Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Predictors of success after in vitro fertilization.

The last few decades have witnessed a rise in the global uptake of in vitro fertilization (IVF) treatment. To ensure optimal use of this technology, it is important for patients and clinicians to have access to tools that can provide accurate estimates of treatment success and understand the contribution of key clinical and laboratory parameters that influence the chance of conception after IVF treatment. The focus of this review was to identify key predictors of IVF treatment success and assess their impact in terms of live birth rates. We have identified 11 predictors that consistently feature in currently available prediction models, including age, duration of infertility, ethnicity, body mass index, antral follicle count, previous pregnancy history, cause of infertility, sperm parameters, number of oocytes collected, morphology of transferred embryos, and day of embryo transfer.

Cost-effectiveness of testosterone treatment utilising individual patient data from randomised controlled trials in men with low testosterone levels.

BACKGROUND: Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle-aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle-aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost-effectiveness of testosterone treatment in such men with low testosterone compared with no treatment. METHODS: A cost-utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10-year-time horizon. Clinical outcomes were obtained from an individual patient meta-analysis of placebo-controlled, double-blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality-adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost-effectiveness ratios and cost-effectiveness acceptability curves for selected scenarios. RESULTS: Ten-year excess treatment costs for testosterone compared with non-treatment ranged between £2306 and £3269 per patient. Quality-adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index-derived quality-adjusted life years data, testosterone was cost-effective (incremental cost-effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost-effective in men aged >75 years in models assuming increased morbidity and/or mortality. CONCLUSIONS AND FUTURE RESEARCH: Our data suggest that testosterone is cost-effective in men <75 years when Beck depression index-derived quality-adjusted life years data are considered; cost-effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer-term cost-utility data are needed to verify our conclusion.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

In vitro fertilisation for unexplained subfertility.

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

External validation of models for predicting cumulative live birth over multiple complete cycles of IVF treatment.

STUDY QUESTION: Can two prediction models developed using data from 1999 to 2009 accurately predict the cumulative probability of live birth per woman over multiple complete cycles of IVF in an updated UK cohort? SUMMARY ANSWER: After being updated, the models were able to estimate individualized chances of cumulative live birth over multiple complete cycles of IVF with greater accuracy. WHAT IS KNOWN ALREADY: The McLernon models were the first to predict cumulative live birth over multiple complete cycles of IVF. They were converted into an online calculator called OPIS (Outcome Prediction In Subfertility) which has 3000 users per month on average. A previous study externally validated the McLernon models using a Dutch prospective cohort containing data from 2011 to 2014. With changes in IVF practice over time, it is important that the McLernon models are externally validated on a more recent cohort of patients to ensure that predictions remain accurate. STUDY DESIGN, SIZE, DURATION: A population-based cohort of 91 035 women undergoing IVF in the UK between January 2010 and December 2016 was used for external validation. Data on frozen embryo transfers associated with these complete IVF cycles conducted from 1 January 2017 to 31 December 2017 were also collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA). The predictive performances of the McLernon models were evaluated in terms of discrimination and calibration. Discrimination was assessed using the c-statistic and calibration was assessed using calibration-in-the-large, calibration slope, and calibration plots. Where any model demonstrated poor calibration in the validation cohort, the models were updated using intercept recalibration, logistic recalibration, or model revision to improve model performance. MAIN RESULTS AND THE ROLE OF CHANCE: Following exclusions, 91 035 women who underwent 144 734 complete cycles were included. The validation cohort had a similar distribution age profile to women in the development cohort. Live birth rates over all complete cycles of IVF per woman were higher in the validation cohort. After calibration assessment, both models required updating. The coefficients of the pre-treatment model were revised, and the updated model showed reasonable discrimination (c-statistic: 0.67, 95% CI: 0.66 to 0.68). After logistic recalibration, the post-treatment model showed good discrimination (c-statistic: 0.75, 95% CI: 0.74 to 0.76). As an example, in the updated pre-treatment model, a 32-year-old woman with 2 years of primary infertility has a 42% chance of having a live birth in the first complete ICSI cycle and a 77% chance over three complete cycles. In a couple with 2 years of primary male factor infertility where a 30-year-old woman has 15 oocytes collected in the first cycle, a single fresh blastocyst embryo transferred in the first cycle and spare embryos cryopreserved, the estimated chance of live birth provided by the post-treatment model is 46% in the first complete ICSI cycle and 81% over three complete cycles. LIMITATIONS, REASONS FOR CAUTION: Two predictors from the original models, duration of infertility and previous pregnancy, which were not available in the recent HFEA dataset, were imputed using data from the older cohort used to develop the models. The HFEA dataset does not contain some other potentially important predictors, e.g. BMI, ethnicity, race, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. WIDER IMPLICATIONS OF THE FINDINGS: Both updated models show improved predictive ability and provide estimates which are more reflective of current practice and patient case mix. The updated OPIS tool can be used by clinicians to help shape couples' expectations by informing them of their individualized chances of live birth over a sequence of multiple complete cycles of IVF. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. S.B. has a commitment of research funding from Merck. D.J.M. and M.B.R. declare support for the present manuscript from Elphinstone scholarship scheme at the University of Aberdeen and Assisted Reproduction Unit at Aberdeen Fertility Centre, University of Aberdeen. D.J.M. declares grants received by University of Aberdeen from NHS Grampian, The Meikle Foundation, and Chief Scientist Office in the past 3 years. D.J.M. declares receiving an honorarium for lectures from Merck. D.J.M. is Associate Editor of Human Reproduction Open and Statistical Advisor for Reproductive BioMed Online. S.B. declares royalties from Cambridge University Press for a book. S.B. declares receiving an honorarium for lectures from Merck, Organon, Ferring, Obstetric and Gynaecological Society of Singapore, and Taiwanese Society for Reproductive Medicine. S.B. has received support from Merck, ESHRE, and Ferring for attending meetings as speaker and is on the METAFOR and CAPRE Trials Data Monitoring Committee. TRIAL REGISTRATION NUMBER: N/A.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Perinatal outcomes in singleton live births after blastocyst transfer: an analysis of 60,926 in vitro fertilization cycles from the United Kingdom.

