Potential roles of the interactions between gut microbiota and metabolites in LPS-induced intrauterine inflammation (IUI) and associated preterm birth (PTB).

BACKGROUND: Prenatal exposure to intrauterine inflammation (IUI) is a crucial event in preterm birth (PTB) pathophysiology, increasing the incidence of neurodevelopmental disorders. Gut microbiota and metabolite profile alterations have been reported to be involved in PTB pathophysiology. METHOD AND RESULTS: In this study, IUI-exposed PTB mouse model was established and verified by PTB rate and other perinatal adverse reactions; LPS-indued IUI significantly increased the rates of PTB, apoptosis and inflammation in placenta tissue samples. LPS-induced IUI caused no significant differences in species richness and evenness but significantly altered the species abundance distribution. Non-targeted metabolomics analysis indicated that the metabolite profile of the preterm mice was altered, and differential metabolites were associated with signaling pathways including pyruvate metabolism. Furthermore, a significant positive correlation between Parasutterella excrementihominis and S4572761 (Nb-p-coumaroyltryptamine) and Mreference-1264 (pyruvic acid), respectively, was observed. Lastly, pyruvic acid treatment partially improved LPS-induced IUI phenotypes and decreased PTB rates and decreased the apoptosis and inflammation in placenta tissue samples. CONCLUSION: This study revealed an association among gut microbiota dysbiosis, metabolite profile alterations, and LPS-induced IUI and PTB in mice models. Our investigation revealed the possible involvement of gut microbiota in the pathophysiology of LPS-induced IUI and PTB, which might be mediated by metabolites such as pyruvic acid. Future studies should be conducted to verify the findings through larger sample-sized animal studies and clinical investigations.

Effect of prematurely elevated late follicular progesterone on pregnancy outcomes following ovarian stimulation-intrauterine insemination for unexplained infertility: secondary analysis of the AMIGOS trial.

STUDY QUESTION: What is the relationship between late follicular phase progesterone levels and clinic pregnancy and live birth rates in couples with unexplained infertility undergoing ovarian stimulation with IUI (OS-IUI)? SUMMARY ANSWER: Late follicular progesterone levels between 1.0 and <1.5 ng/ml were associated with higher live birth and clinical pregnancy rates while the outcomes in groups with higher progesterone levels did not differ appreciably from the <1.0 ng/ml reference group. WHAT IS KNOWN ALREADY: Elevated late follicular progesterone levels have been associated with lower live birth rates after fresh embryo transfer following controlled ovarian stimulation and egg retrieval, but less is known about whether an association exists with outcomes in OS-IUI cycles. Existing studies are few and have been limited to ovarian stimulation with gonadotrophins, but the use of oral agents, such as clomiphene citrate and letrozole, is common with these treatments and has not been well studied. STUDY DESIGN, SIZE, DURATION: The study was a prospective cohort analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial. Frozen serum was available for evaluation from 2121 cycles in 828 AMIGOS participants. The primary pregnancy outcome was live birth per cycle, and the secondary pregnancy outcome was clinical pregnancy rate per cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples with unexplained infertility in the AMIGOS trial, for whom female serum from day of trigger with hCG was available in at least one cycle of treatment, were included. Stored frozen serum samples from day of hCG trigger during treatment with OS-IUI were evaluated for serum progesterone level. Progesterone level <1.0 ng/ml was the reference group for comparison with progesterone categorized in increments of 0.5 ng/ml up to ≥3.0 ng/ml. Unadjusted and adjusted risk ratios (RR) and 95% CI were estimated using cluster-weighted generalized estimating equations to estimate modified Poisson regression models with robust standard errors. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to the reference group with 110/1363 live births (8.07%), live birth rates were significantly increased in cycles with progesterone 1.0 to <1.5 ng/ml (49/401 live births, 12.22%) in both the unadjusted (RR 1.56, 95% CI 1.14, 2.13) and treatment-adjusted models (RR 1.51, 95% CI 1.10, 2.06). Clinical pregnancy rates were also higher in this group (55/401 clinical pregnancies, 13.72%) compared to reference group with 130/1363 (9.54%) (unadjusted RR 1.46, 95% CI 1.10, 1.94 and adjusted RR 1.42, 95% CI 1.07, 1.89). In cycles with progesterone 1.5 ng/ml and above, there was no evidence of a difference in clinical pregnancy or live birth rates relative to the reference group. This pattern remained when stratified by ovarian stimulation treatment group but was only statistically significant in letrozole cycles. LIMITATIONS, REASONS FOR CAUTION: The AMIGOS trial was not designed to answer this clinical question, and with small numbers in some progesterone categories our analyses were underpowered to detect differences between some groups. Inclusion of cycles with progesterone values above 3.0 ng/ml may have included those wherein ovulation had already occurred at the time the IUI was performed. These cycles would be expected to experience a lower success rate but pregnancy may have occurred with intercourse in the same cycle. WIDER IMPLICATIONS OF THE FINDINGS: Compared to previous literature focusing primarily on OS-IUI cycles using gonadotrophins, these data include patients using oral agents and therefore may be generalizable to the wider population of infertility patients undergoing IUI treatments. Because live births were significantly higher when progesterone ranged from 1.0 to <1.5 ng/ml, further study is needed to clarify whether this progesterone range may truly represent a prognostic indicator in OS-IUI cycles. STUDY FUNDING/COMPETING INTEREST(S): Oklahoma Shared Clinical and Translational Resources (U54GM104938) National Institute of General Medical Sciences (NIGMS). AMIGOS was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, and U10HD055925. Research made possible by the funding by American Recovery and Reinvestment Act. Dr Burks has disclosed that she is a member of the Board of Directors of the Pacific Coast Reproductive Society. Dr Hansen has disclosed that he is the recipient of NIH grants unrelated to the present work, and contracts with Ferring International Pharmascience Center US and with May Health unrelated to the present work, as well as consulting fees with May Health also unrelated to the present work. Dr Diamond has disclosed that he is a stockholder and a member of the Board of Directors of Advanced Reproductive Care, Inc., and that he has a patent pending for the administration of progesterone to trigger ovulation. Dr Anderson, Dr Gavrizi, and Dr Peck do not have conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Association between the length of in vitro embryo culture, mode of ART, and the initial endogenous hCG rise in ongoing singleton pregnancies.

