BEYOND: a randomized controlled trial comparing efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus antagonist protocol during the first ovarian stimulation cycle.

STUDY QUESTION: How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation? SUMMARY ANSWER: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS). WHAT IS KNOWN ALREADY: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively). LIMITATIONS, REASONS FOR CAUTION: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown. WIDER IMPLICATIONS OF THE FINDINGS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol. STUDY FUNDING/COMPETING INTEREST(S): The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40. TRIAL REGISTRATION DATE: 7 April 2019. DATE OF FIRST PATIENT'S ENROLMENT: 2 May 2019.

Home-based monitoring of ovulation to time frozen embryo transfers in the Netherlands (Antarctica-2): an open-label, nationwide, randomised, non-inferiority trial.

BACKGROUND: The growing field of assisted reproductive techniques, including frozen-thawed embryo transfer (FET), should lead the way to the best sustainable health care without compromising pregnancy chances. Correct timing of FET is crucial to allow implantation of the thawed embryo. Nowadays, timing based on hospital-controlled monitoring of ovulation in the natural cycle of a woman is the preferred strategy because of the assumption of favourable fertility prospects. However, home-based monitoring is a simple method to prevent patient travel and any associated environmental concerns. We compared ongoing pregnancy rates after home-based monitoring versus hospital-controlled monitoring with ovulation triggering. METHODS: This open-label, multicentre, randomised, non-inferiority trial was undertaken in 23 hospitals and clinics in the Netherlands. Women aged between 18 and 44 years with a regular ovulatory menstrual cycle were randomly assigned in a 1:1 ratio via a web-based randomisation program to home-based monitoring or hospital-controlled monitoring. Those who analysed the data were masked to the groups; those collecting the data were not. All endpoints were analysed by intention to treat and per protocol. Non-inferiority was established when the lower limit of the 90% CI exceeded -4%. This study was registered at the Dutch Trial Register (Trial NL6414). FINDINGS: 1464 women were randomly assigned between April 10, 2018, and April 13, 2022, with 732 allocated to home-based monitoring and 732 to hospital-controlled monitoring. Ongoing pregnancy occurred in 152 (20·8%) of 732 in the home-based monitoring group and in 153 (20·9%) of 732 in the hospital-controlled monitoring group (risk ratio [RR] 0·99 [90% CI 0·81 to 1·22]; risk difference [RD] -0·14 [90% CI -3·63 to 3·36]). The per-protocol analysis confirmed non-inferiority (152 [21·0%] of 725 vs 153 [21·0%] of 727; RR 1·00 (90% CI 0·81 to 1·23); RD -0·08 [90% CI -3·60 to 3·44]). INTERPRETATION: Home-based monitoring of ovulation is non-inferior to hospital-controlled monitoring of ovulation to time FET. FUNDING: The Dutch Organisation for Health Research and Development.

Value-based healthcare in fertility care using relevant outcome measures for the full cycle of care leading towards shared decision-making: a retrospective cohort study.

OBJECTIVE: To determine if the introduction of value-based healthcare (VBHC) in fertility care can help to create realistic expectations in patients resulting in increased patient value, by demonstrating the relevance of defining outcome measures that truly matter to subfertile patients. DESIGN: Retrospective cohort study. SETTING: Tertiary fertility centre. RESULTS: Time to pregnancy (TTP) and ongoing pregnancy rate (OPR), as a proxy for the live birth rate, for the full cycle of fertility care, regardless of which and how many treatment cycles performed, were identified as the most relevant medical outcome measures. Outcome measures were incorporated into a digital dashboard by using anonymised and validated patient data from the electronic patient file. We were able to present the TTP and OPR for the population as a whole as well as stratified for age, diagnosis, gravidity and type of gamete source used thereby resulting in a virtual 'patient like me' resembling the individual patient in the consultation room. CONCLUSION: We have shown that, by applying VBHC principles, relevant outcome measures can be generated and stratified for different patient characteristics, in order to develop a virtual 'patient like me'. This virtual 'patient like me' can be used in the consulting room in the form of a digital dashboard, attributing to create realistic patient expectations. This facilitates healthcare providers and patients in shared decision-making.

A multicentre double-blinded randomized controlled trial on the efficacy of laser-assisted hatching in patients with repeated implantation failure undergoing IVF or ICSI.

