In vitro fertilisation for unexplained subfertility.

BACKGROUND: In vitro fertilisation (IVF) is a treatment for unexplained subfertility but is invasive, expensive, and associated with risks. OBJECTIVES: To evaluate the effectiveness and safety of IVF versus expectant management, unstimulated intrauterine insemination (IUI), and IUI with ovarian stimulation using gonadotropins, clomiphene citrate (CC), or letrozole in improving pregnancy outcomes. SEARCH METHODS: We searched following databases from inception to November 2021, with no language restriction: Cochrane Gynaecology and Fertility Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL. We searched reference lists of articles and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing effectiveness of IVF for unexplained subfertility with expectant management, unstimulated IUI, and stimulated IUI. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: IVF versus expectant management (two RCTs) We are uncertain whether IVF improves live birth rate (LBR) and clinical pregnancy rate (CPR) compared to expectant management (odds ratio (OR) 22.0, 95% confidence interval (CI) 2.56 to 189.37; 1 RCT; 51 women; very low-quality evidence; OR 3.24, 95% CI 1.07 to 9.8; 2 RCTs; 86 women; I2 = 80%; very low-quality evidence). Adverse effects were not reported. Assuming 4% LBR and 12% CPR with expectant management, these would be 8.8% to 9% and 13% to 58% with IVF. IVF versus unstimulated IUI (two RCTs) IVF may improve LBR compared to unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12; 2 RCTs; 156 women; I2 = 60%; low-quality evidence). We are uncertain whether there is a difference between IVF and IUI for multiple pregnancy rate (MPR) (OR 1.03, 95% CI 0.04 to 27.29; 1 RCT; 43 women; very low-quality evidence) and miscarriage rate (OR 1.72, 95% CI 0.14 to 21.25; 1 RCT; 43 women; very low-quality evidence). No study reported ovarian hyperstimulation syndrome (OHSS). Assuming 16% LBR, 3% MPR, and 6% miscarriage rate with unstimulated IUI, these outcomes would be 18.5% to 49%, 0.1% to 46%, and 0.9% to 58% with IVF. IVF versus IUI + ovarian stimulation with gonadotropins (6 RCTs), CC (1 RCT), or letrozole (no RCTs) Stratified analysis was based on pretreatment status. Treatment-naive women There may be little or no difference in LBR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.19, 95% CI 0.87 to 1.61; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 1.63, 95% CI 0.91 to 2.92; 2 RCTs; 221 women; I2 = 54%; low-quality evidence); or between IVF and IUI + CC (OR 2.51, 95% CI 0.96 to 6.55; 1 RCT; 103 women; low-quality evidence). Assuming 42% LBR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 26% LBR with IUI + gonadotropins (1 IVF to 1 IUI cycle), LBR would be 39% to 54% and 24% to 51% with IVF. Assuming 15% LBR with IUI + CC, LBR would be 15% to 54% with IVF. There may be little or no difference in CPR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.17, 95% CI 0.85 to 1.59; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 4.59, 95% CI 1.86 to 11.35; 1 RCT; 103 women; low-quality evidence); or between IVF and IUI + CC (OR 3.58, 95% CI 1.51 to 8.49; 1 RCT; 103 women; low-quality evidence). Assuming 48% CPR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 17% with IUI + gonadotropins (1 IVF to 1 IUI cycle), CPR would be 44% to 60% and 28% to 70% with IVF. Assuming 21% CPR with IUI + CC, CPR would be 29% to 69% with IVF. There may be little or no difference in multiple pregnancy rate (MPR) between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 0.82, 95% CI 0.38 to 1.77; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 0.76, 95% CI 0.36 to 1.58; 2 RCTs; 221 women; I2 = 0%; low-quality evidence); or between IVF and IUI + CC (OR 0.64, 95% CI 0.17 to 2.41; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in OHSS between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 6.86, 95% CI 0.35 to 134.59; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference in OHSS with 1 IVF to 1 IUI cycle (OR 1.22, 95% CI 0.36 to 4.16; 2 RCTs; 221 women; I2 = 0%; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.53, 95% CI 0.24 to 9.57; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in miscarriage rate between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 0.31, 95% CI 0.03 to 3.04; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference with 1 IVF to 1 IUI cycle (OR 1.16, 95% CI 0.44 to 3.02; 1 RCT; 103 women; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.48, 95% CI 0.54 to 4.05; 1 RCT; 102 women; low-quality evidence). In women pretreated with IUI + CC IVF may improve LBR compared with IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57; 1 RCT; 280 women; low-quality evidence). Assuming 22% LBR with IUI + gonadotropins, LBR would be 39% to 65% with IVF. IVF may improve CPR compared with IUI + gonadotropins (OR 14.13, 95% CI 7.57 to 26.38; 1 RCT; 280 women; low-quality evidence). Assuming 30% CPR with IUI + gonadotropins, CPR would be 76% to 92% with IVF. AUTHORS' CONCLUSIONS: IVF may improve LBR over unstimulated IUI. Data should be interpreted with caution as overall evidence quality was low.