OBJECTIVE: To compare perinatal outcomes between singleton live births after blastocyst-stage and cleavage-stage fresh embryo transfer using data from all United Kingdom licensed fertility clinics. DESIGN: A cohort study. SETTING: Not applicable. PATIENT(S): A total of 60,926 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles resulting in a singleton live birth after blastocyst-stage and cleavage-stage fresh embryo transfer between 2012 and 2018. INTERVENTION(S): Baseline characteristics between IVF/ICSI blastocyst and cleavage-stage transfer groups were compared using the χ2 test for categorical/dichotomized variables and the Mann-Whitney test for continuous variables. Statistical significance was set at <.05. Association between perinatal outcomes and blastocyst transfer compared with cleavage-stage transfer was assessed using multinomial logistic regression, adjusting for confounders selected using directed acyclic graphs (95% confidence interval [CI], adjusted relative risk ratio [aRRR]). A subgroup analysis included cycles in women undergoing their first IVF/ICSI cycle. MAIN OUTCOMES MEASURE(S): Gestational age at birth and birth weight. RESULT(S): The blastocyst group comprised 42,677 IVF/ICSI cycles and cleavage-stage group 18,249 cycles. There was likely little to no difference in the risk of preterm (aRRR, 1.07; 95% CI, 1.00-1.15) and very preterm birth (aRRR, 1.05; 95% CI, 0.91-1.21) in singleton live births after fresh blastocyst and cleavage-stage transfer. Risks of low birth weight (aRRR, 1.02; 95% CI, 0.95-1.09), very low birth weight (aRRR 0.96; 95% CI, 0.83-1.11), high birth weight (aRRR, 0.97; 95% CI, 0.90-1.04), and very high birth weight (aRRR, 0.91; 95% CI, 0.77-1.08) were likely similar between the groups. The findings were consistent in the subgroup analysis. CONCLUSION(S): Fresh blastocyst transfer does not appear to have a negative impact on gestational age at birth and birth weight in singleton live births compared with fresh cleavage-stage transfer.

A comparison of perinatal outcomes following fresh blastocyst or cleavage stage embryo transfer in singletons and twins and between singleton siblings.

