For women with diminished ovarian reserve or of advanced age, controlled ovarian stimulation presents a significant challenge during in vitro fertilization cycles. This multi-center, open-label, randomized controlled trial enrolled 318 women with diminished ovarian reserve (defined as an antral follicle count < 5 or anti-Müllerian hormone level of 0.1-1.1 ng/mL) or advanced age (40-45 years) between 2020 and 2023. Participants were assigned to either a modified letrozole protocol (mLP, n = 159) or a gonadotropin-releasing hormone antagonist protocol (n = 159). Primary outcomes, cumulative clinical pregnancy rate and cumulative live birth rate, were analyzed using both the full analysis set and the per-protocol set. Secondary outcomes, including live birth rate, clinical pregnancy rate, and pregnancy loss rate, were analyzed using the per-protocol set. Results from the full analysis set showed comparable cumulative clinical pregnancy rates (32.1% vs 34.0%; RR 0.94, 95% CI: 0.69-1.29) and cumulative live birth rates (24.5% vs 22.6%; RR 1.08, 95% CI: 0.73-1.61) between the two groups. The per-protocol analysis also demonstrated comparable cumulative clinical pregnancy rates (33.3% vs 36.0%; RR 0.93, 95% CI: 0.68-1.27). Notably, the mLP was associated with a significantly higher clinical pregnancy rate among patients with diminished ovarian reserve who underwent dual cleavage-stage fresh embryo transfers (65.8% vs 36.4%; RR 1.81, 95% CI: 1.15-2.85). Although primary outcomes were similar between protocols, the mLP improved clinical pregnancy rates in fresh embryo transfers for women with diminished ovarian reserve, suggesting its potential to enhance in vitro fertilization efficacy in this population. Fresh transfers demonstrated non-significant difference of mLP for live birth rate (34.0% vs 22.2%; RR 1.53, 95% CI: 0.96-2.43), non-significant reduced biochemical pregnancy loss rate (22.0% vs 34.3%; RR 0.59, 95% CI: 0.29-1.21) and miscarriage rate (20.0% vs 26.7%; RR 0.75, 95% CI: 0.32-1.77). Trial registration: ChiCTR2000029272.

Background:We have previously reported that, in metropolitan Melbourne, mitigation measures implemented to mitigate SARS-CoV-2 transmission were associated with a reduced preterm birth (PTB) rate, both in spontaneous and iatrogenic births <34 weeks. Here, we assess the impact of mitigation measures on PTB in relation to mid-pregnancy cervical length (CL). Methods:We conducted a comparative cohort study in three maternity hospitals in Melbourne, Australia, between women with a previous PTB <32 weeks who were exposed to COVID-19 mitigation measures while pregnant (lockdown cohort, estimated conception November 1, 2019 to February 29, 2020) and women who were pregnant before mitigation measures (pre-lockdown cohort, estimated conception November 1, 2018 to February 28, 2019). In our clinics, women with a previous PTB <32 weeks routinely undergo targeted assessment of CL at around 20 weeks. Within each cohort, we assessed the relationship between CL and perinatal outcomes. Results:We studied 113 women, of whom 60 were in the lockdown group and 53 in the pre-lockdown group. Baseline characteristics, including CL measurements taken on average at 20.4 and 20.3 weeks of gestation, respectively, were comparable. Mean CL was 38.4 ± 8.8 mm versus 35.8 ± 9.7 mm (p = 0.141). Progesterone usage occurred in 5% (lockdown cohort) versus 23% (pre-lockdown cohort) of women (p = 0.006). After adjusting for age, BMI, smoking status, and parity, the rates of PTB <37 weeks were 20% and 26%, respectively (adjusted odds ratio [aOR], 0.60; 95% confidence interval [CI], 0.27-1.35; p = 0.199), while rates of PTB <34 weeks were 5% and 19% (aOR, 0.21; 95% CI, 0.06-0.82; p = 0.038). In the pre-lockdown cohort, CL measurements predicted PTB (aOR, 0.79; 95% CI, 0.65-0.90; p = 0.009), but this association was not present in the lockdown cohort (aOR, 1.21; 95% CI, 0.95-1.73; p = 0.169). Conclusion:COVID-19 mitigation measures were associated with a reduction in PTB. The predictive capacity of CL disappeared during mitigation measures. This effect may be attributed to a reduction of PTB in women with a short CL. While the underlying mechanism remains unclear, these findings suggest a potentially modifiable risk factor in lifestyle in high-risk women with a short CL, warranting further investigation through larger prospective studies.

