181:377-383). Similarly, a Dutch study of 530,000 planned home births showed no differences in maternal or neonatal mortality or admission to an intensive care unit (de Jonge A, et al. BJOG. 2009;116:1177-1184). And a much-quoted study of 5400 US and Canadian home births showed lower rates of intervention than, and similar intrapartum and neonatal mortality to, hospital births (Johnson KC, Daviss

over hospital births. This generated widespread concern and comment, and has spurred a formal review of the data that is unpublished to date. can Hospital Births Be more “Homelike”? The theory of “birth territory” is a concept that connects the birth environment with birth outcomes. It suggests that a positive outcome depends on the laboring woman having a safe environment that contains elements that reduce fear (Table), physical space that focuses on her needs, and power and control placed in her hands. Home births that occur in accordance with this theory “can teach us something,” Ms Adams suggested. In a 2009 article, Hodnett and colleagues described their redesign of the hospital labor room to eliminate the standard hospital bed and include items “to promote relaxation, mobility, and calm,” which they called the “ambient room” (Birth. 2009;36:159-166). Not only were patients very satisfied with the

change, but nurses lingered in the room longer, therefore, the patients received more labor support. In other studies, the same researchers found that homelike environments are associated with less need for anesthesia, more vaginal deliveries, and more breastfeeding. “If we pay attention to the environment, we will make a difference in outcomes,” she said. “We need to work on this. Our patient satisfaction rates will increase and our perinatal outcomes will improve.” enhancing the transport scenario “So if home birth is safe and if it is what women want, then why are we uncomfortable with the notion?” Ms Adams asked. Beyond nurses’ comfort with having equipment close at hand, there is simply a degree of “mutual hostility and distrust” between home birth and hospital providers, she said. “If our worlds only intersect when things collide, we compromise quality of care,” she maintained. “The transport scenario makes us shiver,” she said. “Botched home births are something we quake about.” There remains the feeling that home deliveries are unsafe, and resentment is felt when hospital providers must assume the risk of caring for another’s patient. “Turf power happens,” she added. Nurses can ease the tension surrounding a transfer through appropriate, reassuring communication. The laboring mother, for example, is not a “failed home birth,” but a “successful transport.” Nurses should also treat the attendant with respect and understand that she can provide helpful information. She suggested that nurses also try to establish productive communication with the home birth movement within their communities, and develop “cultural sensitivity” toward its members. “Until we all give up the need to be in charge,” Ms Adams concluded, “we won’t be able to collaborate.” n

program is proactive about perinatal mood Disorders By Caroline Helwick

Denver, CO—The number 1 complication of pregnancy is not diabetes or hypertension—it is the development of a mood disorder. And the risk does not end with pregnancy; it extends from conception through the first year postpartum. At the Association of Women’s Health, Obstetric and Neonatal Nurses 2011 annual convention, Pat Bradley, BS, RNC, a nurse at Edward Hospital,

Naperville, IL, described her institution’s commitment to recognizing and treating this common condition. “This is really a community effort. When we got active in this area, counselors in the community volunteered their time for support groups,” she said. “People are passionate about this topic and are devoted to getting help to these patients.” What makes the program special is

OCTOBER 2011 l VOLUME 3, NUMBER 5

the buy-in from the whole medical community. The intervention does not begin and end in the obstetrician’s office, but extends to pediatricians, family physicians, and of course, a host of mental health specialists—all united in the mission of improving the lives of these patients, said Ms Bradley, who presented the findings of a study on the pilot screening program. Among pregnant women, 5 of 100

develop diabetes, and 6 of 100 have hypertension. But 20 of 100 women suffer from a perinatal mood disorder, she said. “Many are diagnosed with a mood disorder prior to pregnancy, but pregnancy complicates it,” she said. “On top of that, 20% of all pregnant patients develop a mood disorder during pregnancy. Our physicians tell us that many Continued on page 9

AWHONN Highlights program is proactive... Continued from page 8

have anxiety that interferes with daily life,” she said. Perinatal mood disorders include generalized anxiety and depression (15%-20%), panic disorder (10%), posttraumatic stress disorder (6%), obsessive-compulsive disorder (3%5%), bipolar disorder (0.5%-1.5%), and psychosis (0.1%-0.2%). Edward Hospital recognized the need to be proactive in this area, and partnered with the behavioral health service at Linden Oaks at Edward 4 years ago to develop a multifaceted screening and treatment program. In the pilot program, all obstetric patients were screened immediately postpartum for postpartum depression with the Boyer screening tool. Depending on the patient’s response, the woman would receive a follow-up phone call, assessment with a psychiatric nurse liaison and/or social worker, counseling with a trained psychologist, or referral to a psychiatrist.

phone call regarding an at-risk patient,” she said. “A behavioral health specialist takes it from there, assessing the patient, hooking her into the appropriate service, and reporting back to the physician.” Nurses or behavioral health specialists check on mothers via telephone and if mood changes are detected, patients are rescreened and referred for help, as indicated. Outpatient services now

include support groups led by mental health specialists, as well as a dedicated phone line. After delivery, pediatricians and family physicians become part of the network. “We recognized the need to shift over to the doctor who sees her regularly,” she noted. “We want these doctors to do formal screening, and some do (using the Edinburgh Postnatal Depression Scale), but in the very least, they know

they should ask the mother, ‘how’s it going?’ and key in to her response.” Although the investigators do not have formal data on the program’s effectiveness, they do know that referrals to behavioral health specialists in the network and in the community have increased, and, anecdotally, women seen through this service report feeling less depressed and more capable of caring for their infants. n

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The percentage of patients scoring “at risk”—around 20%—mirrored the latest research in postpartum depression. Of the women screened, 2% to 3% required a psychiatric service of some sort, Ms Bradley said. The pilot evolved into a comprehensive program involving a multidisciplinary team, with screening occurring at multiple points in time. Four obstetric practices and the Edward Hospital highrisk perinatal clinic now screen their patients using a modified Boyer risk assessment tool in the first trimester and the Edinburgh Postnatal Depression Scale in the second trimester. “The physician needs to make only 1

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OCTOBER 2011 l VOLUME 3, NUMBER 5

AWHONN Highlights

www.helpingbabiesbreathe.org Helping Babies to Breathe wherever they Are Born By Caroline Helwick

Denver, CO—“Helping Babies Breathe,” a life-saving program from the American Academy of Pediatrics, is reaching underserved neonatal populations around the globe. At the Association of Women’s Health, Obstetric and Neonatal Nurses 2011 annual convention, Susan Niermeyer, MD, MPH, Professor of Pediatrics, Section of Neonatology, University of Colorado School of Medicine, Denver, described the program she heads up, which is aimed at protecting neonates during “the golden minute” of life.

In Tanzania, where more than 7000 deliveries have occurred after the training of traditional birth attendants, neonatal deaths within 24 hours have been reduced by 54%.

Accentuating the huge disparity between the most and the least developed countries, Dr Niermeyer noted that 98% of babies who die are born in low- to middle-income countries. “Even within countries, there are health disparities wherever you look, down to the level of the community,” she said. Globally, inadequate coverage and quality of intrapartum care is a characteristic of 60 million births that occur within homes each year. The consequences of acute intrapartum events are often neonatal encephalopathy and long-term impairment, and for 814,000 newborns, death. Almost half of these neonatal deaths occur in the first 24 hours, “the time of lowest coverage with skilled attention” in the developing world, she said. This is most often the result of preterm birth, severe infections, or asphyxia. Mechanical problems of labor and placental insufficiency are frequent reasons for a baby to be born not breathing, she added. It has been especially hard to intervene against asphyxia. In countries such as Kenya, for example, more than 50% of births occur in the home, only 22% are managed by an attendant trained in neonatal resuscitation, and only 7% have the benefit of resuscitation equipment. Strong evidence indicates that resuscitation training could prevent many of these complications, “but there has

Neonatal simulator

Master trainers in Tanzania invite everyone to follow the latest developments with Helping Babies Breathe on the website, www.helpingbabiesbreathe.org. Helping Babies Breathe is also on Facebook and linked on the Healthy Newborn Network.

Figure This neonatal simulator is purpose-built with crying, breathing, and heart rate (umbilical cord pulse). The mannequin ships flat, but when filled with 2 liters of warm water, it has the weight, the warmth, and the tone of a baby who needs help to breathe.

not been a readily available tool that can be taken around the world,” Dr Niermeyer said. A systematic problem Neonatal complications in the acute intrapartum period represent a “systematic problem” that begins at the household and community level and extends to the highest level of the healthcare system. Delays in seeking care are common. “A crucial first step is for mothers to decide they can benefit from going to facilities to deliver,” she said. Second, transportation to such centers often is lacking; and third, highquality care may be lacking as well. In

OCTOBER 2011 l VOLUME 3, NUMBER 5

general, in-facility births do offer better care and should be the primary target for interventions, she said. “However, the whole system must be impacted to make meaningful improvements in neonatal survival,” she added. interventions that work In helping newborns to breathe, at least 80% of the effort should be aimed at proper assessment and routine intrapartum care. Ten percent should be aimed at infants who need drying, warming, clearing the airway, and stimulation. About 6% should be directed toward aid with bag and mask ventilation, and 1% toward those requiring

chest compressions and medications. “We translated this information into a program that emphasizes basic steps that will be effective in most situations,” Dr Niermeyer said. “A huge part is to draw attention to the moment of birth as the time of greatest risk: the golden minute, when a simple intervention can be life-saving if it is timely and is done correctly.” The Helping Babies Breathe program, supported by scientific evidence, is harmonized with international health policy and has been evaluated formally for content and methodology by field testing in Kenya, Pakistan, Tanzania, India, and Bangladesh. The program is aimed at attendants who are the sole person at the birth responsible for the baby, “which is the reality in most countries,” she pointed out. “Even having a single person at the delivery is a luxury for many women.” The program is based on visual imagery, using simple pictorial aids and flip charts that are linked to an action plan geared to the 5th- or 6th-grade learning level. The facilitator starts by teaching that most babies cry at birth, and one who does not cry needs help to breathe. This progresses to skill building using a hands-on approach with the use of a neonatal simulator that has the weight and tone of a baby needing resuscitation (Figure). The simulator is not only “a powerful learning paradigm” for attendants, but is also something of a “selling point” to women who are skeptical about delivering in a facility. A nurse in Kenya claimed to have nothing to convince families to come into the facility to deliver, but after training on the simulator, she can attest to the potential for a safer birth there. “For the first time, this moves her community to a more modern level of neonatal care delivery,” Dr Niermeyer said. The program is being implemented in 25 countries. Outcomes data are just emerging, showing improved survival and health status for births attended by persons trained in this program. In Tanzania, where more than 7000 deliveries have occurred after the training of traditional birth attendants, neonatal deaths within 24 hours have been reduced by 54%. In India, with more than 5000 posttraining deliveries, neonatal deaths have not changed but stillbirths have been reduced by 27%, she reported. “We think these are encouraging results,” Dr Niermeyer said. “Training does make a difference in important outcomes.” n

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The enrollment process is easy and takes just a few minutes: 1. Go to IVFInsuranceProgram.com 2. Enter the information required along with a credit card for the one-time $25 fee 3. A member ID number is sent via email 4. To receive discounts, patient or physician must call or fax prescriptions to Walgreens along with the member ID number Walgreens is committed to fertility pharmacy excellence for your patients. When patients sign up for the card, you can feel confident that Walgreens will provide the exceptional care to help fertility patients navigate through an anxious time: • Compassionate support from our pharmacists and nurses 24/7, including holidays • Teach and Touch program that offers personal phone consultation with a nurse at no extra cost • State-of-the-art compounding facilities • Insurance verification • Interactive educational tools Fertility Pharmacy Care Card now includes additional savings on Crinone®. Along with the $100 discount on every $1,000 purchase of stimulation medication, card members who fill a prescription for Crinone® (progesterone gel 8%) will also get a $30 coupon toward their purchase. The $30 savings will be offered with each Crinone prescription filled.

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AWHONN Highlights

perinatal Depression: still Overlooked, Undertreated By Caroline Helwick

Denver, CO—A packed room for a presentation on perinatal depression at the Association of Women’s Health, Obstetric and Neonatal Nurses 2011 annual convention made clear that although the risk for depression in pregnancy and postpartum is well known, its treatment still frustrates healthcare providers and patients. Jeanne Watson Driscoll, PhD, PMHCNS-BC, is a clinical nurse specialist in adult psychiatric-mental health, and President, JWD Association, Wellesley, Massachusetts. She provides psychotherapy and pharmacotherapy for women who experience mood and/or anxiety disorders through the childbearing years, and currently is writing a book on posttraumatic stress disorder related to childbearing. “While psychopharmacology works in many patients, psychotherapy is a priority with me,” Dr Driscoll said. “Every woman’s metabolic system is different, but the typical approach is, ‘She’s crying. Give her Zoloft.’” Dr Driscoll takes a decidedly comprehensive approach to her patients. She pointed out that “context is critical,” and emphasized the need for a collaborative approach that involves psychotherapy, not just medication.