Endometriosis and oocyte quality: an analysis of 13 614 donor oocyte recipient and autologous IVF cycles.

STUDY QUESTION: Does endometriosis affect live birth following donor oocyte recipient versus autologous IVF? SUMMARY ANSWER: There was no significant difference in the live birth rate (LBR) in women with endometriosis undergoing donor oocyte recipient cycles versus autologous IVF cycles. WHAT IS KNOWN ALREADY: For infertile women with endometriosis, IVF is often considered as a treatment option. Lower implantation and pregnancy rates have been observed following IVF in women with endometriosis. It has been debated whether the lower pregnancy rate is due to the effect on oocyte quality or the endometrium, thus affecting implantation. To delineate whether endometriosis affects oocyte quality or the endometrium, we planned a study, using a donor oocyte recipient model, where the recipients were women diagnosed with endometriosis and compared their outcomes with women who underwent autologous IVF, who had also been diagnosed with endometriosis. STUDY DESIGN SIZE DURATION: Human Fertilization and Embryology Authority (HFEA) anonymized data from 1996 to 2016 were analyzed. This comprised of a total of 758 donor oocyte recipients, where the recipients were women diagnosed with endometriosis, and 12 856 autologous IVF cycles where the women were diagnosed with endometriosis as the sole cause of infertility. PARTICIPANTS/MATERIALS SETTING METHODS: Data on all women with endometriosis undergoing donor oocyte recipient and autologous IVF cycles were analyzed to compare live birth outcomes. Logistic regression analysis was performed adjusting for number of previous IVF cycles, previous live birth, period of treatment, day of embryo transfer, number of embryos transferred and fresh or frozen embryo transfer cycle. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient fresh embryo transfer cycles compared to women undergoing autologous IVF fresh embryo transfer cycles (31.6% vs 31.0%; odds ratio (OR) 1.03, 99.5% CI 0.79-1.35). After adjusting for confounders, there was no significant difference in LBR in women with endometriosis undergoing donor oocyte recipient fresh embryo transfer cycles versus autologous fresh embryo transfer cycles (adjusted OR (aOR) 1.05, 99.5% CI 0.79-1.41).There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient frozen embryo transfer cycles compared to women undergoing autologous frozen embryo transfer cycles (19.6% vs 24.0%; OR 0.77, 99.5% CI 0.47-1.25). After adjusting for potential confounders, there was no significant difference in the LBR in women undergoing donor oocyte recipient frozen embryo transfer cycles compared with autologous frozen embryo transfer cycles (aOR 0.85, 99.5% CI 0.51-1.41). LIMITATIONS REASONS FOR CAUTION: Although the analysis was adjusted for potential confounders, there was no information on the extent and classification of endometriosis as well as oocyte number. Furthermore, adenomyosis is thought to co-exist in women with endometriosis and may have independent pathophysiological mechanisms affecting fertility, for which there was no information. WIDER IMPLICATIONS OF THE FINDINGS: The study shows no difference in LBR between donor oocyte recipient cycles in which all recipients had endometriosis compared to autologous IVF cycles in women with endometriosis. Therefore, this study finding suggests that there may be a minimal or no effect of oocyte quality on IVF outcomes in women with endometriosis. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained. M.S.K. is an associate editor with Human Reproduction Open. He was not involved in the editorial or peer review process for the manuscript. TRIAL REGISTRATION NUMBER: N/A.

Female causes of infertility are associated with higher risk of preterm birth and low birth weight: analysis of 117 401 singleton live births following IVF.