STUDY QUESTION: Is there an association between the length of in vitro culture, mode of ART and the initial endogenous hCG rise, in cycles with a foetal heartbeat after single embryo transfer (ET) and implantation? SUMMARY ANSWER: Both the length of in vitro culture and the mode of ART have an impact on the initial endogenous rise in hCG in singleton pregnancies. WHAT IS KNOWN ALREADY: Different factors have been identified to alter the kinetics of hCG in pregnancies. Current studies show conflicting results regarding the kinetics of hCG after different types of ART (fresh vs frozen ET (FET)), the inclusion or not of preimplantation genetic testing (PGT), and the length of time in in vitro culture. STUDY DESIGN, SIZE, DURATION: This was a multicentre cohort study, using prospectively collected data derived from 4938 women (5524 treatment cycles) undergoing IUI (cycles, n = 608) or ART (cycles, n = 4916) treatments, resulting a in singleton ongoing pregnancy verified by first-trimester ultrasound scan. Data were collected from the Danish Medical Data Centre, used by the three participating Danish public fertility clinics at Copenhagen University hospitals: Herlev Hospital, Hvidovre Hospital, and Rigshospitalet, from January 2014 to December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: The fresh ET cycles included cleavage-stage (2 or 3 days in vitro) and blastocyst (5 days in vitro) transfers. FET cycles included cleavage-stage (3 days in vitro before cryopreservation) or blastocyst (5 or 6 days in vitro before cryopreservation) transfers. The IUI cycles represented no time in vitro. To attain a comparable interval for serum-hCG (s-hCG), the ovulation induction time was identical: 35-37 h before oocyte retrieval or IUI. The conception day was considered as: the insemination day for pregnancies conceived after IUI, the oocyte retrieval day for fresh ET, or the transfer day minus 3 or 5 as appropriate for FET of Day 3 or 5 embryos. Multiple linear regression analysis was used, including days post-conception for the hCG measurement as a covariate, and was adjusted for the women's age, the cause of infertility, and the centre. For FET, a sensitivity analysis was used to adjust for endometrial preparation. MAIN RESULTS AND THE ROLE OF CHANCE: The study totally includes 5524 cycles: 2395 FET cycles, 2521 fresh ET cycles, and 608 IUI cycles. Regarding the length of in vitro culture, with IUI as reference (for no time in in vitro culture), we found a significantly lower s-hCG in pregnancies achieved after fresh ET (cleavage-stage ET or blastocyst transfer). S-hCG was 18% (95% CI: 13-23%, P < 0.001) lower after fresh cleavage-stage ET, and 23% (95% CI: 18-28%, P < 0.001) lower after fresh blastocyst transfer compared to IUI. In FET cycles, s-hCG was significantly higher after blastocyst transfers compared to cleavage-stage FET, respectively, 26% (95% CI: 13-40%, P < 0.001) higher when cryopreserved on in vitro Day 5, and 14% (95% CI: 2-26%, P = 0.02) higher when cryopreserved on in vitro Day 6 as compared to Day 3. Regarding the ART treatment type, s-hCG after FET blastocyst transfer (Day 5 blastocysts) cycles was significantly higher, 33% (95% CI: 27-45%, P < 0.001), compared to fresh ET (Day 5 blastocyst), while there was no difference between cleavage-stage FET (Days 2 + 3) and fresh ET (Days 2 + 3). S-hCG was 12% (95% CI: 4-19%, 0.005) lower in PGT FET (Day 5 blastocysts) cycles as compared to FET cycles without PGT (Day 5 blastocysts). LIMITATIONS, REASONS FOR CAUTION: The retrospective design is a limitation which introduces the risk of possible bias and confounders such as embryo score, parity, and ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: This study elucidates how practices in medically assisted reproduction treatment are associated with the hCG kinetics, underlining a potential impact of in vitro culture length and mode of ART on the very early embryo development and implantation. The study provides clinicians knowledge that the type of ART used may be relevant to take into account when evaluating s-hCG for the prognosis of the pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. AP has received consulting fees, research grants, or honoraria from the following companies: Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos, Merck A/S, and Organon. AZ has received grants and honoraria from Gedeon Richter. NLF has received grants from Gedeon Richter, Merck A/S, and Cryos. MLG has received honoraria fees or research grants from Gedeon Richter, Merck A/S, and Cooper Surgical. CB has received honoraria from Merck A/S. MB has received research grants and honoraria from IBSA. MPR, KM, and PVS all report no conflicts of interest. TRIAL REGISTRATION NUMBER: The study was registered and approved by the Danish Protection Agency, Capital Region, Denmark (Journal-nr.: 21019857). No approval was required from the regional ethics committee according to Danish law.