“But bear in mind, in your assessment, if you ask questions the wrong way, you won’t get enough information,” she added. “And if you pick up on something during questioning, reschedule another visit and listen to your gut.” Dr Driscoll recommended screening with the Edinburgh Postnatal Depression Scale and the Postpartum Depression Screening Scale. Typical symptoms of major perinatal depression include: • Disturbed sleep (ie, too little or too much) • Appetite changes • Mood lability • Sense of failure in the maternal role • Anxiety or irritability • Excessive fears regarding the baby’s health • Inability to be reassured • Panic attacks • Suicidal ideation • Physiological symptoms, such as headaches, stomach aches, and bowel changes. “Assessment is critical. Listening to your patient’s story is important, and devaluation of her mental status will just make things worse,” Dr Driscoll said. “Never say, ‘You’ll be fine, it’s just your hormones.’”

Understanding the condition Perinatal depression is not limited to the immediate postpartum period; it can strike anytime up to 1 year after delivery. Early recognition is important to avoid a “public health emergency” that places both mother and baby at risk. “This patient does not have time to wait,” she emphasized. The probable etiology of perinatal depression is a convergence of hormonal factors, genetics, and life stressors and the woman’s response to them, according to Dr Driscoll. Women most at risk for major depression during the perinatal period are those with a history of depression or bipolar disorder or a family history of mental illness. Posttraumatic history, poor coping history, history of infertility, marital conflict, lower socioeconomic status, and lack of social support are also part of the risk factor constellation that should be assessed during antenatal visits. “I tell patients at risk that they have a 72% chance of developing postpartum depression if they have a prior history of depression, and that they deserve a wonderful postpartum, so they need to be treated,” she said. “I promise them they will get better. And, in truth, I’ve never seen anyone not get better in my 30 years of experience.”

treatment issues When a woman is known to be at risk or is already receiving antidepressants, planning is critical, she stressed. Because any woman of childbearing age can become pregnant, providers should

Drugs and perinatal Depression: what’s safe for your patients? Tips from Dr Jeanne Watson Driscoll Benzodiazepines • Use lowest dose possible, if needed. • Try tricyclic antidepressants or selective serotonin reuptake inhibitors: adverse effects in pregnancy are rare with these agents, although doxepin and fluoxetine are not recommended in breastfeeding mothers. mood stabilizers • Lithium use depends on severity of illness and rapid cycling; fetal car-

this is not possible, she noted. “Unfortunately, there are still obstetrical providers who will say a pregnant woman cannot be on these, but I would tell this patient to get a new doctor who is up to date and listening to you,” she said. In a 2011 study, a small increased risk for spontaneous abortions and preterm delivery were the only adverse outcomes definitively associated with the use of antidepressants in pregnancy (Lorenzo L, et al. Expert Opin Drug Saf. 2011 May 5. Epub ahead of print). Women should try to avoid starting antidepressants until the second tri-

“Assessment is critical. Listening to your patient’s story is important, and devaluation of her mental status will just make things worse. Never say, ‘You’ll be fine, it’s just your hormones.’” —Jeanne Watson Driscoll, PhD, PMHCNS-BC

prescribe any antidepressant cautiously before a pregnancy. They should stay abreast of the latest data regarding medication safety in pregnancy, use those with proven track records in the lowest effective doses, obtain informed consent, document the decision-making process, and communicate with all care providers (Sidebar). Ideally, antidepressants would be avoided in pregnant women, but often

OCTOBER 2011 l VOLUME 3, NUMBER 5

mester. For those who present for perinatal care and already are receiving medication, the medication should not be rapidly discontinued, because of the potential for withdrawal effects. Dr Driscoll emphasized that women with perinatal depression should receive not just a pill, but also psychotherapy. This can enlarge a woman’s capacity to bear the symptoms, reinforce coping strategies, and provide a safe place for her

diac ultrasound recommended at 16 to 20 weeks gestation; taper by 25% to 30% before delivery and supplement with folate. • Avoid carbamazepine and valproic acid. • Olanzapine data look positive. Antipsychotics • Can use high potency (haloperidol) if needed. • Olanzapine data look positive.

to work on problematic issues, she said, adding that “this relationship is vital.” Finally, she emphasized that there is no excuse for a woman to remain symptomatic throughout her pregnancy, because with collaborative interventions, virtually all women can be helped. However, patients and providers should not expect a quick fix. “Remember, pregnancy and postpartum are processes that take about 2 years,” Dr Driscoll pointed out. n

Did you know… 1 in 5 pregnant women experience depression and 1 in 10 experience postpartum depression. —Mercy Hospital and Medical Center, Chicago

Men’s Health

pelvic floor muscle training provides No Benefit for men with incontinence By Jessica A. Smith

ne-to-one physical therapy to instruct incontinent men in pelvic floor muscle training provides neither clinical benefit nor cost benefit, according to 2 parallel randomized, controlled trials (Glazener C, et al. Lancet. 2011;378:328-337). Pelvic floor exercises often are recommended for men with urinary incontinence, although their effect on the condition has not been proved conclusively. To determine whether personal pelvic floor training reduces incontinence, the researchers conducted 2 trials in men with urinary incontinence

pelvic floor exercise is widely available, one-to-one conservative physical therapy for men who are incontinent after

prostate surgery is unlikely to be effective or cost-effective,” the researchers concluded. “The high rates of persisting

incontinence after 12 months suggest a substantial unrecognized and unmet need for management in these men.” n

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

The Power of

Five Apolipoprotein A1

ơ2 microglobulin

Transthyretin

CA125-II

Transferrin

Five Markers, One Result “One-to-one conservative physical therapy for men who are incontinent after prostate surgery is unlikely to be effective or costeffective.” —Cathryn Glazener, PhD

6 weeks after radical prostatectomy or transurethral resection of the prostate (TURP). Both trials compared 4 pelvic floor muscle training therapy sessions over 3 months with standard care and lifestyle advice. For men who underwent prostatectomy, about 75% still had urinary incontinence at 1 year. No significant difference was seen between those who underwent therapy and those who received standard treatment. Men who underwent TURP had similar results: a 62% to 65% rate of continued incontinence at 1 year, regardless of the care provided. In addition, the pelvic floor muscle training resulted in higher mean costs per patient in both trials, but showed no economically significant difference in quality-adjusted life-years. “In settings where information about

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

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

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

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

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ova-1.com

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

OCTOBER 2011 l VOLUME 3, NUMBER 5

Infertility Updates

secondary infertility...

Brian R. Kaplan, MD

oocytes, which deteriorate in quantity and quality with increased age. Menopause is the point in time when the

Continued from page 1

oocyte pool has been exhausted. The decrease in fertility with age is significant after 35 years and becomes dramatic after 40 years. This decrease in ovarian reserve results in not only a decline in pregnancy rates, but also a significant increase in miscarriage rates, because of the increasing fragility of the eggs. Often with secondary infertility, there has been a change of partners, which creates a different paradigm. Therefore, a full workup is necessary for both partners. Also in secondary infertility, there is often an increase in time elapsed between pregnancy attempts. During this period various pathologies can evolve or worsen, decreasing the potential for fertility. Endometriosis, uterine pathology (especially fibroids), and deterioration of sperm parameters

are some of the most common etiologies, and they should be assessed vigorously.

Often with secondary infertility, there has been a change of partners, which creates a different paradigm. Therefore, a full workup is necessary for both partners. The history of the initial pregnancy is also important. Delay in conception with a first pregnancy may indicate a lower fertility potential manifest-

ing itself with increasing time. Complications during delivery and postpartum, such as retained placenta and postpartum dilation and curettage, also may lead to uterine pathology with intrauterine adhesion formation and, subsequently, secondary infertility. In addition, lifestyle changes increasingly are being associated with diminishing fertility. Excessive weight gain and the role of stress and anxiety have been shown to have significant reproductive repercussions. In conclusion, secondary infertility is a very common problem that is often ignored, with treatment delayed as a result of mistaken beliefs. For these couples, both partners should have an aggressive workup and treatment, designed appropriately, as with primary infertility. n

thrombophilia and recurrent pregnancy loss By Eve C. Feinberg, MD, FACOG Fertility Centers of Illinois

ecurrent pregnancy loss can be devastating to a couple, both physically and emotionally. When a couple has more than 1 pregnancy loss, a thorough review of the couple’s history should be undertaken. Recurrent pregnancy loss is a complex problem and can be a result of aneuploidy, anatomic factors, endocrinologic and/or immunologic abnormalities, and thrombophilias. The relationship between pregnancy loss and thrombophilia is a much debated topic. A 2003 meta-analysis (Rey E, et al. Lancet. 2003;361:901-908) combined data from 31 studies judged to be of good quality. The researchers concluded that there was an increased prevalence of thrombophilias in women with unexplained recurrent pregnancy

“Despite mounting evidence contrary to the association between thrombophilias and recurrent pregnancy loss, antiphospholipid antibodies remain implicated.” —Eve C. Feinberg, MD, FACOG

loss compared with women without a history of adverse pregnancy outcomes. A more recent study examined the natural history of women with thrombophilias and pregnancy outcomes,

Table Antiphospholipid Antibody Syndrome Criteria Laboratory Criteria • Medium or high titers present of anticardiolipin immunoglobin G (>40 GPL) and/or immunoglobin M (>40 MPL) Note: The same antibody must be positive twice when drawn at least 12 weeks apart. Clinical Criteria • ≥1 clinical episodes of arterial, venous, or small-vessel thrombosis • ≥1 unexplained pregnancy losses of a morphologically normal fetus of at least 10 weeks of gestation • ≥1 premature births of a morphologically normal newborn at or before week 34 of gestation, because of severe pregnancy-induced hypertension or severe placental insufficiency • ≥3 unexplained consecutive miscarriages before 10 weeks of gestation, with anatomic, hormonal, and parental structural genetic factors excluded

OCTOBER 2011 l VOLUME 3, NUMBER 5

including miscarriage (Said JM, et al. Obstet Gynecol. 2010;115:5-13). Of interest, this study showed that asymptomatic carriers of the prothrombin gene mutation had a 3.6-fold increase in the risk for adverse pregnancy outcomes (mostly placental abruption) and patients who were heterozygous for the MTHFR 1298 polymorphism had reductions in adverse events. Most important, this study demonstrated that most asymptomatic patients with inherited thrombophilias experienced problem-free pregnancies. Another recent study similarly failed to show a negative prognostic impact of thrombophilias (specifically, factor V Leiden and prothrombin mutations) on the likelihood of miscarriage (Lund M, et al. Hum Reprod. 2010;25:2978-2984). Antiphospholipid Antibodies remain implicated Despite mounting evidence contrary

to the association between thrombophilias and recurrent pregnancy loss, antiphospholipid antibodies remain implicated. Anti-phospholipid antibodies are directed against negatively charged phospholipid molecules on the cell surface and in organelles. Lupus anticoagulant, an immunoglobulin antiphospholipid antibody, interferes with phospholipid-dependent in vitro coagulation. There is consensus that antiphospholipid antibodies should be looked for in recurrent pregnancy loss patients, because not only are they found with increased prevalence, they also worsen obstetric outcomes. Because there is a chance that the odds of a live birth can be improved with heparin and low-dose aspirin therapy in these patients, diagnosis remains important. Diagnosis of antiphospholipid antibody syndrome requires 1 laboratory and 1 clinical criterion (Table). As of yet, no randomized, controlled trials have evaluated the efficacy of thromboprophylaxis with heparin and aspirin in women with factor V Leiden, prothrombin G20210A, protein C and protein S deficiency, and antithrombin III deficiency to optimize pregnancy outcomes. Until these trials are completed, treatment with heparin and lowdose aspirin is not evidence-based, and a careful discussion of the risks and benefits of thromboprophylaxis must be discussed in detail with each patient. For patients with MTHFR polymorphisms and hyperhomocysteinemia, 4 mg of folic acid daily is sufficient. n

Infertility Updates

New techniques for preimplantation... a single blastomere is removed from an embryo containing at least 6 cells. The blastomeres then are tested concurrently while the embryo continues to grow and develop into a blastocyst. On day 5, only euploid embryos are transferred. Two things must happen for an embryo transfer to occur. First, the biopsy must show normal results. Second, the embryo from which the cells were removed must continue to grow and develop into a blastocyst. The technical aspects of embryo biopsy, as well as optimal culture conditions to grow blastocysts, are major impediments for many in vitro fertilization (IVF) programs providing this technology. At Fertility Centers of Illinois (FCI), our experts in embryo biopsy and our laboratory’s choice of blastocyst culture medium place our group at the forefront of this technology.

and there are problems inherent in this visualization. Now as the field of genetic testing expands, much of that technology is applied preimplantation and on blastomeres.1 One such test is microarray, and FCI now offers blastomere screening with the use of microarray platforms. The microarray chip enables testing of all 23 chromosomes, with timely results that

New technology improves Accuracy PGS methodology is changing rapidly. The traditional method of screening chromosomes was through the use of fluorescence in-situ hybridization (FISH). This technology relied on DNA probes that recognized the centromeres of a select number of chromosomes. A major criticism of PGS with FISH was that it did not screen all 23 chromosomes, meaning that although embryos could have normal PGS results, they could still be aneuploid. In addition, the technology relied on the ability to visualize the fluorescent probes,

allow for transfer on day 5. Day-3 testing, however, may not be as accurate, because of some characteristics inherent in day-3 embryos. For example, there is a significant percentage of mosaicism, or coexistence of separate cell lines, within a single day-3 embryo. If the aneuploid cell line is tested, the embryo may be misread as aneuploid, and vice versa—if the euploid cell line is tested, the embryo may be misread as euploid. Mosaicism rates in day-3 embryos have been reported to be as high as 10%.2 In addition, it has been hypothesized that self-correction occurs in day-3

The microarray chip enables testing of all 23 chromosomes, with timely results that allow for transfer on day 5.

