Anthony P. Cheung

Pregnancy Outcomes After Assisted Reproductive Technology

OBJECTIVE To 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. OPTIONS Perinatal outcomes of ART pregnancies in subfertile women are compared with those of spontaneously conceived pregnancies. Perinatal outcomes are compared between different types of ART. OUTCOMES This 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. EVIDENCE The 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. VALUES The 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. BENEFITS, HARMS, AND COSTS The 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. RECOMMENDATIONS 1. 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).

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).

Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome.

OBJECTIVE To assess the role of endometrial thickness on vaginal ultrasound assessment and menstrual history in predicting endometrial hyperplasia in women with polycystic ovary syndrome (PCOS) who presented with infertility due to anovulation. METHODS This was a prospective study in a university referral‐based fertility and endocrine clinic. Fifty‐six women with PCOS presenting with infertility due to anovulation underwent both vaginal ultrasound assessments and endometrial biopsies. The main outcome measures were the predictive value of sonographic endometrial thickness (primary objective) and the menstrual history with other clinical characteristics (secondary objective) for proliferative endometrium and endometrial hyperplasia in logistic regression analysis. Their predictive value was further examined by receiver operating characteristic curve analysis. RESULTS Thirty‐six PCOS patients (64.3%) had proliferative endometrium and 20 (35.7%) had endometrial hyperplasia. Five of the latter (25%) had cytologic atypia. Endometrial thickness less than 7 mm or intermenstrual interval less than 3 months (corresponding to more than four menstrual periods yearly) was associated with proliferative endometrium only. The endometrial thickness correlated positively with endometrial hyperplasia (P = .018) and, together with the average intermenstrual interval, were significant predictors of endometrial hyperplasia (P < .001). CONCLUSION These findings point to the usefulness of obtaining a detailed menstrual history in women with PCOS by identifying those at increased risk of endometrial hyperplasia and who require an endometrial biopsy. The endometrial thickness corroborates this clinical impression and is particularly useful when the menstrual history is uncertain. Endometrial hyperplasia in this population is effectively excluded when the endometrial thickness is less than 7 mm.

Childless women's knowledge of fertility and assisted human reproduction: identifying the gaps.

OBJECTIVE To determine the knowledge about fertility and assisted human reproduction (AHR) treatments of a large sample of childless women. DESIGN Self-report questionnaire comprising two self-ratings of current fertility and AHR knowledge, and 16 knowledge questions related to fertility and AHR. SETTING Online. PATIENT(S) A total of 3,345 childless women between the ages of 20 and 50. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Knowledge of fertility and AHR. RESULT(S) The majority of participants rated themselves as having some knowledge or being fairly knowledgeable about fertility and AHR. However, on the 16 knowledge questions, overall knowledge was low, with 50% or more of the sample answering only 6 of 16 questions correctly. CONCLUSION(S) The data suggest that the women in the study have no coherent body of knowledge regarding age-related fertility and AHR treatment options. With an increasing number of women electing to delay childbearing, there is a critical need for public education regarding age-related fertility declines and the availability, costs, and limitations of AHR. This study offers important mental health contributions to infertility prevention and public health education efforts.

Guidelines for the Number of Embryos toTransfer Following In Vitro Fertilization

OBJECTIVE To 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. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared. OUTCOMES Clinical pregnancy, multiple pregnancy, and live birth rates. EVIDENCE The 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. VALUES Available 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. BENEFITS, HARMS, AND COSTS This 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.