Survey on ART and IUI: legislation, regulation, funding, and registries in European countries-an update.

STUDY QUESTION: How are ART and IUI regulated, funded, and registered in European countries, and how has the situation changed since 2018? SUMMARY ANSWER: Of the 43 countries performing ART and IUI in Europe, and participating in the survey, specific legislation exists in only 39 countries, public funding varies across and sometimes within countries (and is lacking or minimal in four countries), and national registries are in place in 33 countries; only a small number of changes were identified, most of them in the direction of improving accessibility, through increased public financial support and/or opening access to additional subgroups. WHAT IS KNOWN ALREADY: The annual reports of the European IVF-Monitoring Consortium (EIM) clearly show the existence of different approaches across Europe regarding accessibility to and efficacy of ART and IUI treatments. In a previous survey, some coherent information was gathered about how those techniques were regulated, funded, and registered in European countries, showing that diversity is the paradigm in this medical field. STUDY DESIGN, SIZE, DURATION: A survey was designed using the SurveyMonkey tool consisting of 90 questions covering several domains (legal, funding, and registry) and considering specific details on the situation of third-party donations. New questions widened the scope of the previous survey. Answers refer to the situation of countries on 31 December 2022. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: All members of the EIM were invited to participate. The received answers were checked and initial responders were asked to address unclear answers and to provide any additional information considered relevant. Tables resulting from the consolidated data were then sent to members of the Committee of National Representatives of ESHRE, requesting a second check. Conflicting information was clarified by direct contact. MAIN RESULTS AND THE ROLE OF CHANCE: Information was received from 43 out of the 45 European countries where ART and IUI are performed. There were 39 countries with specific legislation on ART, and artificial insemination was considered an ART technique in 33 of them. Accessibility is limited to infertile couples only in 8 of the 43 countries. In 5 countries, ART and IUI are permitted also for treatments of single women and all same sex couples, while a total of 33 offer treatment to single women and 19 offer treatment to female couples. Use of donated sperm is allowed in all except 2 countries, oocyte donation is allowed in 38, simultaneous donation of sperm and oocyte is allowed in 32, and embryo donation is allowed in 29 countries. Preimplantation genetic testing (PGT)-M/SR (for monogenetic disorders, structural rearrangements) is not allowed in 3 countries and PGT-A (for aneuploidy) is not allowed in 10; surrogacy is accepted in 15 countries. Except for marital/sexual situation, female age is the most frequently reported limiting criterion for legal access to ART: minimal age is usually set at 18 years and the maximum ranges from 42 to 54 with some countries not using numeric definition. Male maximum age is set in very few countries. Where third-party donors are permitted, age is frequently a limiting criterion (male maximum age ranging from 35 to 50; female maximum age from 30 to 37). Other legal restrictions in third-party donation are the number of children born from the same donor (or, in some countries, the number of families with children from the same donor) and, in 12 countries, there is a maximum number of oocyte donations. How countries deal with the anonymity is diverse: strict anonymity, anonymity just for the recipients (not for children when reaching legal adulthood age), a mixed system (anonymous and non-anonymous donations), and strict non-anonymity. Inquiring about donors' genetic screening showed that most countries have enforced either mandatory or scientific recommendations that exclude the most prevalent genetic diseases, although, again, diversity is evident. Reimbursement/compensation systems exist in more than 30 European countries, with around 10 describing clearly defined maximum amounts considered acceptable. Public funding systems are extremely variable. One country provides no financial assistance to ART/IUI patients and three offer only minimal support. Limits to the provision of funding are defined in the others i.e. age (female maximum age is the most used), existence of previous children, BMI, maximum number of treatments publicly supported, and techniques not entitled for funding. In a few countries reimbursement is linked to a clinical policy. The definitions of the type of expenses covered within an IVF/ICSI cycle, up to which limit, and the proportion of out-of-pocket costs for patients are also extremely dissimilar. National registries of ART are in place in 33 out of the 43 countries contributing to the survey and a registry of donors exists in 19 of them. When comparing with the results of the previous survey, the main changes are: (i) an extension of the beneficiaries of ART techniques (and IUI), evident in nine countries; (ii) public financial support exists now in Albania and Armenia; (iii) in Luxembourg, the only ART centre expanded its on-site activities; (iv) donor-conceived children are entitled to know the donor identity in six countries more than in 2018; and (v) four more countries have set a maximum number of oocyte donations. LIMITATIONS, REASONS FOR CAUTION: Although the responses were provided by well-informed and committed individuals and submitted to double checking, no formal validation by official bodies was in place. Therefore, possible inaccuracies cannot be excluded. The results presented are a cross-section in time, and ART and IUI frameworks within European countries undergo continuous modification. Finally, some domains of ART activity were deliberately left out of the scope of this survey. WIDER IMPLICATIONS OF THE FINDINGS: Our results offer a detailed updated view of the ART and IUI situation in European countries. It provides extensive answers to many relevant questions related to ART usage at the national level and could be used by institutions and policymakers at both national and European levels. STUDY FUNDING/COMPETING INTEREST(S): The study has no external funding, and all costs were covered by ESHRE. There were no competing interests.