STUDY QUESTION: Does the cause of infertility affect the perinatal outcomes preterm birth (PTB) and low birth weight (LBW) following IVF treatment? SUMMARY ANSWER: The risk of PTB and LBW was higher with female causes of infertility-ovulatory disorders, tubal disorders and endometriosis-compared to unexplained infertility but the absolute increase in risk was low. WHAT IS KNOWN ALREADY: Infertility is associated with an increased risk of adverse perinatal outcomes. Risk of adverse perinatal outcomes is also higher following ART compared to spontaneous conceptions. Infertility can result from female and/or male factors or is unexplained when the cause cannot be delineated by standard investigations. Given that infertility and ART are contributory to the adverse perinatal outcomes, it is a matter of interest to delineate if the specific cause of infertility influences perinatal outcomes following IVF treatment. STUDY DESIGN, SIZE, DURATION: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). The HFEA has collected data prospectively on all ART cycles performed in the UK since 1991. Data from 1991 to 2016 comprising a total of 117 401 singleton live births following IVF with or without ICSI (IVF ± ICSI) for sole causes of infertility were analysed for PTB and LBW. Cycles having more than one cause of infertility and/or multiple births were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on all women undergoing stimulated IVF ± ICSI treatment cycles were analysed to compare perinatal outcomes of PTB and LBW among singleton live births based on the cause of infertility (ovulatory disorders, tubal disorders, endometriosis, male factor, unexplained). Logistic regression analysis was performed, adjusting for female age category, period of treatment, previous live births, IVF or ICSI, number of embryos transferred and fresh or frozen embryo transfer cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to unexplained infertility, the risk of PTB was significantly higher with ovulatory disorders (adjusted odds ratio (aOR) 1.31, 99.5% CI 1.17 to 1.46); tubal disorders (aOR 1.25, 99.5% CI 1.14 to 1.38) and endometriosis (aOR 1.17, 99.5% CI 1.01 to 1.35). There was no significant difference in the risk of PTB with male factor causes compared to unexplained infertility (aOR 1.01, 99.5% CI 0.93, 1.10). The risk of LBW was significantly higher with ovulatory disorders (aOR 1. 29, 99.5% CI 1.16 to 1.44) and tubal disorders (aOR 1.12, 99.5% CI 1.02 to 1.23) and there was no increase in the risk of LBW with endometriosis (aOR 1.11, 99.5% CI 0.96 to 1.30) and male factor causes (aOR 0.94, 99.5% CI 0.87, 1.03), compared to unexplained infertility. LIMITATIONS, REASONS FOR CAUTION: Although the analysis was adjusted for several important confounders, there was no information on the medical history of women during pregnancy to allow adjustment. The limitations with observational data would apply to this study, including residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to address the causes of infertility affecting perinatal outcomes of PTB and LBW. The information is important for the management of pregnancies and the underlying reasons for the associations observed need to be further understood. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles.

RESEARCH QUESTION: How much the variability in patients' response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients' basal characteristics? DESIGN: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. RESULTS: Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients' characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). CONCLUSIONS: The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients' characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

Concordance between systematic reviews of randomized controlled trials in assisted reproduction: an overview.

STUDY QUESTION: Are systematic reviews published within a 3-year period on interventions in ART concordant in their conclusions? SUMMARY ANSWER: The majority of the systematic reviews published within a 3-year period in the field of assisted reproduction on the same topic had discordant conclusions. WHAT IS KNOWN ALREADY: Systematic reviews and meta-analyses have now replaced individual randomized controlled trials (RCTs) at the top of the evidence pyramid. There has been a proliferation of systematic reviews and meta-analyses, many of which suffer from methodological issues and provide varying conclusions. STUDY DESIGN SIZE DURATION: We assessed nine interventions in women undergoing ART with at least three systematic reviews each, published from January 2015 to December 2017. PARTICIPANTS/MATERIALS SETTING METHODS: The systematic reviews which included RCTs were considered eligible for inclusion. The primary outcome was extent of concordance between systematic reviews on the same topic. Secondary outcomes included assessment of quality of systematic reviews, differences in included studies in meta-analyses covering the same search period, selective reporting and reporting the quality of evidence. MAIN RESULTS AND THE ROLE OF CHANCE: Concordant results and conclusions were found in only one topic, with reviews in the remaining eight topics displaying partial discordance. The AMSTAR grading for the majority of the non-Cochrane reviews was critically low whilst it was categorized as high for all of the Cochrane reviews. For three of the nine topics, none of the included systematic reviews assessed the quality of evidence. We were unable to assess selective reporting as most of the reviews did not have a pre-specified published protocol. LIMITATIONS REASONS FOR CAUTION: We were limited by the high proportion of reviews lacking a pre-specified protocol, which made it impossible to assess for selective reporting. Furthermore, many reviews did not specify primary and secondary outcomes which made it difficult to assess reporting bias. All the authors of this review were Cochrane review authors which may introduce some assessment bias. The categorization of the review's conclusions as beneficial, harmful or neutral was subjective, depending on the tone and wording of the conclusion section of the review. WIDER IMPLICATIONS OF THE FINDINGS: The majority of the systematic reviews published within a 3-year period on the same topic in the field of assisted reproduction revealed discordant conclusions and suffered from serious methodological issues, hindering the process of informed healthcare decision-making. STUDY FUNDING/COMPETING INTERESTS: All the authors are Cochrane authors. M.S.K. is an editorial board member of Cochrane Gynaecology and Fertility group. No grant from funding agencies in the public, commercial or not-for-profit sectors was obtained.

ESHRE guideline: ovarian stimulation for IVF/ICSI†.

