Gillian R. Graves

Pregnancy Outcomes After Assisted Reproductive Technology

OBJECTIVEnTo review the effect of assisted reproductive technology (ART) on perinatal outcomes, to provide guidelines to optimize obstetrical management and counselling of Canadian women using ART, and to identify areas specific to birth outcomes and ART requiring further research.nnnOPTIONSnPerinatal outcomes of ART pregnancies in subfertile women are compared with those of spontaneously conceived pregnancies. Perinatal outcomes are compared between different types of ART.nnnOUTCOMESnThis guideline discusses the adverse outcomes that have been recorded in association with ART, including obstetrical complications, adverse perinatal outcomes, multiple gestations, structural congenital abnormalities, chromosomal abnormalities, imprinting disorders, and childhood cancer.nnnEVIDENCEnThe Cochrane Library and MEDLINE were searched for English-language articles from 1990 to February 2005, relating to assisted reproduction and perinatal outcomes. Search terms included assisted reproduction, assisted reproductive technology, ovulation induction, intracytoplasmic sperm injection (ICSI), embryo transfer, and in vitro fertilization (IVF). Additional publications were identified from the bibliographies of these articles as well as the Science Citation Index. Studies assessing gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) were excluded since they are rarely used in Canada. All study types were reviewed. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Key studies and supporting data for each recommendation are summarized with evaluative comments and referenced.nnnVALUESnThe evidence collected was reviewed by the Genetics Committee and the Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Examination.nnnBENEFITS, HARMS, AND COSTSnThe type and magnitude of benefits, harms, and costs expected for patients from guideline implementation. This guideline has been reviewed by the Genetics Committee and the Reproductive Endocrinology and Infertility Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society.nnnRECOMMENDATIONSn1. Spontaneous pregnancies in untreated infertile women may be at higher risk for obstetrical complications and perinatal mortality than spontaneous pregnancies in fertile women. Further research is required to clarify the contribution of infertility itself to adverse obstetrical and perinatal outcomes. (II-2A) 2. All men with severe oligozoospermia or azoospermia should be offered genetic/clinical counselling for informed consent and offered karyotyping for chromosomal abnormalities before attempting IVF-ICSI. They should be made aware of the availability of tests for Y chromosome microdeletion. Some patients may consider the option of donor insemination. (II-3B) 3. Couples exploring IVF-ICSI when the man has obstructive azoospermia should be offered genetic/clinical counselling for informed consent and offered genetic testing for alterations in genes associated with cystic fibrosis (CF) before attempting IVF-ICSI. (II-2A) 4. Pregnancies achieved by ovarian stimulation with gonadotropins and intrauterine insemination are at higher risk for perinatal complications, and close surveillance during pregnancy should be considered. It remains unclear if these increased risks are attributable to the underlying infertility, characteristics of the infertile couple, or use of assisted reproductive techniques. Multiple gestations remain a significant risk of gonadotropin treatment. (II-2A) 5. Pregnancies achieved by IVF with or without ICSI are at higher risk for obstetrical and perinatal complications than spontaneous pregnancies, and close surveillance during pregnancy should be considered. It remains unclear if these increased risks are attributable to the underlying infertility, characteristics of the infertile couple, or use of assisted reproductive techniques. (II-2A) 6. Women undergoing ART should be informed about the increased rate of obstetrical interventions such as induced labour and elective Caesarean delivery. (II-2A) 7. Couples suffering from infertility who are exploring treatment options should be made aware of the psychosocial implications of ART. Further research into the psychosocial impact of ART is needed. (II-2A) 8. Singleton pregnancies achieved by assisted reproduction are at higher risk than spontaneous pregnancies for adverse perinatal outcomes, including perinatal mortality, preterm delivery, and low birth weight, and close surveillance during pregnancy should be available as needed. (II-2A) 9. A significant risk of ART is multiple pregnancies. Infertile couples need to be informed of the increased risks of multifetal pregnancies. Although dichorionic twins are most common, the incidence of monochorionic twins is also increased. Risks of multiple pregnancies include higher rates of perinatal mortality, preterm birth, low birth weight, gestational hypertension, placental abruption, and placenta previa. Perinatal mortality in assisted conception twin pregnancies appears to be lower than in spontaneously conceived twin pregnancies. (II-2A) 10. When multifetal reduction is being considered for high-order multiple pregnancies, psychosocial counselling should be readily available. Careful surveillance for fetal growth problems should be undertaken after multifetal reduction. (II-2A) 11. To reduce the risks of multiple pregnancies associated with ART and to optimize pregnancy rates, national guidelines should be developed on the number of embryos replaced according to characteristics such as patients age and grade of embryos. (II-2A) 12. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks to childhood and long-term growth and development associated with ART. (II-2A) 13. Discussion of options for prenatal screening for congenital structural abnormalities in pregnancies achieved by ART is recommended, including appropriate use of biochemical and sonographic screening. (II-2A) 14. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks of congenital abnormalities associated with ART. (II-2A) 15. Couples considering IVF-ICSI for male-factor infertility should receive information, and if necessary formal genetic counselling, about the increased risk of de novo chromosomal abnormalities (mainly sex chromosomal anomalies) associated with their condition. Prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis should be offered to these couples if they conceive. (II-2A) 16. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks of chromosomal abnormalities associated with ART. (II-2A) 17. Discussion of options for prenatal screening and testing for aneuploidy in pregnancies achieved by ART, adapted for maternal age and number of fetuses, is recommended, including appropriate use of biochemical and sonographic screening. (II-2A) 18. The precise risks of imprinting and childhood cancer from ART remain unclear but cannot be ignored. Further clinical research, including long-term follow-up, is urgently required to evaluate the prevalence of imprinting disorders and cancers associated with ART. (II-2A) 19. The clinical application of preimplantation genetic diagnosis must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. Further ethical discussion and clinical research is required to evaluate appropriate indications for preimplantation genetic diagnosis. (III-B).