How successful is intrauterine insemination after failed IVF? A study of 551 women.

RESEARCH QUESTION: What is the success rate of intrauterine insemination (IUI) after failing IVF? DESIGN: This retrospective cohort study evaluated the pregnancy outcomes of 551 patients who underwent a total of 992 IUI cycles at an academic fertility centre between October 2008 and April 2018. RESULTS: The study participants (n = 551) had previously failed one to three fresh IVF cycles and any resultant embryo transfers, and subsequently underwent a total of 992 IUI cycles. When comparing demographics, women with ongoing pregnancies, clinical pregnancies and positive pregnancies were significantly younger (P = 0.037, P = 0.025 and P = 0.049, respectively) compared with women who did not conceive. The cumulative ongoing pregnancy rate for all IUI cycles was 7.44% per patient (41 pregnancies in 551 patients), and the ongoing pregnancy rate after the first IUI cycle was 4.72%. In single women who had previously failed six IUI cycles before undergoing IVF cycles with donor sperm, the cumulative ongoing pregnancy rate was 15.8% in donor sperm IUI cycles compared with 5.1% in women who used their partner's sperm for both IVF and IUI cycles, with an adjusted odds ratio of 6.1. Patient age, number of previous pregnancies, daily gonadotrophin dose for IVF, number of mature follicles at trigger, and number of failed IVF cycles failed to predict pregnancy outcomes. CONCLUSION: Ongoing pregnancy following IUI after failed IVF occurs at a rate of approximately 5% per cycle, and this rate is higher if donor sperm is used for both IVF and IUI cycles. This can be considered with proper counselling in women aged <40 years, and may be discouraged in women aged ≥43 years.

Optimizing intrauterine insemination: A systematic review and meta-analysis of the effectiveness and safety of clinical treatment add-ons.

INTRODUCTION: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add-on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta-analysis is to assess the effectiveness and safety of add-on interventions to the standard IUI protocol and to provide evidence-based recommendations on techniques used to optimize the clinical outcomes of IUI treatment. MATERIAL AND METHODS: Systematic review and meta-analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta-analysis based on random effects was performed for each outcome and add-on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857. RESULTS: Sixty-six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09-1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03-2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00-1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions. CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add-ons could benefit specific patient groups.

Analysis of factors associated with IUI pregnancy outcomes in elderly and young patients.

OBJECTIVE: The objective of this study was to investigate the correlation between various factors and the clinical outcomes of Intrauterine Insemination (IUI) in both young and aged patients, aiming to provide a theoretical basis for clinical consultations. METHODS: This retrospective analysis examined a total of 4,221 IUI cycles conducted at the Reproductive Center of Changzhou Maternal and Child Health Hospital between January 2016 and December 2020. The patients were categorized into two groups based on age: the elder group (≥ 35 years) and the young group (< 35 years). RESULTS: The findings of this study revealed a significant association between woman's age and BMI with pregnancy outcomes (0.93, 95% CI: 0.89-0.97) (1.04, 95% CI: 1.01-1.06). Moreover, in young women, both age and Body Mass Index (BMI)were found to be related to pregnancy outcomes (0.97, 95% CI: 0.89-0.97) (1.08, 95% CI: 1.01-1.06). Additionally, BMI and the number of cycles in aged IUI patients were found to be associated with pregnancy outcomes. The pregnancy rate in the second cycle was approximately 1.9 times higher than that in the first cycle (1.9, 95% CI: 0.97-3.77), and in the third cycle, it was approximately 3 times higher than that in the first cycle (3.04, 95% CI: 1.43-6.42). CONCLUSIONS: In conclusion, there is an association between woman's age and BMI and the clinical outcomes of IUI. However, the number of cycles did not affect the pregnancy outcomes in young women. Conversely, in elder women, the number of cycles was found to be related to the IUI pregnancy outcomes, with significantly higher pregnancy rates observed in the second and third cycles compared to the first cycle.