STUDY QUESTION: What is the recommended management of ovarian stimulation, based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group formulated 84 recommendations answering 18 key questions on ovarian stimulation. WHAT IS KNOWN ALREADY: Ovarian stimulation for IVF/ICSI has been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems, and the Royal Australian and New Zealand College of Obstetricians and Gynaecologist has published a statement on ovarian stimulation in assisted reproduction. There are, to our knowledge, no evidence-based guidelines dedicated to the process of ovarian stimulation. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 8 November 2018 and written in English were included. The critical outcomes for this guideline were efficacy in terms of cumulative live birth rate per started cycle or live birth rate per started cycle, as well as safety in terms of the rate of occurrence of moderate and/or severe ovarian hyperstimulation syndrome (OHSS). PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 84 recommendations: 7 recommendations on pre-stimulation management, 40 recommendations on LH suppression and gonadotrophin stimulation, 11 recommendations on monitoring during ovarian stimulation, 18 recommendations on triggering of final oocyte maturation and luteal support and 8 recommendations on the prevention of OHSS. These include 61 evidence-based recommendations-of which only 21 were formulated as strong recommendations-and 19 good practice points and 4 research-only recommendations. The guideline includes a strong recommendation for the use of either antral follicle count or anti-Müllerian hormone (instead of other ovarian reserve tests) to predict high and poor response to ovarian stimulation. The guideline also includes a strong recommendation for the use of the GnRH antagonist protocol over the GnRH agonist protocols in the general IVF/ICSI population, based on the comparable efficacy and higher safety. For predicted poor responders, GnRH antagonists and GnRH agonists are equally recommended. With regards to hormone pre-treatment and other adjuvant treatments (metformin, growth hormone (GH), testosterone, dehydroepiandrosterone, aspirin and sildenafil), the guideline group concluded that none are recommended for increasing efficacy or safety. LIMITATIONS REASON FOR CAUTION: Several newer interventions are not well studied yet. For most of these interventions, a recommendation against the intervention or a research-only recommendation was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in ovarian stimulation, based on the best evidence available. In addition, a list of research recommendations is provided to promote further studies in ovarian stimulation. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. F.B. reports research grant from Ferring and consulting fees from Merck, Ferring, Gedeon Richter and speaker's fees from Merck. N.P. reports research grants from Ferring, MSD, Roche Diagnositics, Theramex and Besins Healthcare; consulting fees from MSD, Ferring and IBSA; and speaker's fees from Ferring, MSD, Merck Serono, IBSA, Theramex, Besins Healthcare, Gedeon Richter and Roche Diagnostics. A.L.M reports research grants from Ferring, MSD, IBSA, Merck Serono, Gedeon Richter and TEVA and consulting fees from Roche, Beckman-Coulter. G.G. reports consulting fees from MSD, Ferring, Merck Serono, IBSA, Finox, Theramex, Gedeon-Richter, Glycotope, Abbott, Vitrolife, Biosilu, ReprodWissen, Obseva and PregLem and speaker's fees from MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Gedeon Richter, Glycotope, Abbott, Vitrolife and Biosilu. E.B. reports research grants from Gedeon Richter; consulting and speaker's fees from MSD, Ferring, Abbot, Gedeon Richter, Merck Serono, Roche Diagnostics and IBSA; and ownership interest from IVI-RMS Valencia. P.H. reports research grants from Gedeon Richter, Merck, IBSA and Ferring and speaker's fees from MSD, IBSA, Merck and Gedeon Richter. J.U. reports speaker's fees from IBSA and Ferring. N.M. reports research grants from MSD, Merck and IBSA; consulting fees from MSD, Merck, IBSA and Ferring and speaker's fees from MSD, Merck, IBSA, Gedeon Richter and Theramex. M.G. reports speaker's fees from Merck Serono, Ferring, Gedeon Richter and MSD. S.K.S. reports speaker's fees from Merck, MSD, Ferring and Pharmasure. E.K. reports speaker's fees from Merck Serono, Angellini Pharma and MSD. M.K. reports speaker's fees from Ferring. T.T. reports speaker's fees from Merck, MSD and MLD. The other authors report no conflicts of interest. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.) †ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.

Management Strategies for POSEIDON Group 2.

Although individualization of ovarian stimulation aims at maximal efficacy and safety in assisted reproductive treatments, in its current form it is far from ideal in achieving the desired success in women with a low prognosis. This could be due a failure to identify such women who are likely to have a low prognosis with currently used prognostic characteristics. Introduction of the patient-oriented strategies encompassing individualized oocyte number (POSEIDON) concept reinforces recognizing such low prognosis groups and stratifying in accordance with important prognostic factors. The POSEIDON concept provides a practical approach to the management of these women and is a useful tool for both counseling and clinical management. In this commentary, we focus on likely management strategies for POSEIDON group 2 criteria.