STUDY QUESTION: Does assisted hatching increase the cumulative live birth rate in subfertile couples with repeated implantation failure? SUMMARY ANSWER: This study showed no evidence of effect for assisted hatching as an add-on in subfertile couples with repeated implantation failure. WHAT IS KNOWN ALREADY: The efficacy of assisted hatching, with regard to the live birth rate has not been convincingly demonstrated in randomized trials nor meta-analyses. It is suggested though that especially poor prognosis women, e.g. women with repeated implantation failure, might benefit most from assisted hatching. STUDY DESIGN, SIZE, DURATION: The study was designed as a double-blinded, multicentre randomized controlled superiority trial. In order to demonstrate a statistically significant absolute increase in live birth rate of 10% after assisted hatching, 294 participants needed to be included per treatment arm, being a total of 588 subfertile couples. Participants were included and randomized from November 2012 until November 2017, 297 were allocated to the assisted hatching arm of the study and 295 to the control arm. Block randomization in blocks of 20 participants was applied and randomization was concealed from participants, treating physicians, and laboratory staff involved in the embryo transfer procedure. Ovarian hyperstimulation, oocyte retrieval, laboratory procedures, embryo selection for transfer and cryopreservation, the transfer itself, and luteal support were performed according to local protocols and were identical in both the intervention and control arm of the study with the exception of the assisted hatching procedure which was only performed in the intervention group. The laboratory staff performing the assisted hatching procedure was not involved in the embryo transfer itself. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were eligible for inclusion in the study after having had either at least two consecutive fresh IVF or ICSI embryo transfers, including the transfer of frozen and thawed embryos originating from those fresh cycles, and which did not result in a pregnancy or as having had at least one fresh IVF or ICSI transfer and at least two frozen embryo transfers with embryos originating from that fresh cycle which did not result in a pregnancy. The study was performed at the laboratory sites of three tertiary referral hospitals and two university medical centres in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative live birth rate per started cycle, including the transfer of fresh and subsequent frozen/thawed embryos if applicable, resulted in 77 live births in the assisted hatching group (n = 297, 25.9%) and 68 live births in the control group (n = 295, 23.1%). This proved to be statistically not significantly different (relative risk: 1.125, 95% CI: 0.847 to 1.494, P = 0.416). LIMITATIONS, REASONS FOR CAUTION: There was a small cohort of subfertile couples that after not achieving an ongoing pregnancy, still had cryopreserved embryos in storage at the endpoint of the trial, i.e. 1 year after the last randomization. It cannot be excluded that the future transfer of these frozen/thawed embryos increases the cumulative live birth rate in either or both study arms. Next, at the start of this study, there was no international consensus on the definition of repeated implantation failure. Therefore, it cannot be excluded that assisted hatching might be effective in higher order repeated implantation failures. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated no evidence of a statistically significant effect for assisted hatching by increasing live birth rates in subfertile couples with repeated implantation failure, i.e. the couples which, based on meta-analyses, are suggested to benefit most from assisted hatching. It is therefore suggested that assisted hatching should only be offered if information on the absence of evidence of effect is provided, at no extra costs and preferably only in the setting of a clinical trial taking cost-effectiveness into account. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR 3387, NL 3235, https://www.clinicaltrialregister.nl/nl/trial/26138). TRIAL REGISTRATION DATE: 6 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 28 November 2012.

Insights into ovarian response with a fixed low dose FSH stimulation in an IUI programme: the PRORAILS study.

STUDY QUESTION: Are patients' characteristics, such as anti-Müllerian hormone (AMH) and BMI, reliable factors to predict ovarian response in couples with unexplained subfertility undergoing IUI with ovarian hyperstimulation (IUI-OH)? SUMMARY ANSWER: We observed no solid relationship between serum AMH and ovarian response. WHAT IS KNOWN ALREADY: Ovarian stimulation during IUI treatment could lead to a higher chance of pregnancy, but also a higher incidence of multiple pregnancies, unless strict cancellation criteria are being used. Several factors could influence the result of the stimulation, such as age, BMI and hormonal status of the female. In IVF treatment, AMH has shown to be a useful predictor of ovarian stimulation to optimize the outcome; however, in a milder stimulation protocol, such as IUI, this has not been investigated. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study and evaluated the first IUI stimulation cycle of 492 patients. The study was conducted between 2012 and 2017. Follow-up ended if patients were not pregnant after the first cycle. If pregnancy did occur, follow-up lasted until delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS: PRORAILS is a large multicentre nationwide cohort study executed in the Netherlands. Eligible women aged 18-43 years who were diagnosed with unexplained subfertility or mild male subfertility according to the Dutch guideline, with a regular indication for IUI-OH, were asked to participate. Ovarian response was assessed using a transvaginal ultrasound 5-7 days after initiation of the stimulation and was repeated according to the size of the leading follicles. Ovarian response was defined as optimal or suboptimal based on the total number of dominant follicles >15 mm. A successful stimulation was defined as the presence of two to three follicles >15 mm on the day of hCG administration. Serum AMH (µg/l) was measured by ELISA, and samples were taken on day 2, 3 or 4 of the menstrual cycle. Poisson regression was used to estimate the risk of a suboptimal ovarian response. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 492 participants, the mean age was 33 years and the mean subfertility duration was 2.5 years. The median serum AMH was 2.1 (µg/l). The majority of patients had a suboptimal response: 326 women (66%), of whom 224 (45%) had a hypo response (defined as 15 mm) and 102 (21%) had a hyper response (defined as more than three follicles sized >15 mm). The lowest AMH category showed a trend towards a smaller risk of a suboptimal response (relative risk ratio 0.76 (95% CI 0.54, 1.06)), but this effect did not reach statistical significance. In the prediction models, BMI and serum basal FSH were significant predictors of a hypo response, while for hyper response the factors age, BMI and serum FSH were significant. A higher BMI showed a higher risk for hypo response, as did a higher FSH whereas a lower BMI and lower FSH showed a higher risk for hyper response. The addition of AMH to the models did not improve the predictive abilities. LIMITATIONS, REASONS FOR CAUTION: Although the study was prospective, the main analyses were cross-sectional with characteristics measured at one time-point. The study was not powered to provide insight into predictors of pregnancy and live births and, therefore, the result for pregnancy should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: This was the first large multicentre study that investigated the characteristics of ovarian response categories using standardized methods and centrally analysed laboratory measures. PRORAILS is a nationwide study with 15 hospitals and, therefore, these results are generalizable to other hospitals in the Netherlands. This study provides high-quality outcomes advancing the subfertility research field. Future studies would benefit from a randomized design investigating the effectiveness of an individualized approach versus a fixed dose. Also, the relation between a good ovarian stimulation and pregnancy rate could be further investigated. STUDY FUNDING/COMPETING INTEREST(S): The PRORAILS study is sponsored by Merck B.V., Schiphol-Rijk, the Netherlands, an affiliation of Merck KGaA, Darmstadt, Germany (EMR700623_612). Merck KGaA, Darmstadt, Germany, reviewed the manuscript prior to submission. The opinions remain those of the authors. Merck KGaA, Darmstadt, Germany, had no influence on the use of medication in this study. The recombinant FSH was mostly provided by Merck B.V. or MSD. F.B. is a member of the external advisory board for Merck B.V., Schiphol-Rijk, the Netherlands, and has received a research grant from Merck B.V., Schiphol-Rijk. H.v.B. is an employee from IQVIA, which is a commercial data-analysing company, and received payment for her part in the article. TRIAL REGISTRATION NUMBER: NCT01662180.

