Clinical aspects of oocyte retrieval and embryo transfer: tips and tricks for the novice and the expert.

Oocyte retrieval (ovum pick-up) and embryo transfer (ET) are essential steps in in-vitro fertilization and intracytoplasmic sperm injection and over the years, the two procedures were developed in order to improve the clinical outcome. Many suggestions were proposed and applied before, during and after oocyte retrieval such as timing of HCG trigger, pre-operative pelvic scan, vaginal cleansing, type of anesthesia, type and gauge of aspiration needles, aspiration pressure, follicle flushing, and the need for prophylactic antibiotics. Similarly, many steps were suggested and implemented before, during and after ET including patient's position, type of anesthesia/analgesia, dummy (mock) ET, ultrasound-guidance, HCG injection in the uterine cavity, use of relaxing agents, full bladder, removal of the cervical mucus, flushing the cervix with culture medium, type of ET catheter, embryo loading techniques, site of embryo deposition, the use of adherence compounds, as well as bed rest after ET. Complications were also reported with oocyte retrieval and ET. The aim of this review is to evaluate the current practice of these two procedures in the light of available evidence.

A randomised controlled trial to assess the clinical effectiveness and safety of the endometrial scratch procedure prior to first-time IVF, with or without ICSI.

STUDY QUESTION: What is the clinical-effectiveness and safety of the endometrial scratch (ES) procedure compared to no ES, prior to usual first time in vitro fertilisation (IVF) treatment? SUMMARY ANSWER: ES was safe but did not improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF cycle, with or without intracytoplasmic sperm injection (ICSI). WHAT IS KNOWN ALREADY: ES is an 'add-on' treatment that is available to women undergoing a first cycle of IVF, with or without ICSI, despite a lack of evidence to support its use. STUDY DESIGN, SIZE, DURATION: This pragmatic, superiority, open-label, multi-centre, parallel-group randomised controlled trial involving 1048 women assessed the clinical effectiveness and safety of the ES procedure prior to first time IVF, with or without ICSI, between July 2016 and October 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants aged 18-37 years undergoing their first cycle of IVF, with or without ICSI, were recruited from 16 UK fertility clinics and randomised (1:1) by a web-based system with restricted access rights that concealed allocation. Stratified block randomisation was used to allocate participants to TAU or ES in the mid-luteal phase followed by usual IVF with or without ICSI treatment. The primary outcome was live birth after completing 24 weeks gestation within 10.5 months of egg collection. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1048 women randomised to TAU (n = 525) and ES (n = 523) were available for intention to treat analysis. In the ES group, 453 (86.6%) received the ES procedure. IVF, with or without ICSI, was received in 494 (94.1%) and 497 (95.0%) of ES and TAU participants respectively. Live birth rate was 37.1% (195/525) in the TAU and 38.6% (202/523) in the ES: an unadjusted absolute difference of 1.5% (95% CI -4.4% to 7.4%, P = 0.621). There were no statistical differences in secondary outcomes. Adverse events were comparable across groups. LIMITATIONS, REASONS FOR CAUTION: A sham ES procedure was not undertaken in the control group, however, we do not believe this would have influenced the results as objective fertility outcomes were used. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest trial that is adequately powered to assess the impact of ES on women undergoing their first cycle of IVF. ES was safe, but did not significantly improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF or ICSI cycle. We recommend that ES is not undertaken in this population. STUDY FUNDING/COMPETING INTEREST(S): Funded by the National Institute of Health Research. Stephen Walters is an National Institute for Health Research (NIHR) Senior Investigator (2018 to present) and was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2011-2017), NIHR HTA Commissioning Strategy Group (2012 to 2017); NIHR Programme Grants for Applied Research Committee (2020 to present); NIHR Pre doctoral Fellowship Committee (2019 to present). Dr. Martins da Silva reports grants from AstraZeneca, during the conduct of the study; and is Associate editor of Human Reproduction and Editorial Board member of Reproduction and Fertility. Dr. Bhide reports grants from Bart's Charity and grants and non-financial support from Pharmasure Pharmaceuticals outside the submitted work. TRIAL REGISTRATION NUMBER: ISRCTN number: ISRCTN23800982. TRIAL REGISTRATION DATE: 31 May 2016. DATE OF FIRST PATIENT'S ENROLMENT: 04 July 2016.

