Arpil 2010 Vol 2, No 2 by Novellus Healthcare Communications, LLC

She depends on your guidance...

Only ONE vaginal progesterone is proven as effective as IM It’s a fact. CRINONE is proven equivalent to IM progesterone in the largest prospective, randomized, well-controlled clinical trial study ever conducted comparing vaginal to IM progesterone.1

CRINONE 8% (progesterone gel) is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (ART) treatment for infertile women with progesterone deficiency. Important Safety Information The most common side effects of CRINONE 8% include breast enlargement, constipation, somnolence, nausea, headache, and perineal pain. CRINONE 8% is contraindicated in patients with active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders, missed abortion, undiagnosed vaginal bleeding, liver dysfunction or disease, and known or suspected malignancy of the breast or genital organs.

www.crinoneusa.com

This study, conducted at Brigham and Women’s Hospital, adds to the 12 p prior trials 2-13 demonstrating the comparable efficacy of CRINONE and IM progesterone. No other vaginal progesterone can make this claim. In fact, CRINONE is the single most studied and widely used vaginal progesterone worldwide. When she asks about progesterone, give her the facts.

The only ONE

CRI8-PAD-005

Clinical News Risk for a Stillborn Quadruples with Use of IVF/ICSI Results of a new study show that the use of artificial reproductive technology (ART), particularly IVF and intracytoplasmic sperm injection (ICSI), increases the risk for a singleton pregnancy resulting in a stillbirth by more than 4-fold (Wisborg K, et al. Hum Reprod.

2010 Feb 23. Epub ahead of print). Researchers at the Department of Pediatrics, Perinatal Epidemiology Research Unit, Aarhus University Hospital, Denmark, used data from the Aarhus Birth Cohort registry on 20,166 singleton pregnancies in primiparous women without chronic diseases. After adjusting for maternal age, body mass index, education, smoking,

CRINONE® 4% CRINONE® 8% (progesterone gel)

See package insert for full prescribing information. 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 hormoneassociated 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 Crinone-treated 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, open-label 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 more 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 reported in 5% or more of women treated with Crinone

and alcohol and coffee intake during pregnancy, women who conceived by IVF/ICSI were 4.08 times more likely to have a stillborn than fertile women who conceived by natural means. Conversely, fertile women were 25% as likely as women who conceived by IVF/ICSI to have stillbirths. Women who were subfertile were 33% as likely, and women who became pregnant by

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. This brief summary is based on the current Crinone package insert (Version 40405010007, Revised December 2006). How Supplied Crinone is available in the following strengths: 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-55056-0806-2 - 6 Single-use prefilled applicators. NDC-55056-0818-2 - 18 Single-use prefilled applicators. Each applicator is wrapped and sealed in a foil overwrap. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Rx only. U.S. Patent Number 5,543,150. Manufactured for: Columbia Laboratories, Inc. Livingston, NJ 07039 Manufactured by: Fleet Laboratories Ltd., Watford, United Kingdom © 2007, Columbia Laboratories, Inc. Printed in USA 6/07

References: 1. Yanushpolsky EH. Comparison of Crinone 8% intravaginal gel and intramuscular progesterone (IMP) for luteal phase support: largest prospective randomized trial to date. Slides presented at: American Society for Reproductive Medicine, 2009. 2. Berger B, Phillips JA. A retrospective analysis of pregnancy outcomes in recipients of anonymously donated oocytes at a large ART center. Fertil Steril. 2008;89:S11–S12. Abstract P-7. 3. Saucedo LLE, Batiza V, Arenas L, et al. Progesterone for luteal support: randomized, prospective trial comparing vaginal and i.m. administration. Paper presented at the 19th Annual Meeting of the European Society for Human Reproduction & Embryology; July 2003; Madrid, Spain. Abstract P-383. 4. Anserini P, Costa M, Remorgida V, Sarli R, Guglielminetti E, Ragni N. Luteal phase support in assisted reproductive cycles using either vaginal (Crinone 8) or intramuscular (Prontogest) progesterone: results of a prospective, randomized study [in Italian]. Minerva Ginecol. 2001;53:297–301. 5. Coutifaris C, Patrizio P, Schafer D, Bunso S, Bucci J, Barnhart K. Is the use of Crinone for support of the luteal phase detrimental to pregnancy outcome after transfer of non-cryopreserved embryos in good prognosis patients? A preliminary report. Fertil Steril. 2000;74(suppl 1):S205. Abstract P-350. 6. Alper MM, Penzias AS. Crinone® offers excellent implantation rates in patients undergoing IVF. Paper presented at the 16th Annual Meeting of the European Society for Human Reproduction & Embryology; June 2000; Bologna, Italy. Abstract P-059. 7. Schoolcraft WB, Hesla JS, Gee MJ. Experience with progesterone gel for luteal support in a highly successful IVF programme. Hum Reprod. 2000;15:1284–1288. 8. Saucedo LLE, Galache VP, Hernández AS, Santos HR, Arenas ML, Patrizio P. Randomized trial of three different forms of progesterone supplementation in ART: preliminary results. Fertil Steril. 2000;74(suppl 1):S150. Abstract P-175. 9. Williams SC, Donahue J, Muasher SJ. Vaginal progesterone therapy during programmed cycles for frozen embryo transfer: an analysis of serum progesterone levels and pregnancy rates. Fertil Steril. 2000;74(suppl 1):S209. Abstract P-363. 10. Levine H. Luteal support from the vaginal progesterone (P) gel Crinone 8%: preliminary results of multicenter trial show higher pregnancy rates than historical controls. J Soc Gynecol Investig. 2000;7(suppl). Abstract 571. 11. Chantilis SJ, Zeitoun KM, Patel SI, et al. Use of Crinone vaginal progesterone gel for luteal support in in vitro fertilization cycles. Fertil Steril. 1999;72:823– 829. 12. Gibbons WE, Toner JP, Hamacher P, Kolm P. Experience with a novel vaginal progesterone preparation in a donor oocyte program. Fertil Steril. 1998;69:96–101. 13. Berger BM, Phillips JA. A retrospective analysis of pregnancy outcomes in recipients of frozen/thawed embryos (FET) from donated oocytes at a large assisted reproductive technology (ART) center. Fertil Steril. 2008;90(suppl 1):S459. Abstract A-260.

Columbia Laboratories, Inc. Livingston, NJ 07039

non-IVF ART were 13% as likely to have a stillborn. The researchers concluded that the increased risk of stillbirth is associated with the use of fertility treatment or ART, although the exact mechanism is not yet clear.

First Investigational Drug Targeting Menstrual Cramps Etiology An investigational drug, VA111913, is currently in phase 2 clinical trials for the treatment of dysmenorrhea, or menstrual pain. Although still in the early stage of development, this is the first attempt to develop a drug that targets the cause rather than the symptoms of dysmenorrhea. Preliminary results were presented at the American Chemical Society in March 2010. “We hope that the drug will provide a more effective treatment option for millions of women worldwide with this painful condition,” said Andrzej R. Batt, a scientist working at Vantia, the UK-based manufacturer of this product. This drug is intended to block the hormone vasopressin to thwart the frequent uterine contractions that are at the root of dysmenorrhea.

Exercise in Second Half of Pregnancy Contributes to Low-Weight Babies Regular aerobic exercise contributes to lower birth weight but is not associated with maternal insulin sensitivity, according to a new, randomized, controlled trial (Hopkins SA, et al. J Clin Endocrinol Metab. 2010 Mar 24. Epub ahead of print). Researchers investigated the effects of aerobic exercise during the second half of pregnancy on neonatal outcomes and maternal insulin sensitivity, citing previous studies suggesting that regular exercise could influence neonatal size by regulating the supply of nutrients to the fetus. A total of 84 healthy nulliparous women took part in a home-based stationary cycling exercise program, starting at 20 weeks of gestation through delivery. Women who exercised during pregnancy gave birth to neonates with lower birth weight and lower body mass index than those who did not. The offspring of women who exercised also had lower cord serum insulinlike growth factor (IGF)-1 and IGF-2. The reduction in maternal insulin sensitivity in late pregnancy was not related to exercise or to the size effect on the offspring.

Pregnancy after Breast Cancer Increases Survival Rate A new meta-analysis suggests that pregnancy is safe in women who are breast cancer survivors. In fact, this study suggests that breast cancer survivors who become pregnant have a better chance of survival than their Continued on page 27

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april 2010 I Vol 2, no 2

CONTENTS

april 2010

Vol 2, no 2

PUBLISHING STAFF

Managing Director Jack Iannaccone jack@infertilitynurse.org 732-992-1537 Editorial Director Dalia Buffery dalia@novellushc.com 732-992-1889 Associate Editor Lara J. Reiman lara@novellushc.com 732-992-1892 Editorial Assistant Jessica A. Smith Director, Client Services Russell Hennessy russell@novellushc.com 732-992-1888 Director, Client Services Mark Timko mark@novellushc.com 732-992-1897 Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto Editorial Contact: Telephone: 732-992-1892 Fax: 732-656-7938 MISSION STATEMENT The OB/GYN and Infertility Nurse is the official publication of the American Academy of OB/GYN and Infertility Nurses. The OB/GYN and Infertility Nurse provides practical, authoritative, cutting-edge information on the physiologic, medical, and psychological aspects of human reproduction, focusing on the role of the OB/GYN, infertility, and urology nurse in patient care. Our journal offers a forum for nurses, nurse practitioners, physician assistants, administrators, researchers, and all others involved in OB/GYN, infertility, and urology to discuss the entire scope of current and emerging diagnostic and therapeutic options, as well as counseling and patient follow-up for men and women throughout their reproductive years and beyond. Written by nurses for nurses, The OB/GYN and Infertility Nurse promotes peer-to-peer collaboration among all nursing professionals toward the advancement of integrated services for optimal care delivery. The journal offers continuing education for all nurses involved in these interrelated fields of patient management. The OB/GYN and Infertility Nurse, ISSN 2151-8394 (print); ISSN 2151-8408 (online), is published 6 times a year by Novellus Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831. Copyright ©2010 by Novellus Healthcare Communications, LLC. All rights reserved. The OB/GYN and Infertility Nurse is a trademark of Novellus Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. The ideas and opinions expressed in The OB/GYN and Infertility Nurse do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in The OB/GYN and Infertility Nurse should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issue, $17.00. Orders will be billed at individual rates unless proof status is confirmed. SUBSCRIPTIONS/CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, The OB/GYN and Infertility Nurse, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831; Fax: 732656-7938.

april 2010 I Vol 2, no 2

CLINICAL NEWS

3 Risk for a Stillborn Quadruples with Use of IVF/ICSI First Investigational Drug Targeting Menstrual Cramps Etiology Exercise in Second Half of Pregnancy Contributes to Low-Weight Babies Pregnancy after Breast Cancer Increases Survival Rate 27 Multivitamins Not Protective against Cancer, CVD in Postmenopausal Women Prostatitis, STDs Increase Risk for Prostate Cancer

CONTINUING EDUCATION

10 Reproductive Depressions 12 Commentary: Postpartum Depression 18

THE OB/GYN NURSE

13 Early Stroke Treatment Benefits Women More than Men 14 First Term-Stillbirth Caused by Translocation of Oral Bacteria Rates of Vaginal Birth after Cesarean Are Plummeting 15 Patient Surveillance by Gynecologic Oncologists Spotty after Ovarian Cancer Treatment 16 Alcohol and Obesity Increase Risk of Breast Cancer Recurrence Effect of Vaginal Estrogen in Breast Cancer Patients Uncertain, but Serum Estradiol Levels Do Rise 17 High-Dose Vitamin D May Relieve AI-Related Joint Pain For Borderline Pap Smears, Referral for HPV Testing Less Stressful for Patients

PHARMACY CORNER

19 Infertility Medication Storage LEGAL MATTERS

20 Legal Guidance for Clinicians Assisting in Gestational Carrier

Arrangements

THE INFERTILITY NURSE

21 Lifestyle Choices that Influence Fertility Antiestrogens May Protect Against Lung Cancer 22 The Benefits of Preconception Genetic Counseling, Indications for Referral 23 Surplus Quality Embryos to Freeze Linked to IVF Success 24 Romance on the Rocks? Frozen Embryo Transfer Shows Better Perinatal Outcomes than Fresh Embryo Transfer

THE UROLOGY NURSE

25 More Evidence for Semen Damage from Cell Phones NUTRITION

26 Vitamin D Deficiency a Contributor to Depression, Insulin Resistance

CORRECTION In the February 2010 issue on page 5, the “Ask the Expert” response by Debra Moynihan contained an error, stating that birth at 36 weeks is considered preterm. It should have stated that babies born at 36 weeks gestation or earlier (≤36 weeks) are considered preterm. Those born at 37 weeks or later are considered full term. The answer itself was correct.

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From the Editors

Co-Editor-in-Chief Debra Moynihan, WHNP-BC, MSN Carolina OB/GYN

Ask the Expert

Co-Editor-in-Chief Sue Jasulaitis, RN, MS Fertility Centers of Illinois

By Sue Jasulaitis

Question: Recently we have used the multi-dose protocol of methotrexate and Citrovorum factor for a patient diagnosed with ectopic pregnancy. Can you tell me how effective this treatment is, and explain how Citrovorum factor acts to minimize the side effects of methotrexate? Answer: Until the mid-1980s, the treatment of ectopic pregnancy was exclusively surgical. Today, medical management has widely replaced surgery for this condition. Medical intervention for ectopic pregnancy involves the use of methotrexate therapy. Methotrexate, one of the oldest chemotherapy drugs used in cancer management,1 stops the proliferation (growth) of ectopic fetal tissue, while saving the fallopian tube. Although not FDA indicated for the treatment of ectopic pregnancy, the use of methotrexate in the outpatient setting has become common. Methotrexate acts by inhibiting folic acid production in proliferating fetal cells, causing a planned folic acid deficiency, which results in cell death. This cellular destruction affects diseased and normal cells, which can cause side effects, such as low blood counts (ie, neutropenia, anemia, thrombopenia), as well as hair loss, stomatitis, and liver, lung, nerve, and kidney damage.2 Folic acid is a vitamin that performs a critical role in the synthesis of DNA and RNA, repairing damaged DNA and

EDITORIAL BOARD Co-Editor-in-Chief Debra Moynihan, WHNP-BC, MSN Women’s Health Nurse Practitioner Carolina OB/GYN, SC Co-Editor-in-Chief Sue Jasulaitis, RN, MS Clinical Research Manager Fertility Centers of Illinois, Chicago Donielle Abbruscato, RNC Clinical Nursing Manager Brunswick Hills OB/GYN, NJ Barbara Alice, RN, APN-C, MSN Nursing Manager, IVF Coordinator South Jersey Fertility Center

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rionic gonadotropin (hCG) titers.3 A systematic review of patients treated with multi-dose regimens showed a 96% success rate, with a resolution rate averaging 35 to 40 days; 10% of patients required only single-dose methotrexate to achieve ectopic resolution.4 Because most patients treated with multi-dose methotrexate have responded with decreasing levels before the peak effect of the second and third injection, it has been theorized that many patients could be treated successfully with single-dose methotrexate.2 This led to the current 2 protocols for methotrexate, single dose and multiple dose. Which one is the best protocol remains controversial. The most popular protocol is currently the single-dose methotrexate regimen, using a single IM methotrexate dose of 50 mg/m2; this has been associated with a 94% success rate, with an average of 27 days to ectopic resolution.5 Approximately 14% of these cases will require a second dose of methotrexate, extending the resolution period to 35 days.5 The single most important factor in determining the success of treatment, or

when multi-dose methotrexate needs to be considered, is the serum hCG concentration at the time of diagnosis.5 Optimal candidates for medical management with methotrexate are patients who are hemodynamically stable, with hCG concentration <5000 IU/L and ectopic mass size <3.5 cm.3 Once these criteria are met, deciding which medical management protocol to use can be difficult. The final decision is determined based on the clinical findings at diagnosis and the comfort level of the treating physician. Before administering methotrexate, counsel the patient about the risks and benefits of treatment, the expected duration, and the importance of strict follow-up.

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

Jennifer Iannaccone, RNC

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

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

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

facilitating DNA growth and prevention of cellular death. To counter the effects of high-dose methotrexate, multi-dose protocols are designed to limit cellular destruction and inhibit toxic damage to surrounding cells. Known as cell “rescue,” this process is achieved by alternating folic acid– depleting methotrexate with a folic acid supplement—Citrovorum factor (leucovorin calcium). By timing the administration of methotrexate and folic acid (ie, Citrovorum), the toxic effect of methotrexate is rapidly blocked, allowing it to work for about 24 hours to destroy the target (fetal) cells, then being stopped before it damages healthy cells. Methotrexate is the only cancer drug for which a viable antidote (ie, Citrovorum) exists.1 Initially, all methotrexate protocols were multi-dose, alternating methotrexate with Citrovorum rescue. This regimen administers intramuscular (IM) methotrexate (1 mg/kg) on days 1, 3, 5, and 7, then oral Citrovorum factor (0.1 mg/kg) on days 2, 4, 6, and 8. This is continued until achieving a 15% decline in 2 consecutive daily human cho-

Kit Devine, MSN, ARNP Advanced Nurse Practitioner Fertility & Endocrine Associates, Kentucky Gina Paoletti-Falcone, RN, BSN Clinical Services Manager Freedom Fertility Pharmacy Byfield, MA Sandra Fernandez, RPh, PharmD Pharmacist Mandell’s Clinical Pharmacy, NJ

Nursing Manager IVF Coordinator IVF New Jersey

Jill Marchetti, RN Director, Egg Donor Program IVF New Jersey Mary McGregor, RN IVF Coordinator The Fertility Institute of New Orleans Norah S. Nutter, MSN, WHNP-BC, IBCLC Women’s Health Nurse Practitioner Magnolia OB/GYN Myrtle Beach, SC

References 1. Djerassi I, Mills T, Ohanissian L. Elimination of the hazards of high-dose methotrexate with improved citrovorum factor (CF) rescue. Am Soc Clin Oncol. 1980;21:Abstract 361. 2. Lipscomb GH. Medical therapy for ectopic pregnancy. Semin Reprod Med. 2007;25:93-98. 3. Tulandi T. Nonsurgical treatment of ectopic pregnancy. Int J Gynaecol Obstet. 1992;38:107-113. 4. Stovall TG, Ling FW, Gray LA, et al. Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol. 1991;77:749-753. 5. Merisio C, Anfuso S, Berretta R, et al. Single-dose methotrexate for ectopic pregnancy treatment: preliminary data. Acta BioMed. 2005;76:33-36.