Agents for ovarian stimulation for intrauterine insemination (IUI) in ovulatory women with infertility.

BACKGROUND: Intrauterine insemination (IUI), combined with ovarian stimulation (OS), has been demonstrated to be an effective treatment for infertile couples. Several agents for ovarian stimulation, combined with IUI, have been proposed, but it is still not clear which agents for stimulation are the most effective. This is an update of the review, first published in 2007. OBJECTIVES: To assess the effects of agents for ovarian stimulation for intrauterine insemination in infertile ovulatory women. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trial registers from their inception to November 2020. We performed reference checking and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included truly randomised controlled trials (RCTs) that compared different agents for ovarian stimulation combined with IUI for infertile ovulatory women concerning couples with unexplained infertility. mild male factor infertility and minimal to mild endometriosis. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. MAIN RESULTS: In this updated review, we have included a total of 82 studies, involving 12,614 women. Due to the multitude of comparisons between different agents for ovarian stimulation, we highlight the seven most often reported here. Gonadotropins versus anti-oestrogens (13 studies) For live birth, the results of five studies were pooled and showed a probable improvement in the cumulative live birth rate for gonadotropins compared to anti-oestrogens (odds ratio (OR) 1.37, 95% confidence interval (CI) 1.05 to 1.79; I2 = 30%; 5 studies, 1924 participants; moderate-certainty evidence). This suggests that if the chance of live birth following anti-oestrogens is assumed to be 22.8%, the chance following gonadotropins would be between 23.7% and 34.6%. The pooled effect of seven studies revealed that we are uncertain whether gonadotropins lead to a higher multiple pregnancy rate compared with anti-oestrogens (OR 1.58, 95% CI 0.60 to 4.17; I2 = 58%; 7 studies, 2139 participants; low-certainty evidence). Aromatase inhibitors versus anti-oestrogens (8 studies) One study reported live birth rates for this comparison. We are uncertain whether aromatase inhibitors improve live birth rate compared with anti-oestrogens (OR 0.75, CI 95% 0.51 to 1.11; 1 study, 599 participants; low-certainty evidence). This suggests that if the chance of live birth following anti-oestrogens is 23.4%, the chance following aromatase inhibitors would be between 13.5% and 25.3%. The results of pooling four studies revealed that we are uncertain whether aromatase inhibitors compared with anti-oestrogens lead to a higher multiple pregnancy rate (OR 1.28, CI 95% 0.61 to 2.68; I2 = 0%; 4 studies, 1000 participants; low-certainty evidence).  Gonadotropins with GnRH (gonadotropin-releasing hormone) agonist versus gonadotropins alone (4 studies) No data were available for live birth. The pooled effect of two studies  revealed that we are uncertain whether gonadotropins with GnRH agonist lead to a higher multiple pregnancy rate compared to gonadotropins alone (OR 2.53, 95% CI 0.82 to 7.86; I2 = 0; 2 studies, 264 participants; very low-certainty evidence).  Gonadotropins with GnRH antagonist versus gonadotropins alone (14 studies) Three studies reported live birth rate per couple, and we are uncertain whether gonadotropins with GnRH antagonist improve live birth rate compared to gonadotropins (OR 1.5, 95% CI 0.52 to 4.39; I2 = 81%; 3 studies, 419 participants; very low-certainty evidence). This suggests that if the chance of a live birth following gonadotropins alone is 25.7%, the chance following gonadotropins combined with GnRH antagonist would be between 15.2% and 60.3%. We are also uncertain whether gonadotropins combined with GnRH antagonist lead to a higher multiple pregnancy rate compared with gonadotropins alone (OR 1.30, 95% CI 0.74 to 2.28; I2 = 0%; 10 studies, 2095 participants; moderate-certainty evidence). Gonadotropins with anti-oestrogens versus gonadotropins alone (2 studies) Neither of the studies reported data for live birth rate. We are uncertain whether gonadotropins combined with anti-oestrogens lead to a higher multiple pregnancy rate compared with gonadotropins alone, based on one study (OR 3.03, 95% CI 0.12 to 75.1; 1 study, 230 participants; low-certainty evidence). Aromatase inhibitors versus gonadotropins (6 studies) Two studies  revealed that aromatase inhibitors may decrease live birth rate compared with gonadotropins (OR 0.49, 95% CI 0.34 to 0.71; I2=0%; 2 studies, 651 participants; low-certainty evidence). This suggests that if the chance of a live birth following gonadotropins alone is 31.9%,  the chance of live birth following aromatase inhibitors would be between 13.7% and 25%. We are uncertain whether aromatase inhibitors compared with gonadotropins lead to a higher multiple pregnancy rate (OR 0.69, 95% CI 0.06 to 8.17; I2=77%; 3 studies, 731 participants; very low-certainty evidence).  Aromatase inhibitors with gonadotropins versus anti-oestrogens with gonadotropins (8 studies) We are uncertain whether aromatase inhibitors combined with gonadotropins improve live birth rate compared with anti-oestrogens plus gonadotropins (OR 0.99, 95% CI 0.3 8 to 2.54;  I2 = 69%; 3 studies, 708 participants; very low-certainty evidence). This suggests that if the chance of a live birth following anti-oestrogens plus gonadotropins is 13.8%, the chance following aromatase inhibitors plus gonadotropins would be between 5.7% and 28.9%. We are uncertain of the effect of aromatase inhibitors combined with gonadotropins compared to anti-oestrogens combined with gonadotropins on multiple pregnancy rate (OR 1.31, 95% CI 0.39 to 4.37;  I2 = 0%; 5 studies, 901 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Based on the available results, gonadotropins probably improve cumulative live birth rate compared with anti-oestrogens (moderate-certainty evidence). Gonadotropins may also improve cumulative live birth rate when compared with aromatase inhibitors (low-certainty evidence). From the available data, there is no convincing evidence that aromatase inhibitors lead to higher live birth rates compared to anti-oestrogens. None of the agents compared lead to significantly higher multiple pregnancy rates. Based on low-certainty evidence, there does not seem to be a role for different combined therapies, nor for adding GnRH agonists or GnRH antagonists in IUI programs.