Time to consider ovarian tissue cryopreservation for girls with Turner's syndrome: an opinion paper.

Turner's syndrome (TS) is the most common sex chromosome abnormality in women. In addition to short stature and gonadal dysgenesis, it is associated with cardiac and renal anomalies. Due to rapid follicular atresia, the majority of women with TS suffer from primary ovarian insufficiency around puberty. Thus far, donor oocyte conception has been the key fertility option for these women. With advancing technology, ovarian tissue cryopreservation (OTCP) has emerged as a clinically justifiable option especially for pre-pubertal girls with cancer. Recently published results following the use of cryopreserved ovarian tissue are reassuring. It would be prudent to consider the extension of these technological and scientific advances to other conditions, such as TS, where accelerated follicular atresia is suspected. It is possible to obtain competent oocytes from cryopreserved ovaries of girls with TS provided the ovaries were preserved before ovarian failure. However, it is a complex decision whether and when to offer OTCP as a fertility preservation (FP) option for girls with TS. The rate of decline in fertility is variable in girls with TS and can be more complex in cases with mosaicism. On the other hand, OTCP has shown some promising results in patients with cancer, which can potentially be replicated in TS and other benign indications of patients at risk of premature ovarian failure. There are proven psychological and clinical benefits of FP. Thus, an argument could be made for offering OTCP to these patients to endow these girls with the option of having biological fertility using this innovative technology. Ethical, clinical and psychological dilemmas should be considered, discussed and addressed before considering such a novel approach. We believe that the time has come to start this discussion and open this avenue of FP for girls with TS.

Strategies to improve fertilisation rates with assisted conception: a systematic review.

Successful fertilisation is one of the key steps determining success of assisted conception. Various factors including sperm or oocyte pathology and environmental factors have a significant impact on fertilisation rates. This systematic review is aimed to evaluate the existing evidence about factors affecting fertilisation and strategies to improve fertilisation rates. A literature search was performed using Ovid MEDLINE ® (Jan 1950-April 2016), EMBASE (Jan 1950-April 2016), Ovid OLDMEDLINE ®, Pre-MEDLINE (Jan 1950-April 2016) and the Cochrane Library. Relevant key words were used to combine sets of results and a total 243 papers were screened. Only qualitative analysis was performed, as there was major heterogeneity in study design and methodology for quantitative synthesis. Factors affecting fertilisation were divided into sperm- and oocyte-related factors. The methods to improve fertilisation rates were grouped together based on the approach used to improve fertilisation rates. Optimising laboratory condition and procedural effects in techniques is associated with improved fertilisation rates. Various techniques are described to improve fertilisation rates including assisted oocyte activation, physiological intracytoplasmic sperm injection (PICSI) and intracytoplasmic morphologically selected sperm injection (IMSI). This review highlights the promising strategies under research to enhance fertilisation rates. Adequately powered multicentre randomised trials are required to evaluate these techniques before considering clinical application.

Cycle regimens for frozen-thawed embryo transfer.