Guidelines for the Number of Embryos toTransfer Following In Vitro Fertilization

OBJECTIVEnTo review the effect of the number of embryos transferred on the outcome of in vitro fertilization (IVF), to provide guidelines on the number of embryos to transfer in IVF-embryo transfer (ET) in order to optimize healthy live births and minimize multiple pregnancies.nnnOPTIONSnRates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared.nnnOUTCOMESnClinical pregnancy, multiple pregnancy, and live birth rates.nnnEVIDENCEnThe Cochrane Library and MEDLINE were searched for English language articles from 1990 to April 2006. Search terms included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), ntracytoplasmic sperm injection (ICSI), multiple pregnancy, and multiple gestation. Additional references were identified through hand searches of bibliographies of identified articles.nnnVALUESnAvailable evidence was reviewed by the Reproductive Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Exam.nnnBENEFITS, HARMS, AND COSTSnThis guideline is intended to minimize the occurrence of multifetal gestation, particularly high-order multiples (HOM), while maintaining acceptable overall pregnancy and live birth rates following IVF-ET.

Canadian Consensus Conference on Menopause, 2006 Update

OBJECTIVEnTo provide guidelines for health care providers on the management of menopause in asymptomatic healthy women as well as in women presenting with vasomotor symptoms, urogenital, sexual, and mood and memory concerns and on specific medical considerations, and cardiovascular and cancer issues.nnnOUTCOMESnPrescription medications, complementary and alternative medicine (CAM), and lifestyle interventions are presented according to their efficacy in treating menopausal symptoms.nnnEVIDENCEnMEDLINE and the Cochrane database were searched for articles from March 2001 to April 2005 in English on subjects related to menopause, menopausal symptoms, urogenital and sexual health, mood and memory, hormone therapy, CAM, and on specific medical considerations that affect the decision of which intervention to choose.nnnVALUESnThe quality of evidence is rated using the criteria described in the report of the Canadian Task Force on the Periodic Health Examination. Recommendations for practice are ranked according to the method described in this report (see Table 1).nnnSPONSORSnThe development of this consensus guideline was supported by unrestricted educational grants from Berlex Canada Inc, Lilly Canada, Merck Frosst, Novartis, Novogen, Novo Nordisk, Proctor and Gamble, Schering Canada, and Wyeth Canada.

In vitro fertilization: diurnal and seasonal variation in luteinizing hormone surge onset and pregnancy rates *

The authors studied 740 consecutive in vitro fertilization (IVF) cycles over a 3-year period to compare the results of cycles in which an endogenous luteinizing hormone (LH) surge occurred with cycles in which human chorionic gonadotropin (hCG) was administered for induction of follicular maturation. Clomiphene citrate (100 to 150 mg daily on cycle days 5 to 9) and human menopausal gonadotropin (hMG; 75 to 150 IU daily from cycle day 6) were used for stimulation. Embryo transfer (ET) occurred in 164 (81.2%) of the LH surge cycles and 452 (84%; P = not significant [NS] of the hCG cycles. The first urinary rise in LH was detected in the 6 or 9 A.M. collections in 78 (47.3%) of the LH surge cycles, a greater number (P less than 0.01) than expected if LH surge onset was random. A total of 107 pregnancies was achieved, for an overall pregnancy rate of 17.4% per ET. The pregnancy rate in the hCG-stimulated cycles was 13.9% per ET (63/452) and, in spontaneous LH surge cycles, was 28.8% (44/166; P less than 0.001). The spontaneous abortion rate was 9.1% in LH surge cycles, compared with 25.4% in hCG-triggered cycles (P less than 0.001). The result was a 2.4 times increase in live births for LH surge cycles compared with cycles in which hCG was administered. In this program, occurrence of an LH surge is a favorable event, associated with higher pregnancy and live birth rates than hCG-stimulated cycles, and usually occurring in the early morning, allowing oocyte retrieval during normal working hours.