Double versus single intrauterine insemination (IUI) in stimulated cycles for subfertile couples.

BACKGROUND: In subfertile couples, couples who have tried to conceive for at least one year, intrauterine insemination (IUI) with ovarian hyperstimulation (OH) is one of the treatment modalities that can be offered. When IUI is performed a second IUI in the same cycle might add to the chances of conceiving. In a previous update of this review in 2010 it was shown that double IUI increases pregnancy rates when compared to single IUI. Since 2010, different clinical trials have been published with differing conclusions about whether double IUI increases pregnancy rates compared to single IUI. OBJECTIVES: To determine the effectiveness and safety of double intrauterine insemination (IUI) compared to single IUI in stimulated cycles for subfertile couples. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase and CINAHL in July 2020 and LILACS, Google scholar and Epistemonikos in February 2021, together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled, parallel trials of double versus single IUIs in stimulated cycles in subfertile couples. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We identified in nine studies involving subfertile women. The evidence was of low quality; the main limitations were unclear risk of bias, inconsistent results for some outcomes and imprecision, due to small trials with imprecise results. We are uncertain whether double IUI improves live birth rate compared to single IUI (odds ratio (OR) 1.15, 95% confidence interval (CI) 0.71 to 1.88; I2 = 29%; studies = 3, participants = 468; low quality evidence). The evidence suggests that if the chance of live birth following single IUI is 16%, the chance of live birth following double IUI would be between 12% and 27%. Performing a sensitivity analysis restricted to only randomised controlled trials (RCTs) with low risk of selection bias showed similar results. We are uncertain whether double IUI reduces miscarriage rate compared to single IUI (OR 1.78, 95% CI 0.98 to 3.24; I2 = 0%; studies = 6, participants = 2363; low quality evidence). The evidence suggests that chance of miscarriage following single IUI is 1.5% and the chance following double IUI would be between 1.5% and 5%. The reported clinical pregnancy rate per woman randomised may increase with double IUI group (OR 1.51, 95% CI 1.23 to 1.86; I2 = 34%; studies = 9, participants = 2716; low quality evidence). This result should be interpreted with caution due to the low quality of the evidence and the moderate inconsistency. The evidence suggests that the chance of a pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%. We are uncertain whether double IUI affects multiple pregnancy rate compared to single IUI (OR 2.04, 95% CI 0.91 to 4.56; I2 = 8%; studies = 5; participants = 2203; low quality evidence). The evidence suggests that chance of multiple pregnancy following single IUI is 0.7% and the chance following double IUI would be between 0.85% and 3.7%. We are uncertain whether double IUI has an effect on ectopic pregnancy rate compared to single IUI (OR 1.22, 95% CI 0.35 to 4.28; I2 = 0%; studies = 4, participants = 1048; low quality evidence). The evidence suggests that the chance of an ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%. AUTHORS' CONCLUSIONS: Our main analysis, of which the evidence is low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. Our sensitivity analysis restricted to studies of low risk of selection bias for both outcomes is consistent with the main analysis. Clinical pregnancy rate may increase in the double IUI group, but this should be interpreted with caution due to the low quality evidence. We are uncertain whether double IUI has an effect on multiple pregnancy rate and ectopic pregnancy rate compared to single IUI.

Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology.

BACKGROUND: Long-term effects of assisted reproductive technology (ART) on ovarian tumor risk are unknown. METHODS: This nationwide cohort study comprises 30 625 women who received ovarian stimulation for ART in 1983-2000 and 9988 subfertile women not treated with ART. Incident invasive and borderline ovarian tumors were ascertained through linkage with the Netherlands Cancer Registry and the Dutch Pathology Registry until July 2018. Ovarian tumor risk in ART-treated women was compared with risks in the general population and the subfertile non-ART group. Statistical tests were 2-sided. RESULTS: After a median follow-up of 24 years, 158 invasive and 100 borderline ovarian tumors were observed. Ovarian cancer risk in the ART group was increased compared with the general population (standardized incidence ratio [SIR] = 1.43, 95% confidence interval [CI] = 1.18 to 1.71) but not when compared with the non-ART group (age- and parity-adjusted hazard ratio [HR] = 1.02, 95% CI = 0.70 to 1.50). Risk decreased with higher parity and with a larger number of successful ART cycles (resulting in childbirth, Ptrend = .001) but was not associated with the number of unsuccessful ART cycles. Borderline ovarian tumor risk was increased in ART-treated women compared with the general population (SIR = 2.20, 95% CI = 1.66 to 2.86) and with non-ART women (HR = 1.84, 95% CI = 1.08 to 3.14). Risk did not increase with more ART cycles or longer follow-up time. CONCLUSIONS: Increased ovarian cancer risk in ART-treated women compared with the general population is likely explained by nulliparity rather than ART treatment. The increased risk of borderline ovarian tumors after ART must be interpreted with caution because no dose-response relationship was observed.

Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?