OBJECTIVES:Systematic reviews (SRs) of randomized controlled trials (RCTs) are crucial for shaping clinical practice, but are only as good as the RCTs on which they are based. We aimed to summarize tools to prevent untrustworthy RCTs from entering meta-analysis. We propose six checkpoints: prepublication checks, postpublication checks, checks during aggregate-data meta-analysis, checks of individual participant data (IPD), and checks for umbrella reviews and guidelines. STUDY DESIGN AND SETTING:We searched PubMed for tools assessing RCTs for trustworthiness. RESULTS:Before publication, trialists must guarantee trustworthiness by providing registration details, protocol, datasets, and code. Journals should enhance data-sharing policies for RCTs. Research users should evaluate trials postpublication and report concerns to journals or platforms like PubPeer. Journals should be automatically alerted to comments, mark retracted references, expedite investigations, and communicate findings transparently. We found seven tools for both prepublication and postpublication checks and an international consensus set of statements for postpublication checks. Four were piloted, while one has been published as preprint (INveStigating ProblEmatic Clinical Trials in SR [INSPECT-SR]). Three were achieved by non-Delphi consensus, while INSPECT-SR used a Delphi process. No tools were formally validated; one (IPD-Integrity) underwent preliminary validation. All address trial ethics, registration, follow-up plausibility, and baseline data; 6 of 7 tools assess the plausibility of the authors' group size relative to trial context, recruitment timelines, and outcome data. Three were recommended for research user and editor checks. Systematic reviewers should assess RCTs for trustworthiness. All seven tools were recommended for systematic reviewers. Positive systematic reviewer screening for major issues can eliminate trials after study selection but before data extraction. Studies with unresolved issues should be excluded; their count should appear in the flow diagram with reasons. All tools assess study-level data. IPD-level checks should detect unexpected values and data patterns; IPD-Integrity and a developing INSPECT-SR extension can do so. Umbrella reviews should check whether original reviews assessed trustworthiness and, if needed, perform primary RCT assessments or only include SRs that have conducted checks. Guidelines should evaluate the trustworthiness of included studies. CONCLUSION:Six levels of trustworthiness checks can prevent untrustworthy RCTs from influencing practice. At the SR level, trustworthiness assessments should be integrated in Preferred Reporting Items for Systematic Reviews and Meta-analyses.

INTRODUCTION:Despite advances in maternity care, stillbirth remains a major burden. It disproportionately affects black and Asian mothers, those with obesity and women over the age of 35 years. Induction of labour may benefit these women, but there is no clear evidence to guide recommendations on optimal timing of induction because of variations in the intervention and insufficient power in primary trials for rare outcomes such as stillbirth and perinatal mortality, or to assess whether effects differ by maternal characteristics. We will conduct an individual participant data (IPD) meta-analysis of randomised trials to assess the overall and differential effect of induction of labour, according to timing of induction and maternal characteristics, on adverse perinatal and maternal outcomes. We will also rank induction of labour timing strategies by their effectiveness to inform clinical and policy decision-making. METHODS AND ANALYSIS:We will identify randomised trials on induction of labour by searching MEDLINE, CINAHL, EMBASE, BIOSIS, LILACS, Pascal, SCI, CDSR, ClinicalTrials.gov, ICTRP, ISRCTN registry, CENTRAL, DARE and Health Technology Assessment Database, without language restrictions, from inception to June 2025. Primary researchers of identified trials will be invited to join the OPTIMAL Collaboration and share the original trial data. Data integrity and trustworthiness assessment will be performed on all eligible trials. We will check each study's IPD for consistency with the original authors before standardising and harmonising the data. Study quality of included trials will be assessed by the Cochrane Risk of Bias tool. We will perform a series of one-and-two-stage random-effects meta-analyses to obtain the summary intervention effect on composite adverse perinatal outcome (stillbirth, neonatal death or severe morbidity requiring admission to neonatal unit) with 95% CIs and summary treatment-covariate interactions (maternal age, ethnicity, parity, socioeconomic status, body mass index and method of conception). Heterogeneity will be summarised using tau2, I2 and 95% prediction intervals for effect in a new study. Sensitivity analysis to explore robustness of statistical and clinical assumptions will be carried out. Small study effects (potential publication bias) will be investigated using funnel plots. ETHICS AND DISSEMINATION:The study is registered on PROSPERO (CRD420251066346) and ethics approval is not required. We will disseminate findings widely to women, healthcare professionals and policymakers through academic, professional bodies and social media channels, and in peer-reviewed journals to achieve impact. PROSPERO REGISTRATION NUMBER:CRD420251066346.

Introduction Induction of labour (IOL) is a commonly performed obstetric intervention, particularly when delivery is deemed more beneficial than continuing the pregnancy due to maternal or fetal indications. When the cervix is unfavourable for delivery, cervical ripening is performed prior to IOL. A wide variety of mechanical, pharmacological and combination methods are used, but the optimal approach balancing efficacy, safety and patient experience remains uncertain. Conventional aggregate data (AD) meta-analyses lack individual-level data, limiting exploration of patient-level factors for personalised medicine and do not address concerns about the trustworthiness of data presented in peer-reviewed randomised controlled trials (RCTs). This protocol describes an individual participant data (IPD) network meta-analysis (NMA) designed to evaluate and rank cervical ripening methods for IOL using only high quality, trustworthy data. Methods and analysis We will identify eligible parallel-group RCTs enrolling pregnant women with a singleton, cephalic fetus at ≥34 weeks’ gestation requiring cervical ripening, through comprehensive searches of Ovid MEDLINE, Embase, Emcare, Scopus, Cochrane Pregnancy and Childbirth Register, WHO International Clinical Trials Registry Platform, clinicaltrials.gov and reference lists of prior reviews. The interventions we consider will be selected via Delphi consensus with international clinical experts. Eligible trial investigators will be invited to contribute de-identified IPD; AD will be used if IPD is unavailable. Trials will be assessed for trustworthiness using the Trustworthiness in RAndomised Clinical Trials checklist and the IPD Integrity Tool, with only eligible studies included in the primary analysis. All statistical analyses will follow a pre-specified statistical analysis plan (SAP) finalised before any analyses are conducted. A two-stage, contrast-based, frequentist IPD-NMA will compare cervical ripening methods for three co-primary outcomes: vaginal birth, composite adverse perinatal outcomes and composite adverse maternal outcomes. Subgroup analyses will assess effect modifiers (eg, parity, age and previous caesarean), with treatment rankings presented using the surface under the cumulative ranking curve and rank-heat plots. Sensitivity analyses will examine the impact of bias, missing data and population criteria. Ethics and dissemination This study has been approved by the Monash University Human Research Ethics Committee (No. 48189). IPD will be de-identified and securely transferred for storage on a Monash University-hosted shared network drive. Findings will be disseminated via peer-reviewed publications, conference abstracts and the Cervical Ripening for Induction of Labour Collaborative Evidence Network Meta-Analysis (CIRCLE-NMA) website ( https://circlenma.com ). Patient and public involvement will guide the communication and interpretation of results. PROSPERO registration number CRD420251077464.