Objective measurement of hot flushes associated with the premenstrual syndrome

Because the majority of women with PMS complain of sweats and chills resembling menopausal flushes, we attempted to document the physiologic changes during these episodes. A 26-year-old nulliparous woman with PMS described the occurrence of hot flush-like episodes coincident with PMS symptoms. The patient completed prospective self-rating scales for two consecutive cycles to establish the pattern and severity of PMS. On day 26 of the first cycle when PMS symptom scores were elevated, continuous monitoring of skin resistance and finger temperature and frequent blood sampling for LH were performed for 8 hours. The patient experienced five flush episodes, each of which was associated with a drop in skin resistance of up to 4000 ohms and was coincident with an LH pulse. Three of the flushes were associated with a rise in finger temperature of up to 10 degrees C. These physiologic changes are identical to those seen during menopausal flushes and suggest that PMS may be associated with neuroendocrine events typical of E withdrawal.

Directive clinique en ce qui concerne le nombred’embryons à transférer à la suite de la fécondation in vitro

Resume Objectifs Examiner leffet du nombre dembryons transferes surlissue de la fecondation in vitro (FIV). Fournir des lignesdirectrices quant au nombre dembryons a transferer dans le cadrede la « fecondation in vitro et transfert dembryon » (FIVETE), afindoptimiser le nombre de naissances vivantes dun foetus en santeet de minimiser le nombre de grossesses multiples. Options Les taux de naissance vivante, de grossesse clinique et degrossesse ou de naissance multiple par nombre dembryonstransferes sont compares. Issues Taux de grossesse clinique, de grossesse multiple et denaissance vivante. Resultats Des recherches ont ete menees dans la Cochrane Library et MEDLINE afin den tirer les articles de langue anglaise, publiesentre 1990 et avril 2006, comportant les mots cles suivants : embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), multiple pregnancyet multiple gestation . Des references supplementaires ont eteidentifiees au moyen de recherches manuelles menees dans lesbibliographies des articles issus des recherches susmentionnees. Valeurs Les resultats disponibles ont ete analyses par le comitedendocrinologie de la reproduction et infertilite et le comite demedecine fœto-maternelle de la Societe des obstetriciens etgynecologues du Canada, ainsi que par le Conseil de la Societecanadienne de fertilite et dandrologie, et leur qualite a ete evalueeen fonction des lignes directrices sur levaluation des resultatselaborees par le Groupe detude canadien sur lexamen medicalperiodique. Avantages, desavantages et couts La presente directive clinique apour but de minimiser la frequence de la gestation multifoetale,particulierement celle des gestations multiples de rang eleve(MRE), tout en assurant le maintien de taux globaux acceptablesde grossesse et de naissance vivante a la suite de la FIVETE. Recommendations Les recommandations formulees dans la presente directiveclinique sont principalement inspirees detudes portant sur desembryons qui en etaient au stade de la segmentation (embryonsmis en culture pendant deux ou trois jours). 1.Chacun des programmes de FIVETE devrait evaluer ses propresdonnees afin didentifier les determinants de limplantation et de lanaissance vivante propres a la patiente, a lembryon et au cycle, etce, en vue delaborer des politiques de transfert dembryonspermettant de minimiser la frequence de la gestation multifoetale,tout en assurant le maintien de taux globaux acceptables degrossesse clinique et de naissance vivante. (III-B) 2.En general, il faudrait envisager davoir recours au transfert demoins dembryons en etant au stade du blastocyste quedembryons en etant au stade de la segmentation, et ce,particulierement chez les femmes qui presentent un excellentpronostic et des blastocystes de grande qualite. (I-A) 3.Chez les femmes de moins de 35 ans, pas plus de deux embryonsdevraient etre transferes dans le cadre dun cycle frais deFIVETE. (II-2A) 4.Chez les femmes de moins de 35 ans qui presentent un excellentpronostic, le transfert dun seul embryon devrait etre envisage. Par« femmes qui presentent un excellent pronostic », on entend lesfemmes qui se soumettent a leur premier ou deuxieme cycle deFIVETE, ou qui sy soumettent immediatement a la suite dun cyclede FIVETE reussi, et qui presentent au moins deux embryons degrande qualite disponibles aux fins du transfert. (I-A) 5.Chez les femmes dont lâge se situe entre 35 et 37 ans, pas plusde trois embryons devraient etre transferes dans le cadre duncycle frais de FIVETE. Chez celles qui disposent dembryons degrande qualite et qui presentent un pronostic favorable, le transfertdun ou de deux embryons au cours du premier ou du secondcycle devrait etre envisage. (II-2A) 6.Chez les femmes de 38 et de 39 ans, pas plus de trois embryonsdevraient etre transferes dans le cadre dun cycle frais de FIVETE.