RESEARCH QUESTION: What are the obstetric and neonatal risks for women conceiving via frozen-thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method. DESIGN: A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies. RESULTS: Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference -124 g [-363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08-0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different. CONCLUSIONS: The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.

Intra-uterine insemination for unexplained subfertility.

BACKGROUND: Intra-uterine insemination (IUI) is a widely-used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rates. OBJECTIVES: To determine whether, for couples with unexplained subfertility, the live birth rate is improved following IUI treatment with or without OH compared to timed intercourse (TI) or expectant management with or without OH, or following IUI treatment with OH compared to IUI in a natural cycle. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 17 October 2019, together with reference checking and contact with study authors for missing or unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IUI with TI or expectant management, both in stimulated or natural cycles, or IUI in stimulated cycles with IUI in natural cycles in couples with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, quality assessment and data extraction. Primary review outcomes were live birth rate and multiple pregnancy rate. MAIN RESULTS: We include 15 trials with 2068 women. The evidence was of very low to moderate quality. The main limitation was very serious imprecision. IUI in a natural cycle versus timed intercourse or expectant management in a natural cycle It is uncertain whether treatment with IUI in a natural cycle improves live birth rate compared to treatment with expectant management in a natural cycle (odds ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.78; 1 RCT, 334 women; low-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle to be 16%, that of IUI in a natural cycle would be between 15% and 34%. It is uncertain whether treatment with IUI in a natural cycle reduces multiple pregnancy rates compared to control (OR 0.50, 95% CI 0.04 to 5.53; 1 RCT, 334 women; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a stimulated cycle It is uncertain whether treatment with IUI in a stimulated cycle improves live birth rates compared to treatment with TI in a stimulated cycle (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs, 208 women; I2 = 72%; low-quality evidence). If we assume the chance of achieving a live birth with TI in a stimulated cycle was 26%, the chance with IUI in a stimulated cycle would be between 23% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle reduces multiple pregnancy rates compared to control (OR 1.46, 95% CI 0.55 to 3.87; 4 RCTs, 316 women; I2 = 0%; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a natural cycle In couples with a low prediction score of natural conception, treatment with IUI combined with clomiphene citrate or letrozole probably results in a higher live birth rate compared to treatment with expectant management in a natural cycle (OR 4.48, 95% CI 2.00 to 10.01; 1 RCT; 201 women; moderate-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle was 9%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle results in a lower multiple pregnancy rate compared to control (OR 3.01, 95% CI 0.47 to 19.28; 2 RCTs, 454 women; I2 = 0%; low-quality evidence). IUI in a natural cycle versus timed intercourse or expectant management in a stimulated cycle Treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, 342 women: moderate-quality evidence). If we assume the chance of a live birth with expectant management in a stimulated cycle was 13%, the chance of a live birth with IUI in a natural cycle would be between 14% and 34%. It is uncertain whether treatment with IUI in a natural cycle results in a lower multiple pregnancy rate compared to control (OR 1.05, 95% CI 0.07 to 16.90; 1 RCT, 342 women; low-quality evidence). IUI in a stimulated cycle versus IUI in a natural cycle Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle (OR 2.07, 95% CI 1.22 to 3.50; 4 RCTs, 396 women; I2 = 0%; low-quality evidence). If we assume the chance of a live birth with IUI in a natural cycle was 14%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 36%. It is uncertain whether treatment with IUI in a stimulated cycle results in a higher multiple pregnancy rate compared to control (OR 3.00, 95% CI 0.11 to 78.27; 2 RCTs, 65 women; low-quality evidence). AUTHORS' CONCLUSIONS: Due to insufficient data, it is uncertain whether treatment with IUI with or without OH compared to timed intercourse or expectant management with or without OH improves cumulative live birth rates with acceptable multiple pregnancy rates in couples with unexplained subfertility. However, treatment with IUI with OH probably results in a higher cumulative live birth rate compared to expectant management without OH in couples with a low prediction score of natural conception. Similarly, treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with timed intercourse with OH. Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle.

Semen preparation techniques for intrauterine insemination.