Optimizing timing for intrauterine insemination (IUI) in donor sperm cycles: pre- versus post-ovulation insemination in natural cycles.

PURPOSE: To investigate whether pregnancy outcomes of natural cycle intrauterine insemination (IUI) with donor sperm can be improved by performing insemination after confirmation of ovulation. METHODS: This retrospective cohort study evaluated 751 couples undergoing 1170 cycles of artificial insemination with donor sperm (AID) in natural cycles between January 2018 and January 2021. Patients underwent AID either within 6-12 h after spontaneous luteinizing hormone (LH) surge (pre-ovulation group) or after ovulation was confirmed by ultrasound (post-ovulation group). Propensity score matching was performed to account for differences in baseline characteristics between groups. The main outcome measures of this study were clinical pregnancy rate and live birth rate. RESULTS: After propensity score matching, each group comprised 216 cycles. No significant differences were observed between the pre-ovulation and post-ovulation groups in terms of clinical pregnancy rate (30.6% vs 27.3%, respectively, p = .458) and live birth rate (25.0% vs 22.7%, respectively, p = .651). However, upon excluding cases of luteinized unruptured follicle syndrome (LUFS) from the pre-ovulation group, the clinical pregnancy rate (33.5% vs 27.3%, respectively, p = .043) and live birth rate (27.4% vs 22.7%, respectively, p = .039) were significantly higher in the pre-ovulation group. CONCLUSIONS: For fertile women undergoing AID in natural cycles, pre-ovulation insemination timing yielded superior pregnancy outcomes compared to post-ovulation insemination when ovulation was achieved. However, due to the occurrence of LUFS, pre- and post-ovulation AID resulted in comparable overall pregnancy outcomes in natural cycles.

Bacterial vaginosis in a subfertile population undergoing fertility treatments: a prospective cohort study.

PURPOSE: This study investigates the role of bacterial vaginosis (BV) on pregnancy rates during various fertility treatments. BV is known to influence several obstetric outcomes, such as preterm delivery and endometritis. Only few studies investigated the effect of BV in subfertile women, and studies found a negative effect on fecundity especially in the in vitro fertilisation population. METHODS: Observational prospective study, 76 couples attending a fertility clinic in the Netherlands between July 2019 and June 2022, undergoing a total of 133 attempts of intra uterine insemination, in vitro fertilization or intra cytoplasmatic sperm injection. Vaginal samples taken at oocyte retrieval or insemination were analysed on qPCR BV and 16S rRNA gene microbiota analysis of V1-V2 region. Logistic regression with a Generalized Estimated Equations analysis was used to account for multiple observations per couples. RESULTS: A total of 26% of the 133 samples tested positive for BV. No significant differences were observed in ongoing pregnancy or live birth rates based on BV status (OR 0.50 (0.16-1.59), aOR 0.32 (0.09-1.23)) or microbiome community state type. There was a tendency of more miscarriages based on positive BV status (OR 4.22 (1.10-16.21), aOR 4.28 (0.65-28.11)) or community state type group III and IV. On baseline qPCR positive participants had significantly higher body mass index and smoked more often. Odds ratios were adjusted for smoking status, body mass index, and socioeconomic status. CONCLUSION: Bacterial vaginosis does not significantly impact ongoing pregnancy rates but could affect miscarriage rates.

Pregnancy outcomes after superovulation-intrauterine insemination (SO-IUI) using gonadotropins versus letrozole in the obese population.

PURPOSE: To compare fertility outcomes of obese patients (body mass index [BMI] ≥ 30 kg/m2) undergoing superovulation and intrauterine insemination (SO-IUI) using gonadotropins versus letrozole. METHODS: A single centre retrospective cohort study of obese patients undergoing SO-IUI using gonadotropins or letrozole between January/2019 and June/2022. Primary outcome was clinical pregnancy rate (intrauterine pregnancy with positive fetal heart rate). Secondary outcomes included rates of multifollicular development, multiple pregnancy, spontaneous abortion and cycle cancellation. Subgroup analysis was done stratifying by obesity class. A multivariate logistic regression model was used for primary/secondary outcomes, adjusting for clinically determined covariates. RESULTS: Out of 802 total identified SO-IUI cycles, 715 cycles were completed (518-gonadotropins and 197-letrozole cycles). The clinical pregnancy rates were not significantly different in obese patients undergoing SO-IUI with gonadotropins versus letrozole when adjusted for age, gravidity, parity, cause of infertility, IUI cycle number, endometrial thickness, sperm source and post-wash motile sperm count (adjusted odds ratio [aOR] 1.37, 95% confidence interval [CI] 0.72-2.59). Similarly, no significant associations were found in spontaneous abortion (aOR1.46, 95%CI 0.42-5.08), multiple pregnancy (aOR1.33, 95%CI 0.20-8.88) or cancellation rates (OR0.89, 95%CI 0.55-1.45) between the two groups. The rates of multifollicular development were also comparable between the two groups (aOR0.51, 95% CI 0.19-1.38). For cycles involving gonadotropins, higher BMI classes required higher total gonadotropin dose (p < 0.001). CONCLUSION: After adjusting for patient and cycle factors, gonadotropins and letrozole led to comparable odds of achieving pregnancy in obese patients undergoing SO-IUI. Future research in the obese population will help to better understand how to optimize fertility treatments for this growing population.