BACKGROUND: Among subfertile couples undergoing assisted reproductive technology (ART), pregnancy rates following frozen-thawed embryo transfer (FET) treatment cycles have historically been found to be lower than following embryo transfer undertaken two to five days following oocyte retrieval. Nevertheless, FET increases the cumulative pregnancy rate, reduces cost, is relatively simple to undertake and can be accomplished in a shorter time period than repeated in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles with fresh embryo transfer. FET is performed using different cycle regimens: spontaneous ovulatory (natural) cycles; cycles in which the endometrium is artificially prepared by oestrogen and progesterone hormones, commonly known as hormone therapy (HT) FET cycles; and cycles in which ovulation is induced by drugs (ovulation induction FET cycles). HT can be used with or without a gonadotrophin releasing hormone agonist (GnRHa). This is an update of a Cochrane review; the first version was published in 2008. OBJECTIVES: To compare the effectiveness and safety of natural cycle FET, HT cycle FET and ovulation induction cycle FET, and compare subtypes of these regimens. SEARCH METHODS: On 13 December 2016 we searched databases including Cochrane Gynaecology and Fertility's Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. Other search sources were trials registers and reference lists of included studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing the various cycle regimens and different methods used to prepare the endometrium during FET. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth rates and miscarriage. MAIN RESULTS: We included 18 RCTs comparing different cycle regimens for FET in 3815 women. The quality of the evidence was low or very low. The main limitations were failure to report important clinical outcomes, poor reporting of study methods and imprecision due to low event rates. We found no data specific to non-ovulatory women. 1. Natural cycle FET comparisons Natural cycle FET versus HT FETNo study reported live birth rates, miscarriage or ongoing pregnancy.There was no evidence of a difference in multiple pregnancy rates between women in natural cycles and those in HT FET cycle (odds ratio (OR) 2.48, 95% confidence interval (CI) 0.09 to 68.14, 1 RCT, n = 21, very low-quality evidence). Natural cycle FET versus HT plus GnRHa suppressionThere was no evidence of a difference in rates of live birth (OR 0.77, 95% CI 0.39 to 1.53, 1 RCT, n = 159, low-quality evidence) or multiple pregnancy (OR 0.58, 95% CI 0.13 to 2.50, 1 RCT, n = 159, low-quality evidence) between women who had natural cycle FET and those who had HT FET cycles with GnRHa suppression. No study reported miscarriage or ongoing pregnancy. Natural cycle FET versus modified natural cycle FET (human chorionic gonadotrophin (HCG) trigger)There was no evidence of a difference in rates of live birth (OR 0.55, 95% CI 0.16 to 1.93, 1 RCT, n = 60, very low-quality evidence) or miscarriage (OR 0.20, 95% CI 0.01 to 4.13, 1 RCT, n = 168, very low-quality evidence) between women in natural cycles and women in natural cycles with HCG trigger. However, very low-quality evidence suggested that women in natural cycles (without HCG trigger) may have higher ongoing pregnancy rates (OR 2.44, 95% CI 1.03 to 5.76, 1 RCT, n = 168). There were no data on multiple pregnancy. 2. Modified natural cycle FET comparisons Modified natural cycle FET (HCG trigger) versus HT FETThere was no evidence of a difference in rates of live birth (OR 1.34, 95% CI 0.88 to 2.05, 1 RCT, n = 959, low-quality evidence) or ongoing pregnancy (OR 1.21, 95% CI 0.80 to 1.83, 1 RCT, n = 959, low-quality evidence) between women in modified natural cycles and those who received HT. There were no data on miscarriage or multiple pregnancy. Modified natural cycle FET (HCG trigger) versus HT plus GnRHa suppressionThere was no evidence of a difference between the two groups in rates of live birth (OR 1.11, 95% CI 0.66 to 1.87, 1 RCT, n = 236, low-quality evidence) or miscarriage (OR 0.74, 95% CI 0.25 to 2.19, 1 RCT, n = 236, low-quality evidence) rates. There were no data on ongoing pregnancy or multiple pregnancy. 3. HT FET comparisons HT FET versus HT plus GnRHa suppressionHT alone was associated with a lower live birth rate than HT with GnRHa suppression (OR 0.10, 95% CI 0.04 to 0.30, 1 RCT, n = 75, low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 0.64, 95% CI 0.37 to 1.12, 6 RCTs, n = 991, I2 = 0%, low-quality evidence) or ongoing pregnancy (OR 1.72, 95% CI 0.61 to 4.85, 1 RCT, n = 106, very low-quality evidence).There were no data on multiple pregnancy. 4. Comparison of subtypes of ovulation induction FET Human menopausal gonadotrophin(HMG) versus clomiphene plus HMG HMG alone was associated with a higher live birth rate than clomiphene combined with HMG (OR 2.49, 95% CI 1.07 to 5.80, 1 RCT, n = 209, very low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 1.33, 95% CI 0.35 to 5.09,1 RCT, n = 209, very low-quality evidence) or multiple pregnancy (OR 1.41, 95% CI 0.31 to 6.48, 1 RCT, n = 209, very low-quality evidence).There were no data on ongoing pregnancy. AUTHORS' CONCLUSIONS: This review did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for FET in subfertile women with regular ovulatory cycles. The most common modalities for FET are natural cycle with or without HCG trigger or endometrial preparation with HT, with or without GnRHa suppression. We identified only four direct comparisons of these two modalities and there was insufficient evidence to support the use of either one in preference to the other.