Continued from page 1

embryos. In other words, the embryo may be aneuploid on day 3, but may self-correct to euploid, discarding the aneuploid cells as growth continues. Therefore, microarray blastomere screening in day-3 embryos could produce an overestimation of abnormal results, causing providers to discard potentially euploid embryos.2 To get around the inherent problems associated with day-3 embryo testing, providers can conduct a biopsy on the trophectoderm cells of a blastocyst. The rate of mosaicism and self-correction in blastocysts is markedly lower than in day-3 embryos.3 For an IVF program to use this technology, the laboratory must be able to culture embryos at the blastocyst stage. The laboratory also must have personnel skilled in blastocyst biopsy. In addition, the laboratory must have the ability to freeze and thaw embryos without diminishing their implantation rate. Vitrification technology allows this to occur. Once the embryos are cultured to day 5, several trophectoderm cells can be removed. Blastocysts are generally more resilient than day-3 embryos, and are better able to tolerate biopsy. Furthermore, the cells destined to become the fetus (inner-cell mass) are not disturbed during biopsy. In addition, providers can remove a greater number of trophectoderm cells and obtain more DNA for more sophisticated testing methods. In addition to microarray testing, DNA can be subjected to comparative genomic hybridization. Both of these

tests allow screening of all 23 chromosomes. Microarray is able to screen for single-gene disorders as well as aneuploidy. The potential downside of these tests is that the embryo must be frozen while the testing is taking place. Currently, the turnaround time for testing does not afford same-day or next-day results. Therefore, at FCI we conduct a biopsy of the blastocyst, and then freeze it using vitrification technology. When the results return, the patient undergoes a frozen embryo transfer cycle. It is, therefore, a 2-step process. Preliminary data from the handful of centers currently offering this technology have shown that it is worth the wait, with increased pregnancy rates and decreased spontaneous abortion rates.4 As the field of genetics rapidly expands, and as we partner with our colleagues in the field, the options for preimplantation genetic testing and PGS will increase. n references 1. Munné S. Preimplantation genetic diagnosis of numerical and structural chromosome abnormalities. Reprod Biomed Online. 2002;4:183-196. 2. Wilton L, Thornhill A, Traeger-Synodinos J, et al. The causes of misdiagnosis and adverse outcomes in PGD. Hum Reprod. 2009;24:1221-1228. Epub 2009 Jan 20. 3. Munné S, Velilla E, Colls P, et al. Self-correction of chromosomally abnormal embryos in culture and implications for stem cell production. Fertil Steril. 2005; 84:1328-1334. 4. Schoolcraft WB, Treff NR, Stevens JM, et al. Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients. Fertil Steril. 2011;96:638-640. Epub 2011 Jul 23.

progesterone supplementation in early pregnancy By Brian R. Kaplan, MD Fertility Centers of Illinois

lassic studies point to the importance of progesterone in the maintenance of early pregnancy. Before 7 weeks of gestation, progesterone is derived mainly from the corpus luteum, whereas after 9 weeks gestation, it is derived mostly from the trophoblasts, leading the luteal-placental shift in pregnancy. Single and even serial measurements of serum progesterone have limited clinical value, because of their pulsatile secretion. Because endometrial tissue for histologic assessment can produce widely discrepant results, progesterone supplementation is largely empiric and given liberally in many situations where progesterone may not be optimally present.

Administration and Dosing Routes of progesterone administration include oral, vaginal, and intramuscular

injection. Oral micronized progesterone is convenient for the patient, and can be considered for supplementation in patients who secrete endogenous progesterone, such as those undergoing natural cycle in vitro fertilization (IVF) or ovulation induction with clomiphene citrate or gonadotropins. Progesterone supplementation is essential for patients undergoing assisted reproduction, because gonadotropinreleasing hormone agonists or antagonists used to prevent premature luteinizing hormone surge often result in poor luteal function, owing to their suppression of pituitary luteinizing hormone secretion. Although intramuscular progesterone in oil generates high serum levels of progesterone, vaginal administration results in very high local progesterone concentration in endometrial tis-

sue. A recent Cochrane Review showed that similar pregnancy rates were observed with intramuscular or vaginal routes of progesterone administration with IVF (Glujovsky D, et al. Cochrane Database Syst Rev. 2010;1:CD006359). Typical doses of progesterone supplementation include oral micronized 200 mg (Prometrium) once or twice daily. Available vaginal progesterone supplementation includes compounded progesterone suppositories 200 mg once or twice daily, progesterone vaginal gel 8% (Crinone; Prochieve) once daily, or as a vaginal insert with an applicator, 100 mg 2 or 3 times daily (Endometrin). Progesterone administered via intramuscular injection in oil is dosed at 50 mg daily. There is wide variation among physicians regarding the optimal duration of progesterone supplementation in preg-

nancy. At the Fertility Centers of Illinois, we discontinue progesterone supplementation between 9 and 12 weeks of gestation. Evidence suggests that the most common forms of progesterone supplementation are safe in early pregnancy. Earlier reports of a possible link between exposure to progestogens and an increased risk for hypospadias have been discounted. The US Food and Drug Administration conducted a thorough review of the relevant published studies and found that there is no increase in congenital anomalies, including genital abnormalities, in male or female infants resulting from exposure to progesterone or 17 alphahydroxyprogesterone in the first 4 months of pregnancy (Fed Regist. 1999;64:17985-17988). n

OCTOBER 2011 l VOLUME 3, NUMBER 5

Infertility Updates

Ovarian preservation effect of GnrH Agonists confirmed By Caroline Helwick

emporary suppression of ovarian function with triptorelin, (Trelstar; Decapeptyl) a gonadotropin-releasing hormone (GnRH) analog, reduced the incidence of chemotherapy-induced early menopause in premenopausal women with breast cancer, Italian investigators recently reported (Del Mastro L, et al. JAMA. 2011;306:269-276). The study was led by Lucia Del Mastro, MD, of the National Institute for Cancer Research, Genoa. The twin specters of infertility and early menopause stemming from the use of adjuvant chemotherapy are serious concerns for young women who develop breast cancer. Women younger than 40 years account for 6% of new breast cancer diagnoses, and youth is a predictor of worse outcome. Chemotherapy and hormone therapy place these women at high risk for amenorrhea, which occurs in at least 40% of premenopausal patients and increases with age.

py, and then every 4 weeks during treatment. Women with hormone-sensitive tumors and return of menses continued to receive triptorelin monthly, plus tamoxifen, for a total of at least 2 years. The occurrence of early menopause,

“This treatment can be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy.” —Lucia Del Mastro, MD

This study is the largest trial to date examining the use of a GnRH analog to suppress temporarily the ovaries in an attempt to preserve function later. Triptorelin is used currently in treating prostate cancer. Phase 2 studies showed that ovarian suppression with a GnRH analog reduces ovarian toxicity and protects ovaries in 67% to 96% of women undergoing chemotherapy. This finding was tested in a multicenter, randomized phase 3 study (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6) that evaluated the efficacy of triptorelin in reducing the incidence of early menopause in women aged 18 to 45 years with stage I, II, or III breast cancer. The 282 patients in the study received chemotherapy alone or chemotherapy plus triptorelin given intramuscularly at least 1 week before starting chemothera-

OCTOBER 2011 l VOLUME 3, NUMBER 5

defined as no resumption of menstruation and postmenopausal levels of follicle- stimulating hormone (FSH) and estradiol 1 year after ending chemotherapy, was significantly more likely for women receiving chemotherapy alone:

26% compared with 9% of patients receiving triptorelin (P <.001). This translated to a 72% reduction in the risk for chemotherapy-induced early menopause. “Our results suggest that temporarily

We’re committed to you and your patients At Ther-Rx, we take our commitment to you and your patients seriously. We have heard your concerns and have taken steps to make Makena™ (hydroxyprogesterone caproate injection) more accessible for clinically eligible patients. We believe every woman deserves access to FDA-approved and regulated medications. As the only FDA-approved medication of its kind, Makena helps fulfill important unmet needs for certain at-risk women. We understand the responsibility associated with bringing Makena to market in a reliable manner for the thousands of moms in need of therapy every year.

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

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

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

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

Infertility Updates suppressing ovarian function by administering triptorelin reduces the incidence of chemotherapy-induced early menopause,” Dr Del Mastro and colleagues wrote in conclusion. “This treatment can therefore be offered to premenopausal patients with breast cancer who wish to decrease the risk of permanent ovarian failure associated with chemotherapy.” Only 6 patients needed to be treated to

prevent 1 case of early menopause in the cohort. Resumption of menses, independent of hormone levels, occurred in significantly fewer patients in the group that received chemotherapy alone: 50% versus 63% in the triptorelin group (P <.03). Resumption of menstrual activity had not been reached in the chemotherapy-alone group by study’s end, compared with a median time of less than 7 months in the triptorelin group.

In a subset of patients who underwent FSH evaluation, no significant differences in minimum median FSH values or in maximum median estradiol values were observed between the 2 groups. In an accompanying editorial (Rugo HS, et al. JAMA. 2011;306:312-314), breast cancer specialists commented that the results “are intriguing and represent an important and encouraging addition to the study of ovarian preservation for

women in this difficult situation.” “GnRH agonist therapy to suppress ovarian function during chemotherapy is an additional treatment that can potentially expand fertility possibilities,” said Hope S. Rugo, MD, and Mitchell P. Rosen, MD, of the University of California, San Francisco. “Although recovering menses is not the same as fertility preservation, it is one step in the right direction.” n

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

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

Please see next page for brief summary of prescribing information.

OCTOBER 2011 l VOLUME 3, NUMBER 5

Infertility Updates

Varicocele and infertility By Jane M. Nani, MD Fertility Centers of Illinois

aricocelesâ&#x20AC;&#x201D;abnormally dilated scrotal veinsâ&#x20AC;&#x201D;are present in approximately 15% of the male population and in up to 40% of men presenting with infertility. Larger varico-

celes, which are often easily palpable, have been associated concretely with infertility. Varicoceles lead to infertility when spermatogenesis is altered as a result of adverse effects of venous reflux

and testicular temperature elevation. Although it may appear that varicocele repair would be an easy remedy, the clinical benefit of varicocele repair in improving fertility has not been estab-

Table 2 Selected Maternal Complications Pregnancy Complication

Makena N=310 %

Control N=153 %

13.8

BRIEF SUMMARY OF PRESCRIBING INFORMATION Please consult full prescribing information.

Admission for preterm labor1

8.8

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

Gestational diabetes

Oligohydramnios

Preeclampsia or gestational hypertension

Other than delivery admission.