Adenomyosis, an estrogen-dependent condition characterized by endometrial invasion into the myometrium, is associated with reduced live birth rates and increased miscarriage risk in women undergoing assisted reproductive technologies (ART). Gonadotropin-releasing hormone agonists (GnRH-a) are commonly used for pretreatment before frozen-thawed embryo transfer (FET) in adenomyosis patients, but optimal duration remains unclear. Letrozole, an aromatase inhibitor, may enhance GnRH-a efficacy by mitigating its flare-up effect and reducing peripheral estrogen production, yet high-level evidence on their combined effect is lacking. This study aims to compare the live birth rate and other pregnancy outcomes between one and two doses of GnRH-a pretreatment with or without letrozole supplementation in women with adenomyosis undergoing FET. This is a 2 × 2 factorial, multi-center, open-label, randomized controlled trial (RCT) conducted at three reproductive medical centers in China, with a planned enrollment of 432 women aged 20–38 years with sonographically diagnosed adenomyosis scheduled for single blastocyst FET. This study is designed as a superiority trial. Recruitment will be conducted by trained clinical research coordinators. Participants are randomized in a 1:1:1:1 ratio to four arms: one dose of GnRH-a (3.75 mg), two doses of GnRH-a, one dose of GnRH-a with letrozole (2.5 mg daily for 28 days), or two doses of GnRH-a with letrozole (2.5 mg daily for 28 days). The primary outcome is live birth rate. Secondary outcomes include fertility outcomes, pregnancy and obstetric outcomes, and neonatal outcomes. Safety outcomes, including the incidence and severity of low-estrogen-related adverse events (e.g., hot flashes, bone loss, vaginal dryness) and other serious adverse events, will be collected and compared. An internal pilot phase will assess procedural feasibility when approximately 25 participants are randomized per arm. Data are collected via medical records and follow-up assessments up to 6 months postpartum. This factorial RCT is the first to assess the synergistic effects of GnRH-a dosage and letrozole supplementation, overcoming limitations of single-factor studies. By comprehensively evaluating pregnancy outcomes, the study aims to optimize pretreatment strategies, inform clinical guidelines, and improve pregnancy outcomes for adenomyosis patients undergoing FET. ClinicalTrials.gov NCT07065539. Registered on 14 July 2025. https://clinicaltrials.gov/study/NCT07065539. The first participant was enrolled in August 2025.

We aimed to assess the landscape of endometriosis randomised-controlled trials (RCTs) between 1990 and 2024 by characterising RCTs by management type, primary outcome, country of origin, trial registration, sample size and minimum detectable difference based upon standard RCT power targets of 80