Definition and epidemiology of unexplained infertility.

The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations,which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after.

Oocyte vitrification in the 21st century and post-warming fertility outcomes: a systematic review and meta-analysis.

Oocyte cryopreservation is a rapidly developing technology, which is increasingly being used for various medical, legal and social reasons. There are inconsistencies in information regarding survival rate and fertility outcomes. This systematic review and meta-analysis provides evidence-based information about oocyte survival and fertility outcomes post warming to help women to make informed choices. All randomized and non-randomized, controlled and prospective cohort studies using oocyte vitrification were included. The primary outcome measure was ongoing pregnancy rate/warmed oocyte. Sensitivity analysis for donor and non-donor oocyte studies was performed. Proportional meta-analysis of 17 studies, using a random-effects model, showed pooled ongoing pregnancy and clinical pregnancy rates per warmed oocyte of 7%. Oocyte survival, fertilization, cleavage, clinical pregnancy and ongoing pregnancy rates per warmed oocyte were higher in donor versus non-donor studies. Comparing vitrified with fresh oocytes, no statistically significant difference was observed in fertilization, cleavage and clinical pregnancy rates, but ongoing pregnancy rate was reduced in the vitrified group (odds ratio 0.74), with heterogeneity between studies. Considering the age of women and the reason for cryopreservation, reasonable information can be given to help women to make informed choices. Future studies with outcomes from oocytes cryopreserved for gonadotoxic treatment may provide more insight.

Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis.

BACKGROUND Poor fertility outcomes in women with recurrent implantation failure (≥ RIF) present significant challenges in assisted reproduction, and various adjuncts, including heparin, are used for potential improvement in pregnancy rates. We performed this systematic review and meta-analysis to evaluate the effect of low-molecular-weight heparin (LMWH) on live birth rates (LBRs) and implantation rates (IRs) in women with RIF and undergoing IVF. METHODS Studies comparing LMWH versus control/placebo in women with RIF were searched for on MEDLINE, EMBASE, Cochrane Library, conference proceedings and databases for registered and ongoing trials (1980-2012). Statistical analysis was performed using Review Manager 5.1. The main outcome measure was LBR per woman. RESULTS Two randomized controlled trials (RCTs) and one quasi-randomized trial met the inclusion criteria. One study included women with at least one thrombophilia ( Qublan et al., 2008) and two studies included women with unexplained RIF ( Urman et al., 2009; Berker et al., 2011). Pooled risk ratios in women with ≥ 3 RIF (N = 245) showed a significant improvement in the LBR (risk ratio (RR) = 1.79, 95% confidence interval (CI) = 1.10-2.90, P = 0.02) and a reduction in the miscarriage rate (RR = 0.22, 95% CI = 0.06-0.78, P = 0.02) with LMWH compared with controls. The IR for ≥ 3 RIF (N = 674) showed a non-significant trend toward improvement (RR = 1.73, 95% CI 0.98-3.03, P = 0.06) with LMWH. However, the beneficial effect of LMWH was not significant when only studies with unexplained RIF were pooled. The summary analysis for the numbers needed to be treated with LMWH showed that approximately eight women would require treatment to achieve one extra live birth. CONCLUSIONS In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group; however, this is to be considered with caution, since the overall number of participants in the studies was small. Further evidence from adequately powered multi-centered RCTs is required prior to recommending LMWH for routine clinical use. This review highlights the need for future basic science and clinical research in this important field.

Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis.

Mechanical endometrial injury (biopsy/scratch or hysteroscopy) in the cycle preceding ovarian stimulation for IVF has been proposed to improve implantation in women with unexplained recurrent implantation failure (RIF). This is a systematic review and meta-analysis of studies comparing the efficacy of endometrial injury versus no intervention in women with RIF undergoing IVF. All controlled studies of endometrial biopsy/scratch or hysteroscopy performed in the cycle preceding ovarian stimulation were included and the primary outcome measure was clinical pregnancy rate. Pooling of seven controlled studies (four randomized and three non-randomized), with 2062 participants, showed that local endometrial injury induced in the cycle preceding ovarian stimulation is 70% more likely to result in a clinical pregnancy as opposed to no intervention. There was no statistically significant heterogeneity in the methods used, clinical pregnancy rates being twice as high with biopsy/scratch (RR 2.32, 95% CI 1.72-3.13) as opposed to hysteroscopy (RR 1.51, 95% CI 1.30-1.75). The evidence is strongly in favour of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained RIF. However, large randomized studies are required before iatrogenic induction of local endometrial injury can be warranted in routine clinical practice. Some women undergoing IVF treatment fail to conceive despite several attempts with good-quality embryos and no identifiable reason. We call this 'recurrent implantation failure' (RIF) where the embryo fails to embed or implant within the lining of the womb. Studies have shown that inducing injury to the lining of the womb in the cycle before starting ovarian stimulation for IVF can help improve the chances of achieving pregnancy. Injury can be induced by either scratching the lining of the womb using a biopsy tube or by telescopic investigation of the womb using a camera. We performed a collective review of the available good-quality studies that used the above two methods in the cycle prior to starting ovarian stimulation for IVF. We pooled results from seven studies, which included 2062 women with RIF and assessed the difference in clinical pregnancy rates for those undergoing injury to the womb lining compared with no injury prior to IVF. The results suggest that inducing injury is 70% more likely to result in a clinical pregnancy as opposed to no treatment. Furthermore, scratching of the lining was 2-times more likely to result in a clinical pregnancy compared with telescopic evaluation of the lining of the womb. This study suggests that in women with RIF, inducing local injury to the womb lining in the cycle prior to starting ovarian stimulation for IVF can improve pregnancy outcomes. However, large studies are required before this can be warranted in routine clinical practice.

Evidence-based management of endometrioma.

Endometrioma is commonly seen in women of reproductive age who may wish to preserve their ovarian function. Surgical treatment is associated with a high recurrence rate and its employment for women undergoing assisted conception has recently been challenged. Medical treatment has not been shown to be effective in controlling symptoms or improving fertility potential. The results of retrospective and non-randomized studies have been inconsistent and created an ongoing debate between gynaecologists and fertility specialists. This manuscript reviews and critically appraises the evidence for management of endometrioma in women of reproductive age. In asymptomatic women, surgical treatment is usually recommended for women above the age of 40 and for large endometriomas. Except for pelvic clearance, there is insufficient evidence to suggest that surgical treatment of endometrioma is better than medical treatment with respect to the long-term relief of symptoms and quality of life. Laparoscopic excision of ovarian endometrioma prior to IVF does not offer any additional benefit over expectant management. A large, well-designed, adequately powered randomized controlled study that compares the effects of surgical removal versus expectant management of endometrioma on ovarian performance and pregnancy outcomes in women undergoing IVF is warranted.