STUDY QUESTION: Are perinatal outcomes following fresh blastocyst versus fresh cleavage stage embryo transfer (ET) different in singletons, twins, and between singleton siblings? SUMMARY ANSWER: Singleton babies conceived following fresh blastocyst, versus cleavage stage, ET are less likely to be small for gestational age (SGA) or to have a congenital anomaly (a result confirmed by comparing singleton siblings), while singletons born following fresh blastocyst ET were at a higher risk of being large for gestational age (LGA) than their sibling born following fresh cleavage stage ET. WHAT IS KNOWN ALREADY: Blastocyst stage transfer is now the preferred strategy in most IVF units. Previous studies have suggested that babies conceived through blastocyst transfer are at increased risk of preterm birth and LGA. STUDY DESIGN SIZE DURATION: A national population-based retrospective cohort study was performed using linked Human Fertilisation and Embryology Authority (HFEA) data on 130 516 IVF and ICSI livebirths occurring from 103 062 women between 2000 and 2017. PARTICIPANTS/MATERIALS SETTING METHODS: We included women who had at least one singleton livebirth resulting from IVF/ICSI fresh embryo treatment, using their own eggs and partner's sperm. A linked HFEA dataset was analysed using a multilevel framework, which accommodated repeated IVF cycles resulting in livebirths in the same woman. A population-averaged robust Poisson model was used for binary outcomes and a multinomial logistic regression model was used for categorical outcomes. Unadjusted and adjusted risk ratios (aRRs) (95% CI) were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: There were 130 516 livebirths in 103 062 women, including 86 630 singletons, 43 886 twin births, and 5384 pairs of singleton siblings. In comparison with fresh cleavage stage ET, fresh blastocyst stage transfer in singletons was associated with a lower risk of low birthweight (aRR = 0.92; 95% CI 0.86, 0.99), lower risk of being SGA (0.83; 0.78, 0.89), and lower risk of congenital anomaly (0.79; 0.71, 0.89). This analysis did not show an increase in risk associated with preterm birth (1.00; 0.94, 1.06), high birthweight (0.99; 0.93, 1.06), LGA (0.99; 0.93, 1.05), and the chance of healthy singleton baby (1.00; 1.00, 1.02). Twins resulting from fresh blastocyst stage ET were at slightly higher risk of preterm birth (1.05; 1.02, 1.10) compared with twins conceived following fresh cleavage stage ET. There was insufficient evidence for an association with the other perinatal outcomes. Singleton siblings born following fresh blastocyst stage ET were at a higher risk of being LGA (1.57; 1.01, 2.46) and at lower risk of having a congenital anomaly (0.52; 0.28, 0.97) compared to their singleton siblings born following cleavage stage ET. There was some evidence of excess risk of preterm birth (1.42; 0.97, 2.23) associated with blastocyst stage transfer. However, we could not confirm an association between blastocyst stage ET and low birthweight (1.35; 0.81, 2.27), high birthweight (1.19; 0.80, 1.77), and the chance of being a healthy baby (0.97; 0.86, 1.09). LIMITATIONS REASONS FOR CAUTION: This was an observational study where we were unable to adjust for some key confounders, such as maternal smoking status and BMI, which may change from one pregnancy to another and are not recorded in the HFEA dataset. WIDER IMPLICATIONS OF THE FINDINGS: In the largest study of its kind, our analysis of singleton siblings, corrected for unmeasured, non-time varying maternal factors, confirms the previously reported association between blastocyst transfer and LGA babies, and shows a reduced risk of congenital anomaly following blastocyst transfer. Our sibling analysis did not confirm a decreased risk of low birthweight following blastocyst transfer. Overall, absolute risks are low and there is insufficient evidence to challenge the practice of extended culture of embryos. STUDY FUNDING/COMPETING INTERESTS: This project is financed by an NHS Grampian Endowment Research Grant, project number 17/052. One of the authors, S.B., was the Editor in Chief of HROpen until 31 December 2022 and would have been in that role when the paper was first submitted. As an invited speaker, S.B. has received travel expenses, accommodation and honoraria from Merck, Organon, and Ferring. A.M. has received travel expenses, accommodation, and honoraria from Merck Serono, Cook Medical, Pharmasure, Gedeon Richter, and Ferring. D.J.M. is currently a HROpen Associate Editor. TRIAL REGISTRATION NUMBER: N/A.