BACKGROUND: Semen preparation techniques for assisted reproduction, including intrauterine insemination (IUI), were developed to select the motile morphologically normal spermatozoa. The yield of many motile, morphologically normal spermatozoa might influence treatment choices and therefore outcomes. OBJECTIVES: To compare the effectiveness of three different semen preparation techniques (gradient; swim-up; wash and centrifugation) on clinical outcomes (live birth rate; clinical pregnancy rate) in subfertile couples undergoing IUI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, Science Direct Database, National Research Register, Biological Abstracts and clinical trial registries in March 2019, and checked references and contacted study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the efficacy in terms of clinical outcomes of semen preparation techniques used for subfertile couples undergoing IUI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes are live birth rate and clinical pregnancy rate per couple. MAIN RESULTS: We included seven RCTS in the review; we included six of these, totalling 485 couples, in the meta-analysis. No trials reported the primary outcome of live birth. The evidence was of very low-quality. The main limitations were (unclear) risk of bias, signs of imprecision and inconsistency in results among studies and the small number of studies/participants included.Swim-up versus gradient technique Considering the quality of evidence, we are uncertain whether there was a difference between clinical pregnancy rates (CPR) for swim-up versus a gradient technique (odds ratio (OR) 0.83, 95% CI 0.51 to 1.35; I² = 71%; 4 RCTs, 370 participants; very low-quality evidence). The results suggest that if the chance of pregnancy after the use of a gradient technique is assumed to be 24%, the chance of pregnancy after using the swim-up technique is between 14% and 30%. We are uncertain whether there was a real difference between ongoing pregnancy rates per couple (OR 0.39, 95% CI 0.19 to 0.82; heterogeneity not applicable; 1 RCT, 223 participants; very low-quality evidence). Considering the quality of evidence, we are uncertain whether there was a difference between multiple pregnancy rates (MPR) per couple comparing a swim-up versus gradient technique (MPR per couple 0% versus 0%; 1 RCT, 25 participants; very low-quality of evidence). Considering the quality of evidence, we are also uncertain whether there was a difference between miscarriage rates (MR) per couple comparing a swim-up versus gradient technique (OR 0.85, 95% CI 0.28 to 2.59; I² = 44%; 3 RCTs, 330 participants; very low-quality evidence). No studies reported on ectopic pregnancy rate, fetal abnormalities or infection rate.Swim-up versus wash techniqueConsidering the quality of evidence, we are uncertain whether there is a difference in clinical pregnancy rates after a swim-up technique versus wash and centrifugation (OR 0.41, 95% CI 0.15 to 1.13; I² = 55%; 2 RCTs, 78 participants; very low-quality evidence). The results suggest that if the chance of pregnancy after the use of a wash technique is assumed to be 38%, the chance of pregnancy after using the swim-up technique is between 9% and 41%. Considering the quality of evidence, we are uncertain whether there was a difference between multiple pregnancy rates between swim-up technique versus wash technique (OR 0.49, 95% CI 0.02 to 13.28; heterogeneity not applicable; 1 RCT, 26 participants; very low-quality evidence). Miscarriage rate was only reported by one study: no miscarriages were reported in either treatment arm. No studies reported on ongoing pregnancy rate, ectopic pregnancy rate, fetal abnormalities or infection rate.Gradient versus wash techniqueConsidering the quality of evidence, we are uncertain whether there is a difference in clinical pregnancy rates after a gradient versus wash and centrifugation technique (OR 1.78, 95% CI 0.58 to 5.46; I² = 52%; 2 RCTs, 94 participants; very low-quality evidence). The results suggest that if the chance of pregnancy after the use of a wash technique is assumed to be 13%, the chance of pregnancy after using the gradient technique is between 8% and 46%. Considering the quality of evidence, we are uncertain whether there was a difference between multiple pregnancy rates per couple between the treatment groups (OR 0.33, 95% CI 0.01 to 8.83; very low-quality evidence). Considering the quality of evidence, we are also uncertain whether there was a difference between miscarriage rates per couple between the treatment groups (OR 6.11, 95% CI 0.27 to 138.45; very low-quality evidence). No studies reported on ongoing pregnancy rate, ectopic pregnancy rate, fetal abnormalities or infection rate. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend any specific semen preparation technique: swim-up versus gradient versus wash and centrifugation technique. No studies reported on live birth rates. Considering the quality of evidence (very low), we are uncertain whether there is a difference in clinical pregnancy rates, ongoing pregnancy rates, multiple pregnancy rates or miscarriage rates per couple) between the three sperm preparation techniques. Further randomised trials are warranted that report live birth data.

The AID study: protocol for a randomised controlled trial of intrauterine insemination in the natural cycle compared with intracervical insemination in the natural cycle.

INTRODUCTION: At present, studies comparing intrauterine insemination in the natural cycle versus intracervical insemination in the natural cycle in women undergoing artificial insemination with donor sperm are scarce. METHODS AND ANALYSIS: We perform a randomised controlled non-inferiority trial among five secondary and tertiary fertility clinics in the Netherlands and one tertiary fertility clinic in Belgium. Women eligible for artificial insemination with donor sperm are included. We perform six cycles of artificial insemination with donor sperm within a time horizon of 8 months comparing intrauterine insemination in the natural cycle with intracervical insemination in the natural cycle. The primary outcome is ongoing pregnancy leading to live birth conceived within eight months after randomisation. Secondary outcomes are clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, pregnancy complications (preterm birth, birth weight <2500 g, pregnancy induced hypertension, (pre-) eclampsia, Hemolysis Elevated Liver enzymes Low Platelets (HELLP)), time to ongoing pregnancy, direct and indirect costs. To demonstrate the non-inferiority of intracervical insemination with a margin of 12%, we need 208 women per arm. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on research involving human subjects (47330-018-13). The boards of the participating hospitals approved the study. Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NTR4462.

In Vitro Maturation of Oocytes in Women at Risk of Ovarian Hyperstimulation Syndrome-A Prospective Multicenter Cohort Study.

BACKGROUND: In vitro maturation (IVM) is an artificial reproductive technology in which immature oocytes are harvested from the ovaries and subsequently will be matured in vitro. IVM does not require ovarian hyperstimulation (OH) and thus the risk of ovarian hyperstimulation syndrome (OHSS) is avoided. In this study, we assessed the live birth rate per initiated IVM cycle in women eligible for in vitro fertilization/intracytoplasmic sperm injection (IVF/ ICSI) and at risk for OHSS. Furthermore, we followed women who were not pregnant after IVM and committed to a conventional IVF/ICSI procedure. MATERIALS AND METHODS: In this multicenter prospective cohort study, we started 76 IVM cycles using recombinant follicle stimulating hormone (rFSH) priming in 68 patients. There were 66 oocyte retrievals, in which a total of 628 oocytes were collected. We incubated the immature oocytes for 24-48 hours and fertilized those that reached metaphase II by ICSI. RESULTS: Three hundred eighty six (61% oocytes) achieved metaphase II. The fertilization rate was 55%. We performed 59 embryo transfers (1.9 embryos per transfer) in 56 women, including 3 frozen embryo transfers. There were four ongoing pregnancies (5.3% per initiated cycle) leading to the birth of a healthy child at term. None of the patients developed OHSS. The ongoing pregnancy rate of the first conventional IVF/ICSI cycle after an unsuccessful IVM cycle was 44%, which was unexpectedly high. CONCLUSION: We concluded that IVM led to live births but with low effectiveness in our study. Earlier reported IVM success rates are higher which can be caused by a more extended experience in these centers with the intricate laboratory process. However, a possible selection bias in these studies cannot be ruled out. Furthermore, IVM might have a beneficial effect on further IVF/ICSI treatments due to its "ovarian drilling" effect.