Granulocyte-colony stimulating factor administration for subfertile women undergoing assisted reproduction.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in the process of embryo implantation and continuation of pregnancy. It has been used during in vitro fertilisation (IVF) treatment for subfertile women with chronically thin endometrium and those with previous multiple IVF failures. It is currently unknown whether G-CSF is effective in improving results following assisted reproductive technology (ART). OBJECTIVES: To evaluate the effectiveness and safety of G-CSF in women undergoing ART. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform in February 2019. We searched reference lists of relevant articles and handsearched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing G-CSF administration versus no treatment or placebo in subfertile women undergoing IVF treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data, and assessed risk of bias. The primary outcomes were live-birth rate and miscarriage rate following G-CSF administration. We have reported ongoing pregnancy rate in cases where studies did not report live birth but reported ongoing pregnancy. Secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, adverse events, ectopic pregnancy rate, small for gestational age at birth, abnormally adherent placenta, and congenital anomaly rate. We analysed data using risk ratio (RR), Peto odds ratio and a fixed-effect model. We assessed the quality of the evidence using the GRADE criteria. MAIN RESULTS: We included 15 trials involving 622 women who received G-CSF and 631 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 15 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate. We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.42, 95% confidence interval (CI) 0.83 to 2.42; 2 RCTs; participants = 263; I² = 0%; very low-quality evidence). For a typical clinic with 14% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 12% and 35%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.55, 95% CI 0.17 to 1.83; 3 RCTs; participants = 391; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART. We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.63, 95% CI 1.32 to 2.01; 14 RCTs; participants = 1253; I² = 13%; very low-quality evidence). For a typical clinic with 17% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 35%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.11, 95% CI 0.77 to 1.60; 3 RCTs; participants = 404; I² = 0%; low-quality evidence). G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.11, 95% CI 1.56 to 2.85; 7 RCTs; participants = 643; I² = 0%; low-quality evidence). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment. AUTHORS' CONCLUSIONS: In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.

Erratum: ESHRE guideline: ovarian stimulation for IVF/ICSI.

[This corrects the article DOI: 10.1093/hropen/hoaa009.][This corrects the article DOI: 10.1093/hropen/hoaa009.].

Clinical adjuncts in in vitro fertilization: a growing list.

A growing list of clinical adjuncts are being used during in vitro fertilization (IVF) treatment. Most of these IVF add-ons (such as growth hormone, aspirin, heparin, dehydroepiandrostenedione, testosterone, male and female antioxidants, and screening hysteroscopy) are being introduced into routine clinical practice in a hurried manner without any clear evidence of benefit in most cases. These add-ons make the IVF more complicated and increase the overall cost for the treatment, which is borne by the couples and health care providers. Our current review found no high-quality evidence to support the use of these IVF add-ons in routine practice. Large, well-designed, randomized trials must be conducted to evaluate the effectiveness and safety of these interventions. There is also a pressing need to develop an evidence-dictated mechanism for introducing newer interventions into routine clinical settings.

Perinatal Outcomes Following Assisted Reproductive Technology.

As the use of routine assisted reproductive technology (ART) becomes widespread along with the extended applications such as ART with donor gametes, surrogacy, and preimplantation genetic testing (PGT), it becomes more pertinent to evaluate risks associated with them. Perinatal outcomes and long-term safety for the women and children are paramount. In this review, we aimed to detail the perinatal outcomes in relation to the ART procedures routinely applied as the extended applications of ART with a focus on singleton pregnancies. While there seems to be a higher risk of adverse perinatal outcomes with some of the ART procedures, the absolute risk increase is generally low. It is important for clinicians to have this knowledge to better counsel and care for their patients.

Screening hysteroscopy in subfertile women and women undergoing assisted reproduction.

