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Background: During a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper-response are associated with increased chance of cycle cancellation. Hyper-response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes., Objectives: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI., Search Methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies., Selection Criteria: We included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration., Main Results: We included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.Direct dose comparisons in women according to predicted responseAll evidence was low or very low quality.Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I 2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).ORT-algorithm studiesFour trials compared an ORT-based algorithm to a non-ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I 2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I 2 =0%, moderate-quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I 2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I 2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT-based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT-based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs., Authors' Conclusions: We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate-quality evidence suggests that ORT-based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT-based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS.

In this paper, a review of evidence provided to the World Health Organization (WHO) guideline development, who prepare global guidance on the management of ovarian stimulation for women undergoing IVF, is presented. The purpose of ovarian stimulation is to facilitate retrieval of multiple oocytes during a single IVF cycle. Availability of multiple oocytes compensates for inefficiencies in subsequent stages of the cycle, which include oocyte maturation, IVF, embryo culture, embryo transfer, and implantation. Multiple embryos can be transferred in most women, and spare embryos can be frozen to allow for future chances of pregnancy without the need for repeated ovarian stimulation and oocyte retrieval. Our evidence synthesis team addressed 10 clinical questions on management of ovarian stimulation for IVF, prepared a narrative review of the evidence and drafted recommendations to be considered through WHO guideline development processes. Our main outcome measures were live birth, clinical pregnancy, and ovarian hyperstimulation syndrome., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

In women with polycystic ovary syndrome, metformin treatment before or during assisted reproductive technology cycles increases clinical pregnancy rates and decreases the risk of ovarian hyperstimulation syndrome. However, there is no conclusive evidence of a benefit in live birth rates., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Ten per cent to 15% of couples have difficulty in conceiving. A proportion of these couples will ultimately require assisted reproduction. Prior to controlled ovarian hyperstimulation (COH) a baseline ultrasound is performed to detect the presence of ovarian cysts.Previous research has suggested that there is a relationship between the presence of an ovarian cyst prior to COH and poor outcome during IVF., Objectives: The aim of this review was to determine the effectiveness and safety of functional ovarian cyst aspiration prior to ovarian stimulation versus a conservative approach in women with an ovarian cyst who were undergoing IVF or ICSI., Search Methods: We searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov, Google Scholar and PubMed. The evidence was current to April 2014 and no language restrictions were applied., Selection Criteria: We included all randomised controlled trials (RCTs) comparing functional ovarian cyst aspiration versus conservative management of ovarian cysts that have been seen on transvaginal ultrasound (TVS) prior to COH for IVF or ICSI. Ovarian cysts were defined as simple, functional ovarian cysts > 20 mm in diameter. Oocyte donors and women undergoing donor oocyte cycles were excluded., Data Collection and Analysis: Study selection, data extraction and risk of bias assessments were conducted independently by two review authors. The primary outcome measures were live birth rate and adverse events. The overall quality of the evidence for each comparison was rated using GRADE methods., Main Results: Three studies were eligible for inclusion (n = 339), all of which used agonist protocols. Neither live birth rate nor adverse events were reported by any of the included studies. There was no conclusive evidence of a difference between the group who underwent ovarian cyst aspiration and the conservatively managed group in the clinical pregnancy rate (OR 1.40, 95% CI 0.67 to 2.94, 3 studies, 339 women, I(2) = 0%, low quality evidence). This suggested that if the clinical pregnancy rate in women with conservative management was assumed to be 5%, the chance following cyst aspiration would be between 4% and 14%. There was no evidence of a difference between the groups in the mean number of follicles recruited (0.55 follicles, 95% CI -0.48 to 1.59, 2 studies, 159 women, I(2) = 0%, low quality evidence) or mean number of oocytes collected (0.41 oocytes, 95% CI -0.04 to 0.85, 3 studies, 339 women, I(2) = 0%, low quality evidence). Findings for the cancellation rate (two studies) were inconsistent but neither study reported a benefit for the aspiration group. The main limitations of the evidence were imprecision, inconsistency, questionable applicability, and poor reporting of study methods., Authors' Conclusions: There is insufficient evidence to determine whether drainage of functional ovarian cysts prior to controlled ovarian hyperstimulation influences live birth rate, clinical pregnancy rate, number of follicles recruited, or oocytes collected in women with a functional ovarian cyst. The findings of this review do not provide supportive evidence for this approach, particularly in view of the requirement for anaesthesia, extra cost, psychological stress and risk of surgical complications.