$PNNPO "EWFSTF 3FBDUJPOT 5IF NPTU DPNNPO BEWFSTF SFBDUJPO XBT JOKFDUJPO TJUF QBJO XIJDI XBT SFQPSUFE BGUFS BU MFBTU POF JOKFDUJPO CZ PG UIF .BLFOB HSPVQ BOE PG UIF DPOUSPM HSPVQ 5BCMF MJTUT BEWFSTF SFBDUJPOT UIBU PDDVSSFE JO Ăś PG TVCKFDUT BOE BU B IJHIFS SBUF JO UIF .BLFOB HSPVQ than in the control group. Table 3 Adverse Reactions Occurring in â&#x2030;Ľ2% of Makena-Treated Subjects and at a Higher Rate than Control Subjects

CONTRAINDICATIONS Do not use Makena in women with any of the following conditions: t $VSSFOU PS IJTUPSZ PG UISPNCPTJT PS UISPNCPFNCPMJD EJTPSEFST t ,OPXO PS TVTQFDUFE CSFBTU DBODFS PUIFS IPSNPOF TFOTJUJWF DBODFS or history of these conditions t 6OEJBHOPTFE BCOPSNBM WBHJOBM CMFFEJOH VOSFMBUFE UP QSFHOBODZ t $IPMFTUBUJD KBVOEJDF PG QSFHOBODZ t -JWFS UVNPST CFOJHO PS NBMJHOBOU PS BDUJWF MJWFS EJTFBTF t 6ODPOUSPMMFE IZQFSUFOTJPO

Preferred Term *OKFDUJPO TJUF QBJO

WARNINGS AND PRECAUTIONS Thromboembolic Disorders Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs. Allergic Reactions Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use PG .BLFOB PS XJUI PUIFS QSPEVDUT DPOUBJOJOH DBTUPS PJM $POTJEFS EJTDPOUJOVJOH UIF ESVH JG such reactions occur. Decrease in Glucose Tolerance A decrease in glucose tolerance has been observed in some patients on progestin treatment. 5IF NFDIBOJTN PG UIJT EFDSFBTF JT OPU LOPXO $BSFGVMMZ NPOJUPS QSFEJBCFUJD BOE EJBCFUJD women while they are receiving Makena. Fluid Retention Because progestational drugs may cause some degree of fluid retention, carefully monitor women with conditions that might be influenced by this effect (e.g., preeclampsia, epilepsy, migraine, asthma, cardiac or renal dysfunction). Depression Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs. Jaundice $BSFGVMMZ NPOJUPS XPNFO XIP EFWFMPQ KBVOEJDF XIJMF SFDFJWJOH .BLFOB BOE DPOTJEFS XIFUIFS the benefit of use warrants continuation. Hypertension $BSFGVMMZ NPOJUPS XPNFO XIP EFWFMPQ IZQFSUFOTJPO XIJMF SFDFJWJOH .BLFOB BOE DPOTJEFS whether the benefit of use warrants continuation. ADVERSE REACTIONS For the most serious adverse reactions to the use of progestins, see Warnings and Precautions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. *O B WFIJDMF QMBDFCP DPOUSPMMFE DMJOJDBM USJBM PG QSFHOBOU XPNFO BU SJTL GPS TQPOUBOFPVT preterm delivery based on obstetrical history, 310 received 250 mg of Makena and 153 received B WFIJDMF GPSNVMBUJPO DPOUBJOJOH OP ESVH CZ B XFFLMZ JOUSBNVTDVMBS JOKFDUJPO CFHJOOJOH BU UP XFFLT PG HFTUBUJPO BOE DPOUJOVJOH VOUJM XFFLT PG HFTUBUJPO PS EFMJWFSZ XIJDIFWFS occurred first. [See Clinical Studies.] $FSUBJO QSFHOBODZ SFMBUFE GFUBM BOE NBUFSOBM DPNQMJDBUJPOT PS FWFOUT XFSF OVNFSJDBMMZ JODSFBTFE JO UIF .BLFOB USFBUFE TVCKFDUT BT DPNQBSFE UP DPOUSPM TVCKFDUT JODMVEJOH miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables 1 and 2). Table 1 Selected Fetal Complications Makena n/N

Control n/N

Miscarriage (<20 weeks)1

5/209

0/107

Stillbirth (â&#x2030;Ľ20 weeks)2

2/153

Pregnancy Complication

1.3

/ 5PUBM OVNCFS PG TVCKFDUT FOSPMMFE QSJPS UP XFFLT EBZT 2 / 5PUBM OVNCFS PG TVCKFDUT BU SJTL Ăś XFFLT

Makena N=310 %

Control N=153 %

32.7

*OKFDUJPO TJUF TXFMMJOH

17.1

7.8

6SUJDBSJB

12.3

11.1

Pruritus

7.7

5.9

*OKFDUJPO TJUF QSVSJUVT

5.8

3.3

Nausea *OKFDUJPO TJUF OPEVMF Diarrhea

5.8

2.0

2.3

0.7

*O UIF DMJOJDBM USJBM PG TVCKFDUT SFDFJWJOH .BLFOB XFSF SFQPSUFE BT EJTDPOUJOVJOH UIFSBQZ EVF UP BEWFSTF SFBDUJPOT DPNQBSFE UP PG DPOUSPM TVCKFDUT 5IF NPTU DPNNPO BEWFSTF SFBDUJPOT UIBU MFE UP EJTDPOUJOVBUJPO JO CPUI HSPVQT XFSF VSUJDBSJB BOE JOKFDUJPO TJUF QBJO TXFMMJOH FBDI 1VMNPOBSZ FNCPMVT JO POF TVCKFDU BOE JOKFDUJPO TJUF DFMMVMJUJT JO BOPUIFS TVCKFDU XFSF SFQPSUFE BT TFSJPVT BEWFSTF SFBDUJPOT JO .BLFOB USFBUFE TVCKFDUT DRUG INTERACTIONS /P ESVH ESVH JOUFSBDUJPO TUVEJFT XFSF DPOEVDUFE XJUI .BLFOB Drugs Metabolized by CYP1A2, CYP2A6 and CYP2B6 5IF NFUBCPMJTN PG ESVHT NFUBCPMJ[FE CZ $:1 " TVDI BT UIFPQIZMMJOF UJ[BEJOF DMP[BQJOF $:1 " TVDI BT BDFUBNJOPQIFO IBMPUIBOF OJDPUJOF BOE $:1 # TVDI BT efavirenz, bupropion, methadone) may be increased during treatment with Makena [see Clinical Pharmacology]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B: 5IFSF BSF OP BEFRVBUF BOE XFMM DPOUSPMMFE TUVEJFT PG .BLFOB VTF in women during the first trimester PG QSFHOBODZ %BUB GSPN B WFIJDMF QMBDFCP DPOUSPMMFE clinical trial of 310 pregnant women who received Makena at weekly doses of 250 mg by JOUSBNVTDVMBS JOKFDUJPO JO UIFJS TFDPOE BOE UIJSE USJNFTUFST BT XFMM BT MPOH UFSN ZFBST GPMMPX VQ TBGFUZ EBUB PO PG UIFJS JOGBOUT EJE OPU EFNPOTUSBUF BOZ UFSBUPHFOJD SJTLT UP infants from in utero exposure to Makena. 3FQSPEVDUJPO TUVEJFT IBWF CFFO QFSGPSNFE JO NJDF BOE SBUT BU EPTFT VQ UP BOE respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Makena. Makena administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days BOE PG HFTUBUJPO 5IFSF XFSF OP UFSBUPHFOJD FGGFDUT JO FJUIFS TQFDJFT Labor and Delivery Makena is not intended for use to stop active preterm labor. The effect of Makena in active labor is unknown. Nursing Mothers Discontinue Makena at 37 weeks of gestation or upon delivery. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breastfeeding performance, or on the health, growth, or development of the infant. Pediatric Use Makena is not indicated for use in children. Safety and effectiveness in pediatric patients less UIBO ZFBST PG BHF IBWF OPU CFFO FTUBCMJTIFE " TNBMM OVNCFS PG XPNFO VOEFS BHF ZFBST XFSF TUVEJFE TBGFUZ BOE FGGJDBDZ BSF FYQFDUFE UP CF UIF TBNF JO XPNFO BHFE ZFBST BOE above as for users 18 years and older. [See Clinical Studies.]

.BSLFUFE CZ 5IFS 3Y $PSQPSBUJPO 4U -PVJT .0

lished firmly. In addition, intrauterine insemination (IUI) and in vitro fertilization (IVF)/intracytoplasmic sperm injection are options for the management of couples with male-factor infertility associated with a varicocele. The decision on which treatment to use is influenced by several factors. treatment considerations When a man presents with a varicocele, treatment may be considered when all the following conditions are met: â&#x20AC;˘ The varicocele is palpable on physical examination of the scrotum â&#x20AC;˘ The couple has known infertility â&#x20AC;˘ The female partner has normal fertility or a potentially treatable cause of infertility â&#x20AC;˘ The male partner has abnormal semen parameters or abnormal results from sperm function tests. Conversely, varicocele repair as treatment for infertility is not indicated in patients with normal semen parameters or a subclinical varicocele. Varicocele repair has the potential to treat the underlying cause of infertility directly, thereby providing a possible cure. In contrast, IUI and IVF are performed on a cycle-by-cycle basis and are required at each pregnancy attempt. In some cases, the cost-effectiveness of varicocele repair compared with IUI or IVF, especially considering the relative risk or failure of either treatment to result in pregnancy, may be a primary concern. Other factors of major importance include the age of the female partner, the potential risk for multiple pregnancies, and the consequential risk for premature birth with IUI and IVF, along with the possible progressive decline in semen parameters that may accompany untreated varicoceles. Varicocele repair The 2 approaches to varicocele repair are surgery and percutaneous embolization. Open surgical approaches to varicocele repair include retroperitoneal, inguinal and subinguinal, or laparoscopy. The risks associated with surgical varicocele repair are rare and usually mild, but include wound infection, hydrocele, recurrence of varicocele and, very rarely, testicular atrophy. Percutaneous embolization of the varicocele is accomplished by embolization of the refluxing internal spermatic vein or veins. Although surgical treatment successfully eliminates more than 90% of varicoceles, the impact on fertility outcomes is less clear. This is largely Continued on page 19

OCTOBER 2011 l VOLUME 3, NUMBER 5

Infertility Updates

Assisted reproductive technologies and Birth Defects By Jane M. Nani, MD Fertility Centers of Illinois

ssisted reproductive technology (ART) is still a relatively young field compared with other branches of medicine. This 33-year period, however, has seen a dramatic increase in the use of these techniques, as well as a progressive increase in success rates. The most recent report from the Centers for Disease Control and Prevention (CDC) details ART data collected during 2008. According to the CDC, in 2008 alone, 148,055 ART cycles were performed at 436 fertility clinics, resulting in 46,326 live births and 61,426 infants.1 With this growing trend in the use of ART, concern regarding the children born from ART, and IVF in particular, has emerged. As data have accumulated, more research has been undertaken to ascertain whether children conceived via ART are different from children conceived naturally.

expected rate (8.65 for intracytoplasmic sperm injection [ICSI] and 9.0% for IVF, compared with 4.2% in the general population).4 Recently, this study has been criticized, because the control group chosen was considered less than ideal and the definition of “major” birth defect was considered problematic. Additional follow-up studies have suggested that infants conceived through ART have congenital malformation rates that do not differ significantly from the general population.5-7 However, a recent meta-analysis of 15 studies adjusted for maternal age and parity and compared 12,283 singleton infants conceived by IVF with 1.9 million naturally conceived singleton infants. Results showed significantly higher odds of preterm delivery (odds ratio [OR], 2.0), low birth weight (OR, 1.8), very low birth weight (OR, 2.7), and small for gestational age (OR, 1.6) in IVF pregnancies.8

increased risk for Abnormalities Over time, ART has resulted in a 30fold increase in multiple pregnancies compared with the rate of spontaneous twins. Recent data suggest, however, that even when controlling for multiple gestation, ART singleton pregnancies have a higher rate of congenital abnormalities compared with singleton pregnancies conceived naturally.2,3 One of the earliest studies to raise the question of adverse outcomes from IVF came from a large Australian cohort. Among 4916 women, the risk for 1 or more major birth defects in babies conceived with ART was double the

causes of Abnormalities Because no single anomaly has occurred repetitively across various followup studies, it is difficult to determine a specific point within the IVF cycle that may be associated with risk. Many adverse obstetric outcomes associated with ART may be linked to the specific diagnosis and cause of infertility rather than to the treatment. Some researchers have sought to determine whether the manipulation of gametes that occurs with ICSI may lead to adverse outcomes not seen with conventional IVF. Reports on the risk for congenital malformations associated with ICSI compared with