STUDY QUESTION:Does ICSI improve the live birth rate in couples without severe male factor infertility compared to conventional IVF (cIVF)? SUMMARY ANSWER:High-quality evidence showed no benefit of ICSI over cIVF in improving live birth or cumulative live birth rates among couples without severe male factor infertility. WHAT IS KNOWN ALREADY:Although ICSI is an effective method within ART for severe male factor infertility, it is frequently used for other infertility etiologies despite insufficient evidence. The effectiveness of ICSI compared with cIVF in couples with mild male or without severe male factor infertility remains uncertain. STUDY DESIGN, SIZE, DURATION:Systematic review and meta-analysis. PubMed, EMBASE, MEDLINE, Web of Science, Cochrane Library, ProQuest Dissertations & Theses Global, Scopus, CINAHL Plus, Chinese Wan Fang, and CNKI databases were searched from inception to 31 May 2025 without language restrictions. The search strategy encompassed three key domains: ICSI, cIVF, and ART treatment outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS:We included randomized controlled trials (RCTs) comparing outcomes of ICSI versus cIVF per couple. Exclusion criteria were duplicate studies, conference abstracts or proceedings, trial registry records, editorials, letters, non-randomized designs, RCTs that did not randomize participants to ICSI or cIVF, studies comparing effects per oocyte rather than per couple, studies lacking complete outcome data, and those not meeting predefined criteria for trustworthiness. Study characteristics and ART outcomes were extracted. The risk of bias and study trustworthiness were independently evaluated by two investigators using the Cochrane Collaboration's Risk of Bias 2 Tool and TRACT checklist, respectively. GRADE decision-making was used to evaluate the quality of evidence. MAIN RESULTS AND THE ROLE OF CHANCE:Six RCTs reporting on couples without severe male factor infertility were included. The meta-analysis showed no benefit from ICSI over cIVF in live birth rate (four studies, N = 1438, 32.8% vs 34.5%, pooled risk ratio (RR) = 0.96, 95% CI: 0.85-1.09, I2 = 37%, high-quality evidence) or cumulative live birth rate (three studies, N = 1911, 43.2% vs 47.4%, pooled RR = 0.92, 95% CI: 0.84-1.01, I2 = 41%, high-quality evidence). ICSI was associated with a lower preterm birth rate (three studies, N = 222, 4.6% vs 6.0%, pooled RR = 0.77, 95% CI: 0.59-1.00, P = 0.0447, I2 = 0, high-quality evidence). No significant differences were observed for other fertility or pregnancy outcomes. LIMITATIONS, REASONS FOR CAUTION:The findings should be interpreted with caution due to the limited number of high-quality studies reporting live birth data, limited subgroup-specific evidence, and some heterogeneity in outcome measures. WIDER IMPLICATIONS OF THE FINDINGS:Evidence from this meta-analysis shows no advantage of ICSI over cIVF in improving live birth or cumulative live birth rates among couples without severe male factor infertility. Based on current evidence, ICSI should not be routinely recommended for indications other than severe male infertility. STUDY FUNDING/COMPETING INTEREST(S):The study was funded by the National Natural Science Foundation of China (No. 82204052), the National Key Research and Development Program of China (No. 2022YFC2703102), and Peking University Third Hospital (No. BYSYDL2022001, BYSYDL2024003) with salaries for J.Q., Y.W., K.K., Y.F., Y.Y., T.T., F.L., and J.G. The funders of the study played no role in study design, data collection, data analysis, data interpretation, or writing of the report. S.B. has received scientific grants from Gedeon Richter and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Fond. K.V. has received speakers' fees from Gedeon Richter, Merck, and IBSA. L.N.V. has received grants, speakers' fees, and conference fees (including travel support) from Merck Sharp & Dohme, and Ferring, and scientific board fees from Ferring. T.M.H. has received speakers' fees from Merck, Merck Sharp & Dohme, and Ferring. A.P. has received speakers' fees (including those classified as honoraria) from Ferring Pharmaceuticals, Merck, Gedeon Richter, IBSA, Abbott and Consulting fees from Gedeon Richter and Ferring and travel support from Gedeon Richter. H.S.N. received speakers' fees from Ferring Pharmaceuticals, Merck, Astra Zeneca, Cook Medical, Gedeon Richter, Ibsa Nordic, Novo Nordisk, and Bessins. B.W.M. reports consulting fees, travel support, and research funding from Merck and consulting fees from Ferring, Organon, Repronovo, UNILAB, Vitra, and Norgine. N.l.C.F. has received speakers' fees from Merck and Ferring Pharmaceuticals, consulting fees from Merck, and meeting support/registration fees from Merck, Ferring Pharmaceuticals, IBSA, and Gedeon Richter (paid to institution). She is also an unpaid chair in the steering committee for the guideline groups of The Danish Fertility Society. All other authors declare no competing interests. REGISTRATION NUMBER:CRD42023479967.

Background: The H2Oil study demonstrated that in women with unexplained infertility, tubal flushing during hysterosalpingography (HSG) with oil-based contrast resulted in an increased ongoing pregnancy rate of 10% compared to using water-based contrast. It remains unclear if the fertility-enhancing effect of oil-based contrast extends to women with other factors contributing to infertility. Methods: The H2Oil2 study was an open-label, randomised controlled trial, conducted in 11 centres across The Netherlands, China and The United Kingdom (trial registration: CTIS 2024-512571-12-00). Infertile women with an indication to undergo HSG were eligible if they were aged ≥39 years and/or had an ovulation disorder, and/or were at high risk for tubal pathology. After informed consent, women were randomly allocated to HSG with oil-based contrast or with water-based contrast. The primary outcome measure was pregnancy within 6 months after randomisation, leading to live birth. Our analysis followed the intention-to-treat principle. Findings: Between August 2019 and June 2024, 932 women were randomly allocated to HSG with oil-based contrast (n=469) or HSG with water-based contrast (n=463). In the oil-group, 108 women had a live birth, compared to 98 women in the water-group (23·5% vs. 21·5%; adjusted HR 1·18, 95% CI 0·89 to 1·57 p=0·26). Thyroid dysfunction occurred in 75 out of 299 women in the oil-group and in 7 out of 292 women in the water-group (25·1% vs. 2·4%, RR 10·64, % CI 4·96-22·8, p<0·001). Interpretation: In women aged ≥39 years and/or with ovulation disorders, and/or at high risk for tubal pathology, tubal flushing with oil-based contrast does not increase live birth rates compared to tubal flushing with water-based contrast.

