Allison Case

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).

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).

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).

Effect of exercise training combined with isoflavone supplementation on bone and lipids in postmenopausal women: A randomized clinical trial

We determined the effects of 2 years of exercise training and soy isoflavone supplementation on bone mass and lipids in postmenopausal women provided with calcium and vitamin D. Women were randomized to four groups: exercise training (Ex); isoflavone supplementation (Iso: 165 mg/d [105 mg/d aglycone equivalent]); combined Ex and Iso (ExIso); and placebo (control). Exercise included resistance training (2 days/week) and walking (4 days/week). Our primary outcomes were lumbar spine and hip bone mineral density (BMD). Secondary outcomes included hip geometry, tibia and radius speed of sound (SOS), dynamic balance (6 m backward tandem walking), blood lipids, mammography, and endometrial thickness. A total of 351 women (Ex = 86, Iso = 90, ExIso = 87, control = 88) were randomized, with 298 analyzed at 2 years (Ex = 77, Iso = 76, ExIso = 72, control = 73). There was a significant interaction for total hip BMD (p < 0.001) such that ExIso had a greater rate of decrease (absolute change [95% confidence interval] = −0.018 [−0.024, −0.012] g/cm2) than either the Ex or Iso groups alone (−0.005 [−0.01, 0.001] and −0.005 [−0.011, 0.001] g/cm2, respectively). There were no differences between groups for changes in lumbar spine BMD and minimal significant changes in hip geometric properties and bone SOS. Exercise groups improved dynamic balance as measured by a decrease in backward tandem walking time over 6 m (p = 0.017). Isoflavone groups decreased low density lipoproteins (Iso: −0.20 [−0.37, −0.02] mmol/L; ExIso: −0.23 [−0.40, −0.06] mmol/L; p = 0.003) compared to non‐isoflavone groups (Ex: 0.01 [−0.16, 0.18] mmol/L; control: −0.09 [−0.27, 0.08] mmol/L) and had lower adverse reports of menopausal symptoms (14% versus 33%; p = 0.01) compared to non‐isoflavone groups. Isoflavone supplementation did not increase endometrial thickness or abnormal mammograms. We conclude exercise training and isoflavone supplementation maintain hip BMD compared to control, but these two interventions interfere with each other when combined. Isoflavone supplementation decreased LDL and adverse events related to menopausal symptoms.

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.

Development of Asherman syndrome after conservative surgical management of intractable postpartum hemorrhage

OBJECTIVE Describe a case of secondary infertility due to the development of severe Asherman Syndrome after the B-Lynch compression suture and uterine artery ligation, and to review the B-Lynch technique and documented complications. DESIGN Case report. SETTING Tertiary care hospital. PATIENT(S) A 29-year-old primigravida patient. INTERVENTION(S) B-Lynch suture and uterine artery ligation. MAIN OUTCOME MEASURE(S) Development of Asherman syndrome. RESULT(S) Development of secondary infertility due to Asherman syndrome after the B-Lynch suture. CONCLUSION(S) The B-Lynch suture is a highly successful conservative surgical technique used to treat this condition. There is little information regarding any potential for compromised future fertility, although there have been several reports of successful pregnancy after the use of the B-Lynch compression suture. In this report, we present a case of Asherman syndrome with complete obliteration of the uterine cavity after the B-Lynch suture.

DXA-derived abdominal fat mass, waist circumference, and blood lipids in postmenopausal women.