Varicocele…

Continued from page 18

because most controlled studies that have addressed fertility outcomes after varicocele repair have not been randomized and have not included only men with palpable varicoceles, men with abnormal semen parameters, and men with normal female partners. Two well-designed randomized, controlled studies in the 1990s evaluated men with palpable varicoceles along with abnormal semen parameters with normal female partners. One study showed no greater likelihood of pregnancy after varicocele repair, although improvements in semen parameters were significant (Nieschlag E, et al. Hum Reprod. 1998;13:2147-2150). The other study reported a significant improvement in fertility after varicocele repair (Madgar I, et al. Fertil Steril. 1995;63:

120-124). In addition, a 2004 Cochrane meta-analysis of 8 previously published studies reported no effect of varicocele repair on fertility (Evers JH, et al. Cochrane Database Syst Rev. 2008;3:CD000479). Despite the absence of definitive studies on the impact of varicocele repair on fertility, varicocele treatment may be considered in selected cases. When the repair is performed, patients should be evaluated for varicocele recurrence, and postrepair semen analysis should be performed at 3-month intervals during the first year, to assess change and/or improvement in parameters, or until pregnancy is achieved. After 1 year after varicocele repair without pregnancy, however, IUI and IVF should be considered for couples with persistent infertility. n

babies born with conventional IVF have yielded conflicting results.9,10 In contrast, many thousands of babies born after IVF and ICSI with follow-up after birth have not shown any clear increased risk for birth defects. In congenital oligospermia as a result of Y chromosome microdeletion (which has been observed in 3%-15% of men with severe oligospermia), ICSI has facilitated normal fertilization in IVF cycles. In these cases, the Y microdeletion will be transmitted to male offspring.11,12 Furthermore, Cox and colleagues suggested a link between Angelman syndrome and children conceived through ICSI.13 Thus, the possibility was raised that imprinting disorders, including Angelman syndrome and BeckwithWiedemann syndrome (BWS), although few in number (1 in 100,000 and 1 in 300,000, respectively), are increased in children born after IVF. This theory is supported by considerable evidence in animal models of altered gene imprinting in embryos cultured in vitro. In addition, 90% of children with BWS conceived after ART had imprinting disorders compared with 40% to 50% of children with BWS conceived without ART. Associations yet to Be established A recent National Institutes of Health report summarized the current literature suggesting an association between imprinting disorders and the use of ART from 1978 to 2008.14 The available data consisted of case series, case-control studies, and case registries from different populations. Because the incidence of imprinting disorders is rare, conclusions drawn from literature are limited by study design and small sample sizes. Large prospective, multicenter cohort studies are needed to definitively answer this question. Overall, a growing body of evidence suggests an association between ART pregnancies and adverse perinatal outcomes. The most notable recurrent outcome is lower birth weight compared with singletons conceived naturally. The most frequent single preventable cause of poor pregnancy outcome is undoubtedly multiple fetal pregnancies. The current nationwide trend, as strongly advocated by the American Society for Reproductive Medicine, is to limit the number of embryos transferred. Elective singleembryo transfer has been offered increasingly to good-prognosis patients at the Fertility Centers of Illinois, without a decline in pregnancy success. When comparing singleton IVF pregnancies with naturally conceived singletons, pre-

“Many adverse obstetric outcomes associated with ART may be linked to the specific diagnosis and cause of infertility rather than to the treatment.” —Jane M. Nani, MD

natal risk appears to be slightly higher for IVF singletons, although the absolute risk to children conceived through IVF is small. Given the large sample sizes needed to define the exact nature of this risk, no causal relationship has yet been firmly established. n references 1. Centers for Disease Control and Prevention. 2008 Assisted Reproductive Technology Success Rates National Summary and Fertility Clinic Reports. Atlanta, GA: Centers for Disease Control and Prevention; 2010. 2. Schieve LA, Ferre C, Peterson HB, et al. Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States. Obstet Gynecol. 2004;103:1144-1153. 3. Olson CK, Keppler-Noreuil KM, Romiti PA, et al. In vitro fertilization is associated with an increase in major birth defects. Fertil Steril. 2005;84:1308-1315. 4. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725-730. 5. Bergh T, Ericson A, Hillensjö T, et al. Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet. 1999;354:1579-1585. 6. Ericson A, Källén B. Congenital malformations in infants born after IVF: a population-based study. Hum Reprod. 2001;16:504-509. 7. Wennerholm UB, Bergh C, Hamberger L, et al. Incidence of congenital malformations in children born after ICSI. Hum Reprod. 2000;15:944-948. 8. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol. 2004;103:551-563. 9. Palermo GD, Colombero LT, Schattman GL, et al. Evolution of pregnancies and initial follow-up of newborns delivered after intracytoplasmic sperm injection. JAMA. 1996;276:1893-1897. 10. Kurinczuk JJ, Bower C. Birth defects in infants conceived by intracytoplasmic sperm injection: an alternative interpretation. Br Med J. 1997;315:1265-1266. 11. Dohle GR, Halley DJ, Van Hemel JO, et al. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod. 2002;17:13-16. 12. Feng HL. Molecular biology of male infertility. Arch Androl. 2003;49:19-27. 13. Cox GF, Bürger J, Lip V, et al. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet. 2002;71:162-164. 14. Manipalviratn S, DeCherney A, Segars J. Imprinting disorder and assisted reproductive technology. Fertil Steril. 2009;91:305-315.

OCTOBER 2011 l VOLUME 3, NUMBER 5

CONTINUING EDUCATION

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PROGRAM CE26 • RELEASE DATE: OCTOBER 3, 2011 • EXPIRATION DATE: OCTOBER 2, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Aging and infertility in women By Aaron S. Lifchez, MD Medical Director, Fertility Centers of Illinois, Center for Collaborative Reproduction

STATEMENT OF NEED A relatively large group of women is experiencing age-related infertility, because of social trends that lead to deferred childbearing. Age-related female infertility results from genetic oocyte abnormalities associated with decreased ovarian reserve. Central to the infertility evaluation of women of advanced reproductive age is an assessment of ovarian reserve. It is important that those treating women with possible age-related infertility understand each clinical test to estimate ovarian reserve, including folliclestimulating hormone and estradiol levels in the early follicular phase or a clomiphene citrate challenge test, as each test must be timed properly to the cycle. In addition, clinicians need to understand each test’s results and limitations to discuss them with and counsel patients appropriately. TARGET AUDIENCE Nurses whose primary interest is women’s health and infertility. LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Discuss the impact of age-related female infertility and the importance of the infertility evaluation • Compare and contrast ovarian reserve testing methods • Apply the implications of ovarian reserve test results to patient counseling 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” 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 Nurs-

emale fertility begins to decline many years before the onset of menopause, despite continued regular ovulatory cycles. Although there is no strict definition of advanced reproductive age in women, infertility clearly becomes more common beginning at age 35 years. As discussed in the classic American Society for Reproductive Medicine Practice Committee report,1 Menken and colleagues showed that the effect of female age on fertility was such that the percentage of women not using contraception who remained childless increased steadily according to their age at marriage: 6% at ages 20 to 24 years, 9% at ages 25 to 29 years, 15% at ages 30 to 34 years, 30% at ages 35 to 39 years, and 64% at ages 40 to 44 years.2 Similarly, a sharp decline in pregnancy rate with advancing female age has been noted in studies on donor insemination (which controlled for fertility of the male partner and coital frequency) and in vitro fertilization (IVF). The risk for spontaneous abortion also increases with female age, as does the risk for giving birth to a child with aneuploidy.3 A recent review of studies on the effects of male age on semen quality and fertility showed that increasing age is associated with a decline in semen volume, sperm motility, and sperm morphology, but not sperm concentration. Male fertility declines with age—particularly in men aged 50 and older—but the results of many of these studies were confounded by female partner age. There is no absolute age at which men cannot father a child. A couple’s fertility, therefore, is impacted more by the age of the female partner than by the age of the male partner.4

the impact of Age The average age of childbearing has increased over the past 3 decades, as more women have pursued higher education and careers and have postponed marriage. At the same time, the baby boom generation contains a large number of women currently in their late reproductive years, thus increasing the number of women in this age-group seeking assistance for infertility. Not all women of advanced reproductive age who wish to conceive experience infertility. But, older women who present to physicians for infertility may have fertility problems in addition to a decrease in oocyte quantity and quality.

ing, 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: • Dawn Lagrosa has nothing to disclose. • Aaron S. Lifchez, MD, has nothing to disclose. • Jessica Smith has nothing to disclose. • The staff members of Science Care have nothing to disclose.

OCTOBER 2011 l VOLUME 3, NUMBER 5

Age does not appear to have a significant impact on the ability of the endometrium to respond to exogenous hormone therapy. Therefore, there is no age-related decline in IVF cycle delivery rates with oocyte donation.

Menopause reflects near-complete depletion of the oocyte pool. However, subtle changes in early follicular phase serum concentrations—including increases of follicle-stimulating hormone (FSH) and estradiol, and decreases in inhibin B and anti-Müllerian hormone (AMH)—precede changes in menstrual regularity and ovarian hormone production. Risk factors for early decrease in

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

ovarian reserve include smoking, family history of premature ovarian failure/ early menopause, significant ovarian pathology (ie, endometriosis), and previous ovarian surgery.5 Age-related decline in female fertility and increased risk for spontaneous abortion are largely attributable to genetic abnormalities in the oocyte. The meiotic spindle in the oocytes of older women frequently exhibit abnormalities in chromosome alignment and microtubular matrix composition. Higher rates of single chromatid abnormalities in oocytes, as well as aneuploidy in preimplantation embryos and ongoing pregnancies, are observed often in older women. The higher incidence of oocyte aneuploidy is the major cause of increased spontaneous abortion and decreased live-birth rates in women of advanced reproductive age.6 The prevalence of uterine pathology, such as fibroids and endometrial polyps, also increases with age. Little evidence suggests, however, that uterine factors have a significant impact on age-related infertility. In addition, age does not appear to have a significant impact on the ability of the endometrium to respond to exogenous hormone therapy. Therefore, there is no age-related decline in IVF cycle delivery rates with oocyte donation. infertility evaluation Tests to evaluate infertility provide information about current fertility, but do not predict when the onset of agerelated infertility will occur. Infertility often is defined as the inability to conceive after 1 year of unprotected intercourse; however, earlier evaluation of infertility is warranted in women aged

necessarily represent the viewpoint of Science Care or Novellus Healthcare Communications, LLC. COPYRIGHT STATEMENT Copyright © 2011 Science Care. All rights reserved. EDITORIAL BOARD Aaron S. Lifchez, MD Fertility Centers of Illinois Center for Collaborative Reproduction 900 N. Kingsbury Suite RW6 Chicago, IL 60610