Antigen-specific active immunotherapy for ovarian cancer.

BACKGROUND: This is the second update of the review first published in the Cochrane Library (2010, Issue 2) and later updated (2014, Issue 9).Despite advances in chemotherapy, the prognosis of ovarian cancer remains poor. Antigen-specific active immunotherapy aims to induce tumour antigen-specific anti-tumour immune responses as an alternative treatment for ovarian cancer. OBJECTIVES: Primary objective• To assess the clinical efficacy of antigen-specific active immunotherapy for the treatment of ovarian cancer as evaluated by tumour response measured by Response Evaluation Criteria In Solid Tumors (RECIST) and/or cancer antigen (CA)-125 levels, response to post-immunotherapy treatment, and survival differences◦ In addition, we recorded the numbers of observed antigen-specific humoral and cellular responsesSecondary objective• To establish which combinations of immunotherapeutic strategies with tumour antigens provide the best immunological and clinical results SEARCH METHODS: For the previous version of this review, we performed a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2009, Issue 3), in the Cochrane Library, the Cochrane Gynaecological Cancer Group Specialised Register, MEDLINE and Embase databases, and clinicaltrials.gov (1966 to July 2009). We also conducted handsearches of the proceedings of relevant annual meetings (1996 to July 2009).For the first update of this review, we extended the searches to October 2013, and for this update, we extended the searches to July 2017. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs), as well as non-randomised studies (NRSs), that included participants with epithelial ovarian cancer, irrespective of disease stage, who were treated with antigen-specific active immunotherapy, irrespective of type of vaccine, antigen used, adjuvant used, route of vaccination, treatment schedule, and reported clinical or immunological outcomes. DATA COLLECTION AND ANALYSIS: Two reviews authors independently extracted the data. We evaluated the risk of bias for RCTs according to standard methodological procedures expected by Cochrane, and for NRSs by using a selection of quality domains deemed best applicable to the NRS. MAIN RESULTS: We included 67 studies (representing 3632 women with epithelial ovarian cancer). The most striking observations of this review address the lack of uniformity in conduct and reporting of early-phase immunotherapy studies. Response definitions show substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events is frequently limited. Furthermore, reports of both RCTs and NRSs frequently lack the relevant information necessary for risk of bias assessment. Therefore, we cannot rule out serious biases in most of the included trials. However, selection, attrition, and selective reporting biases are likely to have affected the studies included in this review. GRADE ratings were high only for survival; for other primary outcomes, GRADE ratings were very low.The largest body of evidence is currently available for CA-125-targeted antibody therapy (17 studies, 2347 participants; very low-certainty evidence). Non-randomised studies of CA-125-targeted antibody therapy suggest improved survival among humoral and/or cellular responders, with only moderate adverse events. However, four large randomised placebo-controlled trials did not show any clinical benefit, despite induction of immune responses in approximately 60% of participants. Time to relapse with CA-125 monoclonal antibody versus placebo, respectively, ranged from 10.3 to 18.9 months versus 10.3 to 13 months (six RCTs, 1882 participants; high-certainty evidence). Only one RCT provided data on overall survival, reporting rates of 80% in both treatment and placebo groups (three RCTs, 1062 participants; high-certainty evidence). Other small studies targeting many different tumour antigens have presented promising immunological results. As these strategies have not yet been tested in RCTs, no reliable inferences about clinical efficacy can be made. Given the promising immunological results and the limited side effects and toxicity reported, exploration of clinical efficacy in large well-designed RCTs may be worthwhile. AUTHORS' CONCLUSIONS: We conclude that despite promising immunological responses, no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Results should be interpreted cautiously, as review authors found a significant dearth of relevant information for assessment of risk of bias in both RCTs and NRSs.

Influence of endometrial thickness on pregnancy rates in modified natural cycle frozen-thawed embryo transfer.

INTRODUCTION: Pregnancy after frozen-thawed embryo transfer (FET) is a multifactorial process. Although embryo quality is a key factor in determining pregnancy, other factors, including maternal determinants, are also considered to be predictive. Even though an association between endometrial thickness measured by transvaginal ultrasound and pregnancy rates has been reported in patients undergoing various assisted reproductive technology treatments, whether endometrial thickness predicts achieving pregnancy after natural cycle FET (NC-FET) remains unclear. MATERIAL AND METHODS: In this cohort study, 463 patients allocated to the modified NC-FET (mNC-FET) arm of a previously published randomized controlled trial were included. Monitoring in mNC-FET cycles consisted of regular ultrasound scans, measuring both dominant follicle and endometrial thickness. When the dominant follicle reached a size of 16-20 mm, an injection of human chorionic gonadotrophin was administered and embryo thawing and transfer planned. No minimal endometrial thickness was defined below which transfer was to be deferred. The primary endpoint was ongoing pregnancy rate. RESULTS: Overall, the ongoing pregnancy rate per started FET cycle was 12.5%. Multivariate regression analyses showed that embryo quality was the only significant predictor for ongoing pregnancy. Mean endometrial thickness did not differ between patients achieving ongoing pregnancy and those who did not (9.0 vs. 8.8 mm, p = 0.4). Comparable results were obtained with regard to clinical pregnancy, live birth and miscarriage rates. The area under the receiver operator curve was 0.5, indicating little discriminatory value of endometrial thickness. CONCLUSIONS: Given that endometrial thickness was not found to be predictive of pregnancy after mNC-FET, cancellation based on endometrial thickness alone may not be justified.

IUI: review and systematic assessment of the evidence that supports global recommendations.