The purpose of this study was to determine the utility of dual‐energy X‐ray absorptiometry (DXA)‐derived fat mass indices for predicting blood lipid profile in postmenopausal women. A secondary purpose was to determine whether waist circumference is comparable with DXA‐derived measurements in predicting blood lipid profile. Subjects were 423 postmenopausal women (age 58.1 ± 6.3 years). Fat mass was assessed at abdomen, trunk, and total body using DXA. Anthropometric measurements included BMI and waist circumference. Blood samples were analyzed for total cholesterol (TC), triglyceride (TAG), high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), and cholesterol/HDL ratio. Of the DXA‐derived measures, abdominal‐fat mass was the best predictor of blood lipid profiles. DXA‐derived abdominal fat mass and waist girth explained 20 and 16.5% of variation in TC/HDL ratio, respectively, in univariate analysis, with no difference between the slopes of the regression coefficients. Eighty‐four percent of subjects were common to the top quartiles of waist circumference and abdominal fat mass, and blood lipid profiles generally worsened across increasing quartiles. DXA‐derived abdominal fat mass and waist circumference are of equivalent utility for predicting alterations in blood lipids. Waist circumference is, therefore, ideal as an inexpensive means in primary health‐care services for predicting risk of cardiovascular diseases in postmenopausal women.

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).

Thrombosis of subclavian and internal jugular veins following severe ovarian hyperstimulation syndrome: a case report.

BACKGROUND Ovarian hyperstimulation syndrome (OHSS) is a serious, albeit rare, complication of fertility treatment. In its severe form, it may be life-threatening. Increased vascular permeability with hemoconcentration is the hallmark of the syndrome. Vascular thromboembolism is a significant potential complication. CASE A previously healthy 26-year-old nulligravid woman developed severe OHSS following an in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycle. She required hospitalization for treatment comprising IV fluid replacement, albumin infusion, paracentesis, and prophylactic heparin. She presented two days after discharge from hospital with left arm edema and neck pain. Subclavian and internal jugular vein thrombosis was diagnosed. CONCLUSION OHSS is a serious complication of treatment for ovulation induction and is a significant risk factor for vascular thrombosis. Patients remain at risk even if given prophylactic heparin. The clinical presentation of OHSS may be unusual and late, indicating the importance of vigilance on the part of all physicians caring for patients who have undergone fertility treatment.

Synchronization of ovarian stimulation with follicle wave emergence in patients undergoing in vitro fertilization with a prior suboptimal response: a randomized, controlled trial.

OBJECTIVE To test the hypothesis that synchronizing initiation of ovarian stimulation with follicle wave emergence would optimize IVF/intracytoplasmic sperm injection (ICSI) outcomes in patients with a prior suboptimal response. DESIGN Prospective, randomized, controlled trial. SETTING Academic and private reproductive endocrinology and infertility centers. PATIENT(S) Eighty women ≤ 43 years of age with a history of a suboptimal response. INTERVENTION(S) Initiation of recombinant FSH/GnRH antagonist/recombinant LH/hCG on day 1 (n = 39) or day 4 (n = 41). MAIN OUTCOME MEASURE(S) Numbers of clinical and biochemical pregnancies, follicles ≥ 10 and ≥ 15 mm, oocytes collected, fertilized oocytes, cleavage stage embryos, and blastocysts; serum E(2) concentrations. Outcomes were compared between treatment groups. RESULT(S) The numbers of follicles that developed to ≥ 10 and ≥ 15 mm and serum E(2) were greater when recombinant FSH was initiated on day 1 (5.4, 4.3, 5,827.2 pmol/L) versus day 4 (3.6, 2.5, 4,230.1 pmol/L). The numbers of collected, metaphase II, and fertilized oocytes; cleavage stage embryos; and blastocysts were not different between groups. When we evaluated only those cycles that proceeded to oocyte pick-up, a lower implantation rate (16.1%, 56.0%), biochemical pregnancy rate (PR) (16.1%, 48.0%), and clinical PR (12.9% vs. 36.0%) were detected in the day 1 group versus day 4 group. CONCLUSION(S) Synchronizing initiation of ovarian stimulation with follicle wave emergence in patients with a prior suboptimal response resulted in an increase in the number of dominant follicles and serum E(2) concentrations; however, improvements in oocyte, embryo, or pregnancy outcomes did not occur. CLINICAL TRIAL REGISTRATION NUMBER NCT00439829.