Kimberly E. Liu

Advanced Reproductive Age and Fertility

OBJECTIVE To improve awareness of the natural age-related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management, and to review investigations in the assessment of ovarian aging. OPTIONS This guideline reviews options for the assessment of ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility. OUTCOMES The outcomes measured are the predictive value of ovarian reserve testing and pregnancy rates with natural and assisted fertility. EVIDENCE Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated into the guideline to December 2010. VALUES The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). BENEFITS, HARMS, AND COSTS Primary and specialist health care providers and women will be better informed about ovarian aging and the age-related decline in natural fertility and about options for assisted reproductive technology. RECOMMENDATIONS 1. Women in their 20s and 30s should be counselled about the age-related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s. (II-2A) 2. Because of the decline in fertility and the increased time to conception that occurs after the age of 35, women > 35 years of age should be referred for infertility work-up after 6 months of trying to conceive. (III-B) 3. Ovarian reserve testing may be considered for women ≥ 35 years of age or for women < 35 years of age with risk factors for decreased ovarian reserve, such as a single ovary, previous ovarian surgery, poor response to follicle-stimulating hormone, previous exposure to chemotherapy or radiation, or unexplained infertility. (III-B) 4. Ovarian reserve testing prior to assisted reproductive technology treatment may be used for counselling but has a poor predictive value for non-pregnancy and should be used to exclude women from treatment only if levels are significantly abnormal. (II-2A) 5. Pregnancy rates for controlled ovarian hyperstimulation are low for women > 40 years of age. Women > 40 years should consider IVF if they do not conceive within 1 to 2 cycles of controlled ovarian hyperstimulation. (II-2B) 6. The only effective treatment for ovarian aging is oocyte donation. A woman with decreased ovarian reserve should be offered oocyte donation as an option, as pregnancy rates associated with this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a womans own eggs. (II-2B) 7. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. Women should be counselled about and offered appropriate prenatal screening once pregnancy is established. (II-2A) 8. Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women > age 40. (III-B) 9. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum disorders, and schizophrenia. Men > age 40 and their partners should be counselled about these potential risks when they are seeking pregnancy, although the risks remain small. (II-2C).

Addressing Oncofertility Needs: Views of Female Cancer Patients in Fertility Preservation

A total of 41 questionnaires were returned from 64 respondents who consented to receive a questionnaire through the mail. Almost all valued the opportunity to receive consultation to address their fertility concerns and discuss fertility preservation options. Psychological stress, time pressure, and costs were identified as main factors affecting respondents’ decision to proceed with in-vitro fertilization to cryopreserve oocytes or embryos. About one third indicated that the discussion of fertility matters was initiated by themselves, their friends, and families rather than their health care providers. The findings have identified several major barriers encountered by female cancer patients when seeking fertility preservation services.

The Management of Uterine Fibroids in Women With Otherwise Unexplained Infertility

OBJECTIVE To provide recommendations regarding the best management of fibroids in couples who present with infertility. Usual and novel treatment options for fibroids will be reviewed with emphasis on their applicability in women who wish to conceive. OPTIONS Management of fibroids in women wishing to conceive first involves documentation of the presence of the fibroid and determination of likelihood of the fibroid impacting on the ability to conceive. Treatment of fibroids in this instance is primarily surgical, but must be weighed against the evidence of surgical management improving clinical outcomes, and risks specific to surgical management and approach. OUTCOMES The outcomes of primary concern are the improvement in pregnancy rates and outcomes with management of fibroids in women with infertility. EVIDENCE Published literature was retrieved through searches of PubMed, MEDLINE, the Cochrane Library in November 2013 using appropriate controlled vocabulary (e.g., leiomyoma, infertility, uterine artery embolization, fertilization in vitro) and key words (e.g., fibroid, myomectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2013. Grey (unpublished literature) was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The quality of evidence in this document was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS These recommendations are expected to allow adequate management of women with fibroids and infertility, maximizing their chances of pregnancy by minimizing risks introduced by unnecessary myomectomies. Reducing complications and eliminating unnecessary interventions are also expected to decrease costs to the health care system. Summary Statements 1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3) 2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of the target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as a stand-alone treatment for fibroids in the infertile population. (III) 3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III) 4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3) 5. In the infertile population, cumulative pregnancy rates by the laparoscopic and the minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2) 6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendations 1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A) 2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III-B) 3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B) 4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D)  5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2A) 6. Removal of subserosal fibroids is not recommended. (III-D) 7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C) 8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A) 9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A) 10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E).

Advanced reproductive age and fertility: no. 269, November 2011.

To improve awareness of the natural age‐related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management, and to review investigations in the assessment of ovarian aging.