Background: The number of problematic randomized clinical trials (RCTs) has risen sharply in recent decades, posing serious challenges to the integrity of the healthcare evidence ecosystem. Objective: To investigate whether retraction of problematic RCTs could reduce evidence contamination. Design: Retrospective cohort study Setting: A secondary analysis of the VITALITY Study database. Participants: 1,330 retracted RCTs with 847 systematic reviews. Measurements: The difference in the median number (and its interquartile, IQR) of contamination before and after retraction. The association between time-to-retraction and likelihood of evidence contamination. Results: Among these retracted RCTs, 426 led to evidence contamination, resulting in 1,106 contamination events (855 before retraction vs. 251 after retraction). The time interval between RCT publication and first contamination ranged from 0.2 to 30.9 years, with a median of 3.3 years (95% CI: 3.0 to 3.9). The median number of contaminated systematic reviews was lower after retraction than before retraction (1, IQR: 1 to 2 vs. 0, IQR: 0 to 1, P < 0.01). Compared with trials retracted more than 7.5 years after publication, those retracted among 1.0 to 1.8 years (OR = 0.70, 95% CI: 0.60 to 0.80) and retracted within 1.0 year (OR = 0.69, 95% CI: 0.60 to 0.80) were associated with lower likelihood of evidence contamination. Limitations: Only assessed contaminated systematic reviews with quantitative synthesis and limited to retracted RCTs. Conclusions: Retracting problematic RCTs can significantly reduce evidence contamination, and a faster retraction was associated with less contamination. To safeguard the integrity of the evidence ecosystem, academic journals should act promptly in retracting problematic studies to minimize their downstream impact. Primary Funding Sources: The National Natural Science Foundation of China (72204003, 72574229) ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the National Natural Science Foundation of China (72204003, 72574229), the institutional funding by Shanghai Eastern Hepatobiliary Surgery Hospital of Navy Medical University (TengFei Project, TF2024YZRH03), and Hefei Comprehensive National Science Center (0301035204), and ShangHai Shenkang Hospital Development Center (SHDC12025626). Suhail Doi was supported by Program Grant #NPRP-BSRA01-0406-210030 from the Qatar National Research Fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Statistical code and data set: the original data can be found at https://osf.io/gb5ed.

Uterine contractions during labor reduce placental perfusion, which limits fetal oxygenation. Intrapartum fetal hypoxia and acidemia occur when there is insufficient reperfusion time between contractions or when placental dysfunction restricts oxygen transfer. The risks of hypoxic-ischemic injury during labor include intrapartum stillbirth, neonatal death, and neonatal encephalopathy. Emergency cesarean or instrumental deliveries are often required when fetal acidemia is suspected, though these interventions carry increased maternal and neonatal risk. Despite widespread use of electronic fetal heart rate monitoring to detect fetal compromise, rates of cerebral palsy, perinatal mortality, and other neonatal well-being measures have not improved. This highlights the need for more effective strategies to prevent adverse perinatal outcomes related to hypoxic injury. Phosphodiesterase type 5 inhibitors may be used to improve uteroplacental perfusion and enhance vasoconstriction in uterine and spinal arteries. Sildenafil citrate, a PDE5 inhibitor, has been used for indications related to placental dysfunction, to treat maternal hypertension, or both. A previous phase II randomized clinical trial (RCT) found that oral sildenafil reduced operative birth for fetal distress by 51% compared with placebo, but was underpowered to assess perinatal outcomes. The aim of this study was to assess whether oral sildenafil citrate during labor improves perinatal outcomes related to intrapartum hypoxia.The iSEARCH trial was a placebo-controlled, double-blind RCT conducted at 14 Australian hospitals from September 2021 to June 2024. Included were adult women with singleton or dichorionic twin pregnancies attempting vaginal birth at term, either by spontaneous labor or induction of labor. Excluded were those with monochorionic twins, triplets, higher-order multifetal gestation, or severe hepatic or kidney impairment. Also excluded were those taking nitrate-containing medications or other PDE inhibitors. Study participants were randomized 1:1 to receive 50 mg sildenafil citrate or a placebo every 8 hours for a maximum of 3 doses. The primary outcome was a composite of 10 intrapartum or neonatal events, including intrapartum stillbirth, 28-day neonatal death, Apgar score <4 at 5 minutes, acidosis at birth, hypoxic ischemic encephalopathy, neonatal seizure, neonatal respiratory support, admission to the neonatal unit, persistent pulmonary hypertension of the newborn, or meconium aspiration syndrome. Secondary outcomes included the 10 individual primary outcomes and emergency cesarean delivery or instrumental vaginal birth for fetal distress.A total of 3257 women were included in the analysis, with 1626 in the sildenafil citrate group and 1631 receiving placebos. The primary composite outcome occurred in 5.1% of women in the intervention group and 5.2% in the placebo group [relative risk (RR), 1.02; 95% CI, 0.75-1.37]. No cases of infant death occurred. The sildenafil group had no effect on the individual secondary outcomes. There was also no effect on emergency operative birth for fetal distress (RR, 1.12; 95% CI, 0.98-1.29). In conclusion, no differences were observed in the incidence of adverse perinatal outcomes or emergency operative birth between women who received sildenafil citrate or placebo during labor.

Add-ons are non-essential interventions offered in addition to standard infertility treatments, mainly in vitro fertilisation (IVF) and associated procedures, aimed at improving chances of pregnancy and live birth. While existing guidelines provide recommendations on the use of add-ons, they often overlook the trustworthiness of the underlying randomised controlled trials (RCTs), which may lead to misleading conclusions. Furthermore, some add-ons that may offer genuine benefits have been dismissed due to misinterpretation of trial results, or they are reserved for repeated implantation failure based on strategic rather than evidence-based arguments. Here, we propose a framework for an evidence synthesis process to guide the rational use of add-ons. The evaluation should begin with establishing effectiveness through systematic reviews of trustworthy RCTs, ignoring RCTs that do not meet trustworthiness criteria. When assessing effectiveness, the evaluation should consider evidence relating to the biological mechanisms targeted by the add-on, in addition to clinical outcomes such as live birth. For diagnostic add-ons, evaluations should focus on the group of patients whose test result leads to a change in clinical management, rather than analysing all test-exposed patients. Once effectiveness is confirmed, evaluating cost-effectiveness becomes crucial. Its cost per additional live birth should be compared to a benchmark (e.g., $27,000 or £20,000 for a live birth via standard IVF). Finally, once proven cost-effective, add-ons should be offered early, rather than delayed until after repeated treatment failures. It might be that effectiveness and cost-effectiveness increase with progression along the continuum of diagnosis or IVF failure such as recurrent implantation failure. In that case, add-ons may be offered as soon as they are considered cost-effective.