Intergenerational trends in reproduction: Infertility and pregnancy loss.

This review article summarises the evidence for intergenerational trends observed to date within infertility and pregnancy loss. There appears to be evidence of intergenerational trends between mothers and daughters for the age at menopause, endometriosis, polycystic ovarian syndrome (PCOS), male factor infertility and miscarriage. At present, there is no evidence for a predisposition to stillbirth between mothers and daughters. One study found an association with familial predisposition for ectopic pregnancy. Very few studies have considered the potential for paternal transmission of risk of infertility or pregnancy loss. The majority of studies to date have significant limitations because of their observational design, risk of recall bias and risk of confounding. Therefore, high-quality well-designed research, with multi-centre collaboration and utilisation of registry-based data sources and individual patient data, is needed to understand whether infertility and pregnancy loss may have heritable factors. Epidemiological findings need to be followed up and investigated with translational research to determine the possible causalities as well as any implications for clinical practice.

Quality of clinical prediction models in in vitro fertilisation: Which covariates are really important to predict cumulative live birth and which models are best?

The improvement in IVF cryopreservation techniques over the last 20 years has led to an increase in elective single embryo transfer, thus reducing multiple pregnancy rates. This strategy of successive transfers of fresh followed by frozen embryos has resulted in the acceptance of using cumulative live birth over complete cycles of IVF as a critical measure of success. Clinical prediction models are a useful way of estimating the cumulative chances of success for couples tailored to their individual clinical factors, which help them prepare for and plan future treatment. In this review, we describe several models that predict cumulative live birth and recommend which should be used by couples and/or their clinicians and when they should be used. We also discuss the most relevant predictors to consider when either developing new IVF prediction models or updating existing models.

Should we adopt a prognosis-based approach to unexplained infertility?

The treatment of unexplained infertility is a contentious topic that continues to attract a great deal of interest amongst clinicians, patients and policy makers. The inability to identify an underlying pathology makes it difficult to devise effective treatments for this condition. Couples with unexplained infertility can conceive on their own and any proposed intervention needs to offer a better chance of having a baby. Over the years, several prognostic and prediction models based on routinely collected clinical data have been developed, but these are not widely used by clinicians and patients. In this opinion paper, we propose a prognosis-based approach such that a decision to access treatment is based on the estimated chances of natural and treatment-related conception, which, in the same couple, can change over time. This approach avoids treating all couples as a homogeneous group and minimizes unnecessary treatment whilst ensuring access to those who need it early.

Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM): a protocol.

INTRODUCTION: Existing randomised controlled trials (RCTs) comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy have shown conflicting results. A freeze-all or a fresh transfer policy may be preferable for some couples undergoing in-vitro fertilisation (IVF), but it is unclear which couples would benefit most from each policy, how and under which protocols. Therefore, we plan a systematic review and individual participant data meta-analysis of RCTs comparing a freeze-all and a fresh transfer policy. METHODS AND ANALYSIS: We will search electronic databases (Medline, Embase, PsycINFO and CENTRAL) and trial registries (ClinicalTrials.gov and the International Clinical Trials Registry Platform) from their inception to present to identify eligible RCTs. We will also check reference lists of relevant papers. The search was performed on 23 September 2020 and will be updated. We will include RCTs comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy in couples undergoing IVF. The primary outcome will be live birth resulting from the first embryo transfer. All outcomes listed in the core outcome set for infertility research will be reported. We will invite the lead investigators of eligible trials to join the Individual participant data meta-analysis of trials comparing frozen versus fresh embryo transfer strategy (INFORM) collaboration and share the deidentified individual participant data (IPD) of their trials. We will harmonise the IPD and perform a two-stage meta-analysis and examine treatment-covariate interactions for important baseline characteristics. ETHICS AND DISSEMINATION: The study ethics have been granted by the Monash University Human Research Ethics Committee (Project ID: 30391). The findings will be disseminated via presentations at international conferences and publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021296566.

Predicting cumulative live birth for couples beginning their second complete cycle of in vitro fertilization treatment.