BACKGROUND: Screening hysteroscopy in infertile women with unexplained infertility, or prior to intrauterine insemination (IUI) or in vitro fertilisation (IVF) may reveal intrauterine pathology that may not be detected by routine transvaginal ultrasound. Hysteroscopy, whether purely diagnostic or operative may improve reproductive outcomes. OBJECTIVES: To assess the effectiveness and safety of screening hysteroscopy in subfertile women undergoing evaluation for infertility, and subfertile women undergoing IUI or IVF. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL CRSO, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (September 2018). We searched reference lists of relevant articles and handsearched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials comparing screening hysteroscopy versus no intervention in subfertile women wishing to conceive spontaneously, or before undergoing IUI or IVF. DATA COLLECTION AND ANALYSIS: We independently screened studies, extracted data, and assessed the risk of bias. The primary outcomes were live birth rate and complications following hysteroscopy. We analysed data using risk ratio (RR) and a fixed-effect model. We assessed the quality of the evidence by using GRADE criteria. MAIN RESULTS: We retrieved 11 studies. We included one trial that evaluated screening hysteroscopy versus no hysteroscopy, in women with unexplained subfertility, who were trying to conceive spontaneously. We are uncertain whether ongoing pregnancy rate improves following a screening hysteroscopy in women with at least two years of unexplained subfertility (RR 4.30, 95% CI 2.29 to 8.07; 1 RCT; participants = 200; very low-quality evidence). For a typical clinic with a 10% ongoing pregnancy rate without hysteroscopy, performing a screening hysteroscopy would be expected to result in ongoing pregnancy rates between 23% and 81%. The included study reported no adverse events in either treatment arm. We are uncertain whether clinical pregnancy rate is improved (RR 3.80, 95% CI 2.31 to 6.24; 1 RCT; participants = 200; very low-quality evidence), or miscarriage rate increases (RR 2.80, 95% CI 1.05 to 7.48; 1 RCT; participants = 200; very low-quality evidence), following screening hysteroscopy in women with at least two years of unexplained subfertility.We included ten trials that included 1836 women who had a screening hysteroscopy and 1914 women who had no hysteroscopy prior to IVF. Main limitations in the quality of evidence were inadequate reporting of study methods and higher statistical heterogeneity. Eight of the ten trials had unclear risk of bias for allocation concealment.Performing a screening hysteroscopy before IVF may increase live birth rate (RR 1.26, 95% CI 1.11 to 1.43; 6 RCTs; participants = 2745; I² = 69 %; low-quality evidence). For a typical clinic with a 22% live birth rate, performing a screening hysteroscopy would be expected to result in live birth rates between 25% and 32%. However, sensitivity analysis done by pooling results from trials at low risk of bias showed no increase in live birth rate following a screening hysteroscopy (RR 0.99, 95% CI 0.82 to 1.18; 2 RCTs; participants = 1452; I² = 0%).Only four trials reported complications following hysteroscopy; of these, three trials recorded no events in either group. We are uncertain whether a screening hysteroscopy is associated with higher adverse events (Peto odds ratio 7.47, 95% CI 0.15 to 376.42; 4 RCTs; participants = 1872; I² = not applicable; very low-quality evidence).Performing a screening hysteroscopy before IVF may increase clinical pregnancy rate (RR 1.32, 95% CI 1.20 to 1.45; 10 RCTs; participants = 3750; I² = 49%; low-quality evidence). For a typical clinic with a 28% clinical pregnancy rate, performing a screening hysteroscopy would be expected to result in clinical pregnancy rates between 33% and 40%.There may be little or no difference in miscarriage rate following screening hysteroscopy (RR 1.01, 95% CI 0.67 to 1.50; 3 RCTs; participants = 1669; I² = 0%; low-quality evidence).We found no trials that compared a screening hysteroscopy versus no hysteroscopy before IUI. AUTHORS' CONCLUSIONS: At present, there is no high-quality evidence to support the routine use of hysteroscopy as a screening tool in the general population of subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work-up for improving reproductive success rates.In women undergoing IVF, low-quality evidence, including all of the studies reporting these outcomes, suggests that performing a screening hysteroscopy before IVF may increase live birth and clinical pregnancy rates. However, pooled results from the only two trials with a low risk of bias did not show a benefit of screening hysteroscopy before IVF.Since the studies showing an effect are those with unclear allocation concealment, we are uncertain whether a routine screening hysteroscopy increases live birth and clinical pregnancy, be it for all women, or those with two or more failed IVF attempts. There is insufficient data to draw conclusions about the safety of screening hysteroscopy.

Perinatal outcomes of singleton live births with and without vanishing twin following transfer of multiple embryos: analysis of 113 784 singleton live births.