Patricia Rucinsky, RN, BSN Clinical Nurse Manager IRMS, St. Barnabas, NJ Kriston Ward, RN, MS, NP-C Strong Fertility Center University of Rochester Medical Center, Rochester, NY Joan Zaccardi, MS, DrNP Administrative Practice Manager Urogynecology Arts of New Jersey

april 2010 I Vol 2, no 2

Clinic Profile

Fertility Preservation...

Continued from page 1

preservation, this is a medical emergency, and as such, we serve as the emergency department for reproductive medicine. We have developed a system that enables us to see a patient with a medical condition the same day, or within 24 hours, of contacting us.

What are the characteristics of your patient population? Kutluk Oktay, MD, FACOG

need fertility preservation, we offer general infertility services as well. We have a variety of experts who work as a team. I established this division based on my background in internal medicine, OB/GYN, and working with cancer patients and cancer experts. Our team includes a gynecologist oncologist, a psychologist—Allison Rosen, PhD, who is herself a cancer survivor and has worked with many patients with cancer—as well as nurses who are focused on the specific needs of patients with cancer in the context of an IVF program. This is a focused team working together. We are not a mega-unit, because we believe in personalized care for each patient. We currently have 3 nurses and 3 other staff members in various capacities. We also have 4 or 5 research fellows, as well as several residents at any given time, and, of course, we have our embryology team.

How is your clinic different from other fertility clinics? Normally, there is no sense of urgency that infertility is associated with a chronic disease, but this is the reality for many of our patients. When patients call to schedule an appointment for fertility treatment, it could sometimes take weeks or months from their first call to the scheduled treatment, and the workup itself can take months. However, when dealing with patients requiring fertility preservation— whether it is a patient with cancer or a hematologic disease for which he or she has to receive chemotherapy or radiation, or whether it is a boy or a girl who needs to take anticancer drugs—a program that is involved in fertility preservation has to be able to respond quickly to that situation, because time is crucial, and the program must be properly equipped for it. With that in mind, we have established the Institute for Fertility Preservation, which addresses both genders and all ages, from age zero and up, and all cases of fertility preservation, regardless of the type of chronic disease. Fertility preservation is not limited to patients with cancer. In all patients who need fertility

april 2010 I Vol 2, no 2

We treat hundreds of patients for fertility preservation each year. Many of the patients come for multiple cycles or for ovarian stimulation. We provide a unique service that, to my knowledge, does not exist anywhere else in the world. We have no lower age limit, but we usually draw the line around age 50 for egg donation. It is important to remember that fertility preservation is as important for children as it is for adults. Slowly, people are realizing that fertility preservation is important for children too. At this moment, we may be the only center in the country that offers fertility preservation for children, but this may change when it becomes more acceptable. At least three quarters of our patients have some medical issues that require fertility preservation, and the remaining quarter consist of infertility patients with difficult IVF cases, including multiple IVF failures, which usually are referral cases. We hardly see any simple IVF cases, because of our expertise. Standard fertility clinics usually do not treat patients who have medical issues. The key to fertility preservation is the ability to treat patients right away and understand their medical issues, as well as communicate with oncologists. All our treatments are conducted according to a research protocol. As part of the protocol, every patient meets with our psychologist. Ideally, fertility preservation should be done before cancer treatment. However, many patients do not have that opportunity; they have chemotherapy and then they need infertility treatment. For patients who have very low egg reserve, we use specific ovarian stimulation protocols to enable them to get pregnant with their own eggs. But patients with complete ovarian failure, as is the case in those undergoing bone marrow transplant, have to use third-party reproduction, including egg donation or surrogacy.

What is the role of fertility nurses at your clinic? Nurses play a very important role at our center, and one part of that is screening calls from patients. We get a lot of phone calls from patients and from institutions that know of our capabilities, and it is very important

that the nurses understand the urgency of the situation. For example, a patient who calls and says her period has just started, and she is supposed to start chemotherapy in 2 weeks, has to be seen immediately. So the nurses do the screening and make sure patients can be seen right away when necessary. Once patients are seen, the nurses also do the patient education: teaching about the treatment cycle, addressing patients’ concerns, and calling them with specific instructions. In addition, nurses help with data collection when we do a study, and they provide emotional support to patients.

We are one of the few centers in the country that do testicular tissue freezing for prepubescent boys. The nurses also help in coordination with the oncologists of patients with cancer and communicating with their staff. They help with the IVF cycle, as in other fertility clinics, and with the fertility treatments, as well as managing patients’ recovery period. The nurses interface with our research fellows and residents, and work in research. It is an academic practice, which involves a lot of interaction with different departments and groups of people. Our nurses really deal with the full spectrum of the institute. We are currently looking for a nurse who could be in a leadership role to monitor the treatment cycle, the ultrasounds, and if necessary, the inseminations, and potentially help with the egg donation program and the third-party reproduction program. A nurse with experience in IVF and fertility egg donation who may also have some cancer management background is a good fit for our center, or a nurse who is willing to learn and develop in these areas. So our nurses have a similar set of skills as in other fertility centers, but we offer opportunities to develop new skills unique to fertility preservation and dealing with patients with cancer and other chronic diseases affecting fertility.

How do patients find your center? It is obviously a process. This started a little more than 10 years ago, when I performed the first ovarian transplant in 1999. That was the first ovarian transplant with frozen-bank tissue. In that case we did not restore fertility but rather ovarian function, that is, hormonal function (sort of “reversing menopause”). At the time that was “big news” in the scientific community and

the media. That jump-started the interest in this field, and increasingly more and more patients and experts have seen us as fertility preservation experts. With time, as patients presented with different diseases, we developed a variety of protocols for several approaches, including egg freezing, embryo freezing, or use of aromatase inhibitors to keep estrogen levels down for women with breast cancer during ovarian stimulation. After publishing landmark studies and through media coverage of these studies, our expertise in fertility preservation has become known worldwide. Being a member of, and even founder of, many organizations or groups related to fertility preservation helped to increase awareness to this field as well. I co-chaired the American Society of Clinical Oncology Guideline Committee for Fertility Preservation. I have devoted my career to this field, which provides an important service. Much educational information can be found on our website (www.fertilitypreservation. org), where all patients can reach us.

Can you give some examples of patients referred to you from other fertility clinics? A simple example is a patient who needs ovarian tissue freezing, which many places do not do but rather refer to our center. Also, many fertility clinics do not deal with prepubertal boys or girls. These are usually referred to our institute. We are one of the few centers in the country that do testicular tissue freezing for prepubescent boys. Or a patient with breast cancer would often be referred from other IVF clinics to us, because they do not want to give fertility drugs to women with breast cancer. We treat them based on the protocol I developed, using the drug letrozole, which keeps estrogen levels low. Another example is girls with Turner syndrome. These girls do not experience puberty; they lose their eggs very early on. Sometimes they still have eggs at age 14 or 15, and we freeze their eggs before they experience premature ovarian failure. Many IVF clinics would not do an IVF cycle or an egg freezing cycle on an adolescent girl, because it involves many issues, not just technological but also the expertise in dealing with different age groups, and we involve the parents in these cases. With our youngest patients, who are sexually immature and prepubertal, it has to be only testicular or ovarian tissue freezing. If female patients are postpubertal and mature enough (aged 14-16 years), we may do egg freezing, depending on the maturity level. But it predominantly consists of tissue freezing with young children. ■

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Emerging Questions

Will HPV Screening Replace the Pap Smear?... Coming on the heels of these changes, a new debate has emerged on whether human papillomavirus (HPV) testing or the Pap smear should be used for primary screening. With HPV infection now established as the causative agent in most cases of cervical cancer, there is a move to replace the Pap smear with HPV DNA testing as the primary screening tool for cervical cancer. This debate was featured at the American Society of Clinical Pathology annual meeting in November 2009. Several studies have recently shown that HPV screening is more sensitive than cytologic screening, although less specific. The following debate illustrates the pros and cons of each screening method for cervical cancer. Isam A. Eltoum, MD, Professor of Pathology and Director of Cytopathology at the University of Alabama, Birmingham, advocates HPV as the primary screening method. R. Marshall Austin, MD, PhD, of Magee-Women’s Hospital of University of Pittsburgh Medical Center, PA, opposes the change. Rationale for HPV Screening According to Dr Eltoum, in the proposed new paradigm, screening for cervical cancer will shift to screening for HPV infection, and targeted screening will replace mass screening. Using screening by HPV DNA test, women who test negative for HPV would be rescreened every 3 to 5 years. Those testing positive for HPV would have “reflex cytology” as a follow-up test. If the cytology test is negative, the woman would be tested by both methods 6 to 12 months later. If both tests are negative, she would be screened every 3 to 5 years. Women with positive results would be referred for treatment. Dr Eltoum points out that only 15% of women are estimated to test positive for HPV, which would reduce the number of Pap smears from 68 million to 10 million a year. “Cytology has been very successful, but it has reached its limits,” he said, noting that cytology: • Has a low sensitivity rate and a high false-negative rate • Must be repeated often • Has poor reproducibility • Is labor-intensive, and therefore can be expensive. HPV testing is more sensitive than cytology, especially in women aged ≥30 years, but it is slightly less specific. It is objective and reproducible, is automatable and therefore less labor-intensive, and is the best way to monitor the effects of HPV vaccination, he said. The Cytopathology Education and Technology Consortium issued guide-

april 2010 I Vol 2, no 2

lines in 2009 for HPV testing (Am J Clin Pathol. 2009;131:768-769; discussion 770-773). Accordingly, routine HPV testing is considered inappropriate in women aged <30 years, or in conjunction with cervical cytology more often than every 3 years for older women whose tests were negative at last screening. It is also not recommended for women aged <20 years, or for the initial triage of women with abnormal Pap results.

HPV DNA testing detects more CIN2+ and CIN3+ lesions in the first round than cytology. It has been established that HPV testing is more sensitive than a Pap smear. “Common sense says to go with the most sensitive test first for screening, then add a more specific layer [ie, cytology] later,” Dr Eltoum noted. Cotesting with both methods as initial screening adds unnecessary procedures. HPV testing detects more CIN2+ and CIN3+ lesions in the first round than cytology. Total abnormalities detected are the same; 5 years after HPV testing, the risk of developing lesions is reduced compared with cytology, and HPV testing lengthens the interval between screenings. Many international trials are now comparing primary HPV screening with cytology in populations of between 7868 and 44,102 women. The evaluation of the co-testing concept in US studies should determine outcomes for the various scenarios. The focus will be on patients who are cytology-positive but HPV-negative. “If the lesions missed on HPV testing are insignificant, this will be convincing of the value of HPV first, and cytology second,” Dr Eltoum points out. Pap Testing Should Remain Standard of Care These arguments have not convinced Dr Austin, who argues that the Pap test should remain, at least for now, the centerpiece of cervical screening. “Medicine is a complex mix of science, business, and politics, and all 3 factors are at play here.” Dr Austin argues that the industry (ie, vaccine manufacturers) has been too involved in the push for HPV testing, that statements from supporting organizations are “closely associated with commercial messages,” and that cytopathologists and clinicians “in the trenches” have not been included in program development.

Under this new “manufacturerinspired prevention paradigm,” cervical cancer prevention will consist of primary prevention by HPV vaccination and secondary prevention by screening, according to Dr Austin. Funding to support vaccination would be gained by diverting funds from screening; increasing screening intervals, utilizing HPV testing, and decreasing the use of cytology. HPV infection prevention with vaccines is key to this approach, but questions remain about its effectiveness, says Dr Austin. It is assumed that HPV vaccination will: • Prevent cervical cancer • Be proved safe in large-scale, longterm use • Have sufficient uptake in high-risk groups, despite cost, to decrease the rate of precancerous lesions. However, he noted, efficacy in clinical trials does not necessarily translate into reductions in high-grade dysplasia rates and cancer in the population. Universal HPV vaccination of virginal girls would reduce CIN2/3 by 50% and cancer by 70%, but short of this, the population-wide impact would be much less, he notes. Just 18% of US teens have had all 3 shots, and coverage has been highest in low-risk states and lowest in highrisk states (MMWR. 2009;58:997-1001). “Vaccination is mainly for the next generation. Screening is the most effective prevention modality for the current generation of women,” Dr Austin said. Dr Austin acknowledges that the importance of HPV and the availability of vaccines have triggered a paradigm shift. “But paradigm shifts tend to have messy transitional phases.” When successfully implemented, the Pap test reduces cervical cancer rates by between 60% and 90% within 3 years of being introduced to populations not previously screened, Dr Austin says. Cytology sensitivity is 90% to 95% with newer methods, such as liquid-based cytology and computer-assisted screening. Furthermore, less-impressive studies for HPV screening have been disregarded. In a study of 61,000 Finnish women randomized to HPV testing or cytology, HPV testing was not superior in identifying CIN3 and cancer (Eur J Cancer. 2008;44:565-571). Primary HPV screening with reflex cytology finds more CIN lesions compared with conventional screening, but mild lesions are overrepresented, likely resulting in overdiagnosis, because most of the lesions will regress. There is a proved relationship between the positive predictive value of cytology, the cost-effectiveness of

Continued from page 1

diagnostic intervention, and the severity of the abnormality prompting diagnostic follow-up, Dr Austin says. “There are data indicating high sensitivity and safety with already widely used, FDA-approved cytology screening enhancements.” A Change Raises New Issues “The population has learned that Pap testing is effective. It’s an accepted practice. It has been part of women’s wellness visits for the last 50 years, and this is not a minor issue,” said Dr Austin. Women will view less frequent screenings as efforts to “economize, not deliver better care,” he predicts. “An HPV-negative test only represents the moment the test was done. We would never tell an active homosexual with a negative HIV test to check back in 5 years.” Dr Austin is concerned that an HPV-positive test result would cause unnecessary concern among women, because most positive results represent transient infections that will regress. CIN2/3 that is likely to regress cannot now be reliably differentiated from CIN2/3 that is capable of progressing to cervical cancer, he emphasizes. “If you are trying to find who has disease, HPV testing has limited positive predictive value,” he notes. “You need additional testing to see who has disease and go after them.” At the University of Pittsburgh, from 2005 to 2008, sensitivity rates for detecting CIN2/3, adenocarcinoma in situ, and cervical cancer were 96.06% for Pap testing, 95.41% for HPV DNA testing, and 99.91% for co-testing. “I argue that current methods have more power than is generally realized if done properly,” he said. Furthermore, HPV vaccination does not lessen the need for vigilance. The current vaccines protect mostly against HPV 16 and 18, which cause 70% of cervical cancers but just 50% of CIN2/3 lesions. “Their type-restricted protection means that some serious HPV infections will still occur in vaccinated women,” Dr Austin points out. Finally, the FDA has not approved stand-alone HPV testing for primary screening, and this could be a “daunting” challenge. “For the foreseeable future, cervical cancer screening will remain critical to cervical cancer prevention. The maximum reduction in HPV-associated cancer will require the development of second-generation vaccines, with activity against a broader range of HPV types,” suggests Dr Austin. “Such changes will come later, rather than sooner.” ■

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IVF New Jers ey

EMERGING QUESTIONS

How Should Pregnant WoWe Advise the H1N1 Flu men Regarding Vaccine? Donna Makris, RN, BSN, IBCLC Paren

Transitioning to Infertility Nu Interview with rsing Jenni fer Iannaccone , RN

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to The OB/GYN and Infertility Nurse, . Written for nurses by nurses, it covers current and pertinent information on the physiologic, medical, and psychological aspects of human reproduction, with special emphasis on the nurse’s role in patient care ($150 value).

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t Education Coord inator, Saint Peter’ s

bstetricians, midwi ves, and nurse practitioners in the Unite d States agree with the recen national recom t mend nant women shoul ations that prega vaccine for the d have priority once novel H1N1 influe za virus (also know nn as the swine flu) becomes availa ble. At Saint Peter’ s University Hospi tal

•

for issues such as coverage and reimbursement.

Continued on page

CLINIC SPO TLIGHT

IVF New Jersey Roychowdhury, nurses outside the clinic (from left): Jamie Thom Lauren Noble, Jennifer Iannaccone, Zofia Mance as, Leslie Meincke, ra, Cathy Ovacz Ella Terri Nelson. , Jill Marchetti,

Research

Interview with Sue Jasulaitis, RN, MS n her role as Clinic ue Jasulaitis is New Jersey, Jennif al Manager at IVF dure, which Clinic Manager at Fertil al Research precepted many er Iannaccone has has a lower is less intrusive but also ity Centers of nurses to the field success rate. If Illinois (FCI), infertility. In the IUI fails, of the coupl River North, this interview, Chicago. In this e in describes the steps she dure, which then tries an IVF proceinterview she discusses key features has a very good ic to help a new she takes at her clin- rate of the center success nurse at our center. nurse get famili and how s can improve ar with the demands of patient care by The nurse is this field. gesting problem the areas to study basedsugnates the patien one who coordi- their on own t’s daily IVF Do you do only experience. cycle. She writes up the patient’s IVF at IVF New Jerse IVF procedures We assign y? the start dates protocol. What are some Actually we have of medicaof the special tions and once features of FCI? a lot more coupl a protocol is who are doing deterintrauterine insem es mined, schedule her FCI has 10 IVF orientation tion (IUI) than ina- and make offices aroun in d the (IVF). The reason vitro fertilization the appro sure she has undergone all Chicago area, with 2 fully staffed in is that IVF is a priate testing. vitro fertilization intrusive proce (IVF) centers. dure; it is a surgic more dinate with the husba We also coor- one of the FCI is largest al pro- semen cedure that requir nd to have his frozen es general anesth the country, and fertility centers in and involves esia day of retrie , which is used if on the has provided more treatInside River North more couples begin risk. Therefore, a specim val he is unable to produce ment to >100,000 patients . during the matel en. All past with an IUI proce y 60 - of knowledge. this involves a new set specia25 years. We have 11 physic ians support clinical staff, as well as 120 Basic infertility lized in reprod staff employed uctive medicine, may be large at FCI. a team of embry Our main Continued on page ologists, appro 6 xi- quality care goal is to combine the best that expertise, technology,

Inside

Pharmacy Corn Latex allergies in er infertility drugs

Newborn Umb Cord Blood ilical The case of Chloe Levine

Hill Healthcare

Communications, LLC

Fertility Center s of Illinois Influence Infertilit y

How Nurses Can

Page 14

• Obtain to the enhanced, member-only sections at www.obgyn-infertility-nurse.org to network with your peers in a community of OB/GYN, Infertility, and Urology Nursing Professionals. Discuss current and emerging diagnostic and therapeutic options, as well as strategies for counseling and follow-up of patients.