Anti-Müllerian hormone does not predict cumulative pregnancy rate in non-infertile women following four IUI cycles with donor sperm.

PURPOSE: To evaluate the predictive value of serum AMH for clinical pregnancy in non-infertile population undergoing intrauterine insemination with donor sperm (ds-IUI). METHODS: This multicenter prospective study (ClinicalTrials.gov ID: NCT06263192) recruited all non-infertile women undergoing ds-IUI from June 2020 to December 2022 in three different fertility clinics in Spain and Chile. Indications for ds-IUI included severe oligoasthenoteratozoospermia, female partner, or single status. Clinical pregnancy rates were compared between women with AMH ≥ 1.1 and < 1.1 ng/mL. The main outcome measure was the cumulative clinical pregnancy rate after up to 4 ds-IUI cycles. RESULTS: A total of 458 ds-IUI cycles were performed among 245 patients, of whom 108 (44.08%) achieved clinical pregnancy within 4 cycles, 60.2% of these occurring in the first attempt and 84.2% after two attempts. We found no significant differences in AMH levels or other parameters (such as age, BMI, FSH, AFC) between women who became pregnant and those who did not. Cumulative pregnancy rates and logistic regression analysis revealed that AMH ≥ 1.1 ng/mL was not predictive of ds-IUI success. While a high positive correlation was observed between AFC and AMH (r = 0.67, p < 0.001), ROC curve analyses indicated that neither of these ovarian reserve markers accurately forecasts cumulative ds-IUI outcomes in non-infertile women. CONCLUSIONS: The findings of this multicenter study suggest that AMH is not a reliable predictor of pregnancy in non-infertile women undergoing ds-IUI. Even women with low AMH levels can achieve successful pregnancy outcomes, supporting the notion that diminished ovarian reserve should not restrict access to ds-IUI treatments in eligible non-infertile women.

Impact of current and previous sperm findings on outcomes of intrauterine insemination.

Purpose: To examine the association between semen characteristics and outcomes of intrauterine insemination (IUI). Methods: This retrospective analysis examined 1380 IUI procedures involving 421 couples. The association of clinical pregnancy with pre- and post-wash sperm characteristics was assessed. Results: Pre- and post-wash sperm characteristics did not differ between IUI cycles that resulted in pregnancy and those that did not. When the motility of pre-wash sperm was below the normal range (<42%) established by the World Health Organization (WHO), the pregnancy rate was significantly lower. In the IUI cycles when post-wash sperm motility was below the WHO standard, pregnancy was not achieved. The frequency of improvement in post-wash sperm motility in repeated IUI cycles appeared to correlate with the success of future IUI cycles. At the fourth IUI cycle, pregnancy was not achieved unless the post-wash sperm motility was normal in at least two of three attempts. When post-wash sperm concentration was below the normal range, the woman's age did not affect the IUI outcomes. Conclusions: Sperm motility above the lower limit of the WHO criteria in post-wash semen samples is an important factor in IUI outcomes.

Evidence-based guideline: unexplained infertility†.

STUDY QUESTION: What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? SUMMARY ANSWER: The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. WHAT IS KNOWN ALREADY: UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. LIMITATIONS, REASONS FOR CAUTION: Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. 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.).

ART in Europe, 2019: results generated from European registries by ESHRE†.