WWW.THEOBGYNNURSE.COM

older than 35 years. The consequences of undiagnosed infertility factors can be more detrimental to women who have limited time to achieve a successful pregnancy. In addition to infertility testing, the preconception medical evaluation should include screening for significant medical disorders, which are more frequent in older women. In women aged 40 years and older, it is advisable to perform mammography before attempting pregnancy, because infertility medications can increase the risk for breast cancer. Central to the infertility evaluation of women of advanced reproductive age is an assessment of ovarian reserve. The term ovarian reserve describes a woman’s reproductive potential with respect to oocyte quantity, and more importantly, oocyte quality. Ovarian Reserve Testing Ovarian reserve assessment methods fall into 2 categories: passive testing and dynamic testing. The goal of both approaches is to provide information regarding oocyte quality and quantity. Passive methods include cycle day-3 FSH and estradiol, inhibin B, AMH, as well as baseline ultrasound for antral follicle count and ovarian volume. The most commonly used dynamic test is the clomiphene citrate challenge test (CCCT). FSH and estradiol. The earliest test of ovarian response was the cycle day-3 FSH test, later followed by the cycle day-3 estradiol test. If the FSH or estradiol level is high on cycle day 3, patients are more likely to respond poorly to stimulation with gonadotropins and have greatly reduced pregnancy rates with both IVF and ovulation induction with intrauterine insemination (IUI).7 This results from the aging follicle’s failure to produce adequate amounts of inhibin, a hormone that feeds back to the pituitary to suppress FSH production. If the FSH level is elevated earlier in the cycle, the estradiol level also will elevate. An earlier and more marked rise in FSH level will result in earlier follicular recruitment and a shortened follicular phase of the cycle. As a rule, the FSH level should be <8 mIU/mL and the estradiol level should be <70 pg/mL.8 Inhibin B. Levels of inhibin B in cycle day-3 serum offer a newer measure for ovarian reserve. Inhibin B is secreted by the granulosa cells of the ovarian follicle in response to gonadotropins. Inhibins have been defined based on their activity of suppressing pituitary gonadotropin secretion. Thus, the serum concentrations of inhibin B and FSH are related inversely and, at low serum levels of inhibin B, FSH concen-

tration increases. During a normal menstrual cycle, inhibin B serum concentration increases gradually in the follicular phase to a broad peak at 7 days before the luteinizing hormone surge, and may constitute the limiting factor for the duration of the intercycle FSH rise. It has been established that FSH secretion is controlled by inhibin B and thus, inhibin B measurement is a more direct way of assessing follicular functions rather than FSH alone. Whereas FSH is a response to ovarian function, inhibin B is expressed as an ovarian function of the granulosa cells of the ovary.9 For normal inhibin B, the level should be ≥45 pg/mL.10 AMH. AMH, a protein hormone structurally related to inhibin, is expressed by the granulosa cells of the follicle during reproductive age and controls the formation of primary follicles by inhibiting excessive follicular recruitment by FSH. It, therefore, has a role in folliculogenesis. Substantial evidence exists that AMH levels correlate better with ovarian reserve than either FSH or inhibin B levels and, as a consequence, AMH rapidly is surpassing FSH as a more reliable and valid tool to measure ovarian reserve.11 In addition, AMH, unlike FSH, does not require a feedback mechanism. Therefore, it can be measured at any time in the cycle and acts as a reliable indicator of ovarian reserve even while a woman is taking combined oral contraceptive pills. Although not an absolute, a “comfortable” AMH level is in the range of 1 ng/mL to 3.5 ng/mL. Levels <1 ng/mL are worrisome, and levels >5 ng/mL suggest the possibility of polycystic ovaries.12 Antral follicle count and ovarian volume. Another reliable method for ovarian reserve testing uses transvaginal ultrasound. At the beginning of a menstrual cycle, ultrasound imaging allows for visualization and measurement of small follicles available to respond to stimulation in the ovary. A normal follicle will be <10 mm in diameter. Studies have demonstrated that as a woman ages, the visible number of these follicles at the beginning of the menstrual cycle decreases significantly.13 This reduction likely represents a decrease in the number of viable eggs that remain in the ovary. This theory is based on the observation that women with a diminished antral follicle count respond poorly to fertility medications and have a greater likelihood of having IVF cycles cancelled because of a poor response to stimulation. In addition, when these women complete IVF cycles, their pregnancy rates are lower. Studies differ on the exact number of follicles that would be considered

CONTINUING EDUCATION decreased, but most experts agree that a total number <8 should be considered a decreased antral follicle count. As the oocytes are being “lost,” the ovaries become smaller and, as a consequence, decreased ovarian volume also correlates with decreased ovarian reserve. Using transvaginal ultrasound, the volume of each ovary can be calculated by measuring the length, width, and depth. Normal dimensions generally are considered to be 1.5 cm x 2 cm x 3.5 cm.13 CCCT. With this test, clomiphene citrate is given at a dose of 100 mg on days 5 through 9 of the cycle and FSH levels are determined on days 3 and 10. An estradiol level can be done on cycle day 3 as well, to add supportive diagnosis. Various cutoff values have been reported, because of the various laboratory techniques used (and the evolution of international standards for FSH since the time the test was introduced).8 In my opinion, an FSH level >10 mIU/mL for either day 3 or day 10 indicates

It is important to note that a single elevated cycle day-3 FSH value connotes a poor prognosis.

abnormal test results. The rationale for the test is simple. The cycle day-3 value is unstimulated and represents the same basal value used in the cycle day-3 FSH screening, as described. Clomiphene stimulates an increased release of FSH early in the follicular phase, which improves follicular function and, when normal, the follicle produces enough inhibin and estradiol to feed back to the pituitary negatively and suppress FSH production by cycle day 10. Clomiphene adds a provocative element, which uncovers patients who may otherwise not be detected with basal FSH screening. As a practical matter, however, our clinic currently performs CCCT tests on very few patients. patient counseling Regardless of testing methods used, there are several caveats about test results. First, if the test result shows as normal, for example, in a 35-year-old woman, it does not mean that the ovaries are normal for her age. The only conclusion that can be drawn is that the ovaries are functioning similarly to a woman aged <43 years. That patient could enter diminished reserve in 1 or 10 years. Second, studies that have evaluated the tests carefully have not found a stratification of normals and abnormals; test results show as either

Aaron S. Lifchez, MD

positive or negative. In women aged older than 40 years, there are few reported cases of an abnormal test associated with a successful pregnancy. These patients then can be counseled definitively that alternative treatments to “own-egg IVF,” such as donor-egg IVF or adoption, must be considered. Decreased ovarian reserve at any age portends a poor prognosis to treatment including the use of IVF, the most efficacious infertility treatment available today. Alternative stimulation protocols have been proposed, but significant improvements in the pregnancy rate are lacking in patients with diminished ovarian reserve. It has been proposed that even before a clinically detectable abnormal test result, ovarian reserve is declining. Therefore, a significant portion of the population with unexplained infertility who would have a positive test and then an undisclosed number who are nearing the period of diminished ovarian reserve, have abnormal ovarian function. Women with abnormal results for basal FSH testing, estradiol testing, or CCCT have lower live-birth rates with ovulation induction and IUI. Women with diminished ovarian reserve also experience decreased responses to ovulation induction, require higher doses of gonadotropin, have higher IVF cycle cancellation rates, and experience lower pregnancy rates through IVF,14 as well as a higher incidence of spontaneous abortion. It is important to note that a single elevated cycle day-3 FSH value connotes a poor prognosis, even when values in subsequent cycles are normal. As a result, preconception counseling for women aged 35 years and older should include a discussion of the increased risks for aneuploidy, spontaneous abortion, and obstetric complications, such as delivery by cesarean section, hypertension, and gestational diabetes associated with increasing maternal age. Counseling after ovarian reserve testing should include a discussion of the implications of the results. Although they may predict a lower pregnancy rate, abnormal ovarian reContinued on page 22

OCTOBER 2011 l VOLUME 3, NUMBER 5

CONTINUING EDUCATION

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Aging and infertility... Continued from page 21 serve test results do not preclude the possibility of pregnancy, and should not be presented to patients as absolute. Likewise, ovarian reserve testing alone may yield falsely reassuring results, because advanced maternal age and ovarian reserve test results are independent predictors of infertility. Both should be used when counseling couples regarding their chances for conception and a successful pregnancy. treatment Options Treatment options for age-related infertility include controlled ovarian hyperstimulation (COHS) with IUI, IVF, and oocyte donation. Aside from oocyte donation, these treatments are intended to accelerate the time to conception rather than to directly affect oocyte or embryo quality. Expectant management—which should be reserved for couples who do not desire medical intervention—is also considered a treatment option, but is less likely to result in pregnancy in women of advanced reproductive age. COHS/IUI has limited efficacy for women aged older than 40 years with otherwise unexplained infertility, yielding a per-cycle delivery rate of 5% or less, compared with a live-birth rate per cycle of 17% to 22% for women aged younger than 35, and 8% to 10% for women aged 35 to 40 years. The presence of male-factor infertility, tubal disease, endometriosis, or pelvic adhesions would argue for proceeding directly to IVF in women of advanced reproductive age. Pregnancy

rates from IVF are generally higher than from COHS/IUI, but these also decline significantly with age. According to the 2006 national summary of IVF success rates published by the Society for Assisted Reproductive Technologies, live-birth rates per cycle were 38.8% in women aged younger than 35 years, 30.6% in women aged 35 to 37 years, 19.7% in women aged 38 to 40 years, 10.9% in women aged 41 to 42 years, and approximately 4.3% in women aged 43 years and older.15 A recent multicenter review of 431

TAKEAWAY qUICK POINTS ‰ A relatively large group of women is experiencing age-related infertility, because of social trends that lead to deferred childbearing. ‰ Age-related infertility is a result of genetic oocyte abnormalities associated with decreased ovarian reserve. ‰ Clinical tests to estimate ovarian reserve include follicle-stimulating hormone and estradiol levels in the early follicular phase (cycle days 2-4) or a clomiphene citrate challenge test. ‰ Evaluation and treatment of infertility in women aged 35 years and older should not be delayed. ‰ With evidence of decreased ovarian reserve at any age, infertility treatment should be aggressive.

initiated IVF cycles in women aged 41 years and older showed no clinical pregnancies in women aged 45 years or older and no deliveries in women aged older than 43 years. This age-related decline in IVF success is related to decreased ovarian responsiveness to gonadotropins and, more importantly, to a marked decline in embryo implantation rates. Embryonic aneuploidy is likely the major reason for implantation failure in older women.16 Many alternative approaches have been attempted in women with decreased ovarian reserve. Unfortunately, there are no randomized trials to compare the relative efficacy of these approaches. Exclusion of aneuploid embryos with preimplantation genetic diagnosis lowers the spontaneous abortion rate in IVF cycles, but it does not lower the pregnancy rate. However, the technique is expensive and generally not covered by insurance, even for women who have an infertility benefit. Oocyte donation is clearly the most effective treatment for infertility in women aged older than 40 years, and for younger women with compromised ovarian reserve. Although the resulting child will not be biologically related to the birth mother, oocyte donation yields the highest live-birth rate of any assisted reproductive technology treatment. It is the treatment of choice for age-related infertility not successfully addressed by other methods. Pregnancy rates with oocyte donation are dependent on the age of the donor rather than the recipient. n

references 1. The Practice Committee of the American Society for Reproductive Medicine. Aging and infertility in women. Fertil Steril. 2004;82(suppl 1):S102-S106. 2. Menken J, Trussell J, Larsen U. Age and infertility. Science. 1986;233:1389-1394. 3. Smith KE, Buyalos RP. The profound impact of patient age on pregnancy outcome after early detection of fetal cardiac activity. Fertil Steril. 1996;65:35-40. 4. Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001;75:237-248. 5. The Practice Committee of the American Society for Reproductive Medicine. Aging and infertility in women. 2006;86(suppl 4):S248-S252. 6. Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod. 1996;11:2217-2222. 7. Kligman I, Rosenwaks Z. Differentiating clinical profiles: predicting good responders, poor responders, and hyperresponders. Fertil Steril. 2001;76:1185-1190. 8. Hershlag Q, Lesser M, Montefusco D, et al. Intrainstitutional variability of follicle-stimulating hormone and estradiol levels. Fertil Steril. 1992;58:11231126. 9. Creus M, Peñarrubia J, Fabregues F, et al. Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome. Hum Reprod. 2000; 15:2341-2346. 10. Seifer DB, Lambert-Messerlian G, Hogan JW, et al. Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil Steril. 1997;67: 110-114. 11. Nardo LG, Gelbaya TA, Wilkinson H, et al. Circulating basal anti-Müllerian hormone levels as a predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization. Fertil Steril. 2009;92:1586-1593. 12. La Marca A, Pati M, Orvieto R, et al. Serum antimullerian hormone levels in women with secondary amenorrhea. Fertil Steril. 2006;85:1547-1549. 13. Burger HG, Hale GE, Dennerstein L, Robertson DM. Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause. 2008;15:603-612. 14. Levi AJ, Raynault MF, Bergh PF, et al. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril. 2001;76:666-669. 15. US Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2006 Assisted Reproductive Technology Success Rates. Atlanta, GA: Centers for Disease Control and Prevention; 2006. 16. Munné S, Alikani M, Tomkin G, et al. Embryo morphology, developmental rates and maternal age are correlated with chromosome abnormalities. Fertil Steril. 1995;64:382-391.