Medical Cente r, New Brunswick, NJ in New Bruns wick, New Jersey offer a wide array , we of classes for expec tant families, and, as the Paren Education Coord inator, I am certai t that many of n our asking about the participants will be H1N1 flu vaccin fall. OB/GYN nurses and other e this working with pregnant wome nurses n should be prepared to provide inform ation to

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Polar Bodies Screening New techniques enhance genetic diagnosis

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Obesity and Reproduction What nurses need to know

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VOL 1, NO 1

The official pu blication of the American Academy of OB/GYN and Infertility Nu rses

CONTINUING EDUCATION

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PROGRAM OGI2 • RELEASE DATE: APRIL 26, 2010 • EXPIRATION DATE: APRIL 26, 2011 • ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Reproductive Depressions Julianne E. Zweifel, PhD Clinical Psychologist, Department of Obstetrics and Gynecology University of Wisconsin School of Medicine & Public Health, Madison, WI

STATEMENT OF NEED Women most at risk for reproductive depressions often remain unidentified and, therefore, are not diagnosed early. Reproductive nurses should be able to identify the predictors of reproductive depressions and provide timely support. TARGET AUDIENCE Advanced practice nurses, registered nurses, and other interested healthcare professionals. LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Recognize the predictors of the different types of reproductive depressions • Provide early support to women most at risk for reproductive depressions • Identify psychosocial predictors of reproductive depressions

EDITORIAL BOARD Julianne E. Zweifel, PhD Clinical Psychologist Department of Obstetrics and Gynecology University of Wisconsin School of Medicine & Public Health Madison, WI Norah Nutter, MSN, WHNP-BC, IBCLC Women’s Health Nurse Practitioner, Magnolia OB/GYN, Myrtle Beach, SC

ometimes it seems as if it is the same women who are again and again struggling with episodes of depression as they progress through the reproductive landmarks of their lives. Certainly, depression can affect a person at any point in life and can be a reaction to situational stressors. Reproductive depressions, including premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression, are often considered to be a unique subset of depression, because of the presumed involvement of hormones in the onset of the depression.1-3 So what is going on for these women? Are there factors that can help to predict which women may struggle with reproductive depressions? If the woman experiences one type of reproductive depression, is she likely to experience other reproductive depressions? Is it true that her hormones are to blame? Predictors of Reproductive Depressions It is often noted that the best predictor of the future is the past, and this holds true for reproductive depressions. Women who have previously had some type of depression and/or anxiety are more likely to experience premenstrual dysphoric disorder, postpartum depression, or perimenopausal depression.2,4-7 Similarly, women with a family history of depression are more likely to struggle with reproductive depressions.2,4,8 Not

Table 1 Predictors of Reproductive Depressions 1. Individual history of depression 2. Individual history of anxiety 3. Family history of depression or anxiety 4. High stress level 5. High number of life events (positive/negative) 6. Low socioeconomic status 7. Quality/quantity of personal relationships

surprisingly, high levels of stress and/or a high number of significant life events, even positive events, such as a new job or a new home, can make a woman more vulnerable to these depressions.2,4,7 Alternatively, having good social support and healthy relationships can act as a protective factor in these depressions.9 Rounding out the list of general predictors of reproductive depressions is socioeconomic status; lower levels of socioeconomic status are associated with increased rates of reproductive depressions.10 The general predictors of reproductive depressions are listed in Table 1. Although many factors are predictive of all types of reproductive depressions, there are factors that are more specific. For example, vulnerability to postpartum depression can be related to infant temperament, having

PLANNING COMMITTEE Gloria Mui Medical Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604

CONTINUING NURSING EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT Veritas Institute for Medical Education, Inc., is approved by the California Board of Registered Nursing Provider #13986 for 1.0 Contact Hour.

Julie Ann Tagliareni CME Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604

METHOD OF PARTICIPATION 1. Read the article in its entirety 2. Log on to www.obgyn-infertility-nurse.com 3. Click on “CE Credits” 4. Click on “Click here to complete the posttest and obtain a CE certificate online” 5. Register to participate 6. Enter program number OGI2 7. Complete and submit the CE posttest and CE Activity Evaluation and Request for Credit Form online 8. Print your Statement of Completion This activity is provided free of charge to participants.

Anne L. Finger President Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604 Dalia Buffery Editorial Director Novellus Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831

april 2010 I Vol 2, no 2

FINANCIAL DISCLOSURES Veritas Institute for Medical Education, Inc., is required to disclose to the activity audi-

multiples (eg, twins), and childcare stress.10-12 Some studies also suggest that unplanned/unwanted pregnancy is more likely to result in postpartum depression.10-12 The predictors of postpartum depression include10-12: • Infant temperament • Multiple infants • Childcare stress • Unplanned/unwanted pregnancy. Perimenopausal depression seems to be more likely to occur in women who have a low level of physical activity, a negative attitude regarding menopause, and perhaps surprisingly, women who have had children.13,14 The predictors of perimenopausal depression include13,14: • Low level of physical activity • Negative attitude toward menopause • Having had children. The Link between the Types of Reproductive Depressions A quick review of the predictors of reproductive depressions reveals a few surprising facts but also leads to the conclusion that if a woman is vulnerable to developing one type of reproductive depression she may well be vulnerable to all of them. This is, in fact, the case. As shown in Table 2, many studies reviewed by Bloch and Payne have found a correlation between premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression.15,16

ence the relevant financial relationships of the planners and faculty involved in the development of CE content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CE activity content over which the individual has control. In addition, all faculty are expected to openly disclose any unlabeled/unapproved/investigational uses of drugs or devices discussed in this activity. Disclosures are as follows: • Julianne E. Zweifel, PhD, has nothing to disclose. • Norah Nutter, MSN, WHNP-BC, IBCLC, has nothing to disclose. The staffs of Veritas Institute for Medical Education, Inc., and Novellus Healthcare Communications, LLC, have nothing to disclose. DISCLAIMER The opinions expressed in this activity are those of the presenters and do not necessarily reflect the opinions or recommendation of Veritas Institute for Medical Education, Inc. Copyright © 2010 Veritas Institute for Medical Education, Inc. All rights reserved.

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CONTINUING EDUCATION

WWW.OBGYN-INFERTILITY-NURSE.COM With few exceptions, the studies reviewed by Bloch and by Payne (Table 2) suggest that if a woman experiences one type of reproductive depression, she has an increased likelihood of experiencing another reproductive depression.15,16 Indeed, it is possible that a woman could experience premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression. Clearly, however, not all women experience even one type of reproductive depression.

that the fluctuations of estrogen and progesterone across the menstrual cycle, postpartum, or during the menopause in depressed women may differ from the fluctuations in unaffected women.18 Do these hypotheses hold water? As intuitive as these hypotheses may be, they have not been uniformly supported in the literature. As shown in Table 3, estrogen and progesterone levels have not been found to be different between women who experience premenstrual dysphoric disorder and those who do not. Furthermore, although Redei and Freeman did find that progesterone levels were related to depression scores for women with premenstrual dysphoric disorder,20 other studies have not found a relationship between estrogen and progesterone levels and depression scores (Table 3).

Hormonal Levels and Reproductive Depressions As noted above, experts have long considered hormonal profiles (ie, absolute levels of hormones and the fluctuations in hormones) to be implicated in the onset of reproductive depressions.17-19 More specifically, it has been hypothesized that women who experience these reproductive depressions must differ from unaffected women in terms of the level of estrogen and/or progesterone in their system.18 A similar and associated hypothesis is

Postpartum Depression A review of research on hormone levels and depression in postpartum depression is more complex, as reflected in Table 4. Although many studies have shown no association between

hormone levels (ie, estrogen, progesterone, and cortisol) and mood in the postpartum period,21-23 other findings have been mixed. O’Hara and colleagues found no relationship between progesterone and mood in the postpartum period.24 The study did, however, show estrogen levels to be associated with depression scores on day 2 of the postpartum, but not on other measured days.24 Zou and colleagues also found a relationship between lower estrogen levels and higher depression scores.25 In contrast to these studies, 3 other studies have each found higher progesterone levels to be associated with

higher depression scores in the postpartum period.25-27 Results of studies looking at prolactin are also mixed. O’Hara and colleagues found no relationship between prolactin levels and depression,24 while Abou-Saleh and colleagues found lower levels of prolactin to be associated with higher depression scores.27 Perimenopausal Depression Researchers examining hormone levels and depression scores in the perimenopausal period have tended to find no relationship (Table 5). The hormones examined have included estro-

Table 3 Hormone Levels and Premenstrual Dysphoric Disorder Patients, N Hormone levels 36 Estrogen, progesterone

Study Bäckström, et al, 19831 Rubinow, et al, 19882 3

Dennerstein, et al, 1993 4

Redei, et al, 1995

Rapkin, et al, 1997 6

Lentz, et al, 2007

Estrogen, progesterone

Progesterone

Estrogen, progesterone

Table 2 The Associations in Reproductive Depressions Bäckström, et al, 19831

Study Stewart, et al, 19931

PMDD and PMDD and PPD PMD Yes Yes

Chuong, et al, 19952

190

Yes

McGill, et al, 19953

1330

Yes

Sugawara, et al, 19974

1329

Yes

Morse, et al, 1998

Estrogen, progesterone

Redei, et al, 1995

Estrogen Progesterone

No Yes

Hsiao, et al, 20047

Estrogen, progesterone

Gregory, et al, 2000 Binfa, et al, 2004

Aydin, et al, 2005

Bloch, et al, 2005, 2006

PMDD indicates premenstrual dysphoric disorder.

Yes

728

Yes

1800

Yes

Freeman, et al, 2006

231

Yes

Richards, et al, 2006l2

Trend

Haywood, et al, 200713

Payne, et al, 2007

Steinberg, et al, 2008

Yes

116

tion to premenstrual symptoms. Psychoneuroendocrinology. 1995;20:259-267. 5. Rapkin AJ, Morgan M, Goldman L, et al. Progesterone metabolite allopregnanolone in women with premenstrual syndrome. Obstet Gynecol. 1997;90:709-714. 6. Lentz MJ, Woods N, Heitkemper M, et al. Ovarian steroids and premenstrual symptoms: a comparison of group differences and intra-individual patterns. Res Nurs Health. 2007;30:238-249. 7. Hsiao CC, Liu CY, Hsiao MC. No correlation of depression and anxiety to plasma estrogen and progesterone levels in patients with premenstrual dysphoric disorder. Psychiatry Clin Neurosci. 2004;58:593-599.

Patients, N Hormone levels

Study Yes

Yes

PMD indicates perimenopausal depression; PMDD, premenstrual dysphoric disorder; PPD, postpartum depression. 1. Stewart DE, Boydel KM. Psychologic distress during menopause: associations across the reproductive life cycle. Int J Psychiatry Med. 1993;23:157-162. 2. Chuong CJ, Burgos DM. Medical history in women with premenstrual syndrome. J Psychosom Obstet Gynecol. 1995; 16:21-27. 3. McGill H, Burrows VL, Holland LA, et al. Postnatal depression: a Christchurch study. N Z Med J. 1995;108:162-165. 4. Sugawara M, Toda MA, Shima S, et al. Premenstrual mood changes and maternal mental health in pregnancy and the postpartum period. J Clin Psychol. 1997;53:225-232. 5. Morse CA, Dudley E, Guthrie J, Dennerstein L. Relationships between premenstrual complaints and perimenopausal experiences. J Psychosom Obstet Gynaecol. 1998;19:182-191. 6. Gregory RJ, Masand PS, Yohai NH. Depression across the reproductive life cycle: correlations between events. Prim Care Companion J Clin Psychiatry. 2000;2:127-129. 7. Binfa L, Castelo-Branco C, Blümel JE, et al. Influence of psycho-social factors on climacteric symptoms. Maturitas. 2004;48:425-431. 8. Aydin N, Inandi T, Karabulut N. Depression and associated factors among women within their first postnatal year in Erzurum province in eastern Turkey. Women Health.

1. Bäckström T, Sanders D, Leask R, et al. Mood, sexuality, hormones, and the menstrual cycle. II. Hormone levels and their relationship to the premenstrual syndrome. Psychosom Med. 1983;45:503-507. 2. Rubinow DR, Hoban MC, Grover GN, et al. Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. Am J Obstet Gynecol. 1988;158:5-11. 3. Dennerstein L, Brown JB, Gotts G, et al. Menstrual cycle hormonal profiles of women with and without premenstrual syndrome. J Psychosom Obstet Gynaecol. 1993;14:259-268. 4. Redei E, Freeman EW. Daily plasma estradiol and progesterone levels over the menstrual cycle and their rela-

Table 4 Hormone Levels and Depression in Postpartum Depression

509 15

Yes

300 8

PPD and PMD

Yes

291 6

No Related to depression score No

Association found between Patients, N

Differentiate PMDD/no PMDD No

2005;41:1-12. 9. Bloch M, Rotenberg N, Koren D, Klein E. Risk factors associated with the development of postpartum mood disorders. J Affect Disord. 2005;88:9-18. 10. Bloch M, Rotenberg N, Koren D, Klein E. Risk factors for early postpartum depressive symptoms. Gen Hosp Psychiatry. 2006;28:3-8. 11. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63:375-382. 12. Richards M, Rubinow DR, Daly RC, Schmidt PJ. Premenstrual symptoms and perimenopausal depression. Am J Psychiatry. 2006;163:133-137. 13. Haywood A, Slade P, King H. Is there evidence of an association between postnatal distress and premenstrual symptoms? J Affect Disord. 2007;99:241-245. 14. Payne JL, Roy PS, Murphy-Eberenz K, et al. Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder. J Affect Disord. 2007;99:221-229. 15. Steinberg EM, Rubinow DR, Bartko JJ, et al. A crosssectional evaluation of perimenopausal depression. J Clin Psychiatry. 2008;69:973-980.

O’Hara, et al, 19911 Harris, et al, 1994

Heidrich, et al, 1994

Abou-Saleh, et al, 1998

Progesterone

Yes

Estrogen, progesterone

108

Progesterone, prolactin

Yes

150

Progesterone, cortisol

105

Estrogen, progesterone

Yes

Klier, et al, 2007 Zou, et al, 2009

Yes No No

120 3 4

Ross, et al, 2004

Postpartum day-2 estrogen Estrogen at other times Progesterone, prolactin

Related to depression score

1. O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991;100:63-73. 2. Harris B, Lovett L, Newcombe RG, et al. Maternity blues and major endocrine changes: cardiff puerperal mood and hormone study II. BMJ. 1994;308:949-953. 3. Heidrich A, Schleyer M, Spingler H, et al. Postpartum blues: relationship between not-protein bound steroid hormones in plasma and postpartum mood changes. J Affect Disord. 1994;30:93-98. 4. Abou-Saleh MT, Ghubash R, Karim L, et al. Hormonal aspects of postpartum depression. Psychoneuroendocrinology.

1998;23:465-475. 5. Ross LE, Sellers EM, Gilbert Evans SE, Romach MK. Mood changes during pregnancy and the postpartum period: development of a biopsychosocial model. Acta Psychiatr Scand. 2004;109:457-466. 6. Klier CM, Muzik M, Dervic K, et al. The role of estrogen and progesterone in depression after birth. J Psychiatr Res. 2007;41:273-279. 7. Zou Y, Fan F, Ma A, et al. Hormonal changes and somatopsychologic manifestations in the first trimester of pregnancy and post partum. Int J Gynaecol Obstet. 2009;105:46-49. Erratum in: Int J Gynaecol Obstet. 2009; 107:87.

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use this information to provide support to those most at risk.