STUDY QUESTION: Does transfer of multiple embryos affect perinatal outcomes of resulting singleton live births following ART? SUMMARY ANSWER: There is a higher risk of preterm birth (PTB) and low birthweight (LBW) in singleton live births associated with spontaneous reduction of an initial multiple to singleton gestation following transfer of multiple embryos. WHAT IS KNOWN ALREADY: Singleton pregnancies following ART are at a higher risk of adverse perinatal outcomes compared to spontaneous conceptions. Earlier studies have found an increased risk of PTB and LBW in singletons following transfer of multiple embryos versus single embryo transfer (SET). However, these studies did not address the specific role of vanishing twin, i.e. spontaneous reduction of an initial multiple to singleton gestation. STUDY DESIGN, SIZE, DURATION: Anonymised data on all ART cycles performed in the UK were obtained from the Human Fertilization and Embryology Authority. Data from 1991 to 2011 involving 508 410 fresh and 131 157 frozen autologous ART cycles resulting in 95 779 and 18 005 singleton live births, respectively, were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fresh and frozen ART cycles were analyzed separately to compare perinatal outcomes of PTB and LBW of singleton live births resulting from transfer of multiple (≥2) embryos versus SET. Logistic regression analysis was performed adjusting for confounders. Subgroup analyses were carried out for perinatal outcomes of singleton live births with initial multiple or initial single gestational sacs following transfer of multiple embryos versus singleton live births following SET. MAIN RESULTS AND THE ROLE OF CHANCE: In fresh cycles, there was a significantly higher risk of PTB (adjusted odds ratio (aOR) 2.70, CI 2.37-3.05) and LBW (aOR 2.76, CI 2.44-3.13) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.08, CI 1.00-1.16) or LBW (aOR 1.08, CI 1.00-1.16) in singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. In frozen cycles, there was a significantly higher risk of PTB (aOR 2.13, CI: 1.55-2.93) and LBW (aOR 2.61, CI: 1.87-3.64) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.02, CI: 0.88-1.18) or LBW (aOR 0.91, CI: 0.77-1.07) in the singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. LIMITATIONS, REASONS FOR CAUTION: While the analysis was adjusted for a number of known confounders, the dataset had no information for confounders such as smoking, BMI, previous obstetric history and comorbid medical conditions during pregnancy. The lack of information about the timing of occurrence of the vanishing phenomenon is another limitation because poorer perinatal outcomes of a surviving twin have been reported following second trimester fetal demise compared to the first trimester. WIDER IMPLICATIONS OF THE FINDINGS: The study results suggest that the vanishing twin phenomenon is associated with increased risk of PTB and LBW in the resulting singleton live births and there was no increased risk when there was a single gestational sac from the outset following transfer of multiple embryos. STUDY FUNDING/COMPETING INTERESTS: Nil.

New strategies of ovarian stimulation based on the concept of ovarian follicular waves: From conventional to random and double stimulation.

The theory of a multicyclic development of follicles during the menstrual cycle prompted new approaches to ovarian stimulation, such as starting gonadotrophins for ovarian stimulation at any time during the menstrual cycle or using double stimulation during it, with stimulation in both the follicular and luteal phases. Because of the asynchrony between endometrial receptivity and embryo development with a 'non-conventional start' stimulation, all the oocytes/embryos are generally cryopreserved and transferred subsequently. This deferred transfer policy is currently possible given the advances in vitrification techniques, with success rates comparable to those following transfer with 'fresh' embryos. New stimulation approaches, together with advanced cryopreservation techniques, allow for a total 'disarticulation' between the time of the menstrual cycle, ovarian stimulation start and embryo transfer. This new approach to ovarian stimulation is particularly useful for women seeking fertility preservation, especially where a shortened time to starting cancer treatment is desirable. Also, poor responders could benefit from the new stimulation protocols by continuing ovarian stimulation after the first oocyte retrieval, thereby obtaining more oocytes or embryos compared with the conventional approach.

Perinatal outcomes following IVF with use of donor versus partner sperm.

It is a matter of interest whether pregnancies with the use of donor sperm are associated with a higher risk of adverse perinatal outcomes compared with partner sperm. Anonymized data were obtained from the Human Fertilization & Embryology Authority. Data from 1991 to 2011 involving a total of 95,787 singleton births (4523 with donor sperm and 91,264 with partner sperm) following fresh IVF/intracytoplasmic sperm injection (ICSI) were analysed to compare perinatal outcomes of preterm birth (PTB), low birthweight (LBW) and high birthweight (HBW). The risk of LBW was significantly lower (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI]: 0.79-0.99) following donor sperm versus partner sperm IVF/ICSI. There was no significant difference in the risk of PTB (aOR 0.93, 95% CI: 0.83-1.04), early PTB (aOR 0.86, 95% CI: 0.67-1.11), very LBW (aOR 0.95, 95% CI: 0.75-1.20), HBW (aOR 1.09, 95% CI: 0.98-1.21) and very HBW (aOR 1.15, 95% CI: 0.90-1.45) following donor sperm versus partner sperm IVF/ICSI. The current study did not demonstrate an increased risk of adverse perinatal outcomes following donor sperm compared with partner sperm IVF/ICSI treatment.

Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis.

Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials. Perinatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA) and congenital anomalies. Data from four studies, which included a total of 96,996 and 704 singleton live births after stimulated IVF and natural or modified natural cycle IVF, were included in the meta-analysis. The risk of PTB (RR 1.27, 95% CI 1.03 to 1.58) and LBW (RR 1.95, 95% CI 1.03 to 3.67) were significantly higher after stimulated compared with natural or modified natural cycle IVF. Data from one study were available for SGA, LGA, congenital anomalies and no significant differences were reported between the groups. This study suggests a higher risk of PTB and LBW after stimulated IVF compared with natural or modified natural IVF, although the absolute increase in risk may be low.