Introduction Increasing publication of fraudulent clinical trials poses a serious threat to evidence-based medicine. In the VITALITY Study I, we demonstrated that contamination by retracted trials significantly distorts evidence synthesis. The upcoming VITALITY Study II will take a step further and investigate how such problematic evidence undermines the credibility of guideline recommendations.Methods and analyses The VITALITY Study II will adopt a retrospective cohort design and will be structured as three work packages (WPs). To start with, a cohort of clinical practice guidelines (CPGs) that were contaminated by retracted trials and/or meta-analyses that included retracted trials will be established based on forward citation searching (WP1). Then, recommendations from these CPGs that used evidence from retracted trials and/or meta-analyses that synthesised these retracted trials will be re-evaluated after removing such problematic evidence, in terms of both the direction and strength of effect sizes (WP2). Finally, the subsequent impact on patient outcomes attributable to distorted recommendations will be estimated on a hypothetical population, measured by the number of expected benefit loss and the number of expected harm increment per 100 000 patients (WP3).Ethics and dissemination Formal ethical approval is not necessary for this study as it does not involve human or animal participants, nor does it involve the collection of primary data. We will disseminate the findings through publication in peer-reviewed journals and, whenever possible, presentations at academic conferences.

RATIONALE:Induction of labour (IoL) aims to initiate labour when the risks of continuing pregnancy outweigh the benefits. Over 10 methods are currently available, yet the most effective and safest method remains unclear. OBJECTIVES:To compare the benefits and harms of various cervical ripening and IoL methods at or beyond term labour and to rank the methods. SEARCH METHODS:We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the WHO ICTRP until 1 February 2023. ELIGIBILITY CRITERIA:We included randomised controlled trials (RCTs) evaluating IoL methods among women with a live fetus at or beyond term labour (gestational age ≥ 37 weeks). We focused on the methods currently recommended by international guidelines and those proposed by previous Cochrane reviews. OUTCOMES:Our critical outcomes included failure to achieve vaginal delivery within 24 hours, caesarean section due to any causes, caesarean section due to non-reassuring fetal status, uterine hyperstimulation with changes in the heartbeat of the baby before birth, perinatal death, and severe neonatal morbidity. RISK OF BIAS:We assessed bias and trustworthiness using the Cochrane RoB 1 tool and the Cochrane Pregnancy and Childbirth Trustworthiness Tool (CPS-TST), respectively. The final analyses only included trials that met the CPS-TST. SYNTHESIS METHODS:We performed pair-wise meta-analyses using a random-effects model and network meta-analyses (NMA) with a frequentist approach. We reported analyses and results separately for two populations: 1) women without a previous caesarean section and a mix of women with or without a previous caesarean section (where more than 50% of participants had no previous caesarean section), and 2) women with a previous caesarean section. We used risk ratio (RR) and mean difference (MD) to present treatment effects with 95% confidence intervals (CIs). We assessed the certainty of evidence for critical outcomes using the GRADE approach for NMA. We used the surface under the cumulative ranking curve (SUCRA) to estimate treatment ranking. INCLUDED STUDIES:The analysis included 106 RCTs assessing 13 IoL methods among 30,348 women. Most trials (84.9%) were conducted in inpatient settings. Only two RCTs recruited women with previous caesarean section, and seven RCTs recruited a mix of women with or without a previous caesarean section. SYNTHESIS OF RESULTS:We evaluated the effects of the following IoL methods: vaginal misoprostol (≤ 50 μg), oral misoprostol (≤ 50 μg), sublingual or buccal misoprostol (≤ 50 μg), controlled-release misoprostol vaginal pessary, vaginal dinoprostone (tablet or gel), controlled-release dinoprostone vaginal pessary, oxytocin (alone), nitric oxide donors, balloon catheters, osmotic cervical dilators, oxytocin plus amniotomy (Oxytocin+Amniotomy), balloon catheters plus oxytocin (Balloon+Oxytocin), balloon catheters plus vaginal/oral misoprostol (≤ 50 μg) (Balloon+Misoprostol ≤ 50 μg), and inactive methods (placebo, no intervention, and expectant management). The following results show the relative effects of NMA for four of the six critical outcomes among women without previous caesarean section and a mix of women with or without previous caesarean section. The findings of women with previous caesarean section are not presented here due to limited evidence. We used vaginal misoprostol (≤ 50 μg) as the reference method for presenting results, where data for this method were available in the network. 1) Failure to achieve vaginal delivery within 24 hours There was no clear evidence that any of the methods were more effective than vaginal misoprostol (≤ 50 μg) in reducing the risk of this outcome. Oxytocin+Amniotomy (RR 0.41, 95% CI 0.14 to 1.24, 22.4% fewer, moderate-certainty evidence), Balloon+Misoprostol ≤ 50 μg (RR 0.85, 95% CI 0.60 to 1.19, 5.7% fewer, high-certainty evidence), and Balloon+Oxytocin (RR 0.94, 95% CI 0.71 to 1.26, 2.3% fewer, low-certainty evidence) likely resulted in little to no difference in this outcome compared with vaginal misoprostol (≤ 50 μg). Despite the comparable relative treatment effects between some methods and vaginal misoprostol (≤ 50 μg), these three methods ranked highest. 2) Caesarean section due to non-reassuring fetal status There was no clear evidence that any of the methods were more effective than vaginal misoprostol (≤ 50 μg) in reducing the risk of this outcome. Balloon+Oxytocin (RR 0.77, 95% CI 0.47 to 1.25, 2.0% fewer, moderate-certainty evidence), controlled-release dinoprostone vaginal pessary (RR 0.86, 0.62 to 1.18, 1.2% fewer, low-certainty evidence), and balloon catheters (RR 0.88, 95% CI 0.70 to 1.11, 1.0% fewer, low-certainty evidence) may result in little to no difference in this outcome when compared with vaginal misoprostol (≤ 50 μg). Despite the comparable relative treatment effects between all methods and vaginal misoprostol (≤ 50 μg), these three methods ranked highest. 3) Uterine hyperstimulation with changes in the heartbeat of the baby before birth Nitric oxide donors (RR 0.05, 95% CI 0.01 to 0.47, 3.9% fewer, moderate-certainty evidence), osmotic cervical dilators (RR 0.07, 95% CI 0.01 to 0.42, 3.8% fewer, moderate-certainty evidence), balloon catheters (RR 0.38, 95% CI 0.21 to 0.69, 2.5% fewer, moderate-certainty evidence), and oral misoprostol (≤ 50 μg) (RR 0.62, 95% CI 0.39 to 0.99, 1.6% fewer, moderate-certainty evidence) probably reduce this outcome compared with vaginal misoprostol (≤ 50 μg). When compared with inactive interventions (placebo, no intervention, or expectant management), vaginal misoprostol (≤ 50 μg) (RR 3.47, 95% CI 1.16 to 10.35) probably increases the risk of this outcome. The three highest-ranked methods were nitric oxide donors, osmotic cervical dilators, and inactive methods (placebo, no intervention, and expectant management). 4) Perinatal death There was no clear evidence for this outcome, as it was rare (10 cases reported across trials). AUTHORS' CONCLUSIONS:For women without previous caesarean section and a mix of women with or without previous caesarean section, there was no clear evidence that any of the IoL methods were more effective than vaginal misoprostol (≤ 50 μg) for the outcomes of failure to achieve vaginal delivery within 24 hours, caesarean section due to non-reassuring fetal status, and perinatal death. Nitric oxide donors, osmotic cervical dilators, balloon catheters, and oral misoprostol (≤ 50 μg) probably reduce the risk of uterine hyperstimulation with changes in the heartbeat of the baby before birth. FUNDING:This review had no dedicated funding. REGISTRATION:Protocol (2023): https://doi.org/10.1002/14651858.CD015234.