Table 5 Hormone Levels and Perimenopausal Depression Study

Patients, Hormone levels N

Ballinger, et al, 19871

Cawood, et al, 19962

Related to depression score

Estrogen, progesterone FSH, LH, testosterone, androstenedione, prolactin

144

Estrogen, FSH, LH, testosterone

Saletu, et al, 19963

129

Estrogen, FSH

Barrett-Connor, et al, 19994

669

Estrogen, testosterone, androstenedione, cortisol

Freeman, et al, 20065

438

Estrogen, FSH, LH

Yes

FSH indicates follicle-stimulating hormone; LH, luteinizing hormone. 1. Ballinger CB, Browning MC, Smith AH. Hormone profiles and psychological symptoms in peri-menopausal women. Maturitas. 1987;9:235-251. 2. Cawood EH, Bancroft J. Steroid hormones, the menopause, sexuality and well-being of women. Psychol Med. 1996;26:925-936. 3. Saletu B, Brandstätter N, Metka M, et al. Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls. Maturitas. 1996;23:91-105.

gen, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, androstenedione, and prolactin (Table 5). In 2006, however, Freeman and colleagues found an association between variability in estradiol levels and depression scores.28 Furthermore, this study showed that higher levels of FSH and LH were associated with higher depression scores.28 A Refined Hypothesis So, are a woman’s hormones to blame when she experiences premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression? A review of the literature reveals less support for this hypothesis than may be expected. It is difficult to conclude that the hormonal profiles of women affected by these reproductive depressions differ from the profiles of unaffected women. Leading researchers in this area have concluded that there is little support for the hypothesis that reproductive depressions are related to abnormal hormonal profiles.18 Still, the intuitiveness of the suggestion that hormones have a hand in these depressions persists and spurs on further investigation. Leaders in this research area, Rubinow and Schmidt, have suggested a more refined hypothesis to explain the relationship between mood and hormones.18 They have suggested that reproductive depressions represent an abnormal/depressive response to normal hormone changes. That is, they suggest that a subset of women is particularly sensitive to changes in the reproductive hormonal milieu. These women experience depression in response to “normal” hormone changes. These changes do not affect all women in the same way. Where does this new, refined hypothesis lead? It leads to examinations

4. Barrett-Connor E, von Mühlen D, Laughlin GA, Kripke A. Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo study. J Am Geriatr Soc. 1999;47:685-691. 5. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006;63:375-382.

of deeper scientific explanations, including genetic predispositions,29 neurotransmitter receptor plasticity,30 and differential regulation of the hypothalamic-pituitary-adrenal axis.31 As these leads are followed and spur on new evolved hypotheses, the researchers bring us closer to an understanding. What we know now is that we can use psychosocial predictors to identify women who may be at risk for reproductive depressions. We also know that if a woman experiences one type of reproductive depression, she has an increased likelihood of experiencing other reproductive depressions. We can

References 1. Richards M, Rubinow DR, Daly RC, Schmidt PJ. Premenstrual symptoms and perimenopausal depression. Am J Psychiatry. 2006;163:133-137. 2. Feld J, Halbreich U, Karkun S. The association of perimenopausal mood disorders with other reproductive-related disorders. CNS Spectr. 2005;10:461-470. 3. Soares CN, Zitek B. Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability? J Psychiatry Neurosci. 2008; 33:331-343. 4. Yim IS, Glynn LM, Dunkel-Schetter C, et al. Risk of postpartum depressive symptoms with elevated corticotropin-releasing hormone in human pregnancy. Arch Gen Psychiatry. 2009;66:162-169. 5. Cohen LS, Soares CN, Otto MW, et al. Prevalence and predictors of premenstrual dysphoric disorder in older premenopausal women. The Harvard study of moods and cycles. J Affect Disord. 2002;70:125-132. 6. Amore M, Di Donato P, Papalini A, et al. Psychological status at the menopausal transition: an Italian epidemiological study. Maturitas. 2004;48:115-124. 7. Bromberger JT, Kravitz HM, Matthews K, et al. Predictors of first lifetime episodes of major depression in midlife women. Psychol Med. 2009;39:55-64. 8. Gregory RJ, Masand PS, Yohai NH. Depression across the reproductive life cycle: correlations between events. Prim Care Companion J Clin Psychiatry. 2000;2:127-129. 9. Logsdon MC, Usui W. Psychosocial predictors of postpartum depression in diverse groups of women. West J Nurs Res. 2001;23:563-574. 10. McGill H, Burrows VL, Holland LA, et al. Postnatal depression: a Christchurch study. N Z Med J. 1995;108:162-165. 11. Choi Y, Bishai D, Minkovitz CS. Multiple births are a risk factor for postpartum maternal depressive symptoms. Pediatrics. 2009;123:1147-1154. 12. Beck CT. Predictors of postpartum depression: an update. Nurs Res. 2001;50:275-285. 13. Bauld R, Brown RF. Stress, psychological distress, psychosocial factors, menopause symptoms and physical health in women. Maturitas. 2009;62:160-165. 14. Di Donato P, Giulini NA, Bacchi Modena A, et al, for the Progetto Menopausa Italia Study Group. Factors associated with climacteric symptoms in women around menopause attending menopause clinics in Italy. Maturitas. 2005;52:181-189. 15. Bloch M, Daly RC, Rubinow DR. Endocrine factors in the etiology of postpartum depression. Compr Psychiatry. 2003;44:234-246. 16. Payne JL, Palmer JT, Joffe H. A reproductive subtype of depression: conceptualizing models and moving

toward etiology. Harv Rev Psychiatry. 2009;17:72-86. 17. Arpels JC. The female brain hypoestrogenic continuum from the premenstrual syndrome to menopause. A hypothesis and review of supporting data. J Reprod Med. 1996;41:633-639. 18. Rubinow DR, Schmidt PJ. Gonadal steroid regulation of mood: the lessons of premenstrual syndrome. Front Neuroendocrinol. 2006;27:210-216. 19. Harsh V, Meltzer-Brody S, Rubinow DR, Schmidt PJ. Reproductive aging, sex steroids, and mood disorders. Harv Rev Psychiatry. 2009;17:87-102. 20. Redei E, Freeman EW. Daily plasma estradiol and progesterone levels over the menstrual cycle and their relation to premenstrual symptoms. Psychoneuroendocrinology. 1995;20:259-267. 21. Heidrich A, Schleyer M, Spingler H, et al. Postpartum blues: relationship between not-protein bound steroid hormones in plasma and postpartum mood changes. J Affect Disord. 1994;30:93-98. 22. Ross LE, Sellers EM, Gilbert Evans SE, Romach MK. Mood changes during pregnancy and the postpartum period: development of a biopsychosocial model. Acta Psychiatr Scand. 2004;109:457-466. 23. Klier CM, Muzik M, Dervic K, et al. The role of estrogen and progesterone in depression after birth. J Psychiatr Res. 2007;41:273-279. 24. O’Hara MW, Schlechte JA, Lewis DA, Varner MW. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991;100:63-73. 25. Zou Y, Fan F, Ma A, et al. Hormonal changes and somatopsychologic manifestations in the first trimester of pregnancy and post partum. Int J Gynaecol Obstet. 2009;105:46-49. Erratum in: Int J Gynaecol Obstet. 2009;107:87. 26. Harris B, Lovett L, Newcombe RG, et al. Maternity blues and major endocrine changes: cardiff puerperal mood and hormone study II. BMJ. 1994;308:949-953. 27. Abou-Saleh MT, Ghubash R, Karim L, et al. Hormonal aspects of postpartum depression. Psychoneuroendocrinology. 1998;23:465-475. 28. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch General Psychiatry. 2006;63:375-382. 29. Huo L, Straub RE, Roca C, et al. Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Biol Psychiatry. 2007;62:925-933. 30. Maguire J, Mody I. GABAAR plasticity during pregnancy: relevance to postpartum depression. Neuron. 2008;59:207-213. 31. Roca CA, Schmidt PJ, Altemus M, et al. Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls. J Clin Endocrinol Metab. 2003; 88:3057-3063.

COMMENTARY

Postpartum Depression A Common Reality in the OB/GYN Office Norah Nutter, MSN, WHNP-BC, IBCLC Women’s Health Nurse Practitioner, Magnolia OB/GYN, Myrtle Beach, SC

hile reading the article on reproductive depressions, I was intrigued by the concept that certain depressions may be hormonally linked, and that women who have had one type of reproductive depression may be more likely to experience another type. Focusing this commentary on postpartum depression is justified, because this type of depression is a very common reality in the OB/GYN office. The following picture is familiar: The disheveled new mom with a baby in a car seat presents to your office. The look is in her eyes: dark circles showing exhaustion, little eye contact, sadness, and tears streaming. She

reveals she is not coping well with new motherhood, and it is not what she expected. Often associated with shame and fear of failure, depression also may be hidden, exposed accidentally during the interview. The Burden of Postpartum Depression Several celebrities have brought postpartum depression to the attention of the public with their own experiences. Brooke Shields developed postpartum depression after the birth of her first daughter. In her book, Down Came the Rain, she writes about postpartum depression and the feelings she experienced.1 She admitted to having

thoughts of “jumping out of a window” and “seeing her baby thrown against a wall.”1 She was able to overcome postpartum depression with the help of antidepressants and a helpful nanny.1 Entertainer Marie Osmond also spoke frankly about postpartum depression in her book Behind the Smile, My Journey Out of Postpartum Depression. After the birth of her third child in 1999, this mother of 8 children described her experience as empty, overwhelmed, and lonely. She handed over her newborn son to a caretaker and left to get psychiatric help.2 “Baby blues” is a common, temporary, mild form of postpartum depression characterized by tearfulness and Continued on page 13

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COMMENTARY Postpartum Depression... Continued from page 12 mild depression, an anxious, overwhelmed feeling, poor appetite, and exhaustion from lack of sleep.3 These short-term symptoms of the “blues” are reported by between 40% and 85% of mothers, usually occurring around day 3 postpartum, with resolution typically from 24 to 72 hours later.3 Postpartum depression—ICD-9 diagnosis code 648.44, mental disorders complicating pregnancy, childbirth to the puerperium—is more profound, and can occur anytime during the first year after delivery. Postpartum depression usually requires some form of treatment. According to a 2004-2005 report from the Centers for Disease Control and Prevention, between 11.7% and 20.4% of women self-report symptoms of postpartum depression.4 Other less known postpartum psychiatric disorders include postpartum obsessive compulsive disorder (3%5%), postpartum panic disorder (10%), and the most serious form, postpartum or puerperal psychosis (prevalence rate, 1-2/1000).3,5,6 Postpartum psychosis is accompanied by hallucinations, presents within the first 4 weeks, has a 5% suicide rate

and a 4% infanticide rate, and requires prompt in-patient treatment.3,6 Helping New Mothers What can we do as healthcare providers to help decrease the incidence of postpartum depression and make life better for new mothers? First, I would recommend getting a good health history at the prenatal intake, with special emphasis on: • Personal and family history of depression • Current or a history of antidepressant use • A history of violence or substance abuse • Recent loss (eg, death, job, or move) • Availability of support of significant other and extended family. In addition, a woman who develops depression during pregnancy should be evaluated carefully and frequently for postpartum depression. Use prenatal visits to give the woman practical information about postpartum realities, such as sleep deprivation, tips for dealing with infant crying, and coping techniques. The hospital stay should be educa-

tional, with the supportive postpartum nurse providing attentive supervision and assistance to get breastfeeding and bonding well established. Suggest rooming in with the baby to learn how to respond to the new baby. Encourage patients to consider hiring a doula or nurse, or enlisting a family member to assist at home postpartum. Treatment Options Be sure to review the signs of postpartum depression with patients and family members to assist in the early diagnosis of depression, and treat it promptly. There are many successful treatment options to consider. Medications, such as selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline, citalopram) and serotonin-norepinephrine reuptake inhibitors (eg, bupropion, venlafaxine), at the lowest effective dose are the best choice with breastfeeding; however, the baby should be monitored closely any time maternal medication is used.7 Benzodiazepines and tricyclics should be used cautiously, because of their side effect profile.3,8 Other treatment options include counseling, psychotherapy, support

groups, exercise, lifestyle modification, and spiritual guidance. Also encourage new mothers to find community resources such as La Leche League, church-sponsored mother/baby programs, playgroups, public library reading groups, and community classes, such as infant massage or mother/baby yoga. With early recognition and treatment of postpartum depression, we can make a difference in the new mother’s life. References 1. Shields B. Down Came the Rain. New York, NY: Hyperion; 2005. 2. Osmond M, Wilkie M, Moore J. Behind the Smile: My Journey Out of Postpartum Depression. New York, NY: Warner Books; 2001. 3. Leopold KA, Zoschnick LB. Postpartum depression. OBGYN.net; August 2007. www.obgyn.net/femalepatient/ femalepatient.asp?page=leopold. Accessed March 16, 2010. 4. Centers for Disease Control and Prevention. Prevalence of self-reported postpartum depressive symptoms—17 states, 2004-2005. MMWR Morb Mortal Wkly Rep. 2008;57:361-366. 5. Zauderer C. Postpartum depression: how childbirth educators can help break the silence. J Perinat Educ. 2009;18:23-31. 6. Indman PE. Postpartum psychiatric illnesses. OBGYN. net, 1999. www.obgyn.net/pregnancy-birth/pregnancybirth.asp?page=/pb/articles/pp_psychiatric_indman_ 0299. Accessed March 16, 2010. 7. Gentile S. The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf. 2005;28:137-152. 8. Tschudin S, Lapaire O. Antidepressants and pregnancy [in German]. Ther Umsch. 2005;62:17-22.

The OB/GYN Nurse

Early Stroke Treatment Benefits Women More than Men Immediate Therapy Essential in Women By Rosemary Frei, MSc

new retrospective cohort study demonstrated that women were 11.8% less likely than men to achieve a good outcome 6 months after a stroke if they did not receive thrombolysis with recombinant tissue-plasminogen activator (tPA), but they were just as likely as men to achieve a good outcome if they did receive the potent therapy early on. Therefore, the researchers concluded that thrombolysis reverses the significant negative differential between men and women in stroke survival (Neurology. 2010;74:767-771). This result mirrors a pooled analysis of clinical trials, which was the first study to probe this question in depth (Stroke. 2005;36:62-65). In that study, women were significantly more likely than men to benefit from recombinant tPA treatment. “It had been well-established by previous research that women have worse outcomes without thrombolysis

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after stroke. But we showed that they have similar outcomes with treatment, and therefore, overall, that women benefit significantly more than men from the treatment,” said David Kent, MD, Associate Professor, Department of Medicine, Tufts University School

and who did not receive tPA after their strokes, and another 138 men and 96 women did. Patients who received tPA were less likely than those who did not receive tPA to receive antiplatelet therapy before hospital admission, have more

“It had been well-established by previous research that women have worse outcomes without thrombolysis after stroke. But we showed that they have similar outcomes with treatment, and therefore, overall, that women benefit significantly more than men from the treatment.” —David Kent, MD of Medicine, Boston. “And the new study is further confirmation....It shows precisely the same pattern we saw.” This new study compiled outcomes from patients in the Registry of the Canadian Stroke Network. The analysis involved a total of 1058 men and 823 women who had an acute stroke

severe stroke, have been transported to the hospital by ambulance and have faster onset-to-computed tomography times. The women also had slightly more severe strokes, a lower prevalence of hyperlipidemia, and slightly lower hematocrit and blood glucose levels than men.

The results indicated that in the non-tPA group 6 months poststroke, 70% of men had a good outcome, as determined by a Stroke Impact Scale16 (SIS-16) score of >75, compared to 58% of women (P <.001). In contrast, in the tPA group, men and women were equally likely to achieve a good outcome at 6 months. A multiple regression logistic analysis confirmed the significant effect of sex on outcome. “David Kent and I have worked on this issue for several years, and he is absolutely right, this study is confirmatory,” Michael Hill, MD, Associate Professor of Neurology, Department of Clinical Neurosciences, University of Calgary, Alberta, and lead investigator of the study, told OB/GYN & Infertility Nurse. “If you look at different groups of people and you find the same thing, it gives you more confidence that what you’re finding is real.” This study confirms the importance of therapy for women immediately after a stroke event. ■

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The OB/GYN Nurse

First Term-Stillbirth Caused by Translocation of Oral Bacteria By Wayne Kuznar

he first documented case of a term stillbirth caused by a bacterium (Fusobacterium nucleatum) that originated in the mother’s mouth has been reported recently by a microbiologist, Yiping W. Han, PhD, Department of Periodontics, School of Dental Medicine at Case Western Reserve University, Cleveland (Obstet Gynecol. 2010;115:442-445). Intrauterine infection of F nucleatum had been suspected to originate from the mouth, but had not been proven until now, according to Dr Han. F nucleatum was isolated from the lung and stomach of the stillborn fetus during an autopsy. The mother reported excessive gum bleeding during her pregnancy, and submitted to a fullmouth periodontal examination 3 weeks postpartum. According to Dr Han, the bacterium was found in the mother’s mouth but not in her vaginal or rectal floras. At the time of her periodontal examination, she showed minimal gingival

inflammation and no signs of periodontitis, suggesting a pregnancy-associated gingivitis. Approximately 75% of pregnant women have gingivitis.

The mother reported excessive gum bleeding during her pregnancy, and submitted to a fullmouth periodontal examination 3 weeks postpartum. The connection between F nucleatum, preterm birth, and stillbirth has been studied for a decade. “Part of the reason that the role of oral bacteria was underestimated may be because the majority of oral species are uncultivated and thus cannot be detected by the routine culturing methods used by the hospital microbiology laboratories,” Dr Han explained.

Safety of VTE Prophylaxis... Continued from page 1

Medicine, University of Western Ontario, Canada, at the American Society of Hematology annual meeting. Women with a history of VTE have a higher risk of recurrence during and after pregnancy. The highest risk period for a pregnancy-associated VTE is in the first 4 weeks postpartum, said Dr Kovacs. “The standard antepartum and postpartum approach to treatment of these patients depends on the nature of the previous event,” he said. At his institution, women whose previous event was idiopathic receive prophylactic LMWH antepartum and warfarin or prophylactic LMWH postpartum. Women whose previous event was a result of a transient risk factor are followed closely antepartum (no thromboprophylaxis), and receive prophylactic LMWH or warfarin for 6 weeks postpartum. “For a lot of these patients, there’s a tendency to overintervene,” noted Dr Kovacs. “They are given therapeutic doses of LMWH antepartum when it’s not really necessary. You’re placing them at higher risk of bleeding. Especially for the idiopathic population, you would put them on prophylactic doses of LMWH, whereas a lot of physicians are putting them on therapeutic doses of LMWH, which costs more and has a much higher risk of bleeding,” he explained. The prophylactic dose of dalteparin

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sodium injection (the LMWH used most commonly in this study) is 5000 U/day. “If it’s therapeutic, it’s 200 U/kg, so the average 75-kg woman would get 15,000 U, or one third or less of the dose,” he said. Dr Kovacs and colleagues reviewed hospital charts between 1997 and 2008 for all pregnant women with a history of VTE. Patients were divided into 2 groups, history of idiopathic VTE or history of secondary VTE. Patients with a history of idiopathic VTE (N = 60) were treated with LMWH or LMWH plus aspirin antepartum, and prescribed warfarin or prophylactic LMWH postpartum. Those with a history of secondary VTE (N = 30) were observed antepartum and treated with prophylactic LMWH for 6 weeks postpartum. There were 136 total pregnancies, 99 in the idiopathic group and 37 in the secondary group. Patients were followed during the course of their pregnancies and 6 weeks postpartum. “We found that the recurrent deep-vein thrombosis or pulmonary embolism rate was less than 3% overall, and the bleeding rate was low as well; we had no major bleeds at all,” Dr Kovacs said. In the idiopathic group, there were 3 recurrent VTEs, 6 miscarriages, and no major bleeds. In the secondary group, there was 1 recurrent VTE, 1 miscarriage, and no major bleeds. ■

She notes that the mother had an upper respiratory tract infection a few days before the stillbirth, which may have weakened the woman’s immune system, allowing the bacteria a window of escape to invade the placenta and proliferate quickly. The placenta was small for gestational age and had foci of laminar necrosis in the decidua, she notes. As far as patient management for pregnancy-associated gingivitis, Dr Han concludes that “prophylactic antibiotic therapy may be considered in the presence of multiple infections to prevent

Cultured Fusobacterium nucleatum.

prolonged bacteremia and potential hematogenous translocation of oral bacteria into the uterus.” ■

Rates of Vaginal Birth after Cesarean Are Plummeting By Rosemary Frei, MSc

he National Institutes of Health recently convened a panel to examine the reasons behind the drop in the rate of vaginal births after cesareans (VBACs) in the United States, from approximately 30% of live births in 1996 to the current level of <10% of live births today. VBAC refers to women who have had a previous cesarean section and who, for their next pregnancy, opt for a trial of labor as their first choice and a cesarean as a secondary option. The panel found that 74% of trials of labor after a previous cesarean section are successful. Furthermore, although trial of labor is associated with an increased risk of uterine rupture, it is linked to 3.5-fold lower maternal death rates than elective repeat cesarean deliveries (0.0038% vs 0.0134%, respectively). In addition, there is a longer hospitalization length of stay associated with elective repeat cesarean delivery, and the incidences of placenta accreta, increta, and percreta increase with each cesarean birth. Moreover, although the perinatal mortality rate is 130 per 100,000 trials of labor—versus 50 per 100,000 elective repeat cesarean deliveries—this is comparable to the perinatal mortality rate observed among laboring nulliparous women. The major driver of the switch to VBAC is a 1999 practice guideline issued by the American College of Obstetricians and Gynecologists (ACOG). That guideline changed an earlier recommendation of encouraging VBAC, suggesting that women should be offered trial of labor after a cesarean delivery in the absence of contraindica-

tions. The new guideline also stated that a trial of labor should be performed only in institutions equipped to respond to emergencies, and where physicians are immediately available to perform emergency cesareans.