STUDY QUESTION: What are the data and trends on ART and IUI cycle numbers and their outcomes, and on fertility preservation (FP) interventions, reported in 2019 as compared to previous years? SUMMARY ANSWER: The 23rd ESHRE report highlights the rising ART treatment cycles and children born, alongside a decline in twin deliveries owing to decreasing multiple embryo transfers; fresh IVF or ICSI cycles exhibited higher delivery rates, whereas frozen embryo transfers (FET) showed higher pregnancy rates (PRs), and reported IUI cycles decreased while maintaining stable outcomes. WHAT IS KNOWN ALREADY: ART aggregated data generated by national registries, clinics, or professional societies have been gathered and analyzed by the European IVF-Monitoring (EIM) Consortium since 1997 and reported in a total of 22 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN, SIZE, DURATION: Data on medically assisted reproduction (MAR) from European countries are collected by EIM for ESHRE each year. The data on treatment cycles performed between 1 January and 31 December 2019 were provided by either national registries or registries based on initiatives of medical associations and scientific organizations or committed persons in one of the 44 countries that are members of the EIM Consortium. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 1487 clinics offering ART services in 40 countries reported, for the second time, a total of more than 1 million (1 077 813) treatment cycles, including 160 782 with IVF, 427 980 with ICSI, 335 744 with FET, 64 089 with preimplantation genetic testing (PGT), 82 373 with egg donation (ED), 546 with IVM of oocytes, and 6299 cycles with frozen oocyte replacement (FOR). A total of 1169 institutions reported data on IUI cycles using either husband/partner's semen (IUI-H; n = 147 711) or donor semen (IUI-D; n = 51 651) in 33 and 24 countries, respectively. Eighteen countries reported 24 139 interventions in pre- and post-pubertal patients for FP, including oocyte, ovarian tissue, semen, and testicular tissue banking. MAIN RESULTS AND THE ROLE OF CHANCE: In 21 countries (21 in 2018) in which all ART clinics reported to the registry 476 760 treatment cycles were registered for a total population of approximately 300 million inhabitants, allowing the best estimate of a mean of 1581 cycles performed per million inhabitants (range: 437-3621). Among the reporting countries, for IVF the clinical PRs per aspiration slightly decreased while they remained similar per transfer compared to 2018 (21.8% and 34.6% versus 25.5% and 34.1%, respectively). In ICSI, the corresponding PRs showed similar trends compared to 2018 (20.2% and 33.5%, versus 22.5% and 32.1%) When freeze-all cycles were not considered for the calculations, the clinical PRs per aspiration were 28.5% (28.8% in 2018) and 26.2% (27.3% in 2018) for IVF and ICSI, respectively. After FET with embryos originating from own eggs, the PR per thawing was at 35.1% (versus 33.4% in 2018), and with embryos originating from donated eggs at 43.0% (41.8% in 2018). After ED, the PR per fresh embryo transfer was 50.5% (49.6% in 2018) and per FOR 44.8% (44.9% in 2018). In IVF and ICSI together, the trend toward the transfer of fewer embryos continues with the transfer of 1, 2, 3, and ≥4 embryos in 55.4%, 39.9%, 2.6%, and 0.2% of all treatments, respectively (corresponding to 50.7%, 45.1%, 3.9%, and 0.3% in 2018). This resulted in a reduced proportion of twin delivery rates (DRs) of 11.9% (12.4% in 2018) and a similar triplet DR of 0.3%. Treatments with FET in 2019 resulted in twin and triplet DR of 8.9% and 0.1%, respectively (versus 9.4% and 0.1% in 2018). After IUI, the DRs remained similar at 8.7% after IUI-H (8.8% in 2018) and at 12.1% after IUI-D (12.6% in 2018). Twin and triplet DRs after IUI-H were 8.7% and 0.4% (in 2018: 8.4% and 0.3%) and 6.2% and 0.2% after IUI-D (in 2018: 6.4% and 0.2%), respectively. Eighteen countries (16 in 2018) provided data on FP in a total number of 24 139 interventions (20 994 in 2018). Cryopreservation of ejaculated sperm (n = 11 592 versus n = 10 503 in 2018) and cryopreservation of oocytes (n = 10 784 versus n = 9123 in 2018) were most frequently reported. LIMITATIONS, REASONS FOR CAUTION: Caution with the interpretation of results should remain as data collection systems and completeness of reporting vary among European countries. Some countries were unable to deliver data about the number of initiated cycles and/or deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 23rd ESHRE data collection on ART, IUI, and FP interventions shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Although it is the largest data collection on MAR in Europe, further efforts toward optimization of both the collection and the reporting, from the perspective of improving surveillance and vigilance in the field of reproductive medicine, are awaited. STUDY FUNDING/COMPETING INTEREST(S): The study has received no external funding and all costs are covered by ESHRE. There are no competing interests.

Should IUI replace IVF as first-line treatment for unexplained infertility? A literature review.

BACKGROUND: Unexplained infertility accounts for 25% of infertility causes in the UK. Active intervention methods, such as intrauterine insemination (IUI) or in vitro fertilisation (IVF), are often sought. Despite the National Institute for Health and Care Excellence (NICE) recommending IVF for unexplained infertility, this recommendation has generated an ongoing debate, with few fertility clinics discontinuing the use of IUI as the first-line management of choice. In contrast to NICE, recent guidance released from the European Society for Human Reproduction and Embryology (ESHRE) in August 2023 supports the use of IUI as first-line. High-quality evidence behind such interventions is lacking, with current literature providing conflicting results. AIMS: This review aims to provide a literature overview exploring whether IUI or IVF should be used as first-line treatment for couples with unexplained infertility, in the context of current guidelines. METHODS: The primary outcome used to assess efficacy of both treatment methods is live birth (LB) rates. Secondary outcomes used are clinical pregnancy (CP) and ongoing pregnancy (OP) rates. A comprehensive literature search of 4 databases: Ovid MEDLINE, EMBASE, Maternity & Infant Care and the Cochrane Library were searched in January 2022. Upon removal of duplications, abstract screening, and full-text screening, a total of 34 papers were selected. DISCUSSION/CONCLUSION: This review highlights a large discrepancy in the literature when examining pregnancy outcomes of IUI and IVF treatments. Evidence shows IUI increases LB and CP rates 3-fold compared to expectant management. Literature comparing IUI to IVF is less certain. The review finds the literature implies IVF should be used for first-line management but the paucity of high-quality randomised controlled trials (RCTs), coupled with heterogeneity of the identified studies and a lack of research amongst women > 40 years warrants the need for further large RCTs. The decision to offer IUI with ovarian stimulation (IUI-OS) or IVF should be based upon patient prognostic factors. We suggest that IUI-OS could be offered as first-line treatment for unexplained infertility for women < 38 years, with good prognosis, and IVF could be offered first to those > 38 years. Patients should be appropriately counselled to enable informed decision making.