(III-B) Chez celles qui disposent dembryons de grande qualite etqui presentent un pronostic favorable, le transfert de deuxembryons au cours du premier ou du second cycle devrait etreenvisage. (III-B) 7.Chez les femmes de plus de 39 ans, pas plus de quatre embryonsdevraient etre transferes dans le cadre dun cycle frais de FIVETE.(III-B) Chez celles qui disposent dun plus grand nombredembryons de grande qualite que ce qui savere necessaire pourle transfert, le transfert de trois embryons au cours du premiercycle de FIVETE devrait etre envisage. (III-B) 8.Dans les cas exceptionnels ou des femmes qui presentent unmauvais pronostic ont connu de multiples echecs dans le cadre decycles frais de FIVETE, le transfert dun plus grand nombredembryons que ce qui est recommande ci-dessus peut etreenvisage dans le cadre de cycles frais de FIVETEsubsequents. (III-C) 9.Dans le cadre des cycles donneur–receveur, lâge du donneurdovocyte/embryon devrait etre utilise pour determiner le nombredembryons a transferer. (II-2B) 10.Chez les femmes qui presentent des contre-indicationsobstetricales ou medicales a la gestation multifoetale, un nombremoindre dembryons devraient etre transferes afin de minimiser lesrisques de gestation multifoetale. Dans de tels cas, uneconsultation pretraitement aupres dun specialiste en medecinefœto-maternelle devrait etre mise en oeuvre. (III-C) Lorsque celasavere raisonnable, le transfert dun seul embryon devrait etreenvisage. (II-3B) 11.Les couples devraient beneficier de services de counselingadequats en ce qui a trait aux risques obstetricaux, perinatals etneonatals associes a la gestation multifoetale, et ce, afin de faciliterla prise dune decision eclairee en ce qui concerne le nombredembryons a transferer. (II-3B) La mise dun accent particulier surla naissance vivante dun foetus unique en sante a titre de criterede reussite de la FIVETE savererait benefique, pour ce qui est dela promotion de la baisse du nombre dembryons transferes. (III-C) 12.Une strategie visant le financement public de la FIVETE doit etreelaboree, afin dassurer la mise en oeuvre efficace de lignesdirectrices limitant le nombre dembryons transferes. Dans lecontexte dune telle strategie, les couts de sante totauxconnaitraient une baisse attribuable a la diminution de lincidencedes grossesses et des naissances multifoetales. (III-C) 13.Des efforts devraient etre deployes pour limiter les grossessesmultiples iatrogeniques attribuables a la stimulation ovariennenetant pas associee a la FIVETE, et ce, par lintermediaire delelaboration de lignes directrices convenables visant lannulationde cycle et lelimination des obstacles financiers a laFIVETE. (III-B) Declaration sommaire Les recommandations suivantes visent generalement le transfert,au cours de la deuxieme ou de la troisieme journee, dembryonsen etant au stade de la segmentation. Puisque les embryons enetant au stade du blastocyste presentent des taux dimplantationplus eleves que ceux que presentent les embryons en etant austade de la segmentation, il est possible que lon ait a transferer unnombre moindre dembryons en etant au stade du blastocyste. (II) Validation La presente directive clinique a ete examinee par lecomite dendocrinologie de la reproduction et infertilite et le comitede medecine fœto-maternelle, et a ete approuvee par le comiteexecutif et le Conseil de la Societe des obstetriciens etgynecologues du Canada, ainsi que par le Conseil de la Societecanadienne de fertilite et dandrologie. Commanditaire Societe des obstetriciens et gynecologues duCanada.La qualite des resultats du present document a ete determinee alaide des criteres devaluation decrits dans le rapport du Groupede travail canadien sur lexamen de sante periodique (Tableau 1).