Although trial of labor is associated with an increased risk of uterine rupture, it is linked to 3.5-fold lower maternal death rates than elective repeat cesarean deliveries. This, combined with a 2008 joint statement by ACOG and the American Society of Anesthesiologists calling for immediate availability of appropriate facilities and personnel—including those required for obstetric anesthesia and nurses—and escalating medicolegal concerns have pushed VBAC into the background. Fully 30% of hospital administrators responding to 2 recent surveys said their hospitals have stopped offering trial of labor. The panel members concluded that “Trial of labor is a reasonable option for many pregnant women with a prior low transverse uterine incision.” They urged clinicians and other maternity care providers to conduct their own reviews of the evidence surrounding the shortand long-term benefits and harms to the mother and baby of attempting a trial of labor, and to “incorporate an evidence-based approach into the decision-making process.” ■

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Patient Surveillance by Gynecologic Oncologists Spotty after Ovarian Cancer Treatment number of pelvic examinations recom- strued as evidence of overuse, underuse, By Jill Stein

here is a wide variation in posttreatment surveillance among gynecologist oncologists who treat patients with ovarian cancer, reported Garo Harmandayan, DO, of the St. Louis University School of Medicine, during the recent Society of Surgical Oncology annual symposium. This study was based on a questionnaire completed by 283 members of the Society for Gynecologic Oncologists to identify the current surveillance patterns of credentialed experts. Ovarian cancer is diagnosed in >20,000 women in the United States annually, and the disease is responsible for more deaths than all other gynecologic malignancies combined.

Ovarian cancer is responsible for more deaths than all other gynecologic malignancies combined. “While the surveillance of patients after initial curative-intent treatment of ovarian cancer has important medical implications, the particular modalities used in surveillance by clinicians and how frequently they are recommended are unknown at present,” Dr Harmandayan pointed out. “Routine postoperative surveillance testing is practiced by gynecologists and recommended by many organizations; however, there is a lack of objective evidence to support any particular surveillance strategy in ovarian cancer patients,” he said. For their study, investigators developed a survey based on 4 “idealized” scenarios depicting generally healthy women with ovarian cancer of various Federation of Gynecology and Obstetrics stages. Participants were asked to indicate the number of the following examinations they would recommend each year for 10 years after initial curative-intent treatment: office visits; pelvic examinations; pap smears; complete blood counts; metabolic panels; serum cancer antigen (CA)-125 levels; chest x-rays; abdominal-pelvic computed tomography (CT) scans; chest CTs; abdominal-pelvic magnetic resonance imaging scans; and transvaginal ultrasound examinations. All gynecologic oncologists surveyed said that they performed ovarian cancer surgery and also participated in long-term follow-up. Results showed that the most frequently performed

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tests for each year for all 4 scenarios were office visits, pelvic examinations, and serum CA-125 levels. Imaging studies were rarely recommended. The intensity of surveillance practice varied widely. For example, the

mended in the first postoperative year for women with stage I ovarian cancer ranged from 1 to 12. Also, respondents tended to recommend less testing with increasing postoperative years for all recommended tests. A marked variation in the intensity of a particular strategy is generally con-

and/or misuse of scarce resources, Dr Harmandayan observed. For this reason, further research to evaluate causes of the observed variation is warranted. He pointed out that the study is the first to examine the actual practice of routine surveillance testing for women after primary treatment for ovarian cancer. ■

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Alcohol and Obesity Increase Risk of Breast Cancer Recurrence By Caroline Helwick

or women with breast cancer, being overweight or consuming even a moderate amount of alcohol significantly increases the risk of cancer recurrence, according to several studies presented at the 2009 San Antonio Breast Cancer Symposium. In one of the few studies to evaluate the role of alcohol in breast cancer outcomes, consumption of just a half drink daily, or 2 to 3 weekly, raised the risk of recurrence by 39%. In a second study of nearly 19,000 women, body mass index (BMI) ≥25 kg/m2 increased the risk of distant metastasis by approximately 45%.

Alcohol and Cancer Recurrence Risk Alcohol consumption has been found to increase the risk of developing breast cancer, but its role in survival after a breast cancer diagnosis has been less certain, said Marilyn Kwan, PhD, of the Division of Research at Kaiser Permanente, Oakland, CA. “We found that consuming alcohol may negatively affect breast cancer prognosis, especially among postmenopausal women and those with estrogen receptor–positive tumors,” said Dr Kwan. The Life After Cancer Epidemiology (LACE) study prospectively examined 1898 early-stage breast cancer survivors. At an average time of 2 years postdiagnosis, half the women reported some alcohol use—primarily wine (90%), followed by liquor (43%), and beer (36%). Drinkers tended to be younger, white, well-educated, and former or current smokers. Compared with little or no alcohol consumption, the consumption of ≥6 g/day (equivalent to half an alcoholic drink/day) was associated with a 34% increased risk of recurrence overall, a 51% increased risk among postmenopausal women, and a 58% increased risk among women who were overweight or obese. Alcohol consumption was also associated with a 51% increased risk of death from breast cancer, but not death from other causes. The most increased risk was observed among wine drinkers, who drank at least 2 drinks daily compared with none, which raised their risk by 37%. Dr Kwan said that lifestyle changes for breast cancer patients are not recommended until these findings can be confirmed in other large prospective trials, but she added, “After a breast cancer diagnosis, women should consider limiting their consumption of alcohol.” This may especially be advisable, she said, for postmenopausal or overweight women.

Obesity Linked to Earlier Deaths Obesity was implicated in poorer outcomes in a study from Denmark of 53,816 women treated for early breast cancer. Long-term follow-up data were available for 18,967 women.

“After 10 or more years, the [chemotherapy] treatment effect did not last in the obese patients, who had a poorer survival.” —Marianne Ewertz, MD

“Within the first 10 years of followup, chemotherapy and endocrine treatments were equally effective in lean and obese patients, but after 10 or more years, the treatment effect did not last in the obese patients, who had a poorer survival,” reported Marianne Ewertz, MD, of the University of Southern Denmark. “Adjuvant treatment seems to lose its effect sooner in the obese.” Compared with patients with a BMI

<25 kg/m2, those with a higher BMI were older; most often postmenopausal; had larger tumors; had more grade III tumors; and had more lymph nodes removed, more positive nodes, and more nodes with invasion into deep fascia. The risk of a local or regional cancer recurrence was not related to BMI, but the risk of distant metastases rose according to increased BMI levels, and the risk of dying remained elevated for obese women through 30 years of observation, Dr Ewertz reported. “Patients with a BMI ≥25 kg/m2 had a 42% to 46% increased risk of developing distant metastases, and a 26% to 38% increased risk of dying from breast cancer 10 or more years after diagnosis,” she said. What Does This Mean for Women? Michelle Holmes, MD, DrPH, of Brigham and Women’s Hospital, Boston, MA, discussed the findings at the meeting, praising the investigators for conducting well-designed studies to shed light on these issues. “While these are not randomized controlled trials, such trials are unlikely to be conducted

on lifestyle factors, and these 2 studies are as good as it gets—and they are pretty good,” she said. The LACE study has the advantage of being based on data from an HMO, which offers excellent follow-up for recurrence, Dr Holmes noted. The study also controlled for factors that would predispose women for better survival. The Danish obesity study is the largest study and the one with the longest follow-up—30 years. “It allows for a detailed look at subgroups,” Dr Holmes observed, “and confirms what others have reported—that there is an increased risk of breast cancer death for heavy women with breast cancer.” Other trial investigators suggested that there may be more to the findings than meets the eye. Hope Rugo, MD, of the University of California, San Francisco, noted that people tend to underestimate the amount of alcohol they consume, suggesting that the safe lower limit may be more than 3 to 4 drinks weekly. She also pointed out that fat intake and exercise were not evaluated, and that these could be contributing factors. ■

Effect of Vaginal Estrogen in Breast Cancer Patients Uncertain, but Serum Estradiol Levels Do Rise

or postmenopausal breast cancer patients taking aromatase inhibitors (AIs), vaginal estrogen creams (used to alleviate symptoms of atrophic vaginitis) may be systemically absorbed; however, breast cancer risks associated with this are uncertain, investigators reported at the 2009 San Antonio Breast Cancer Symposium. The development of atrophic vaginitis is common in breast cancer patients taking AIs, and this has a substantial impact on quality of life. Vaginal estrogens have been used to alleviate the condition in postmenopausal women without breast cancer, but the effect of this practice in breast cancer patients has not been well studied. The concern is that the estrogen, which is related to breast cancer development, is systemically absorbed, explained Shannon Wills, PhD, of William Beaumont Hospital, Royal Oak, MI. “Our objective was to determine the degree of estrogen absorption from either chronic E2 tablet or ring use in postmenopausal breast cancer survivors receiving an AI or serum estrogen receptor modulator,” she said. The study included 24 postmenopausal patients who were taking anastrozole (Arimidex), exemestane (Aromasin),

letrozole (Femara), tamoxifen, (Nolvadex) or raloxifene (Evista) as adjuvant breast cancer treatment and using vaginal estrogen for the treatment of atrophic vaginitis. Subjects had used estrogen for an average of 20 months before enrollment. Serving as controls were 24 similar breast cancer patients taking AIs or serum estrogen receptor modulators (SERMs), but not using the estrogen. The estrogen products were 17 betaestradiol vaginal tablets (eg, E2 tablet, Vagifem, FemCare), 1 tablet inserted

Elevated Serum Levels Observed For patients using the tablets, E2 levels before insertion were an average of 4.7 pmol/L higher for those in the case group than in those in the control group, but this difference was not significant. However, 12 hours after tablet insertion, the patients’ mean E2 levels were 76 pmol/L higher than their own baseline levels, which was very significant, Dr Wills reported. Several patients’ E2 levels spiked much higher, including 1 whose level

Dr Will’s advice was to try to keep patients on their hormonal therapy, “and if she has tried everything else—KY, Replens, olive oil—and nothing works, and they are suffering, then use vaginal estrogen, but to me this should be the last option.” twice weekly for at least 3 months, and the 17 beta-estradiol vaginal ring (eg, E2 ring, Estring) inserted once every 90 days for at least 2 months. E2 levels were measured before ring insertion and 30 days and 60 days afterward, or the morning before tablet insertion and 12 hours after insertion. Serum samples were also obtained from the control patients.

reached 300 pmol/L. Serum measurements taken for 1 patient at both 12 hours and 24 hours showed that the level had returned to baseline, suggesting that the elevated effect lasts less than 24 hours, she added. For the E2 ring patients, mean preinsertion levels were 14.2 pmol/L higher in patients in the case group than those in the control group, which Continued next page

april 2010 I Vol 2, no 2

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The OB/GYN Nurse

High-Dose Vitamin D May Relieve AI-Related Joint Pain By Caroline Helwick

igh doses of vitamin D can relieve musculoskeletal pain associated with aromatase inhibitors (AIs) in women with breast cancer, according to a study presented at the San Antonio Breast Cancer Symposium. “Our pilot data suggest that highdose vitamin D significantly improves muscle and joint tenderness associated with anastrozole, and that this beneficial effect disappears once vitamin D is given monthly rather than weekly,” said principal investigator Antonella Rastelli, MD, internist with the Survivorship Program at the Siteman Cancer Center, Washington University School of Medicine, St Louis, MO. Musculoskeletal pain is a known adverse effect of AIs, and breast cancer patients have deficient or at least insufficient levels of 25-hydroxy (OH) vitamin D, she said. The randomized, double-blind, placebo-controlled study evaluated highdose vitamin D supplementation compared with placebo for 6 months in 60 patients with early breast cancer taking anastrozole (Arimidex) as hormone therapy for hormone receptor–positive disease. Patients were required to have serum calcium levels ≤10.3 mg/dL, marginal 25-OH vitamin D levels (1029 ng/mL), 24-hour urinary calcium excretion levels ≤250 mg/g, and a history of generalized musculoskeletal pain that developed or worsened since starting anastrozole. All patients received calcium (1000 mg/day) and vitamin D3 (400 IU/day). The active group also received vitamin

D2 (50,000 IU/week), administered for 8 weeks if they had 25-OH vitamin D levels ≥20 ng/mL and <30 ng/mL, or for 16 weeks if they had 25-OH vitamin D levels ≥10 ng/mL and <20 ng/mL. The control group received placebo for the same duration.

“Our pilot data suggest that high-dose vitamin D significantly improves muscle and joint tenderness associated with anastrozole, and that this beneficial effect disappears once vitamin D is given monthly rather than weekly.” —Antonella Rastelli, MD Patients were given questionnaires for pain and impairment at baseline and at 2 months, 4 months, and 6 months, including the Brief Pain Inventory (BPI), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI). Bone mineral density (BMD) measurements of the lumbar spine and proximal femur were taken at baseline and at 6 months. Pain Relieved in High-Dose Vitamin D Group At the 2-month follow-up visit, patients in the high-dose vitamin D group reported a significant reduction in pain on the BPI (P = .009) and FIQ (P = .01) questionnaires compared with the placebo arm. Significantly improved scores were also reported for walking on flat ground and climbing steps (P = .04) in the HAQ-DI. There were also favorable trends on the BPI interference score, the

Effect of Vaginal Estrogen... was very significant (P = .0001). Eight weeks postinsertion, mean E2 levels had increased by >30 pmol/L, compared with baseline levels (P <.001), indicating “continuous absorption in serum E2 levels in most E2 ring patients during the 3-month insertion,” Dr Wills reported. In contrast, 2 patients had no increase in E2 levels 60 days after ring insertion or at any other time. “With the tablet, the levels go up and then go back down. With the ring, there is a continuous elevation for 90 days, but whether this will influence tumor growth, we do not know,” she said. Because of the small study size, investigators did not differentiate findings between AI and SERM patients. “Vaginal estrogens result in a significant increase in serum estradiol levels in both AI and SERM patients,” Dr Wills said. “The E2 ring results in per-

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FIQ total score, and the HAQ-DI total score, Dr Rastelli reported. Patients in the placebo group also had some improvements in pain, although not as robust as those in the high-dose vitamin D group. “They were getting some vitamin D, and they

Continued from page 16

sistence of higher levels in the majority of patients for the 3 months of its use and the E2 tablet results in absorption for 12 to 24 hours after insertion twice weekly, but returns to lower levels until the next insertion.” “The increase in serum estradiol levels from vaginal estrogens are of concern in patients where the goal of therapy with an AI is to lower E2 levels,” she added. Investigators hope to replicate the study in a larger population and follow the patients over time to observe if there are differences in breast cancer outcomes. Dr Will’s advice was to try to keep patients on their hormonal therapy, “and if she has tried everything else— KY, Replens, olive oil—and nothing works, and they are suffering, then use vaginal estrogen, but to me this should be the last option.”—CH ■

seemed to be getting some relief,” Dr Rastelli said. Most of the beneficial effects disappeared at 4 and 6 months after the dosing was cut back from weekly to monthly. Patients receiving high-dose vitamin D also showed a trend of maintaining BMD of the femoral neck compared with the placebo group, she added. Need to Monitor Urine Although high-dose vitamin D was well tolerated, some patients showed a propensity for higher urinary calcium excretion, which can lead to kidney stones, Dr Rastelli pointed out. Four of

the 30 active-treatment patients were excluded 2 months into the study because of this, as was 1 patient in the control group. “You have to monitor for urinary calcium when you are giving 50,000 IUs of vitamin D long-term, which is very potent,” she emphasized. Secondary hyperparathyroidism was also observed in a few patients. At baseline, 6 patients (10%) had secondary hyperparathyroidism from low 25-OH vitamin D levels, which resolved for 2 patients during treatment but persisted in 4 patients (8.5%). Secondary hyperparathyroidism can lead to bone loss. Researchers are seeking to conduct a multicenter trial to confirm the findings, ideally maintaining high-dose treatment for a longer period of time, including women whose vitamin D levels are considered normal, and possibly using cholecalciferol, which keeps serum levels more stable than ergocalciferol. “We used ergocalciferol and weekly dosing,” Dr Rastelli noted. “We don’t know if alternative forms of vitamin D, such as cholecalciferol, and daily dosing would similarly improve muscle-joint pain and BMD.” ■ See also article on page 26.