The Prevention of Ovarian Hyperstimulation Syndrome

OBJECTIVE To review the clinical aspects of ovarian hyperstimulation syndrome and provide recommendations on its prevention. OPTIONS Preventative measures, early recognition, and prompt systematic supportive care will help avoid poor outcomes. OUTCOMES Establish guidelines to assist in the prevention of ovarian hyperstimulation syndrome, early recognition of the condition when it occurs, and provision of appropriate supportive measures in the correct setting. EVIDENCE Published literature was retrieved through searches of Medline, Embase, and the Cochrane Library from 2011 to 2013 using appropriate controlled vocabulary ([OHSS] ovarian hyperstimulation syndrome and: agonist IVF, antagonist IVF, metformin, HCG, gonadotropin, coasting, freeze all, agonist trigger, progesterone) and key words (ovarian hyperstimulation syndrome, ovarian stimulation, gonadotropin, human chorionic gonadotropin, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to February 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I) 2. Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III) 3. Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2) 4. The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I) 5. There is no clear published evidence that lowering the human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III) 6. Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2) 7. Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2) 8. Pregnancy rates are not affected when using gonadotropin-releasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) Recommendations 1. The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A) 2. Gonadotropin dosing should be carefully individualized, taking into account the patients age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B) 3. Cycle cancellation before administration of human chorionic gonadatropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C) 4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B) 5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C) 6. Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E) 7. Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C) 8. Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase support. (I-A) 9. Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B).

Oocyte Cryopreservation in Canada: A Survey of Canadian ART Clinics

OBJECTIVE To determine the status of oocyte cryopreservation in Canadian assisted reproductive technology (ART) clinics. METHODS An online survey was sent to the medical directors of all Canadian ART clinics between December 2010 and February 2011. The survey included questions about the availability of, the indications for, and the elements of consent for oocyte cryopreservation. Clinics were also asked whether they offered social egg freezing. RESULTS Twenty of the 28 Canadian ART clinics (71.4%) participated in this survey, and 16 (80%) of those clinics offered oocyte cryopreservation. Forty-five percent of the clinics offered elective oocyte cryopreservation (social egg freezing) for healthy women seeking to prolong fertility. Although most clinics counselled patients that oocyte cryopreservation is experimental, most clinics (87.5%) did not perform the procedure under a protocol approved by a research ethics board. The majority of clinics included most of the essential elements of informed consent during their counselling process. Most clinics that offered social egg freezing performed the procedure for women up to the age of 42, although some clinics did not offer the procedure for women under the age of 35 (28.6%) or over the age of 38 (42.9%). CONCLUSION More than one half of Canadian ART clinics are offering oocyte cryopreservation, although not all clinics offer social egg freezing for healthy women to prolong fertility. Most clinics described the technique as experimental, and the majority included most of the elements of informed consent in their counselling process.

The Effect of Age, Ethnicity, and Level of Education on Fertility Awareness and Duration of Infertility

OBJECTIVE An increasing number of Canadian women are delaying child-bearing, despite a decrease in fertility with age. A longer duration of infertility is associated with a significant decrease in live birth rate, reinforcing the need for prompt access to fertility treatment. This study aimed to assess the fertility awareness of women attending a fertility clinic to determine whether fertility awareness is a factor in accessing treatment. METHODS A quantitative cross-sectional survey evaluated fertility awareness and collected information about ethnicity, education level, and the duration of infertility for new patients. Fertility awareness was evaluated with questions about prevalence, causes, and treatment of infertility. RESULTS The mean age of participants in the study was 34 years (range 23 to 44; n = 140). The duration of infertility before new patients first sought medical advice for infertility was less than one year in 52.9%, one to two years in 28.6%, two to three years in 12.9%, and four or more years in 5.0% of study participants. Fertility awareness was calculated as the percentage of correct responses to the survey questions. The mean fertility awareness for all study participants was 49.9% and this ranged from the lowest score of 9.1% to the highest score of 90.9% correct. Women waiting for longer than two years to seek medical help had lower fertility awareness (P = 0.038). In addition, fertility awareness was greater in women who had previously sought medical help for infertility from a family doctor, a gynaecologist, or another fertility clinic (P = 0.001). Higher fertility awareness correlated with a higher level of education (linear trend P < 0.001). Finally, fertility awareness also varied with ethnicity (ANOVA P = 0.025), but the age at which women of different ethnicities sought treatment was similar (ANOVA P = 0.13). CONCLUSION Fertility awareness is associated with time to seek treatment, ethnicity, and level of education among new patients seeking medical treatment. This study demonstrates the need to educate women of reproductive age and identifies particular patient populations in Canada that would most benefit from further education about infertility.