Optimizing hormone therapy for future reproductive performance in women with premature ovarian failure.

With increasing success in treatment of childhood cancer there is a growing population of women with premature ovarian failure (POF) seeking fertility treatment. Various preparations of estrogen and progestogen are prescribed for young women with POF. While the dose and duration of hormone therapy (HT) is usually adjusted according to the patient's height and the Tanner's stage of development for young pre-pubertal women, the optimal effective HT regimen to maximise the reproductive potential for young as well as for the older age group remains unclear. Furthermore, there is a paucity of evidence to support the preferential effectiveness of the different regimens used. Assisted reproduction using donated gametes or embryos remains the only realistic option to enable women with POF to conceive. Successful outcomes are primarily dependant on successful implantation and placentation. Consequently, the success of assisted reproduction is determined by uterine and endometrial development, which is largely influenced by the modality of HT as well as the age at which it is commenced. In this review, we critically appraise the current practices and published data for management of women with POF. We aim to focus on the effect of HT on uterine development in women with primary and irreversible POF.

Management of endometrioma prior to IVF: compliance with ESHRE guidelines.

Management of endometrioma before IVF remains controversial. As well as some measurable benefits from surgical treatment, there are also potential risks that should be discussed with the patients to help them make an informed decision. When surgery is compared with expectant management, there appear to be no statistically significant differences in pregnancy rate and ovarian response to exogenous stimulation. The objectives of this European Society of Human Reproduction and Embryology (ESHRE)-sponsored survey were to acquire knowledge of current strategies for the management of endometrioma (>3 cm) prior to IVF and to explore adherence to ESHRE guidelines. A validated, peer-reviewed online questionnaire made of 14 questions was sent to 396 members of the ESHRE Special Interest Groups (Reproductive Surgery and Endometriosis/Endometrium), with a response rate of 27%. Surgical management is the most common treatment (82.2%), with drainage and excision of the cyst wall being the preferred surgical approach (78.5%). Monthly depot gonadotrophin-releasing hormone analogues are the preferred choice of medical treatment of endometriomas before IVF, with an average duration of treatment of 3 months. The findings demonstrate that surgery remains the commonest treatment offered for women with endometrioma before IVF. This is in line with the recommendations of the ESHRE guidelines.

Management of endometrial polyps in subfertile women: a systematic review.

The aim of this systematic review is to evaluate the evidence for the impact of polypectomy on fecundity, implantation and live birth rates in women who are trying to conceive spontaneously or by assisted conception. A literature search was performed to identify all controlled studies that compared the effects of polypectomy or conservative management of the polyp on pregnancy outcome. Among the three studies that met the inclusion criteria, only one was a randomized controlled trial, which reported a significantly higher pregnancy rates after polypectomy in women undergoing intrauterine insemination. The other two studies were retrospective and suggested no beneficial effects of polypectomy on women undergoing assisted conception. Meta-analytic pool was not feasible as the studies varied in their design and the characteristics. While there is some evidence from basic science studies to suggest a detrimental effect of polyps on fertility, the evidence from clinical studies is scarce and conflicting. Polyps diagnosed prior to commencement of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) should therefore be removed. The management of polyps seen during the course of COH for IVF should be individualized given the number of embryos created, the previous reproductive history of the patient and the individual clinics' success rates for their frozen embryo programme.

The use of anti-Müllerian hormone and antral follicle count to predict the potential of oocytes and embryos.