For Borderline Pap Smears, Referral for HPV Testing Less Stressful for Patients

omen with a borderline Pap smear result may prefer to be referred immediately for human papillomavirus (HPV) testing rather than return in 6 months for a repeat Pap test, according to a recent study from Australia that found more psychological distress associated with waiting (BMJ. 2010;340:b4491). In a randomized study of 314 women, those who had HPV testing were more satisfied with their care, as were women who were given a choice between HPV testing or returning in 6 months for another Pap smear, reported Kirsten J. McCaffery, PhD, and colleagues, of the University of Sydney School of Public Health. “Although the psychosocial effect was initially worse for women allocated to HPV triage, over the full year of followup this intervention was better for women’s psychosocial health than repeat smear testing,” the investigators wrote. HPV triage can immediately identify women who have a higher or lower risk of more serious cervical abnormalities

that might require follow-up with colposcopy, the authors wrote. It is currently recommended for women whose Pap smears show atypical cells of undetermined significance, but it is not without its downsides. HPV triage can lead to a diagnosis of sexually transmitted infection and more referrals for colposcopy, both of which can increase distress. Whether the potential harms are offset by quicker follow-up and shorter waiting times had not been studied, according to the study authors. The study assessed health-related quality of life, cognitive effects, affective outcomes, specific anxiety about an abnormal Pap smear, and behavioral outcomes during 12 months of follow-up. Two weeks after randomization, the HPV-testing group exhibited multiple signs of increased distress, but over the 12 months of follow-up psychosocial distress was lowest for this group and highest for those allocated to repeat Pap smear.—CH ■ See also Emerging Questions, page 1.

april 2010 I Vol 2, no 2

Clinic Spotlight

The Good, the Bad... given provider in multiphysician practices. In many cases, physicians bring their unique style to the sharing of information, and they may have different interpretation styles and differing practice approaches. This was true at Strong Fertility Center, where nurses were interested in increasing the quality and consistency of the service provided to patients and maximizing patient satisfaction with the information provided to them concerning test results. Because of this, we developed a framework to help guide the discussion of pregnancy test results with patients undergoing fertility treatments. This framework was developed in response to patient dissatisfaction with the existing process for communicating QhCG (ie, pregnancy test) results. Two themes were emerging in discussions with patients: (1) variation in interpretation of QhCG levels, and likelihood of a successful pregnancy varied by provider reviewing results; and (2) lack of consistency in delivering results across the nursing staff. Strong Fertility Center Strong Fertility Center is an academic practice at the University of Rochester Medical Center, NY; at the time of the program redesign it was staffed by 4 reproductive endocrinologists, 1 nurse practitioner, and 7 registered nurses, including a nurse leader who supervises the nursing staff, 2 nurses dedicated to IVF/oocyte donation, 3 nurses dedicated to general infertility patients, and 1 recovery room nurse. Within this group of care providers, each nurse has her own distinct person-

Continued from page 1

ality and style of interacting with patients, and the physicians have varying styles of interaction as well. To address the patients’ dissatisfaction with communication of test results, we designed a consistent approach for interpretation and for the delivery of pregnancy test results to patients. First, we conducted a review of the literature to identify hCG concentrations and their predictive value of pregnancy outcome. In one study, Sugantha and colleagues classified pregnancies into 4 distinct groups, based on initial QhCG levels and rate of QhCG rise over 1 week.1 These pregnancy outcomes were then reported for each group.1 Next, we completed a retrospective review of our IVF pregnancy results, including the QhCG levels and associated live births, miscarriages, and ectopic pregnancies for 2006. When we compared Sugantha and colleagues’ findings to ours for the period between January 2006 and December 2006, the results were similar. Patients with initial QhCG levels >50 IU/L at day 14 had the highest live births outcome. We presented the results of our pregnancy outcomes to the physicians and nurses, and based on this information, we decided that initial QhCG levels >50 IU/L at 2 weeks after embryo transfer or intrauterine insemination (IUI) would be interpreted as a normal result. If the level was <50 IU/L 2 weeks after embryo transfer or IUI, that result would be interpreted as concerning, and the patient would be counseled accordingly. Delivering Test Results We addressed the need for consisten-

Table Suggested Scripts for Pregnancy Test (QhCG) Results QhCG <50 IU/L Your pregnancy test is positive, but the result is a low value Our experience has shown that a pregnancy that starts with such a low value may not result in a viable pregnancy hCG is the hormone that the pregnancy secretes as it grows Do you have questions about what this means? QhCG >50 IU/L Your pregnancy test is positive and this is a good first level We will follow the level to make sure that it is rising appropriately; we expect that this level should roughly double about every 48 hours We will follow the QhCG level several times, and if it is rising appropriately, we will schedule your pregnancy viability ultrasound at about 6.5-7 weeks

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QhCG levels not doubling as expected Your QhCG level has increased, but the result is a lower value than we would hope to see The level should roughly double about every 48 hours We can’t know for sure what the outcome will be until we get further results We understand how hard it can be not to know for sure if you will have a viable pregnancy Do you have questions about what this means? Negative QhCG I am so sorry, but I don’t have good news. The pregnancy test is negative I know this is not what you were hoping to hear You must be so disappointed Is your spouse/partner available to talk with you?

Front row (from left): Connie Kellogg, RNC, BSN; Kriston Ward, MS, RN, NP-C. Back row: Cheryl Passino, RN; Karen Oliver-Proctor, RN, CPAN; Roxann Taylor, RN; Germaine Santoriello, RN, BSN; Martha O’Connor, RN, BSN; Dawn Holden, RNC.

cy in the delivery of test results through a “scripting” process.2 Scripting consists of a sequence of statements and behaviors that give a clear, consistent, and concise message (Table). It establishes expectations and ensures consistent communication of what needs to be said or done. Scripting can also assist in increasing patient satisfaction by reinforcing what has been said, and by providing a framework for others to follow. Scripting sets standards and provides tools for handling difficult situations. In addition to developing standards for consistency in the information provided, we also reinforce the importance of consistency in the ways in which the information is presented. During faceto-face encounters, body language plays a big role in how the message is communicated. We stress the importance of making eye contact, considering the impact of our facial expressions, and attending to whether our posture is open and inviting or closed-armed and unapproachable. Remember the importance of being active listeners, which can be communicated through verbal response and by avoiding interrupting the patient when she is talking. These behaviors should be evident during in-person interactions and while communicating with patients over the phone, which is the case for a majority of patient contacts in our setting. Practical Suggestions When developing scripts for test results, keep the format and content as simple and straightforward as possible. The goal is to have the same message communicated by different people; therefore, the simpler, the better. The message should be concise and to the point, but still communicate empathy and concern. Another important point is to include staff participation in the development of scripts. In general, the staff will be more comfortable communicating a message if they were involved in its development. To address this, we included staff in the identification of content that should be used in the script. We reached a consensus about

what dialogue was appropriate in delivering these results, and this information was distributed to all. Patient Satisfaction Is Key Our ultimate goal is patient satisfaction. Our referring physicians are aware of our patients’ satisfaction or dissatisfaction, and they are going to refer patients to the clinics where the patients are the most satisfied. We are cognizant of the fact that choices for patients are increasing. A consistent message can improve patient satisfaction. “Practices that have consistent systems and refine their systems as needed tend to have higher levels of patient satisfaction.”2 In addition, the ambiguity of interpreting and delivering test results has been minimized using this framework, thereby increasing nursing satisfaction in our practice. ■ References 1. Sugantha SE, Webster S, Sundar E, Lenton EA. Predictive value of plasma human chorionic gonadotropin following assisted conception treatment. Hum Reprod. 2000;15:469-473. 2. Levin R. Consistency. J Am Dent Assoc. 2005;136: 1303-1304.

Strong Fertility Center The Strong Fertility Center (SFC) is part of the University of Rochester Medical Center Women’s Health Pavilion; it includes physicians, nurses, and other health professionals with extensive training and experience. SFC’s comprehensive approach and skilled experts offer many avenues for helping women conceive. The reproductive endocrinologists at SFC include Kathleen Hoeger, MD, MPH; Adam Griffin, MD; Vivian Lewis, MD; and John T. Queenan, MD. Because male factors contribute to approximately 30% to 40% of infertility problems for couples, SFC collaborates with urologist Jeanne O’Brien, MD, who specializes in male factor infertility. SFC is the longest continually operating IVF clinic in upstate New York, with IVF experience for >28 years. Physicians and nurses are actively involved in research, such as on polycystic ovary syndrome (PCOS), stem-cell research, and the effects of nutrition and environmental toxins on male fertility. SFC offers many support groups and educational programs, as well as a Women’s Lifestyle Center for management of weight and PCOS.

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Pharmacy Corner

Infertility Medication Storage Sandra Fernandez, RPh, PharmD Pharmacist, Mandell’s Clinical Pharmacy, Somerset, NJ

ertility testing may be stressful for individuals and for couples. Stepping onto a path of unknown causes, solutions, and financial strain can lead to feelings of inadequacy and anxiety. Although there is no way of completely eliminating anxiety during this

journey, nurses and physicians can provide some tips to their patients that may lessen anxiety and make it easier to cope. One powerful tool healthcare professionals can offer their patients is to have them take an active role in their infertility treatment. Although we have limited time

frames with patients, we can strive to educate them properly, because stress can play a role in the success of fertility treatments. The more familiar individuals become with their procedures and medications, the more comfortable they will be throughout their cycle. Encourage patients to research their insurance coverage to plan financially, to become familiar with the sequence of their treatment cycles, and to know their medication doses, proper injection technique, and storage requirements. The Table shows common medications used in infertility cycles and their respective storage requirements, as well as injection training information.

Refrigerated temperature for storage is 2°C to 8°C (36°F-46°F) and room temperature is 20°C to 25°C (68°F-77°F). Medications should not be used after the expiration date, which is printed on the package. Oral medications (tablets and capsules) should be stored in their original container, in a dry, cool place. Remind patients to keep all medications out of the reach of children. When patients are well informed, they are empowered to make a positive difference in their cycle. We may not be able to completely “destress” patients undergoing infertility treatments, but we can certainly try. ■

Table Common Fertility Drugs and Their Storage Needs Class/Trade name

Storage requirements

Extra information

Injection training website

Bravelle 75-IU vial

Refrigerated or room temperature

Use immediately after mixing with sterile diluents; discard unused material; do not freeze; protect from light

www.ferringfertility.com/medications/trainingguidedownload.asp

Follistim AQ 75-IU vial; 150-IU vial; 300-IU cartridge; 600-IU cartridge; 900-IU cartridge

Refrigerated or room temperature

May be refrigerated until expiration date OR at room temperature for 3 months or up to expiration date; after first use, may be stored for up to 28 days; do not freeze; protect from light

Cartridges: www.follistim.com/Consumer/ FollistimAQCartridge/ FollistimPen/FollistimPeninstructionvideo/index.asp Vials: www.follistim.com/Consumer/FollistimAQvial/Follistim AQvialInstructionalVideo/index.asp

Gonal-f MDV 450 IU; MDV 1050 IU

Refrigerated or room temperature

Reconstituted solution may be stored up to 28 days: refrigerated or at room temperature; discard after 28 days; do not store drug in syringe; do not freeze; protect from light

www.fertilitylifelines.com/resources/gonal-fmulti-dose.jsp

Gonal-f RFF 75-IU vial

Refrigerated or room temperature

Use immediately after reconstitution; discard unused material; do not store drug in syringe; do not freeze; protect from light

www.fertilitylifelines.com/resources/gonal-frff75iuvial.jsp

Gonal-f RFF 300-IU pen; 450-IU pen; 900-IU pen

Refrigerated or room temperature

May be refrigerated until expiration date OR at room temperature for 3 months or up to expiration date; after first use, can only be stored for ≤28 days; do not freeze; protect from light and extreme temperature

www.fertilitylifelines.com/resources/gonal-frffpen.jsp

Refrigerated or room temperature

Use right away after mixing with sterile diluent; discard unused material; do not freeze; protect from light

www.ferringfertility.com/medications/trainingguidedownload.asp

hCG 10,000-IU vial

Room temperature

Use completely within 60 days after reconstitution (stored refrigerated)

Novarel 10,000-IU vial

Room temperature

Excursions permitted to 15°C-30°C (59°F-86°F); reconstituted solution is stable for 30 days when refrigerated

www.ferringfertility.com/medications/trainingguidedownload.asp

Pregnyl 10,000-IU vial

Room temperature

Reconstituted solution is stable for 60 days when refrigerated

www.follistim.com/Consumer/GanirelixPregnyl/Pregnyl/Pregnyl InstructionalVideo/index.asp

Ovidrel 250-µg syringe

Refrigerated or room temperature

May be refrigerated until expiration date OR at room temperature for ≤30 days; store in original package; discard unused material; protect from light

www.fertilitylifelines.com/resources/ovidrelpre-filledsyringe.jsp

Cetrotide 250-µg syringe

Refrigerated

Store in a cool, dry place; keep packaged tray in outer carton to protect from light; use solution immediately after preparation

www.fertilitylifelines.com/resources/cetrotide25mgvideo.jsp

Cetrotide 3-mg syringe

Room temperature

Store in a cool, dry-place; excursions permitted to 15°C-30°C (59°F-86°F); keep packaged tray in outer carton to protect from light; use solution immediately after preparation

www.fertilitylifelines.com/resources/cetrotide3mgvideo.jsp

Ganirelix 250-µg syringe

Room temperature

Excursions permitted to 15°C-30°C (59°F-86°F); protect from light

www.follistim.com/Consumer/GanirelixPregnyl/GanirelixAcetate Injection/GanirelixAcetateInjectionInstructionalVideo/index.asp

Room temperature

Do not freeze; protect from light; store vial in carton until use

Refrigerated or room temperature

Protect from light; store in original package; use immediately after reconstitution; discard unused material

Follitropins

Menotropins Menopur 75-IU vial Repronex 75-IU vial Chorionic gonadotropins

GnRH antagonists

GnRH agonist Leuprolide acetate 2-week kit 1 mg/0.2 mL Lutropin alfa Luveris 75-IU vial

www.fertilitylifelines.com/resources/luveris.jsp

Estradiol valerate Delestrogen 10-mg/mL vial; 20-mg/mL vial

Room temperature

Progesterone Progesterone oil 50 mg/mL

Room temperature

Progesterone olive, ethyl oleate, cottonseed oil 50 mg/mL, 100 mg/mL

Room temperature

Protect from light

Crinone 8% progesterone gel applicators Room temperature

Excursions permitted to 15°C-30°C (59°F-86°F)

www.crinoneusa.com/patients/applying_crinone.html

Endometrin 100-mg vaginal insert

Excursions permitted to 15°C-30°C (59°F-86°F)

www.ferringfertility.com/medications/endometrin/ admin_instructions.pdf

Room temperature

Aqueous compounds Microdose leuprolide (all concentrations) Refrigerated Low-dose hCG (all concentrations)

Use by expiration date assigned by compounding pharmacy; discard 30 days after first use; do not freeze

hCG indicates human chorionic gonadotropin; GnRH, gonadotropin-releasing hormone.

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april 2010 I Vol 2, no 2

Legal Matters

Legal Guidance for Clinicians Assisting in Gestational Carrier Arrangements Melissa B. Brisman, Esq, and Lauren Murray, Esq Ms Brisman is the owner of Melissa B. Brisman, Esq, LLC, Reproductive Possibilities, LLC, and Surrogate Fund Management, LLC. Ms Murray is an associate at Melissa B. Brisman, Esq, LLC

A couple (husband and wife) has tried to conceive a pregnancy for >1 year without success; they decide to consult with an infertility specialist. They discover that the wife has a medical condition that prevents her from conceiving. The physician says that should she conceive, it is unlikely she would successfully carry the pregnancy to full term. The physician advises that the wife’s ova and husband’s sperm appear healthy and capable of developing into a healthy child. If they want to have a biological child, they should consider using a gestational carrier. The couple accepts the recommendation, does the necessary research, and returns months later with a potential gestational carrier, excited to begin their journey to parenthood.

ituations like this are becoming increasingly common, but some of the legal and ethical questions raised by these situations remain unresolved. When the infertile couple—the “IPs”—first approached the physician, they were his patients. Once they returned with a potential gestational carrier (the “carrier”), that carrier also became a patient. Now, the physician must balance the rights of these separate but connected parties regarding decision-making power and confidentiality. What is the best means of balancing the rights of these separate but clearly connected patients? In an ideal situation, the IPs and the carrier, and a carrier’s spouse or partner, if any, have entered into a written agreement in which they agree to the mutual release of confidential medical information related to their arrangement. The IPs want to know that the carrier is healthy and capable of conceiving and carrying a pregnancy. The carrier, similarly, wants to know that the IPs do not have any disease or illness that could be transmitted through the embryos created by the IPs.