Background: Multiple embryo transfer during in vitro fertilisation (IVF) increases multiple pregnancy rates causing maternal and perinatal morbidity. Single embryo transfer is now being seriously considered as a means of minimising the risk of multiple pregnancy. However, this needs to be balanced against the risk of jeopardising the overall live birth rate., Objectives: To evaluate the effectiveness and safety of different policies for the number of embryos transferred in couples who undergo assisted reproductive technology (ART)., Search Methods: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, from inception to July 2013. We handsearched reference lists of articles, trial registers and relevant conference proceedings and contacted researchers in the field., Selection Criteria: We included randomised controlled trials (RCTs) comparing different policies for the number of embryos transferred following IVF or intra-cytoplasmic sperm injection (ICSI) in subfertile women. Studies of fresh or frozen and thawed transfer of one, two, three or four embryos at cleavage or blastocyst stage were eligible., Data Collection and Analysis: Two review authors independently assessed trial eligibility and risk of bias and extracted the data. The overall quality of the evidence was graded in a summary of findings table., Main Results: Fourteen RCTs were included in the review (2165 women). Thirteen compared cleavage-stage transfers (2017 women) and two compared blastocyst transfers (148 women): one study compared both. No studies compared repeated multiple versus repeated single embryo transfer (SET). DET versus repeated SETDET was compared with repeated SET in three studies of cleavage-stage transfer. In these studies the SET group received either two cycles of fresh SET (one study) or one cycle of fresh SET followed by one frozen SET in a natural or hormone-stimulated cycle (two studies). When these three studies were pooled, the cumulative live birth rate after one cycle of DET was not significantly different from the rate after repeated SET (OR 1.22, 95% CI 0.92 to 1.62, three studies, n=811, I(2)=0%, low quality evidence). This suggests that for a woman with a 40% chance of live birth following a single cycle of DET, the chance following repeated SET would be between 30% and 42%. The multiple pregnancy rate was significantly higher in the DET group (OR 30.54, 95% CI 7.46 to 124.95, three RCTs, n = 811, I(2) = 23%, low quality evidence), suggesting that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following repeated SET would be between 0% and 2%. Single-cycle DET versus single-cycle SETA single cycle of DET was compared with a single cycle of SET in 10 studies, nine comparing cleavage-stage transfers and two comparing blastocyst-stage transfers. When all studies were pooled the live birth rate was significantly higher in the DET group (OR 2.07, 95% CI 1.68 to 2.57, nine studies, n = 1564, I(2) = 0%, high quality evidence). This suggests that for a woman with a 40% chance of live birth following a single cycle of DET, the chance following a single cycle of SET would be between 22% and 30%. The multiple pregnancy rate was also significantly higher in the DET group (OR 8.47, 95% CI 4.97 to 14.43, 10 studies, n = 1612, I(2) = 45%, high quality evidence), suggesting that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following a single cycle of SET would be between 1% and 4%. The heterogeneity for this analysis was attributable to a study with a high rate of cross-over between treatment arms. Other comparisons Other fresh cycle comparisons were evaluated in three studies which compared DET versus transfer of three or four embryos. Live birth rates did not differ significantly between the groups for any comparison, but there was a significantly lower multiple pregnancy rate in the DET group than in the three embryo transfer (TET) group (OR 0.36, 95% CI 0.13 to 0.99, two studies, n = 343, I(2) = 0%)., Authors' Conclusions: In a single fresh IVF cycle, single embryo transfer is associated with a lower live birth rate than double embryo transfer. However, there is no evidence of a significant difference in the cumulative live birth rate when a single cycle of double embryo transfer is compared with repeated SET (either two cycles of fresh SET or one cycle of fresh SET followed by one frozen SET in a natural or hormone-stimulated cycle). Single embryo transfer is associated with much lower rates of multiple pregnancy than other embryo transfer policies. A policy of repeated SET may minimise the risk of multiple pregnancy in couples undergoing ART without substantially reducing the likelihood of achieving a live birth. Most of the evidence currently available concerns younger women with a good prognosis.