Higher risk of preterm birth and low birth weight following oocyte donation: A systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of the known literature to assess whether the perinatal outcomes are different after oocyte donation (OD) compared to autologous oocyte (AO) in vitro fertilization (IVF) pregnancies. STUDY DESIGN: A systematic literature search was done for studies published in English from 1980 to 2016. Studies comparing perinatal outcomes of pregnancies following fresh or frozen OD and AO IVF were included. Meta-analysis was performed using the Rev Man 5.3 software (Cochrane Collaboration) for the perinatal outcomes of PTB (<37 weeks), early PTB (<32 weeks), LBW (<2500g), very LBW (<1500g), and SGA (<10th centile). Six studies provided data on PTB, three studies on early PTB, five studies on LBW, four studies on very LBW and three studies on SGA after fresh embryo transfer. Two studies provided data on PTB, early PTB, LBW and very LBW after frozen embryo transfer. RESULTS: There is an increased risk of PTB following fresh embryo transfer in OD pregnancies than in AO IVF pregnancies (OR 1.45, 95% CI 1.20-1.77). If the PTB risk is assumed to be to 9% for pregnancies following AO IVF, then OD pregnancies will have a PTB risk between 10.8% and 15.9%. Similarly, the risk of LBW is higher after fresh embryo transfer in OD pregnancies than AO IVF pregnancies (OR 1.34, 95% CI 1.12-1.60). If the assumed LBW risk is 9% for AO IVF pregnancies, then OD pregnancies have a LBW risk between 10.1% and 14.4%. There is an increased risk of early PTB (OR 2.14, 95% CI 1.40-3.25) and very LBW (OR 1.51, 95% CI 1.17-1.95) in a fresh embryo transfer after OD as compared to AO IVF pregnancies. CONCLUSIONS: There appears to be a higher risk of adverse perinatal outcomes following fresh OD compared to AO IVF pregnancies.

Perinatal outcomes after gestational surrogacy versus autologous IVF: analysis of national data.

Anonymized data were obtained from the Human Fertilization and Embryology Authority to determine whether gestational surrogacy influences perinatal outcomes compared with pregnancies after autologous IVF. A total of 103,160 singleton live births, including 244 after gestational surrogacy, 87,571 after autologous fresh IVF and intractyoplasmic sperm injection (ICSI) and 15,345 after autologous frozen embryo transfers were analysed. Perinatal outcomes of pretern birth (PTB), low birth weight (LBW) and high birth weight (HBW) were compared. No difference was found in the risk of PTB and LBW after gestational surrogacy compared with autologous fresh IVF-ICSI: PTB (adjusted OR 0.90, 95% CI 0.56 to 1.42), LBW (adjusted OR 0.90, 95% CI 0.57 to 1.43) and gestational surrogacy compared with autologous frozen embryo transfers: PTB (adjusted OR 0.96, 95% CI 0.58 to 1.60), LBW (adjusted OR 1.16, 95% CI 0.69 to 1.96). The incidence of HBW was significantly higher after gestational surrogacy compared with fresh IVF-ICSI (adjusted OR 1.94, 95% CI 1.38 to 2.75); no difference was found in HBW between gestational surrogacy and autologous frozen embryo transfers. The dataset is limited by lack of information on confounders, i.e. ethnicity, body mass index, underlying medical history, which could result in residual confounding.

High-risk of preterm birth and low birth weight after oocyte donation IVF: analysis of 133,785 live births.

A higher risk of pregnancy complications occurs after assisted reproductive techniques compared with spontaneously conceived pregnancies. This is attributed to the underlying infertility and assisted reproduction technique procedures involved during treatment. It is a matter of interest whether use of donor oocytes affects perinatal outcomes compared with pregnancies after autologous IVF. Anonymized data were obtained from the Human Fertilization and Embryology Authority. The analysis included 5929 oocyte donation and 127,856 autologous IVF live births. Data from all women who underwent donor oocyte recipient or autologous IVF cycles, both followed with fresh embryo transfer, were analysed to compare perinatal outcomes of preterm birth (PTB) and low birthweight (LBW) after singleton and multiple live births. The risk of adverse perinatal outcomes after oocyte donation was increased: adjusted OR (aOR) 1.56, 99.5% CI 1.34 to 1.80 for PTB and aOR 1.43, 99.5% CI 1.24 to 1.66 for LBW were significantly higher after oocyte donation compared with autologous IVF singletons. The adjusted odds PTB (aOR 1.21, 99.5% CI 1.02 to 1.43) was significantly higher after oocyte donation compared with autologous IVF multiple births. Analysis of this large dataset suggests significantly higher risk of PTB and LBW after ooctye donation compared with autologous IVF pregnancies.