WOMEN’S HEALTH

lifestyle intervention Does Not Appreciably improve Obstetric and Neonatal Outcomes in Obese women By Alice Goodman

San Diego, CA—Obese pregnant women realized a modest improvement in weight control when they participated in a lifestyle intervention in a randomized, controlled trial presented at the 2011 American Diabetes Association Scientific Sessions. The difference in gestational weight gain was significant (P = .014) in favor of the lifestyle intervention, but the small reduction in weight gain did not translate to significant differences in obstetric and neonatal outcomes. “Lifestyle intervention resulted in a higher adherence to the Institute of Medicine weight gain recommendations. However, despite the intervention, a significant number of women

still exceeded the upper threshold for weight gain during pregnancy,” said presenter Christina A. Vinter, MD, of the Odense University Hospital, Denmark. Approximately one third of pregnant women in Denmark are overweight, and more than 12% are obese, having a body mass index (BMI) of ≥30 kg/m2. Obesity during pregnancy increased the risk for gestational diabetes, hypertensive complications, cesarean sections, and infants born larger for gestational age. The researchers randomized 360 obese women with a BMI of 30 to 45 kg/m2 to either lifestyle intervention or the control group during early pregnancy. Women randomized to the lifestyle

OCTOBER 2011 l VOLUME 3, NUMBER 5

intervention group received dietary guidance, free membership in fitness centers, physical training, and personal coaching in group situations. Dietary guidance included individual counseling and calorie restriction to a goal of 5 kg weight gain during pregnancy; physical activity included 30 to 60 minutes of daily physical exercise, weekly aerobic classes, and group coaching. In total, 150 women in the intervention group and 154 in the control group completed the study. At week 35 of gestation, overall gestational weight gain was 7 kg in the intervention group versus 8.6 kg in the control group; gestational weight gain of ≤5 kg was seen in 28.5% and 20% of the women, respec-

tively; gestational weight gain of ≤9 kg was observed in 64.6% and 53.4%, respectively. At week 35 of gestation, systolic and diastolic blood pressures were similar between the 2 groups, as was physical fitness level. Obstetric and neonatal outcomes were not significantly different between groups. “These results suggest that, since the intervention had no clear effect on clinical outcomes, lifestyle intervention should probably be considered [for obese women] prior to getting pregnant to optimize obstetric and neonatal outcomes,” Dr Vinter said, “but further studies of intervention are needed to draw firm conclusions.” n

Womenâ&#x20AC;&#x2122;s Health

No evidence for routine pelvic examination By Rosemary Frei, MSc

s it time for the routine pelvic examination to be phased out? A group of experts says that it is. In a recent article, Carolyn Westhoff, MD, and colleagues note that the American College of Obstetricians and Gynecologists (ACOG) guidelines recommend less frequent cervical screening, and that bimanual examinations do not lead to earlier detection of ovarian cancer (Westhoff CL, et al. J Womens Health [Larchmt]. 2011;20:5-10). They add that â&#x20AC;&#x153;eliminating the speculum

has not performed this procedure in weeks or months?â&#x20AC;? Dr Westhoff, Director, Division of Family Planning and Preventive Services and Family Planning Fellowship; Medical Director, Family Planning Clinics and

Special GYN Services; and Professor of Obstetrics and Gynecology, Epidemiology and Population, and Family Health, Columbia University Mailman School of Public Health, New York City, said that many others share this concern,

but that there are still many women with symptoms, and therefore, â&#x20AC;&#x153;ample opportunityâ&#x20AC;? for clinicians to maintain their skills. â&#x20AC;&#x153;That said, I have already heard from adolescent medicine providers that now Continued on page 24

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

â&#x20AC;&#x153;At some point, with continued patient and provider education, these practices will occur less frequently.â&#x20AC;? â&#x20AC;&#x201D;Joyce King, PhD

Make the connection at www.neevodha.com

examination from most visits and the bimanual examination from all visits of asymptomatic women will free resources to provide services of proven benefit.â&#x20AC;? In Sweden, the Netherlands, and the United Kingdom, the bimanual examination is used solely for symptomatic women, they point out. But how will clinicians retain the skills that are important for examining symptomatic women, asks Joyce King, PhD, Clinical Assistant Professor, Emory University School of Nursing, Atlanta, who was not a coinvestigator. â&#x20AC;&#x153;Iâ&#x20AC;&#x2122;m not saying that this is a reason for performing unnecessary pelvic examinations, but ask yourself the question: If you are a patient with pelvic symptoms, such as pelvic pain or menstrual abnormalities, do you want a clinician who is experienced with this procedure or do you want a clinician who

Prenatal vitamins containing synthetic folic acid have limitations. See if the benefits of NeevoDHAÂŽ are for you.

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OCTOBER 2011 l VOLUME 3, NUMBER 5

Women’s Health

No evidence for routine pelvic... that the Pap is not recommended in that age-group, many are finding only rare opportunities to do this,” Dr Westhoff said. “Thus, providers who now do only occasional pelvic exams may have a greater challenge developing and maintaining these skills. In any case, we must refine our approaches to educating stu-

Continued from page 23

dents on how to do this exam.” She and her colleagues show that in asymptomatic women, the pelvic examination is not needed to screen for sexually transmitted infections or to initiate hormonal contraception, and that it does not increase early detection of ovarian cancer.

“It is time to get asymptomatic women off the table.” — Carolyn Westhoff, MD

Women can use urine and self-collected vaginal swabs for testing for chlamydia and gonorrhea. Furthermore, current guidelines from ACOG and other professional organizations state that a pelvic examination is not required for the initiation of systemic hormonal contraceptives, because the examination’s findings do not change the decision to prescribe the contraceptives. ACOG’s 2009 Practice Bulletin recommended a decrease in the frequency of cytologic screening for cervical cancer. Dr Westhoff and colleagues, however, concede in their paper that, “until primary HPV [human papillomavirus] testing becomes routine or until we have a satisfactory approach to self-sampling for cytology, women will still need occasional speculum examinations for cervical screening. Nevertheless, the frequency of these examinations can be less than many patients currently expect.” They note that the bimanual examination has poor sensitivity and specificity for the detection of ovarian cancer. Therefore, guidelines from ACOG, the American Cancer Society, and the US Preventive Services Task Force do not recommend its use. What about other benefits from pelvic examinations for asymptomatic women, such as diagnosing uterine fibroids or ovarian cysts? The researchers state that there is no evidence of a clinical benefit from finding these lesions. Moreover, overscreening leads to false-positive results and unnecessary procedures, which add to healthcare costs and risks to women. In addition, many women avoid the embarrassment and discomfort that often accompany a pelvic exam. Thus, “it is time to get asymptomatic women off the table,” conclude Dr Westhoff and colleagues. Dr King agrees, but does not expect the practices to stop suddenly. “I see many patients that, no matter what I say, still want to have their annual Pap and pelvic [examination]. I provide the information regarding the guidelines, but often do the procedures, because it provides some level of comfort and security for the patient. At some point, with continued patient and provider education, these practices will occur less frequently.” n

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

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

Description NeevoDHA® is an opaque blue gelatin capsule.

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

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

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

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

Patient Information NeevoDHA® should only be used under medical supervision. NeevoDHA® is certified kosher by Triangle K and Associates. Contains Soy Dosage and Administration Usual adult dose is 1(one) gelatin capsule daily or as directed by your physician. How Supplied Available as a blue, soft gelatin capsule with “Neevo DHA” imprinted on one side in white ink. Commercial product (0525-0621-30) is supplied in bottles of 30 capsules. Sample product (0525-0621-04) is supplied in bottles of 4 capsules. Commercial Product (30 capsules) 0525-0621-30* Use under medical/physician supervision. Sample Product (4 capsules) 0525-0621-04* Professional samples-not for sale * Pamlab, LLC does not represent this product code to be a National Drug Code (NDC) number. Instead, Pamlab has assigned a product code formatted according to standard industry practice to meet the formatting requirements of pharmacy and health insurance computer systems. Storage Store at controlled room temperature 15oC to 30oC (59oF to 86oF) (See USP). Protect from light and moisture. Dispense commercial product in original container. Dispense sample product in original container.

KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN. Patents Some or all of the following patents may apply: U.S. Patent No. 6,207,651 U.S. Patent No. 6,011,040 U.S. Patent No. 5,563,126 U.S. Patent No. 6,254,904 U.S. Patent No. 5,795,873 U.S. Patent No. 6,297,224 U.S. Patent No. 5,997,915 U.S. Patent No. 6,528,496 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 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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OCTOBER 2011 l VOLUME 3, NUMBER 5

Clinic Profile

combining care and convenience... 1994. I came on board in 2002 and purchased the practice in 2003, and then changed the name to the Fertility Centers of New England, after opening several additional satellite offices. We now have 7 locations around the Boston area and in southern New Hampshire. We are among the top 20% to 25% of centers in terms of size, and our success rates are among the best in the country. Our practice is comprised of 4 boardcertified physicians among a total of 42 employees, including 12 registered nurses and 4 medical assistants. We have a very dedicated staff beginning with the person who answers the phone, because healing starts with the person who answers the phone and extends to all personnel. Everyone is inculcated into our service philosophy, which is treating others the way we would like to be treated. It is care, convenience, and cost that separate us from many of the larger centers. Our staff is committed to delivering quality care, as well as patient and referring provider convenience, along with reducing the cost of treatment to improve access for more patients. Our primary facility is in Reading, MA, where our andrology and embryology laboratories are located. Our high level of personalized care is delivered by our individual care teams. Each care team is comprised of the patient, their physician, nurse, medical assistant, and a care coordinator. Our electronic medical records and individual care teams enable us to provide the personalized and compassionate care that each patient deserves. We also have a comprehensive website, with social media outlets. Knowledge is power, and we endeavor to help educate our patients and stay well informed. Importantly, we are very transparent about our patient programs, treatment options, and prices for our self-pay patients, which is why we have received Better Business Bureau awards annually since 2008. How do you make infertility care affordable? The cost for infertility care is expensive, but services can be provided expeditiously and relatively inexpensively, without compromising personalized and compassionate care. Across the country, only 15 states have a mandate to cover or offer infertility treatment. Massachusetts was the first and is one of the most liberal, although 20% of people who live and work in Massachusetts do not have infertility coverage. Other states we serve, including New Hampshire and Maine, do not have an insurance mandate for infertility treatments. A major barrier for infertility patients

needing advanced reproductive technologies like IVF is the financial costs, which is why we implemented IVF Assist, one of the most cost-competitive programs available. We provide IVF/ intracytoplasmic sperm injection (ICSI) for $6800 per cycle, and if pregnancy does not occur after 2 cycles, the third cycle will be provided free of charge. IVF Assist cycles include: cycle monitoring; egg retrieval, including anesthesia; insemination of oocytes with ICSI; embryo culture and transfer from this cycle; and laboratory testing for pregnancy after embryo transfer. We also provide free consultations to firefighters, police officers, and full-time military personnel. It is our way of saying thank you to those who serve to keep us safe. In addition, we have started to work with third-party lenders that offer financing options for our self-pay patients. Approximately 15% of self-pay patients request financing options. However, we are hopeful that our IVF Assist program will help more patients to enter treatment and reduce the need for loans or financing. What is the approach to patient care at your center? We are all about care. It is about trying to determine why someone is having difficulty having a successful pregnancy. Our philosophy regarding oocyte stimulation is not that more is better; instead, we endeavor for quality over quantity. We strive to give our embryologists 5 quality embryos to select the best 1 or 2 for transfer and the remainder to freeze, if embryo quality is sufficient. Thus, we generally do a gentler stimulation than many, which allows us to conserve on medication costs and to decrease inadvertent adverse effects. We also have a very low percentage of high-order multiples, because of our commitment to transfer no more than 2 embryos in anyone aged younger than 41 years. To reduce the twin rate, we offer elective single-embryo transfer (eSET) to appropriate patients. Among women younger than 35 years, 25% have eSET, and among women aged 35 to 37 years, approximately 12% have eSET. For other women younger than 41 years, we transfer 2 embryos. For women aged 41 years or older, we transfer no more than 3 embryos. Our age limit is 43 years, because the chance of having a successful pregnancy after age 43 is less than 5%. We recommend donor eggs to all women older than age 43, to younger women with poor embryo quality, and to those with diminished ovarian reserve. Our donor oocyte recipient program is very competitive in terms of cost and successful pregnancy rates.

Continued from page 1

We also provide many other familybuilding services, which include providing care to singles, as well as gay, lesbian, and transgendered couples, because we believe that any loving person who desires a child deserves to be a parent. We have very successful preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) programs. We perform PGD for couples with in-born single gene mutations or sexlinked disorders. We offer PGS for women aged older than 40 years who are high responders. We also offer PGS for women with high-order pregnancy losses (>4 miscarriages). We are among the few programs in the country that provide family balancing services using PGD.