OBJECTIVE: To investigate whether anti-Müllerian hormone (AMH) is better than antral follicle count (AFC) in predicting oocyte yield and embryo quality after controlled ovarian hyperstimulation for in vitro fertilization (IVF). STUDY DESIGN: This is a prospective observational study involving 162 women (<40 years old) undergoing their first IVF cycle at an IVF unit within a university hospital. AMH and AFC measurements were made on day 3 of the cycle within 3 months of starting ovarian stimulation. A standard long down-regulation protocol using gonadotrophin releasing hormone agonist and recombinant follicle stimulating hormone was used. A maximum of two embryos were transferred on day 2 or 3 following oocyte retrieval. The primary outcome was the number of good quality embryos available for transfer and freezing. Embryos were graded according to the number of blastomeres, the difference in blastomere size and the degree of fragmentation, into grades 1-4. Secondary outcomes included the number of oocytes retrieved and fertilized and the live birth rate. Correlation between different parameters was calculated using Spearman's correlation coefficient. Receiver operating characteristic (ROC) curves were generated for AMH and AFC to compare ability of parameters to predict top quality or frozen embryos and the occurrence of a live birth. RESULTS: Of the 137 women who had fresh embryo transfer, 52 became pregnant (32.1% pregnancy rate per cycle started) and 38 had a live birth (23.5% live birth rate per cycle started). Both AMH and AFC had highly significant correlations with the number of oocytes retrieved and the number of oocytes fertilized (P<0.001). The two markers were also significantly associated with the number of top quality embryos available for transfer and the number of embryos frozen (P<0.01). With regard to live birth, AMH performed better than AFC (P<0.01 and P<0.05, respectively), but both markers were more valuable in predicting the absence rather than the occurrence of live birth (negative predictive value 84%). CONCLUSIONS: AMH and AFC are comparable predictors of oocytes retrieved and of the number of good quality embryos available for transfer and freezing. Prediction of live birth may help clinicians selecting patients suitable for single embryo transfer.

Short and long-term risks to women who conceive through in vitro fertilization.

There are a number of potential risks to women who conceive through in vitro fertilisation (IVF). Among these, ovarian hyperstimulation syndrome and multiple pregnancies are the most serious. Other potential risks include increased levels of anxiety and depression, ovarian torsion, ectopic pregnancy, pre-eclampsia, placenta praevia, placental separation and increased risk of cesarean section. The association between assisted conception and long-term risk of cancer is debatable. The objective of this review is to critically evaluate the current evidence for potential risks to women who conceive through IVF. To assess the relative risk for any condition, a number of factors need to be taken into account including the method used in identifying the study and control group, the women's characteristics and the number of women included in the study. Many conditions such as ectopic pregnancy and pre-eclampsia appear to be commoner in assisted conception than in spontaneous pregnancy. Nevertheless, the increased risk of these conditions is probably related to the woman's subfertility status and/or increased incidence of multiple pregnancy. Currently, all efforts should concentrate on reduction of multiple births from IVF by restricting the number of transferred embryos.

The likelihood of live birth and multiple birth after single versus double embryo transfer at the cleavage stage: a systematic review and meta-analysis.

OBJECTIVE: To determine whether a policy of elective single-embryo transfer (e-SET) lowers the multiple birth rate without compromising the live birth rate. DESIGN: Systematic review and meta-analysis. SETTING: Tertiary referral center for reproductive medicine and IVF unit. PATIENT(S): None. INTERVENTION(S): Searches of the Cochrane Controlled Trials Register, Meta-register for Randomized Controlled Trials (RCTs), EMBASE, MEDLINE, and SCISEARCH with no limitation on language and publication year, 1974 to 2008. SELECTION CRITERIA: randomized, controlled trials comparing e-SET with double-embryo transfer (DET) for live birth and multiple birth rates after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). Nonrandomized trials and studies that included only patients who had blastocyst transfer were excluded. MAIN OUTCOME MEASURE(S): The likelihood of live birth per patient and multiple birth per total number of live births. Other outcomes included implantation rate, pregnancy rate, miscarriage and ectopic pregnancy rates, clinical pregnancy rate, ongoing pregnancy rate per patient, and preterm delivery rate per live birth. RESULT(S): Six trials (n=1354 patients) were included in the meta-analysis. Compared with DET, the e-SET policy was associated with a statistically significant reduction in the probability of live birth (RR 0.62; 95% CI, 0.53-0.72) and multiple birth (RR 0.06; 95% CI, 0.02-0.18). CONCLUSION(S): Elective-SET of embryos at the cleavage stage reduces the likelihood of live birth by 38% and multiple birth by 94%. Evidence from randomized, controlled trials suggests that increasing the number of e-SET attempts (fresh and/or frozen) results in a cumulative live birth rate similar to that of DET. Offering subfertile women three cycles of IVF will have a major impact on the uptake of an e-SET policy.