Randomised controlled trials (RCTs) underpin evidence-based clinical practice and have the potential to improve women's health globally. Mapping obstetric RCTs can offer valuable insights into clinical research practice and help prioritise scarce resources towards local health needs. We provide a comprehensive overview of 6905 obstetric RCTs published between Jan 1, 2013, and May 31, 2025, characterising trial features, geographical distribution, and reporting transparency. RCT publications increased substantially, with the USA, Iran, India, and the European Union member countries as leading contributors. Labour analgesia and anaesthesia were the most researched areas, whereas major causes of maternal and perinatal death, such as hypertensive disorders, preterm birth, and postpartum haemorrhage received comparatively less attention. Considerable cross-country disparities in trial transparency practices were also observed, even after adjustment for national gross domestic product and livebirths. By mapping the global obstetric RCT landscape in its socioeconomic context, we reveal inconsistencies in transparency practices across countries and a misalignment between the current research priorities and global maternal and perinatal health needs.

OBJECTIVES:Development and validation of two prediction models for obstetric anal sphincter injury (OASI). DESIGN:Population-based cohort study. SETTING:Nationwide (the Netherlands). POPULATION:Data from the Netherlands Perinatal Registry, describing nulliparous women who delivered a singleton live born infant in cephalic presentation at term from 2016 to 2020, with spontaneous (SVD) or operative vaginal delivery (OVD). METHODS:Based on literature and clinical expertise, a set of potential predictors was defined and derived from the national perinatal registry. A predictive model was constructed, and accessible nomograms provided. Internal and temporal external validation was performed. MAIN OUTCOME MEASURES:OASI rate. RESULTS:The risk of OASI in 171 046 women with SVD was 4.1%. After logistic regression with step-wise backward selection using Akaike Information Criterion (AIC), ten predictors were retained. These were: mediolateral episiotomy (MLE), expected fetal birth weight, duration of the 2nd stage, occipitoposterior presentation, induction of labour, epidural analgesia, Asian ethnicity, maternal age, gestational age and fetal sex. The final model had a moderate discriminative ability (AUC 0.67, 95% CI 0.67-0.68) and excellent calibration (Brier score 0.039). The average risk of OASI in 37 547 women with OVD was 3.5%. Seven predictors were retained in the model: MLE, expected fetal birth weight, duration 2nd stage of labour, occipitoposterior fetal presentation, epidural analgesia, Asian ethnicity and gestational age. The final model had moderate discrimination (AUC 0.68, 95% CI 0.67-0.70) and excellent calibration (Brier score 0.032). CONCLUSIONS:A prediction model for OASI was developed and validated for both nulliparous women with spontaneous vaginal delivery and with operative vaginal delivery. These models can form a basis to identify women with a high risk of OASI.