Elective Single Embryo Transfer Following In Vitro Fertilization

OBJECTIVE To review the effect of elective single embryo transfer (eSET) compared with double embryo transfer (DET) following in vitro fertilization (IVF), and to provide guidelines on the use of eSET in order to optimize live birth rates and minimize twin pregnancies. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy following eSET and DET are compared. OUTCOMES Live birth, clinical pregnancy, and multiple pregnancy rates, and cost-effectiveness. EVIDENCE Published literature was retrieved through searches of PubMed, Medline, and The Cochrane Library in 2009, using appropriate controlled vocabulary (e.g., elective single embryo transfer) and key words (e.g., embryo transfer, in vitro fertilization, intracytoplasmic sperm injection, assisted reproductive technologies, blastocyst, and multiple pregnancy). Results were restricted to English language systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2009. Additional references were identified through searches of bibliographies of identified articles and international medical specialty societies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES Available evidence was reviewed by the Joint Society of Obstetricians and Gynaecologist of Canada-Canadian Fertility and Andrology Society Clinical Practice Guidelines Committee and the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada, and was qualified using the evaluation of evidence criteria outlined in the report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS This guideline is intended to minimize the occurrence of twin gestations while maintaining acceptable overall live birth rates following IVF-ET. SUMMARY STATEMENTS 1. Indiscriminate application of eSET in populations with less than optimal prognosis for live birth will result in a significant reduction in effectiveness compared with DET. (I) 2. In women aged 38 years and over, eSET may result in a significant reduction in live birth rate compared with DET. (II-2) 3. Selective application of eSET in a small group of good-prognosis patients may be effective in reducing the overall multiple rate of an entire IVF population. (II-3) 4. Given the high costs of treatment, uptake of eSET would be enhanced by public funding of IVF treatment. (II-2) Recommendations 1. Patients should be informed of the reductions in both multiple pregnancy rate and overall live birth rate after a single fresh eSET when compared with DET in good-prognosis patients. (I-A) 2. Because the cumulative live birth rate after fresh eSET followed by transfer of a single frozen-thawed embryo is similar but not equivalent to the rate after fresh DET in good-prognosis patients, the eSET strategy should be used in order to avoid multiple pregnancy. (I-A) 3. Women aged 35 years or less, in their first or second IVF attempt, with at least 2 good quality embryos available for transfer should be considered good-prognosis patients. (I-A) 4. In order to maximize cumulative live birth rates following eSET, effective cryopreservation programs should be in place. (I-A) 5. In order to maintain the reduction in the rate of multiples achieved by fresh eSET, eSET should be performed in subsequent frozen-thawed embryo transfer cycles. (II-2A) 6. Because blastocyst stage embryo transfer generally increases the chance of implantation and live birth compared with cleavage stage embryo transfer, eSET should be performed in good-prognosis patients who have good quality blastocysts available. (I-A) 7. In women aged 36 to 37 years, eSET should be considered in good-prognosis patients with good quality embryos, particularly when blastocysts are available for transfer. (II-2A) 8. In oocyte donor-recipient cycles when the donor has good prognosis and when good quality embryos are available, eSET should be performed. (II-2B) 9. In women with medical or obstetrical contraindications to twin pregnancy, eSET should be performed. (III-B) 10. In order to achieve successful uptake of eSET, it is essential to provide patient and physician education regarding the risks of twin pregnancy and regarding the similar cumulative live birth rate following an eSET strategy and DET. (III-C) 11. When considering both direct health care and societal costs, it should be noted that live birth following eSET is significantly less expensive than DET in good-prognosis patients. (I-A) Therefore, from a cost-effectiveness perspective, eSET is indicated in good-prognosis patients. (III-A).

Bis(maltolato)Oxovanadium(IV) Attenuates Hyperinsulinemia and Hypertension in Spontaneously Hypertensive Rats

We previously reported that bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium complex, decreased plasma insulin concentrations in nondiabetic rats without affecting plasma glucose levels (McNeill JH, Yuen VG, Hoveyda HR, Orvig C: Bis(maltolato)oxovanadium(IV) is a potent insulin mimic. J Med Chem 35:1489–1491, 1992). In this study, chronic oral BMOV treatment was started in 6-week-old spontaneously hypertensive (SH) rats and their Wistar-Kyoto (WKY) controls, and the effects of the drug on insulin sensitivity, plasma insulin, and blood pressure (BP) were studied. BMOV (0.35–0.45 mmol.kg−1.day−1) caused a sustained reduction in plasma insulin (198 ± 6 vs. untreated 366 ± 13.2 pM, P < 0.0001) and systolic BP (149 ± 3 vs. untreated 184 ± 3 mmHg, P < 0.0001) in SH rats. No changes were seen in WKY rats (plasma insulin: treated 228 ± 4.8 vs. untreated 222.6 ± 3.6 pM, P > 0.05; BP: treated 134 ± 3 vs. untreated 134 ± 5 mmHg, P > 0.05). At 13 weeks of age, euglycemic clamps were performed in fasted, conscious, mobile rats. During low-dose insulin infusions (14 pmol.kg−1 · min−1) with concomitant somatostatin administration, neither hepatic glucose output nor total body glucose uptake differed between the untreated SH and WKY rats. Insulin sensitivity, expressed as steady-state glucose clearance per unit of plasma insulin, was higher in the untreated SH compared with the untreated WKY rats (2.1 ± 0.2 vs. 1.2 ± 0.1 ml.kg−1.h−1.pM−1 P < 0.002). BMOV further enhanced insulin sensitivity in SH rats (3.6 ± 0.4, P < 0.002 vs. untreated SH rats). In conclusion, 1) SH rats are hyperinsulinemic but not insulin resistant compared with WKY rats; and 2) BMOV caused concurrent decreases in plasma insulin and BP in SH rats, which suggests that hyperinsulinemia may contribute toward the development of high BP in the SH rat.

Ovulation induction in polycystic ovary syndrome.

OBJECTIVE To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS). OPTIONS This guideline reviews the evidence for the various options for ovulation induction in PCOS. OUTCOMES Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. EVIDENCE Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies. VALIDATION These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC. SPONSOR The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS 1. Weight loss, exercise, and lifestyle modifications have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A) Morbidly obese women should seek expert advice about pregnancy risk. (III-A) 2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate. (I-A) 3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.(I-A) Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity. (I-A) 4. Gonadotropin should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A) 5. Laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, particularly when there are other indications for laparoscopy. (I-A) Surgical risks need to be considered in these patients. (III-A) 6. In vitro fertilization should be reserved for women with PCOS who fail gonadotropin therapy or who have other indications for IVF treatment. (II-2A).

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.