The Limits of Release Documents The physician can assist the IPs and the carrier in signing releases so that relevant information can be shared and the lines of communication between the parties, as well as the physician, can remain open. These releases should comply with HIPAA requirements. Keep in mind, however, that either the IPs or the carrier can revoke their consent to the release of this information at any time, and upon revocation, the physician must not share any information with the other party to the arrangement. Breach of Agreement Physicians should be aware that they may inquire into the existence of an agreement between the parties. However, the physician is not a party to the agreement and is not legally bound by its terms. In the event of a breach of the agreement, for instance,

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if the carrier becomes pregnant on her own before the first embryo transfer, the IPs may sue the carrier for breach of contract and seek monetary damages, but it is unlikely that the IPs could compel the carrier to perform her duties under the agreement. The carrier has ultimate decisionmaking authority over matters related to her body. If she decides to breach the agreement, the carrier is still the patient and, in the absence of a court order to the contrary, the carrier is the sole patient in charge of clinical management of her pregnancy without regard to the IPs’ wishes. She can relinquish that authority to the IPs, but she can revoke that consent at any time before birth. The carrier must consent to the number of embryos to be transferred, even if that number is lower than the IPs request. Similarly, it is solely the carrier’s decision whether to abort or reduce her pregnancy. Pregnancy and OB/GYN When the embryo transfer results in a confirmed pregnancy, the carrier is eventually released to her own obstetrician’s care for the balance of the pregnancy. It is up to the obstetrician and the carrier to determine how best to include the IPs in the process. Must the obstetrician share his patient’s medical information with the IPs? Again, if there is an agreement in place, it is likely that the carrier has already consented to release all medical information related to the pregnancy to the IPs. However, the obstetrician should speak with the carrier about the release of such information. The obstetrician can provide the carrier with the documentation necessary to waive her right to confidentiality with respect to the IPs. Any such documentation should be fully compliant with HIPAA. The obstetrician should try to be open to discussing the status of the pregnancy with the IPs, either in or outside the presence of the carrier, as long as the carrier has legally consented to such disclosure. If at any time the carrier

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changes her mind and revokes her consent, the obstetrician must not share any further medical information about the carrier or her pregnancy with the IPs. In the event that the carrier revokes her consent, she is likely in breach of her agreement with the IPs, and the IPs can initiate a lawsuit seeking monetary damages and specific performance of the carrier’s obligations under their agreement. The physician should comply with any order received by the court concerning the disclosure of the carrier’s medical information. The obstetrician should be aware that the carrier has final decision-making authority over medical decisions affecting her body. This includes decisions involving clinical management of the pregnancy, amniocentesis and other tests designed to detect congenital abnormalities, and delivery. Although the carrier may have initially agreed to undergo an amniocentesis, if she later refuses to undergo the procedure, the obstetrician must honor the carrier’s decision regardless of the wishes of the IPs. In some cases, the IPs may live far away from the carrier and may be concerned that they will not be able to travel from their home to the hospital where the carrier intends to deliver in time to witness the birth. They therefore want the carrier to undergo a scheduled cesarean section. The carrier tells her obstetrician that she wants to deliver vaginally. The obstetrician should advise the carrier of what is best medically, but it is solely the carrier’s decision how and when she will deliver. Ideally, the IPs, the carrier, and the obstetrician remain in close contact and are able to discuss medical issues as they arise so that the final decisions made by the carrier are ones with which all parties are comfortable. Postnatal Issues Once the baby is born, the IPs should have all decision-making authority over the child’s medical care. In an ideal situation, the IPs have consulted with a reproductive attorney throughout the process and they have a birth/

Lauren Murray, Esq

parentage order in place, declaring one or both of them the legal parents of the child. This order should also terminate the carrier’s rights to the child. Generally, a birth order is a legal declaration of parentage issued by a court of law, recognizing the IPs as legal parents and ordering the hospital and the appropriate state office to name the IPs as legal parents on the child’s birth certificate. The birth order is a result of a legal process usually initiated after the first trimester of pregnancy. Birth orders can be signed prebirth or postbirth. If signed prebirth, a certified copy of the order is provided to the hospital where delivery is expected to take place. The hospital places the birth order in the carrier’s file so it is available when the hospital submits the birth registration paperwork to the appropriate state office. The presence of this order protects the interests of the IPs, the carrier, and the medical professionals. When a birth order is in place, the obstetrician and hospital staff must comply with the court order and recognize the IPs as the legal parents of the child. The IPs must have access to the child’s medical records, must be able to make medical decisions about the child from the moment of birth, and must have access to the child in the hospital. When the child is ready for discharge, the IPs discharge the child and take the child home. In the absence of a court order, the IPs and the carrier can execute paperwork transferring authority to make decisions on behalf of the child to the IPs. If the carrier refuses to sign these documents, she is left with legal authority over, and custody of, the child. This is why obtaining a parentage order is critical. As a general rule, medical professionals should remain open-minded and open-hearted, but be aware of their legal obligations and limitations. It is in the interest of all parties that the IPs, the carrier, and the physicians seek legal guidance. With all parties aware of and respecting these boundaries, these arrangements can result in happiness and fulfillment. ■

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The Infertility Nurse

Lifestyle Choices that Influence Fertility Kevin J. Lederer, MD, and Ilynne McGovern, RN Dr Lederer practices at Fertility Centers of Illinois, Orland Park; Ms McGovern is Nurse Coordinator, Highland Park IVF Program, IL

preconception visit at an infertility center presents a unique opportunity to influence lifestyle choices by couples that are trying to conceive. Such couples are very motivated, which can help promote lifelong health habits. Diet, health, exercise, and preventive medical screening are important factors to be addressed. A preconception visit presents the chance to identify pregnancy risk factors for the mother and fetus. Most important, it allows time for appropriate intervention to optimize patients’ fertility and avoid some pregnancy risks.

Tobacco Use Smoking has a clear effect on fertility and on pregnancy. A report by the British Medical Association showed that smokers have up to a 10% to 40% lower monthly fecundity rate. The American Society for Reproductive Medicine has estimated that up to 13% of infertility cases result from tobacco use. The effect is dose-dependent on the number of cigarettes smoked daily. Smoking as few as 5 cigarettes daily has been associated with lower fertility rates. The risks during pregnancy are also substantial. Smoking has been linked to an increased risk of birth defects, such as cleft lip and palate. Tobacco use is also associated with an increased incidence of miscarriage, ectopic gestation, preterm labor, low birth weight, neonatal respiratory infections, inability to breastfeed, and neonatal mortality. Distressingly, studies suggest that children whose parents smoke experience lower achievement in reading and mathematics up to age 16. Smoking has been shown to lower the chance of successful IVF treatment. Studies have shown that female smokers have a 34% lower chance of conceiving when undergoing IVF. The mechanism by which tobacco use diminishes fertility is unknown. Tobacco by-products may be found in follicular fluid. Most significant, ovarian reserve is compromised, and fewer oocytes are retrieved. Smoking may have a deleterious effect on ovarian blood flow. Female smokers usually undergo menopause earlier than nonsmokers. Both chromosomal and DNA damage to human germ cells may result from tobacco smoke exposure. Men are not immune to a smokingrelated decline in fertility. Semen analyses exhibit reductions in ejaculatory volume, sperm density, motility,

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and sperm morphology. Male smokers average a 22% decrease in sperm counts. Laboratory testing has suggested decreased sperm fertilization in smokers. Both acrosomal defects and DNA fragmentation have been noted. Children of men who smoke may have an increased incidence of birth defects, childhood cancers, and infertility in their sons. Smoking has been clearly shown to lead to erectile dysfunction and impotence.

Smoking as few as 5 cigarettes daily has been associated with lower fertility rates. Although not all the adverse effects of smoking on reproduction and pregnancy outcomes have been completely delineated, it is clear that a smoking cessation program should be an important component in preconception counseling. Alcohol Use Data on alcohol use present a more complicated picture. A large Swedish study examined the effects of alcohol intake on fertility. Those who drank 4 glasses of wine (6 oz) per week were considered low consumers. Women drinking 4 to 10 glasses of wine were labeled moderate consumers. Women drinking 10 or more glasses per week were high consumers. High consumers were found more likely to suffer fertili-

ty problems. Low consumers and those who did not drink had an intermediate chance of presenting with infertility. Fertility was actually increased among those women who were moderate drinkers (4-9 glasses/week). Paradoxically, a recent study found that any alcohol intake during an IVF cycle diminishes the chances of success. It is therefore recommended to refrain from ingesting alcohol during the IVF treatment process. Also, consuming more than 1 glass of wine per day has been suggested to increase the risk of breast cancer. When attempting conception, alcohol intake should be limited to the equivalent of 1 glass of wine per day. Patients should not drink during pregnancy, because the safe limit for pregnant women is unknown. High alcohol intake in men has similarly been shown to have a deleterious effect on sperm parameters. The same advice of limiting alcohol intake to 1 to 2 glasses of wine per day should also be given to men. Caffeine Data examining the effects of caffeine use on conception are limited at best. Given all the evidence to date, the American College of Obstetricians and Gynecologists has issued a clinical opinion that caffeine intake be limited to 250 g per day. Women attempting conception should be counseled to not consume more than 2 cups of coffee or 4 cups of black tea per day.

Drug Use Cocaine or heavy marijuana use temporarily reduces the number and quality of sperm by as much as 50%. It has been suggested that marijuana use may impair female and male fertility via the same mechanisms as smoking tobacco. Cessation of any drug use should be strongly recommended. Anabolic steroid use has also been shown to adversely affect semen parameters and clearly cause male infertility. Nursing Interventions Nurses play a key role in the management of all aspects of patient care. Couples may be less willing to expose or share lifestyle issues and concerns with their physician. Nurses need to be acutely aware of the data surrounding detrimental effects these lifestyle factors can cause. In this way, they may respond to patient questions and concerns appropriately. Through early identification and intervention, nursing can guide couples toward a healthy lifestyle that can have a significant impact on their fertility success. Nursing should focus on the issues patients can take active control over, such as smoking and alcohol cessation, limiting caffeine intake, and other healthy lifestyle choices. ■

Antiestrogens May Protect Against Lung Cancer By Caroline Helwick

amoxifen and other antiestrogens may not only protect against breast cancer recurrence but may also decrease the risk of death from lung cancer, according to a large European study presented at the San Antonio Breast Cancer Symposium. “We found a reduction in lung cancer mortality among women treated with antiestrogens for breast cancer,” said Elisabetta Rapiti, MD, MPH, of the Geneva Cancer Registry, University of Geneva, Switzerland. “This work builds on previous studies that had suggested estrogens have a role in lung cancer development and progression.” The study included 6715 Swiss women

diagnosed with breast cancer between 1980 and 2003, totaling 57,100 personyears; 46% of the women received antiestrogen therapy, primarily tamoxifen. At the end of the study, 40 women were diagnosed with lung cancer at least 6 months after the breast cancer diagnosis. Although the incidence of lung cancer was similar to that in the general female population of Switzerland, the mortality risk from lung cancer was significantly lower among women who received antiestrogen therapy. Compared with the general population, the incidence of lung cancer among antiestrogen recipients was 0.63, but it was 1.12 among women not re-

ceiving these agents. The overall lung cancer mortality rate was 31.44 per 100,000 persons, and 44.97 per 100,000 women not receiving antiestrogens, but was just 9.23 per 100,000 for women taking antiestrogens. “This result further supports the role of estrogens in lung cancer prognosis and suggests that exposure to antiestrogens may offer some protection against tumor mortality. Our results are particularly relevant to the research agenda exploring endocrine treatment for lung cancer,” Dr Rapiti said. Phase 2 clinical trials are under way to evaluate hormonal therapies as adjuncts to traditional chemotherapy for lung cancer. ■

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The Infertility Nurse

The Benefits of Preconception Genetic Counseling, Indications for Referral Pamela Callum, MS Certified Genetic Counselor, California Cryobank Genetic Counseling Services, Co-Chair, ART Special Interest Group, National Society of Genetic Counseling

ny patient who is planning a pregnancy may benefit from preconception genetic counseling, regardless of his or her age or method of conception. Patients who use assisted reproductive technologies (ART) are particularly suited for preconception counseling, because they plan the details of their reproductive treatments and interact with healthcare professionals before conception. Therefore, they can be informed about and referred for genetic counseling before initiating a pregnancy. However, too few patients who are using ART are informed about or take advantage of preconception genetic counseling. OB/GYN and infertility nurses can support their patients’ reproductive goals by knowing the indications for referral and by informing their patients of the benefits of preconception genetic consultations.

Patients who plan to use ART are especially likely to benefit from preconception genetic consultations.

Preconception Genetic Counseling Certified genetic counselors have master’s degrees in medical genetics or genetic counseling and have achieved certification through the American Board of Genetic Counseling. Genetic counselors work in diverse clinical settings, including prenatal, oncology, and neurology clinics. Members of the ART special interest group (SIG) of the National Society of Genetic Counseling (NSGC) and the genetic counseling SIG of the American Society of Reproductive Medicine specialize in working with patients who use reproductive technologies. A genetic counseling appointment includes collection of a patient’s family medical history; a risk assessment to identify potential health risks to offspring; and discussion of the inheritance patterns of those risks, preventive measures, and available genetic testing options. Genetic consultations also include support with decisionmaking about which genetic tests, if any, may be right for that patient’s individual reproductive plans. Any patient who is planning a pregnancy may consider preconception genetic counseling for genetic carrier screening, a family history risk assessment, and discussion of the options available for the management of any concerns identified. For example, if a risk for a specific medical problem is identified during the genetic risk assessment, or if both partners test positive as carriers of mutations for the

Too often, patients are left to wonder why no one offered this genetic screening and information before they became pregnant, so that they could have avoided dealing with these stressful and unexpected situations during their pregnancies. Patients who plan to use ART are especially likely to benefit from preconception genetic consultations, because they can be informed about the risks, benefits, and limitations of PGD and other ART procedures. They can also discuss and compare these procedures to prenatal screening and diagnostic testing options. In one study, patients were found to have limited knowledge of PGD even though they had used it to conceive a pregnancy. They often did not understand which types of health issues were screened using this tool, and assumed that they did not need to consider prenatal screening or diagnostic testing during pregnancy if they used PGD. It is not clear if this misinformation may be a result of poor patient comprehension or if physicians and nurses lack the time to provide sufficient education. When patients are not aware that prenatal diagnosis is recommended after using PGD, they can be greatly distressed by this information during pregnancy. The anxiety arises from the realization of unscreened medical risks in their offspring, and the limited time available to make decisions about these procedures. Therefore, precon-

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same genetic condition, such as cystic fibrosis, they can be informed about preimplantation genetic diagnosis (PGD) as an option for their reproductive plans. This is particularly beneficial to patients who are already planning to use IVF. If these health risks are identified postconception, the options for managing them may be limited to taking no action, or using invasive prenatal diagnosis procedures, such as chorionic villus sampling or amniocentesis, and considering possible termination of a much-wanted pregnancy.

ception genetic consultations are ideal, because they provide patients time to carefully consider their options, ask questions, and acquire support in developing their fertility and prenatal management plans. Indications for Referral Patients who are at advanced parental age at the time of delivery— aged ≥35 years for women and ≥45 years for men—or who have a family history of recurrent pregnancy loss, infant death, mental retardation, birth defects, or specific genetic disorders, should be strongly encouraged to schedule a consultation. Patients using fertility treatments as a result of known and unknown causes of infertility are also prime candidates for preconception genetic counseling. It is important for them to be informed that they may pass on inherited forms of infertility to their offspring by using certain reproductive technologies. In addition, certain causes of infertility, such as structural chromosome abnormalities, can lead to miscarriage or the birth of a child with major birth defects and/or mental retardation. Preconception genetic counseling can provide education about alternatives, such as gamete donation, if patients are concerned about transmitting these issues to their offspring. Individuals involved in third-party reproduction, including donors, recipients, surrogates, and intended parents, may all benefit from preconception genetic counseling. Genetic screening of surrogates and egg and sperm donors is variable in the United States. The guidelines for screening these populations are not specific, and each egg and sperm bank and surrogate agency independently determines its own procedures for screening applicants. Genetic screening of a third-party individual may not be sufficient for a specific recipient or intended parent, depending on his or her own medical history. Additional genetic screening of the third party, when appropriate, should be discussed before a pregnancy is initiated, so that all parties have time to agree as to how to proceed. Preconception genetic counseling may allow a surrogate to be informed about the health risks to a child, as elicited from the biological parents’ risk assessment. The biological parents’ history may indicate a need for invasive testing or a risk for medical com-

plications during pregnancy, for which the surrogate may need to be prepared. Even when a legal agreement has been established among all parties before conception, difficult situations can arise during pregnancy if a thorough discussion of health risks and their meanings has not occurred. In one situation, a surrogate who previously agreed to prenatal diagnosis later declined testing after being informed about what the procedure was testing, and that the results may lead to decisions about pregnancy termination or fetal reduction. Barriers to Preconception Genetic Consultations Patients often believe that they are familiar with their own family histories and that they are aware of any risks to their offspring. However, many patients do not truly understand the risks posed by their medical histories and are surprised to learn about possible risks and management options that they may wish to consider. Patients frequently leave a genetic consultation feeling more informed and in control of their plans than they had been when they arrived, because the consultations empowered them with information and support in making decisions that are optimal for their individual circumstances. Individuals who use fertility treatments often feel burdened by multiple medical appointments. In addition, genetic counseling services are available most often in major metropolitan areas. At California Cryobank Genetic Counseling Services, we attempt to address some of these issues by offering appointments outside of traditional clinic hours and by providing in-person and over-the-phone genetic consultations. In-person consultations are preferable whenever possible; however, over-the-phone consultations provide significant benefit compared with no consultation. OB/GYN and infertility nurses can collaborate with genetic counselors to provide excellent patient care by establishing a strong network of relationships for case management and establishing the appropriateness of referrals. Nurses can provide guidance on the benefit of preconception genetic counseling to encourage patients to utilize these services that will enhance their reproductive experiences. To locate a genetic counselor in your area, visit www.nsgc.org. ■

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The Infertility Nurse

Surplus Quality Embryos to Freeze Linked to IVF Success

aving an excess of high-quality embryos to freeze predicts a higher chance of pregnancy from IVF cycles, according to a recent study. “We found a significantly higher clinical pregnancy rate in patients who had surplus embryos to freeze that were transferred on day 3, and we found the same results in patients who had surplus embryos to freeze on day 5,” said lead investigator, Martha Luna, MD, Codirector, Reproductive Medicine Associates of New York, at the 2009 meeting of the American Society of Reproductive Medicine.

clinical pregnancy rates were significantly higher among the groups having surplus embryos frozen. Among the day 3 transfers, the clinical pregnancy rates were 69% in the groups with excess embryos for cryopreservation compared with 58% in those without surplus embryos for freezing. Among the day 5 transfers, the clinical pregnancy rates were 72%

and 55% in the 2 groups, respectively. “Our implantation rates were also significantly higher in both groups of patients who had surplus embryos to freeze,” said Dr Luna. Surplus blastocytes available for freezing may be used as a prognostic indicator of outcome in young women who have undergone an embryo transfer in the same cycle, Dr Luna said. ■

By Wayne Kuznar

Assisted-hatching IVF embryos.