BACKGROUND:Around 18% to 33% of couples with infertility present with tubal occlusion (blocked or damaged fallopian tubes) or hydrosalpinx (fluid-filled tubes). Diagnostic laparoscopy (keyhole surgery) with chromopertubation (methylene blue dye tubal patency testing) is considered the reference standard for ruling out tubal occlusion and hydrosalpinx. However, due to its invasiveness and high costs, alternative, less invasive tests have been carried out using imaging techniques. They include sono-hysterosalpingography (sono-HSG), hysterosalpingography (HSG), outpatient transvaginal hydrolaparoscopy (THL), and magnetic resonance hysterosalpingography (MR-HSG). The choice of test varies in different settings; the choice of contrast, operator skill and test technology are factors that can influence diagnostic quality. Furthermore, the performance of the visual tubal patency tests can vary in different populations, depending on whether the test is carried out in an unselected group or in one classified as high or low risk for having tubal pathology. OBJECTIVES:To determine and compare the diagnostic accuracy of visual tubal patency tests (sono-HSG, HSG, THL, and MR-HSG) for the diagnosis of tubal occlusion. Secondary objectives are to determine and compare the diagnostic accuracy of visual tubal patency tests (sono-HSG, HSG, THL, and MR-HSG) for the diagnosis of hydrosalpinx and to evaluate heterogeneity concerning population characteristics (population risk stratification) and index test characteristics (contrast media, technology, operator skills). SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase and CINAHL, and two trials registers. We also contacted experts in the field for any additional studies (last date of search: 6 November 2023). SELECTION CRITERIA:We included studies on the diagnostic accuracy of a single index test and studies on the comparative diagnostic accuracy of two or more index tests. Index tests included were: sono-HSG, HSG, THL, and MR-HSG. Laparoscopy with methylene blue dye tubal patency testing was the reference standard. We included participants who had been trying to conceive for at least one year. All participants in the included studies should have undergone this reference standard. Target conditions were bilateral tubal occlusion, at least one-sided tubal occlusion, tubal occlusion by tube, and hydrosalpinx. DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data. We performed random-effects meta-analysis in a bivariate model. For each index test, we presented pairs of sensitivity and specificity with their 95% confidence intervals (CIs) for each study, as well as the pooled sensitivity and specificity in a forest plot. We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool for risk of bias assessments. MAIN RESULTS:We identified 11,787 records and included 21 studies (1939 participants). Two studies directly compared both sono-HSG and HSG to the reference test, while the other 19 reported on the diagnostic accuracy of one of the index tests (10 on sono-HSG, 10 on HSG, and 3 on THL). We did not include any studies of MR-HSG. Sono-HSG: for bilateral tubal occlusion, the pooled sensitivity was 0.98 (95% CI 0.19 to 1.00; 3 studies, 259 women; moderate-certainty evidence) and specificity was 0.99 (95% CI 0.93 to 1.00; 4 studies, 259 women; high-certainty evidence). Subgroup analyses showed that colour Doppler was associated with higher specificity than standard ultrasound, but with similar sensitivity. We did not find differences in diagnostic accuracy in the use of 3-dimensional/2-dimensional or 2-dimensional ultrasound, or the use of foam or saline as contrast media. We were unable to perform meta-analysis on the diagnosis of hydrosalpinx. HSG: for bilateral tubal occlusion, the pooled sensitivity was 0.77 (95% CI 0.58 to 0.89; 7 studies, 670 women; very low-certainty evidence) and the pooled specificity was 0.94 (95% CI 0.87to 0.97; 7 studies, 670 women; moderate-certainty evidence). For hydrosalpinx by tube, the pooled sensitivity was 1.00 and specificity was 0.96 (95% CI 0.96 to 0.98; 2 studies, 360 tubes). THL: for bilateral tubal occlusion, the pooled sensitivity and specificity were 0.95 (95% CI 0.30 to 1.00; 3 studies, 172 women; low-certainty evidence) and 0.99 (95% CI 0.84 to 1.00; 3 studies, 172 women; moderate-certainty evidence), respectively. We were unable to perform meta-analysis on the diagnosis of hydrosalpinx. There was insufficient information on operator skills and patient risk stratification for all index tests to carry out further analyses. AUTHORS' CONCLUSIONS:The evidence showed that sono-HSG, HSG and THL are all reliable tests for the diagnosis of double-sided tubal occlusion. Evidence for comparative diagnostic accuracy studies is very limited. We did not include any studies on the diagnostic accuracy of MR-HSG. The certainty of evidence ranged from very low to high. This was mainly due to unclear or high risk of bias, heterogeneity and imprecision. Limited reporting on population risk and operator experience may reduce the generalisability of the findings to routine clinical practice. FUNDING:This Cochrane review had no dedicated funding. REGISTRATION:Protocol (2022) available via: https://doi.org/10.1002/14651858.CD014968.