BACKGROUND: IUI with or without ovarian stimulation (OS) has become a first-line treatment option for many infertile couples, worldwide. The appropriate treatment modality for couples and their clinical management through IUI or IUI/OS cycles must consider maternal and perinatal outcomes, most notably the clinical complication of higher-order multiple pregnancies associated with IUI-OS. With a current global emphasis to continue to decrease maternal and perinatal mortality and morbidity, the World Health Organization (WHO) had established a multi-year project to review the evidence for the establishment of normative guidance for the implementation of IUI as a treatment to address fertility problems, and to consider its cost-effectiveness for lower resource settings. OBJECTIVE AND RATIONALE: The objective of this review is to provide a review of the evidence of 13 prioritized questions that cover IUI with and without OS. We provide summary recommendations for the development of global, evidence-based guidelines based upon methodology established by the WHO. SEARCH METHODS: We performed a comprehensive search using question-specific relevant search terms in May 2015. For each PICO (Population, Intervention, Comparison and Outcomes) drafted by WHO, specific search terms were used to find the available evidence in MEDLINE (1950 to May 2015) and The Cochrane Library (until May 2015). After presentation to an expert panel, a further hand search of references in relevant reviews was performed up to January 2017. Articles that were found to be relevant were read and analysed by two investigators and critically appraised using the Cochrane Collaboration's tool for assessing risk of bias, and AMSTAR in case of systematic reviews. The quality of the evidence was assessed using the GRADE system. An independent expert review process of our analysis was conducted in November 2016. OUTCOMES: This review provides an assessment and synthesis of the evidence that covers 13 clinical questions including the indications for the use of IUI versus expectant management, the sperm parameters required, the best and optimal method of timing and number of inseminations per cycle, prevention strategies to decrease multiple gestational pregnancies, and the cost-effectiveness of IUI versus IVF. We provide an evidence-based formulation of 20 recommendations, as well as two best practice points that address the integration of methods for the prevention of infection in the IUI laboratory. The quality of the evidence ranges from very low to high, with evidence that may be decades old but of high quality, however, we further discuss where critical research gaps in the evidence remain. WIDER IMPLICATIONS: This review presents an evidence synthesis assessment and includes recommendations that will assist health care providers worldwide with their decision-making when considering IUI treatments, with or without OS, for their patients presenting with fertility problems.

The effect of elevated progesterone levels before HCG triggering in modified natural cycle frozen-thawed embryo transfer cycles.

Recent studies suggest that elevated late follicular phase progesterone concentrations after ovarian stimulation for IVF may result in embryo-endometrial asynchrony, reducing the chance of successful implantation after fresh embryo transfer. It remains unclear to what extent elevated late follicular phase progesterone levels may occur in unstimulated cycles before frozen-thawed embryo transfer, or what affect they may have on outcomes. In this cohort study, 271 patients randomized to the modified natural cycle arm of a randomized controlled trial comparing two endometrial preparation regimens underwent late follicular phase progesterone and LH testing. A receiver operating characteristic curve was constructed to identify a progesterone cut-off level with the best predictive value for live birth (progesterone level ≥4.6 nmol/l). A total of 24.4% of patients revealed an isolated elevated serum progesterone of 4.6 nmol/l or greater, and 44.3% showed an elevated progesterone level in association with a rise in LH. Neither endocrine disruption affected outcomes, with live birth rates of 12.9% versus 10.6% (OR 0.6, 95% CI 0.19 to 1.9) and 11.9% versus 17.5% (OR 1.6, 95% CI 0.79 to 3.1), respectively. Whether monitoring of progesterone and LH in natural cycle frozen-thawed embryo transfer has added clinical value should studied further.

Dropout rates in couples undergoing in vitro fertilization and intrauterine insemination.

OBJECTIVE: To compare dropout rates in couples undergoing conventional in vitro fertilization with single embryo transfer (IVF-SET), in vitro fertilization in a modified natural cycle (IVF-MNC) or intrauterine insemination with ovarian stimulation (IUI-OS). STUDY DESIGN: Secondary analysis of a multicentre randomized controlled trial between January 2009 and February 2012. 602 couples with unexplained or mild male subfertility, allocated to IVF-SET (N=201), IVF-MNC (N=194) and IUI-OS (N=207). MAIN OUTCOME MEASURES: Dropouts, defined as couples who discontinued their allocated three cycles of IVF-SET, six cycles of IVF-MNC or IUI-OS, without having achieved a pregnancy. We classified dropouts as "following medical advice" or "patient initiated". RESULT(S): Thirty couples (15%) allocated to IVF-SET dropped out and 45 couples (23%) allocated to IVF-MNC, compared to 26 couples (13%) allocated to IUI-OS; relative risk (RR) 1.2 (95%CI; 0.73-1.9) for IVF-SET and 1.9 (95%CI; 1.2-2.9) for IVF-MNC, both compared to IUI-OS. Nine couples (4.5%) allocated to IVF-SET, 14 (7.2%) allocated to IVF-MNC and 14 (6.8%) allocated to IUI-OS dropped out following medical advice; RR of 0.51 (95%CI; 0.21-1.2) for IVF-SET and 0.84 (95%CI; 0.39-1.80) for IVF-MNC, both versus IUI-OS. Twenty-one couples (10%) allocated to IVF-SET were patient initiated dropouts, as were 31 (16%) allocated to IVF-MNC and 12 (5.8%) allocated to IUI-COS; RR 1.8 (95%CI; 0.91-3.6) for IVF-SET and 2.8 (95%CI; 1.5-5.2) for IVF-MNC both versus IUI-OS. CONCLUSION(S): IVF-SET and IUI-OS result in comparable drop-out rates, while drop-out rates after IVF-MNC are almost twice as high, mainly driven by patient preferences.