Symposium: Update on prediction and management of OHSS. Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence?

There is an ongoing debate over the optimal dose of urinary HCG (u-HCG) that can trigger final oocyte maturation, leading to higher IVF success rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS). A systematic review was conducted of all studies that compared the effect of at least two doses of u-HCG for final oocyte maturation on IVF outcomes and on the incidence of OHSS. The primary outcome was the live birth rate, and the secondary end-points were the number of oocytes retrieved, fertilization, implantation and pregnancy rates, and the incidence of OHSS. Only two amongst the six included studies were randomized controlled trials (RCT). Meta-analytic pool was not feasible due to insufficient number of studies assessing the same outcome and significant heterogeneity. The majority of studies concluded that the clinical outcomes were similar between women receiving 5000 or 10,000 IU of u-HCG. The incidence of OHSS was not reduced in the high-risk population even with lower dose of u-HCG. Until large scale RCT addressing the clinical effectiveness and the adverse outcomes related to various doses of u-HCG are conducted, the dose of u-HCG for final oocyte maturation for women referred for IVF needs to be individualized.

Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization.

OBJECTIVE: To evaluate the clinical value of basal anti-Müllerian hormone (AMH) measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian response to gonadotrophin stimulation. DESIGN: Prospective cohort study. SETTING: Tertiary referral center for reproductive medicine and an IVF unit. PATIENT(S): Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). MATERIALS AND METHODS: Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded. MAIN OUTCOME MEASURE(S): Predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation. RESULT(S): Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other two groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation-AMH area under receiver operating characteristic curve (ROC(AUC)) 0.81, FSH ROC(AUC) 0.66, AFC ROC(AUC) 0.69. For poor response, AMH (ROC(AUC) 0.88) was a significantly better predictor than FSH (ROC(AUC) 0.63) but not AFC (ROC(AUC) 0.81). AMH prediction of ovarian response was independent of age and PCOS. Anti-Müllerian hormone cutoffs of >3.75 ng/mL and <1.0 ng/mL would have modest sensitivity and specificity in predicting the extremes of response. CONCLUSION(S): Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patient's ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.

The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta-analysis.

OBJECTIVE: To investigate the effect of surgical treatment of endometrioma on pregnancy rate and ovarian response to gonadotrophin stimulation in women undergoing IVF. DESIGN: A systematic review and meta-analysis. SETTING: Tertiary referral center for reproductive medicine. PATIENT(S): Subfertile women with endometrioma undergoing IVF. INTERVENTION(S): Surgical removal of endometrioma or expectant management. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate and ovarian response to gonadotrophins (number of gonadotrophin ampoules, peak E(2) levels, number of oocytes retrieved, and number of embryos available for transfer). RESULT(S): A search of three electronic databases for articles published between January 1985 and November 2007 yielded 20 eligible studies. Meta-analysis was conducted for five studies that compared surgery vs. no treatment of endometrioma. There was no significant difference in clinical pregnancy rate between the treated and the untreated groups. Similarly, no significant difference was found between the two groups with regard to the outcome measures used to assess the response to controlled ovarian hyperstimulation with gonadotrophins. CONCLUSION(S): Collectively the available data in the literature show that surgical management of endometriomas has no significant effect on IVF pregnancy rates and ovarian response to stimulation compared with no treatment. Randomized controlled trials are needed before producing best-practice recommendations on this topic.