Pelvic Examinations by Medical Students

Ensuring the quality of medical education is important to ensuring that all Canadians have access to good health care today and in the future; however, patient autonomy should be respected in all clinical and educational interactions. When a medical student is involved in patient care, patients should be told what the student’s roles will be, and patients must provide consent. Patient participation in any aspect of medical education should be voluntary and non-discriminatory. PREAMBLE

Pelvic Examinations by Medical Trainees

SUMMARY Pelvic examination is an essential skill required by all medi-cal trainees, but its sensitive nature makes it challenging tolearn.Consentfor medical traineesto be involved in direct care ofexamining the patient should be obtained in all circum-stancesinclinics,labouranddeliveryareas,andsurgery,andfor procedures using anaesthesia and analgesia.As pelvic examination under anaesthesia is a component ofmost pelvic surgeries, consent for pelvic examination bymedical trainees is contained within consent for a surgicalprocedure.Verbal consent should be obtained for pelvic examinationsby medical trainees in clinics, labour and delivery areas, andemergency roomsMedical trainees should be appropriately chaperoned at alltimes to ensure the safety of the patient and the value of thelearning opportunity. REFERENCES 1. Hicks LK, Lin Y, Robertson DW, Robinson DL, and Woodrow SI.Understanding the clinical dilemmas that shape medical students’ ethicaldevelopment: questionnaire survey and focus group study. BMJ2001;322:709–10.2. Wall LL, Brown D. Ethical issues arising from the performance of pelvicexaminations by medical students on anesthetized patients. Am J ObstetGynecol 2004;190:319–23.3. Ubel PA, Jepson C, Silber-Isenstadt A. Don’t tell, don’t ask: a change inmedical student attitudes after obstetrics/gynecology clerkships towardsseeking consent for pelvic examinations on anesthetized patients. Am JObstet Gynecol 2003;188:575–9.4. American College of Obstetricians and Gynecologists. Statement of theACOG Committee on Ethics regarding ethical implications of pelvicexamination training. Available at: http://www.acog.org/from_home/publications/press_releases/nr04–25–03.cfm. Accessed February 20, 2006.5. Lawton FG, Redman WE, Luesley DM. Patient consent for gynaecologicalexamination. Br J Hosp Med 1990;44:326–9.6. Ubel PA, Silver-Isenstadt A. Are patients willing to participate in medicaleducation? J Clin Ethics 2000;11:230–5.7. Silver-Isenstadt A, Ubel PA. Erosion in medical students’ attitudes abouttelling patients they are students. J Gen Intern Med 1999;14:481–7.8. Bibby J, Boyd N, Redman CW, Luesley DM. Consent for vaginalexamination by students on anaesthetised patients. LancetNov12;2(8620):1150.9. Wilson RF. Unauthoized practice: teaching pelvic examination on womenunder anesthesia. JAMWA 2003;58:217–20.10. Magrane D, Gannon J, Miller CT. Student doctors and women in labor:attitudes and expectations. Obstet Gynecol 1996;88:298–302.11. O’Flynn N, Rymer J. Consent for teaching: the experience of womenattending a gynaecology clinic. MedEduc 2003; 37:1109–14Pelvic Examinations by Medical TraineesAPRIL

A randomized controlled trial of NuvaRing versus combined oral contraceptive pills for pretreatment in in vitro fertilization cycles

OBJECTIVE To determine whether use of the NuvaRing (Merck) for pretreatment in IVF cycles would result in better cycle control and patient satisfaction versus a 30-μg oral contraceptive (OC) pill. DESIGN A prospective randomized, controlled study. SETTING An academic, hospital-based fertility clinic in Toronto, Canada. PATIENT(S) Patients 18-37 years old, undergoing their first IVF or IVF/intracytoplasmic sperm injection (ICSI) cycle. INTERVENTION(S) OC versus NuvaRing for IVF pre-treatment. MAIN OUTCOME MEASURE(S) Patient satisfaction, ovarian suppression, and IVF cycle outcomes. RESULT(S) Demographic data were similar in both groups. There were no significant differences in side effects between the NuvaRing and OC pill group with the exception of more breast discomfort in the OC pill group. There were no differences in the protocols, days of stimulation, and number of oocytes between the groups. Patients in the OC pill group had more embryos on day 3 and more patients had excess embryos for freezing. The number of embryos transferred and clinical pregnancy rates (PR) were similar between the two groups, although more patients in the NuvaRing group had cycles cancelled for poor stimulation. CONCLUSION(S) There was no significant benefit in patient tolerability or side effects with the NuvaRing versus the OC pill for IVF pretreatment; however, side effects overall were low in both groups. Clinical PRs were similar; however, the NuvaRing group had more cancelled cycles and fewer excess embryos for freezing. CLINICAL TRIAL REGISTRATION #NCT01298128.