Ovulation and birth after administration of progesterone trigger-two case reports.

PURPOSE: To determine whether using progesterone as a trigger of a gonadotropin surge will induce ovulation and a competent corpus luteum. METHODS: Patients were administered 5 or 10 mg of progesterone intramuscularly when the leading follicle reached preovulatory size. RESULTS: We demonstrate that progesterone injections result in classical ultrasonographic hallmarks of ovulation about 48 h later and the formation of a corpus luteum competent to support pregnancy. CONCLUSION: Our results support further exploration of using progesterone to trigger a gonadotropin surge in assisted human reproduction.

Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial.

STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain. STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER: Dutch Trial register NL5455 (NTR5599). TRIAL REGISTRATION DATE: 18 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2017.

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.

Intracervical insemination versus intrauterine insemination with cryopreserved donor sperm in the natural cycle: a randomized controlled trial.

STUDY QUESTION: Is intracervical insemination (ICI) non-inferior to IUI with cryopreserved donor sperm in the natural cycle in terms of live birth? SUMMARY ANSWER: ICI with cryopreserved donor sperm in the natural cycle was inferior to IUI in terms of live birth. WHAT IS KNOWN ALREADY: Both ICI and IUI in the natural cycle are performed as first-line treatments in women who are eligible for donor sperm treatment. High-quality data on the effectiveness of ICI versus IUI with cryopreserved donor sperm in the natural cycle in terms of live birth is lacking. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicentre randomized non-inferiority trial in the Netherlands and Belgium. PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomly allocated women who were eligible for donor sperm treatment with cryopreserved donor semen to six cycles of ICI in the natural cycle or six cycles of IUI in the natural cycle. The primary outcome was conception within 8 months after randomization leading to a live birth. Secondary outcomes were ongoing pregnancy, multiple pregnancy, clinical pregnancy, miscarriage and time to conception leading to live birth. We calculated relative risks (RRs) and risk differences (RDs) with 95% CI. Non-inferiority would be shown if the lower limit of the 95% RD CI was <-12%. MAIN RESULTS AND THE ROLE OF CHANCE: Between June 2014 and February 2019, we included 421 women, of whom 211 women were randomly allocated to ICI and 210 to IUI. Of the 211 women allocated to ICI, 2 women were excluded, 126 women completed treatment according to protocol and 75 women did not complete 6 treatment cycles. Of the 210 women allocated to IUI, 3 women were excluded, 140 women completed treatment according to protocol and 62 women did not complete 6 treatment cycles. Mean female age was 34 years (SD ±4) in both interventions. Conception leading to live birth occurred in 51 women (24%) allocated to ICI and in 81 women (39%) allocated to IUI (RR 0.63, 95% CI: 0.47 to 0.84). This corresponds to an absolute RD of -15%; 95% CI: -24% to -6.9%, suggesting inferiority of ICI. ICI also resulted in a lower live birth rate over time (hazard ratio 0.58, 95% CI: 0.41-0.82). Our per-protocol analysis showed that, within the 8 months treatment horizon, 48 women (38%) had live births after ICI and 79 women (56%) had live births after IUI (RR 0.68, 95% CI: 0.52-0.88; RD -18%, 95% CI: -30% to -6%). LIMITATIONS, REASONS FOR CAUTION: The study was non-blinded owing to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: Since ICI in the natural cycle was inferior to IUI in the natural cycle with cryopreserved donor sperm in terms of live birth rate, IUI is the preferred treatment. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw project number 837002407). B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437), reports consultancy for ObsEva and has received research funding from Guerbet, Ferring and Merck. The other authors do not declare a COI. TRIAL REGISTRATION NUMBER: NTR4462. TRIAL REGISTRATION DATE: 11 March 2014. DATE OF FIRST PATIENT'S ENROLMENT: 03 June 2014.

IUI is a better alternative than IVF as the first-line treatment of unexplained infertility.

The treatment of a condition with no known cause, such as unexplained infertility is, unsurprisingly, controversial. The alternatives that have been suggested for the first-line treatment are expectant management, ovarian stimulation, intrauterine insemination (IUI) with or without ovarian stimulation, or IVF. As far as live births are concerned, the choice has realistically been narrowed down to IUI with ovarian stimulation by low-dose gonadotrophins using strict cancellation criteria versus IVF. In several well-designed studies, three cycles of the former have proved as successful as one cycle of IVF. As IUI is less invasive, more comfortable for the patient, markedly less expensive and safe with a high compliance rate, it should be recommended for the first-line treatment of unexplained infertility for couples in whom the woman's age is not more than 38 years.