“Our philosophy regarding oocyte stimulation is not that more is better; instead, we endeavor for quality over quantity.” —Joseph Hill, MD

Our fertility preservation program is also quite successful. We perform egg freezing and fertility preservation using vitrification for women diagnosed with cancer before starting their chemotherapy or radiation treatment, and for young women who are interested in the potential of preserving their fertility. We have a proven record in achieving successful pregnancies in all our programs, and have worked for years with Extend Fertility and the LIVESTRONG Sharing Hope program. To further serve the communities in which we practice, we sponsor each of our employees annually to do 2 full-day volunteer sessions in the community. This initiative has been well received by our employees and the community. Could you talk about the centers’ sex-selection program? We are the only center in New England that offers sex selection for family balancing. We follow the American Society for Reproductive Medicine Ethics Committee guidelines. Their position paper stated that it is ethical to offer sex selection for family balancing as long as a couple has had a previous successful pregnancy. We have provided this service for more than 3 years. Patients who take advantage of this service are primarily in their mid30s with 2 or 3 previous children, and most desire daughters. We do between 25 and 30 such cases annually. This is a relatively small number, given the price

we charge for this service. The price charged by other centers around the country for sex selection is 2 to 3 times our all-inclusive price of $9000. What is your sex-selection success rate? The successful delivery rates depend on the woman’s age, but overall, approximately 60% will have a baby. Diagnostic accuracy regarding sex of choice approaches 100% using PGD. We strongly discourage sex selection for infertile couples. How does sex selection work? We do IVF followed by ICSI. On day 3 after fertilization, we biopsy each embryo so that a blastomere can be analyzed for 3 chromosomes: X for female, Y for male, and 21 to ensure that we are not transferring an embryo with Trisomy 21. The results are obtained on day 4 after retrieval, and blastocyst transfer is done on day 5. We do not discard embryos; all potentially viable embryos are cryopreserved. What other services do you offer? We offer an array of alternative and complementary programs, including a mind–body program, fertility yoga, and acupuncture. Life is stressful, and for those with infertility, stress can reach life-crisis levels. The goal is to learn coping methods. It is my opinion that most people go through life asleep, and those who are awake are either screaming or running. The lucky ones may be able to find a centered space of peace. That is why we offer counseling, biofeedback, meditation, yoga, and acupuncture. Life is truly a miracle, and it is important for us to be cognizant of the honor and privilege we have to be so welltrained, and of our obligation to provide personalized and compassionate care. We are fortunate to be able to help others to achieve their dreams of becoming parents. The Fertility Centers of New England is a center of excellence comprised of proficient, compassionate, dedicated people. No one takes what we do for granted. We provide a soothing and nurturing environment where all are empowered. Care, convenience, and cost are very important to us. We treat others the way we would like to be treated by finding the problem, presenting options, providing support, and helping patients to make informed choices based on realistic expectations. At the Fertility Centers of New England, it is not solely about making babies—it is about providing care, and from that care, babies come. n

OCTOBER 2011 l VOLUME 3, NUMBER 5

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

Rx only

Breast Cancer Awareness

Knowledge of fertility lacking in young women with Breast cancer By Jessica A. Smith

lthough most young women with breast cancer want as much information as possible about fertility at the time of their diagnosis, many of these women have a paucity of knowledge on the subject, according to the first study to evaluate levels of fertility knowledge at diagnosis (Peate M, et al. J Clin Oncol. 2011;29: 1670-1677). This lack of knowledge results in higher levels of uncertainty, or decisional conflict, among these women, which is compounded by the inherent pressure involved in making fertility-related decisions when cancer is a factor, the researchers say. “Young women diagnosed with early breast cancer are faced with a difficult decision with insufficient knowledge, and there appears to be an association between their level of knowledge and the ease in which they make fertilityrelated decisions,” said lead researcher Michelle Peate, PhD, Research Program Manager, Psycho-Oncology Cooperative Research Group, University of Sydney, Australia. The findings were derived from survey results from 111 women, aged 18 to 40 years, who were diagnosed with early breast cancer and had not yet completed their families. The researchers assessed 3 areas in the women’s answers—level of knowledge about fertility and treatment options related to it; predictors of knowledge, decisional conflict, and intentions for treatment; and preferences regarding fertility-related information and decision-making.

fertility Knowledge The mean score among participants

was 5.2 (range, 0-10) from a potential knowledge score of 10 for fertility-related information. Of the women, 45% provided correct answers on 6 or more items on the 10-question true/false survey. “Many young patients with breast cancer were unaware of key facts regarding the impact of breast cancer treatments

chemotherapy has commenced, fertility preservation options are likely to be reduced,” the researchers wrote. Women with lower levels of decisional conflict around fertility-related decisions were found to have higher levels of fertility knowledge, which points to increased patient education helping to

“There appears to be an association between the level of fertility knowledge among young women with breast cancer and the ease in which they make fertility-related decisions.” —Michelle Peate, PhD

on fertility and potential fertility preserving options, as well as pregnancy after breast cancer,” the researchers wrote. The researchers pointed out, however, that the scale used for measuring fertility- and cancer-related knowledge may not be an optimal metric, because what are considered “correct” responses to questions may be debatable among experts with differing data and opinions. Decisional conflict More than 63% of participants were classified as having high levels of decisional conflict surrounding fertility options, with a mean score on the decisional conflict scale of 48.3 (range, 0-100). “Delay in decision-making may have considerable implications, because once

reduce such conflict and aid patients in making informed choices about potential fertility treatments. preferences for receiving fertilityrelated information All the women reported that information related to the effects of their cancer treatment on fertility was important to them, with 65% stating that it was extremely important and 22% stating that it was very important. The entire study population also deemed it important to receive information on interventions that potentially would preserve fertility. A majority (74%) stated that they preferred to receive as much information as possible about the potential

effects of cancer treatments on their future fertility. In addtion, 73% indicated that they wanted to hear both good and bad news. A much smaller percentage (15%), however, reported that they would only prefer to hear good news, and 12% indicated that they preferred to receive only a minimal amount of information. “Because this information was equally important to women, irrespective of anxiety and/or depression levels, clinicians should not avoid providing this information because of concomitant mental health concerns. Additionally, approximately 70% of recruits were childless at diagnosis,” the researchers wrote. Decision-making preferences In decision-making preferences, 40% of the women preferred to make decisions about fertility treatment options after seriously considering their doctor’s opinion, 35% indicated that they preferred to share decision-making responsibility with their doctors, 21% preferred that their doctor make decisions while taking their opinions into account, and 4% preferred that their doctor do all the decision-making. Only 1% of the women preferred to make decisions around fertility treatments without consulting with their doctors. The researchers have developed and evaluated a tool, called a decision aid, to help women with this complex decision-making process. Their hope is to publish the results of this evaluation sometime in the near future, Dr Peate said. The booklet can be found in digital format at www.cancercouncil.com. au/editorial.asp?pageid=2797. n

CHEK2 screening with family History of Breast cancer?

n women with a family history of breast cancer, CHEK2-mutation screening may thwart the significantly increased risk for breast cancer in those with the gene mutation, according to researchers (Cybulski C, et al. J Clin Oncol. 2011 Aug 29. Epub ahead of print). “CHEK2-mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer,” the researchers wrote. “Women with a truncating mutation in CHEK2 and a positive family history of breast

cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemo prevention.” In this large, prospective study, Polish researchers sought to determine the level of risk for breast cancer in women who have a CHEK2 mutation, with or without a family history of breast cancer. The researchers enrolled 7931 patients with invasive breast cancer and a control group of 4346 women without cancer. Truncating CHEK2

mutations were identified in 4.1% of women with breast cancer who had a family history of the disease, in 2.8% of women with breast cancer who had no family history of the disease, and in 0.8% of the control group. A woman with a truncating CHEK2 mutation and no family history of breast cancer has an estimated relative risk for breast cancer of 3.3, according to the researchers. With the 6% average baseline risk for breast cancer in Poland, this translates to a lifetime risk of about 20%. For persons with a truncating CHEK2

mutation and a family history of breast cancer, the risk for the disease increases significantly—to 28% for a woman with 1 second-degree relative with breast cancer, to 34% for a woman with 1 firstdegree relative with breast cancer, and to 44% for a woman with first- and second-degree relatives with breast cancer. “Our results confirm that it is inadequate to offer mutation testing and genetic counseling for CHEK2 without taking into consideration both the family history and the genotype,” the researchers concluded.—JS n

OCTOBER 2011 l VOLUME 3, NUMBER 5

Clinical News Oral contraceptive Adherence...

fetal DNA in maternal Blood provides Accurate sex prediction Free-floating fetal DNA in a mother’s blood can accurately predict fetal sex. When using real-time quantitative (RTQ)-polymerase chain reaction

Continued from page 5

(PCR) to amplify fetal DNA, a simple, noninvasive blood test could provide a viable alternative to invasive cytogenetic determination, according to researchers who conducted a systematic review and meta-analysis on the topic

The randomized trial examined adherence rates among 504 women at an urban family planning clinic who received either a 3-month or a 7-month supply of oral contraceptives. Analyzing self-reported data acquired via Fe (norethindrone and ethinyl estradiol chewable tablets and telephone interview at a 6-month GENERESS™ ferrous fumarate chewable tablets) 0.8 mg/25 mcg postinitiation visit, the researchers Brief Summary found that more than half (51%) of For full prescribing information, see package insert the women who received a 7-month Rx only supply continued to take the contra- WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS ceptive pills compared with 35% of Cigarette smoking increases the risk of serious cardiovascular events from oral contraceptive (COC) use. This risk increases with age, particthe women in the 3-month-supply combination ularly in women over 35 years of age, and with the number of cigarettes group. This finding especially held smoked. For this reason, COCs should not be used by women who are over true for women aged younger than 18 35 years of age and smoke. [See Contraindications (4).] years, with 49% in this age-group 1 INDICATIONS AND USAGE remaining adherent with a 7-month GENERESS Fe is indicated for use by women to prevent pregnancy. supply compared with only 12% of The efficacy of GENERESS Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated. those who received a 3-month supply. 4 CONTRAINDICATIONS Women who received packs of Do not prescribe GENERESS Fe to women who are known to have the following: pills were more likely to adhere to • A high risk of arterial or venous thrombotic diseases. Examples include women their oral contraceptives than those who are known to: who received prescriptions for them. - Smoke, if over age 35 [see Boxed Warning, and Warnings and Precautions (5.1)] The researchers pointed out that - Have deep vein thrombosis or pulmonary embolism, now or in the past [see these results may not be generalizWarnings and Precautions (5.1)] able, because the study population - Have cerebrovascular disease [see Warnings and Precautions (5.1)] - Have coronary artery disease [see Warnings and Precautions (5.1)] represents a limited demographic, - Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for comprised mainly of Hispanic, urexample, subacute bacterial endocarditis with valvular disease, or atrial fibrillaban, poor women. tion) [see Warnings and Precautions (5.1)] fewer complications seen with OB/GyNs who perform more Deliveries OB/GYN providers who deliver a high volume of babies annually have 50% lower odds of maternal complications compared with their counterparts who perform a low volume of deliveries, according to new research (Janakiraman V, et al. Obstet Gynecol. 2011;118:521-527). The nationwide retrospective cohort study evaluated the relationship between hospital and provider delivery volumes and obstetric complication rates among 1365 hospitals and 6963 providers in 2007. Although delivery volume at hospitals did not show any significant correlations with complications, the difference in complications between high- and low-volume OB/GYNs was significant. Those who performed 7 or fewer deliveries annually had higher rates across 4 types of complications assessed (laceration, 4.2%; hemorrhage, 5.7%; infection, 1.3%; operative, 0.1%) and 50% higher overall odds of complications compared with OB/GYNs who performed 90 or more deliveries annually. “These findings raise the possibility that maternal outcomes could be improved by selective referral to higher-volume providers, or by ensuring greater training, possibly tied to credentialing, for the lowest-volume providers,” the researchers concluded.

• •

- 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.

(Devaney SA, et al. JAMA. 2011; 306:627-636). The test, which detects Y chromosome DNA sequences in the maternal blood, showed a sensitivity (proportion of male fetuses with a positive test

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

OCTOBER 2011 l VOLUME 3, NUMBER 5

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.

Clinical News result) of 95.4% and specificity (proportion of female fetuses with a negative test result) of 98.6% from 80 data sets derived from 57 studies. It showed a positive predictive value of 98.8% and a negative predictive value of 94.8%.

DNA testing technique and gestational age had the greatest effect on the test’s performance; tests using urine proved unreliable, as did tests done before 7 weeks of gestation. Testing after 20 weeks provided the greatest reliability. In

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.

addition, RTQ-PCR outperformed standard PCR in sensitivity and specificity. A disadvantage the researchers cited is the test’s inability to validate female sex, because the test only checks for male chromosomes. “Other potential disad-

vantages include that DNA testing is not available at point of care, not presently approved by the Clinical Laboratory Improvement Amendments, and not currently reimbursed by insurers,” they wrote. n

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.

OCTOBER 2011 l VOLUME 3, NUMBER 5

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.

07569

06/11

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

The OB/GYN & Infertility Nurse

OCTOBER 2011 l VOLUME 3, NUMBER 5