“We used to counsel patients that their chances of having a pregnancy will not be impacted by not having surplus embryos to freeze, but surprisingly, we found that it does make a difference,” she said. “The finding helps us to counsel patients and inform them.” Her retrospective study examined women younger than 35 years who had normal levels of follicle-stimulating hormone (<10 IU/L) and who underwent IVF and embryo transfer. Cycles were classified based on the day of embryo transfer (day 3 and day 5) and subclassified based on blastocyte availability for cryopreservation. The criteria for cryopreservation of embryos are rigorous at her center, explained Dr Luna. “We aim to freeze only high-quality embryos likely to result in successful thaw and implantation. Following day 3 embryo transfer, surplus embryos are placed in an extended culture and cryopreserved on day 5 and/or day 6 if morphological criteria are met,” she said. After embryo transfer on day 5, the surplus embryos are evaluated on day 6, and are frozen if the criteria are met. A total of 2071 fresh embryo transfers were identified (990 performed on day 3 and 1081 performed on day 5). The mean number of embryos transferred was similar between the groups with and without cryopreserved embryos for either day 3 or day 5 transfer, but the

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The Midwest Reproductive Symposium (MRS)

Nurse Practicum 2010 June 3-4 • The Drake Hotel (Chicago, IL) June 3rd: Sessions developed by nurses for nurses June 4th: Required sessions at the MRS OPTIONAL - June 5th MRS sessions at no extra cost!

Join your colleagues for a timely and lively discussion of issues relevant to reproductive medicine in a highly interactive, continuing education environment. Discussion and workshop topics include Reproductive Medicine Essentials Update; Managing Infertility – the Nurse Perspective; A Nurse’s Guide to the Embryology Lab; Optimizing Ultrasound; Clinical Dilemmas (PCOS, OHSS, RPL); Male Infertility; Ethics and Legal Dilemmas; Telemedicine; and more! Some of our distinguished faculty: Barry Behr, PhD • Angeline Beltsos, MD • Mark Bush, MD • Ken Cadesky, MD Judy Campisi, LPN • Susan Crockin, JD • Alan DeCherney, MD • Kevin Doody, MD • Melinda Henne, MD • Lawrence Jacobs, MD • Sue Jasulaitis, RN, MS William Kearns, PhD • William Keye, MD • Monica Kuuspalu • Ruth Lathi, MD • Carol Lawrence • Juergen Lieberman, PhD • Craig Niederberger, MD Kutluk Oktay, MD • Ann Scalia, RN, BSN • William Schoolcraft, MD • Peter Schlegel, MD • Christopher Scott • Richard Scott, MD • Al Yuzpe, MD

LOWER REGISTRATION FEES until May 5th: $380 (After May 5th: $440)

FOR MORE INFORMATION about the program, accreditation, and TO REGISTER: Go to www.mwrs.org (or call 888-MBM-MTGS, ext.24).

april 2010 I Vol 2, no 2

The Infertility Nurse

Romance on the Rocks? Helping Couples Maintain Intimacy Marie A. Davidson, PhD Staff Psychologist, Fertility Centers of Illinois, Chicago

ouples experiencing infertility and going through treatment cycles frequently report having sex less often, along with an overall drop in physical and emotional intimacy. Women are most likely to experience a decrease in sexual desire. Men are most likely to resent being called on to perform sexually according to (and sometimes only to) their partner’s ovulation time. Rather than the joy of sex, couples end up with the “job of sex,” or sex only in service of procreation. There is nothing fun or spontaneous about being told by a nurse “when to have intercourse” (which does not sound very loving), or when not to

have it. As one patient told me, “This fertility treatment has sucked every bit of romance out of our marriage.” Sexually intimate partners need the physical part of their relationship to be in some kind of balance to feel united as they go through the fertility journey together. This balance is often hard to achieve. The painful feelings that a fertility obstacle brings up may make honest communication very difficult. Consider the scenario of Ann and Peter. Ann had severe endometriosis, which was probably impeding conception and was pointing the couple toward an IVF treatment that they could barely afford. Peter had no obvious fertility problem. Ann felt shame and guilt, and wondered if Peter should just leave her and find a fertile partner. Peter was disappointed about the fertility issue, but he was more worried about Ann, who was pulling away from him, declining his sexual advances, and behaving as if she did not want him around. Several counseling sessions made all the difference. Peter, understanding the reason for Ann’s frostiness, was able to reassure her that he valued their marriage first and making a family was something they had to face as a couple. Ann, knowing that Peter was

not “blaming” her, was able to let go of much guilt and return to enjoying physical and emotional closeness with her husband. When discussing sex and intimacy with couples, it helps to put the issue into the context of what really happens during a time of infertility struggles. The reality is that almost every couple has problems in this area. Infertility interrupts their usual pattern of lovemaking, just as the appointments at the

“This fertility treatment has sucked every bit of romance out of our marriage.” —Infertility patient fertility clinic disrupt their daily work routine. This is probably not the time to have high expectations for a great sex life. We hope that this will be practice for when their sex lives will take another dip, after their long-awaited baby is born. It helps patients to know that this time of less-satisfying sex is normal and is temporary. Couples should be encouraged to nurture each other and their “coupleness.” I often tell patients, “If there was ever a time to be really considerate and appreciative of each other, this is it.” One of my physician colleagues sometimes hands over a prescription on which he has written, “Go out to dinner and don’t talk about the infertility.

Just enjoy each other.” One of my nurse colleagues told me that she tells couples to “never stop dating.” People can always find ways to be loving and supportive during infertility treatment, and to communicate better about what they need. Women can teach their partners that a hug, cuddling under a blanket watching television, and a gentle stroke on their face is also intimacy and makes them feel good. Husbands can tell their wives that they feel sad and deprived when they are denied physical affection and sex. Here is a radical idea: tell couples to plan to have sex on a day when it would be impossible to get pregnant. There is something sexy about that. One couple described their personalized “intimacy escape.” They created a refuge in their bedroom. For winter, they installed a faux fireplace and had drinks and appetizers by the fire once a week. In summer, they had a weekly picnic, spreading a blanket and eating from a basket of goodies from the deli. It was fun, very inexpensive, and a small celebration of their relationship. Infertility nurses hear everything from patients, often deeply personal things. Just having someone listen to them can be therapeutic for patients. Sometimes, recommending professional counseling is the best advice to give a couple. Every fertility clinic should have a list of counselors to whom they can refer patients when that is needed. The goal is to help patients become parents without losing each other in the process. ■

Frozen Embryo Transfer Shows Better Perinatal Outcomes than Fresh Embryo Transfer By Wayne Kuznar

erinatal outcomes may be better after frozen embryo transfer (FET) compared with fresh embryo transfer, a new study by Finnish researchers suggests. The use of frozen embryos was associated with lower likelihoods of premature birth, babies with low birth weight, and small size for gestational age, they reported (Hum Reprod. 2010;25:914-923. Epub 2010 Feb 2). “Our study, which is one of the largest on FET pregnancies, provides further evidence on the safety of FET,” according to lead investigator Sari Pelkonen, MD, Department of Obstetrics and Gynecology, Oulu University Hospital, Finland. The use of frozen embryos has gained popularity, especially in Europe,

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where singleton transfers are encouraged to prevent multiple pregnancies, Dr Pelkonen stated. Investigators compared obstetric and perinatal outcomes of 2293 children born after FET, 4151 born after fresh embryo transfer, and 31,946 that did not require IVF (spontaneous conception, the reference group). One of 11 babies born after fresh embryo transfer was premature compared with approximately 1 of 16 born after FET. After adjustment for maternal age, parity, socioeconomic status, and the number of fetuses, the FET group had a 17% lower risk of prematurity compared with the fresh embryo transfer group. Frozen embryos were also 26% less likely to be associated with low birth

weight and 37% less likely to be small for gestational age compared with the fresh embryo transfer group. Mean birth weight was 134 g greater in FET singletons compared with fresh embryo transfer singletons.

The FET group had a 17% lower risk of prematurity compared with the fresh embryo transfer group. However, when FET was compared with spontaneous pregnancy, FET was associated with a 45% increased risk of preterm birth and a 22% increased risk

of low birth weight, but a 29% lower risk of small size for gestational age. The investigators concluded that, “This information should further promote clinicians to implement elective single embryo transfer combined with cryopreservation in their IVF programs.” This finding comes on the heels of a recent study conducted at the New York University Fertility Center, which showed that few women use stored embryos to achieve a second pregnancy after a successful fresh embryo transfer (Fertil Steril. 2010 Jan 5. Epub ahead of print). This was especially true of women who gave birth to multiples after their first try. Among that group, 74 of 81 patients did not return to use their cryopreserved embryos. ■

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The Urology Nurse

More Evidence for Semen Damage from Cell Phones But Jury Still Out, as Experts Question Study Methods By Rosemary Frei, MSc

revious studies have suggested potential risk for semen health from the frequent close proximity of cell phones to the testes, but experts continue to debate the evidence and the current conclusions. Results of a new study recently published in Fertility and Sterility (2009; 92:1318-1325) add to this debate further, suggesting that radiation from cell phones can indeed damage human sperm. The study examined the motility and viability, as well as the oxidative stress, of sperm in freshly ejaculated semen samples exposed to radiation from a cell phone. Researchers at the Cleveland Clinic obtained semen samples from 23 healthy men and 9 men who presented at the center’s infertility clinic. The researchers placed the samples 2.5 cm from the antenna of a cell phone that was in talk mode. They chose this distance to mimic the gap between a cell phone in a man’s pants pocket and his testes.

“We can speculate that carrying a cell phone in a pocket may cause deterioration of sperm quality through oxidative stress.”

with conditions closer to real life are needed to verify these findings. Sergey Moskovtsev, MD, PhD, Andrology Director at the CReATe Fertility Centre, Toronto, Ontario, pointed out other significant weaknesses in the study, noting that the researchers overlooked an important potential confounding factor by not measuring leukocyte concentrations in the semen samples.

“Prolonged incubation of spermatozoa with leukocytes would increase the production of radical oxygen species, which are directly linked to oxidative stress, and which would secondarily affect motility and viability,” Dr Moskovtsev told The OB/GYN and Infertility Nurse. He agreed with the researchers that the 2.5-cm distance does not mimic

real-life conditions, because “it does not often happen that a cell phone would be placed on or so near the testes while in the talk mode; I think 20 cm would be more realistic.” Dr Moskovtsev added that the testes are not the area from which sperm are ejaculated. More studies are needed to resolve the debate over whether cell phones are harmful to sperm. ■

CONTINUING EDUCATION CREDITS Current activities at www.COEXM.com include:

—Ashok Agarwal, PhD

The cell phone emitted between 850 watts and 900 watts of radiation, and the samples were exposed to this for 1 hour, at room temperature. The viability and motility of healthy men’s semen decreased significantly after this exposure. Scores on a measure of oxidative stress also decreased significantly for all the semen samples when grouped together. However, the reduction in oxidative stress was not significant for either the healthy men’s semen or the patients’ semen when analyzed separately. The team, led by Ashok Agarwal, PhD, Director of the Center for Reproductive Medicine and Assisted Reproductive Technology Training, and Professor, Cleveland Clinic Lerner College of Medicine, concluded that “we can speculate that carrying a cell phone in a pocket may cause deterioration of sperm quality through oxidative stress.” They admitted that layers of tissue could affect this, and further studies

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Nutrition

Vitamin D Deficiency a Contributor to Depression, Insulin Resistance By Wayne Kuznar

ccumulating evidence shows that vitamin D levels are related to mood and mental disorders, which points to the possibility of vitamin D supplementation to improve mood in persons who have an insufficiency or deficiency of vitamin D, according to Sue Penckofer, PhD, RN, Professor at Loyola University Chicago Marcella Niehoff School of Nursing. Persons who live in northern climates with little sunshine in the winter may be especially vulnerable to vitamin D insufficiency, defined as <30 ng/mL, or vitamin D deficiency, defined as <20-hydroxy ng/mL. Vitamin D deficiency is more common in women than in men, according to data from the National Health and Nutrition Examination Survey, and in those with chronic diseases. An adequate level of vitamin D is considered to be 30 to 60 ng/mL of 25-hydroxy (OH) vitamin D.

“In 2 studies, vitamin D supplements for 1 week to 1 month resulted in a significant increase in [depressed] mood afterward.” —Sue Penckofer, PhD, RN

The evidence linking low vitamin D levels with an increased risk of cardiac events and diabetes complications is more robust than the data regarding mood or psychiatric disorders, said Dr Penckofer. For example, low vitamin D levels correlate with increasing blood pressure (BP) and cardiovascular events. Vitamin D treatment in the form of ultraviolet B exposure or vitamin D supplementation has resulted in BP reductions in patients with mild hypertension and low vitamin D at baseline. Patients with vitamin D insufficiency or deficiency are at risk for diabetes. “If vitamin D deficient, persons are more prone to insulin resistance,” predisposing them to diabetes, said Dr Penckofer. Groups at risk for vitamin D deficiency also have been reported to be at risk for depression, she noted. Depression is also associated with increased insulin resistance, adding to the risk for developing diabetes. Further, observational studies point to higher rates of seasonal affective disorder, alcohol problems, and schizophrenia in vitamin D–deficient persons. Preliminary evidence shows that supplementation with vitamin D2 can lift mood. “In 2 studies, vitamin D supple-

april 2010 I Vol 2, no 2

ments for 1 week to 1 month resulted in a significant increase in [depressed] mood afterward,” she said. Diet alone is probably inadequate to provide sufficient vitamin D in those with an insufficiency or deficiency, said Dr Penckofer. Daily doses to correct vitamin D deficiency are 1000 IU of vitamin D3 or 3000 IU of vitamin D2, along with sun exposure. Dr Penckofer and colleagues are evaluating whether weekly vitamin D supplements improve blood glucose control and mood in women with dia-

betes. Evidence suggests that vitamin D supplementation may decrease insulin resistance, thereby offering the potential to improve blood glucose control and reduce symptoms of depression. The study is enrolling 80 women with stable type 2 diabetes, signs of depression, and vitamin D levels <30 ng/mL. They will be given a weekly dose of 50,000 IU of vitamin D for 6 months. A recent cross-sectional study supports that vitamin D deficiency among young women is widespread (J Clin

Endocrinol Metab. 2010 Feb 17. Epub ahead of print). Findings showed that 59% of young, apparently healthy women had low vitamin D levels, and almost 25% had a serious deficiency (<20 ng/mL). Investigators studied 90 women from southern California, aged 16 to 22 years. In addition to finding a high rate of vitamin D insufficiency, abnormally low levels of vitamin D were linked to excess accumulation of fat in muscle tissue, a contributor to poor muscle strength and poor overall health. ■

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Clinical News Pregnancy after Breast Cancer...Continued from page 3

between the use of multivitamins in this cohort and the risk for a variety of cancers or for CVD. However, the investigators contended that despite a lack of evidence for risk reduction with multivitamins in postmenopausal, “nutritional efforts should remain a principal focus of chronic disease prevention.”

counterparts who do not become pregnant (Azim HA, et al. Eur J Cancer. 2010;8:207). Several studies have suggested a potential protective effect of breast cancer in women who become pregnant, showing lower rates of breast cancer recurrence and mortality compared with those delaying or avoiding pregnancy. This new meta-analysis included 14 studies trials published between 1970 and 2009; combined these studies included 19,476 women with a history of breast cancer, 1417 pregnancies, and 18,059 nonpregnant controls. Women who became pregnant after a breast cancer diagnosis had significantly better survival rate compared with women who did not become pregnant. Pregnancy appears to be correlated with a protective effect among breast cancer survivors, which may be explained by immunologic and endocrine mechanisms, the investigators sugggest.

Prostatitis, STDs Increase Risk for Prostate Cancer Men with a history of prostatitis or

sexually transmitted diseases (STDs) are at an increased risk for prostate cancer, according to results of the California Men’s Health Study (Cheng I, et al. PLoS One. 2010;5:e8736). For this large study, researchers analyzed data of 68,675 men from various ethnic origins; 1658 prostate cancer cases were found during the 4-year followup. A history of prostatitis was associated with a 1.3-fold increased risk of prostate cancer. A long duration of

CRINONE® 4% CRINONE® 8% (progesterone gel)

See package insert for full prescribing information.

kledge@Copyright iStockphotos.com/drbouz

Multivitamins Not Protective against Cancer, CVD in Postmenopausal Women

Despite the prevalence of multivitamin use by postmenopausal women, taking multivitamins has been shown to have no protective properties against various cancers, cardiovascular disease (CVD), or total mortality (Neuhouser ML, et al. Arch Intern Med. 2009;169: 294-304). In this recent analysis of data from the Women’s Health Initiative clinical studies totalling 161,808 women between 1993 and 1998, investigators analyzed data on the use of multivitamins and various types of cancers, CVD, and total mortality. Of the enrolled women, 41.5% used multivitamins. At the end of a median 8-year follow-up, there were 9619 cases of breast, colorectal, endometrial, renal, bladder, stomach, lung, or ovarian cancer; 8751 CVD events; and 9865 deaths. Analysis of the data showed no association

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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 hormoneassociated 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 Crinone-treated 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, open-label 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 more 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%).

symptomatic prostatitis also increased the risk for prostate cancer. Although there was no overall relationship between an STD history and the risk for prostate cancer, Latinos—especially those born outside of the United States—had a greater risk for prostate cancer if they had STDs. The investigators suggest that chronic inflammation and infections with prostatitis and STDs may be linked to prostate cancer susceptibility. ■

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 reported 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. This brief summary is based on the current Crinone package insert (Version 40405010007, Revised December 2006). How Supplied Crinone is available in the following strengths: 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-55056-0806-2 - 6 Single-use prefilled applicators. NDC-55056-0818-2 - 18 Single-use prefilled applicators. Each applicator is wrapped and sealed in a foil overwrap. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Rx only. U.S. Patent Number 5,543,150. Manufactured for: Columbia Laboratories, Inc. Livingston, NJ 07039 Manufactured by: Fleet Laboratories Ltd., Watford, United Kingdom © 2007, Columbia Laboratories, Inc. Printed in USA 6/07

References: 1. Doody KJ, Schnell VL, Foulk RA, et al. Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation. Fertil Steril. 2009;91:1012–1017. 2. Berger BM, Ezcurra D, Phillips JA, Zubovskiy KY. Efficacy of three different progesterones for luteal phase and early pregnancy support in older women with high implantation potential embryos undergoing IVF-ET. Fertil Steril. 2009;92(suppl). Abstract O-76. 3. Endometrin® prescribing information. Parsippany, NJ: Ferring Pharmaceuticals Inc; 2008.

Columbia Laboratories, Inc. Livingston, NJ 07039

april 2010 I Vol 2, no 2

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