STUDY QUESTION: Can we develop an IVF prediction model to estimate individualized chances of a live birth over multiple complete cycles of IVF in couples embarking on their second complete cycle of treatment? SUMMARY ANSWER: Yes, our prediction model can estimate individualized chances of cumulative live birth over three additional complete cycles of IVF. WHAT IS KNOWN ALREADY: After the completion of a first complete cycle of IVF, couples who are unsuccessful may choose to undergo further treatment to have their first child, while those who have had a live birth may decide to have more children. Existing prediction models can estimate the overall chances of success in couples before commencing IVF but are unable to revise these chances on the basis of the couple's response to a first treatment cycle in terms of the number of eggs retrieved and pregnancy outcome. This makes it difficult for couples to plan and prepare emotionally and financially for the next step in their treatment. STUDY DESIGN, SIZE, DURATION: For model development, a population-based cohort was used of 49 314 women who started their second cycle of IVF including ICSI in the UK from 1999 to 2008 using their own oocytes and their partners' sperm. External validation was performed on data from 39 442 women who underwent their second cycle from 2010 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data about all UK IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA) database. Using a discrete time logistic regression model, we predicted the cumulative probability of live birth from the second up to and including the fourth complete cycles of IVF. Inverse probability weighting was used to account for treatment discontinuation. Discrimination was assessed using c-statistic and calibration was assessed using calibration-in-the-large and calibration slope. MAIN RESULTS AND THE ROLE OF CHANCE: Following exclusions, 49 314 women with 73 053 complete cycles were included. 12 408 (25.2%) had a live birth resulting from their second complete cycle. Cumulatively, 17 394 (35.3%) had a live birth over complete cycles two to four. The model showed moderate discriminative ability (c-statistic: 0.65, 95% CI: 0.64 to 0.65) and evidence of overprediction (calibration-in-the-large = -0.08) and overfitting (calibration slope 0.85, 95% CI: 0.81 to 0.88) in the validation cohort. However, after recalibration the fit was much improved. The recalibrated model identified the following key predictors of live birth: female age (38 versus 32 years-adjusted odds ratio: 0.59, 95% CI: 0.57 to 0.62), number of eggs retrieved in the first complete cycle (12 versus 4 eggs; 1.34, 1.30 to 1.37) and outcome of the first complete cycle (live birth versus no pregnancy; 1.78, 1.66 to 1.91; live birth versus pregnancy loss; 1.29, 1.23 to 1.36). As an example, a 32-year-old with 2 years of non-tubal infertility who had 12 eggs retrieved from her first stimulation and had a live birth during her first complete cycle has a 46% chance of having a further live birth from the second complete cycle of IVF and an 81% chance over a further three cycles. LIMITATIONS, REASONS FOR CAUTION: The developed model was updated using validation data that was 6 to 12 years old. IVF practice continues to evolve over time, which may affect the accuracy of predictions from the model. We were unable to adjust for some potentially important predictors, e.g. BMI, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. These were not available in the linked HFEA dataset. WIDER IMPLICATIONS OF THE FINDINGS: By appropriately adjusting for couples who discontinue treatment, our novel prediction model will provide more realistic chances of live birth in couples starting a second complete cycle of IVF. Clinicians can use these predictions to inform discussion with couples who wish to plan ahead. This prediction tool will enable couples to prepare emotionally, financially and logistically for IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

Comparison of perinatal outcomes after frozen or fresh embryo transfer: separate analyses of singleton, twin, and sibling live births from a linked national in vitro fertilization registry.

OBJECTIVE: To determine whether perinatal outcomes following frozen vs. fresh embryo transfer (ET) differ within singletons, within sets of twins, and between siblings. DESIGN: Population-based retrospective cohort study. SETTING: Academic Medical School PATIENT(S): 200,075 live births in 151,561 women who underwent in vitro fertilization with frozen or fresh ET between 1992 and 2017. MAIN OUTCOME MEASURE(S): Gestational age at birth, birthweight, congenital anomaly, and healthy baby (≥37 weeks of gestation, birthweight 2,500-4,000 g, no congenital malformations). RESULT(S): There were 200,075 live births in 151,561 women including 132,679 singletons, 33,698 sets of twins, and 5,723 pairs of singleton siblings. In singletons, frozen ET was associated with a lower risk of very preterm birth (adjusted relative risk [aRR], 0.83; 95% confidence interval [CI], 0.73, 0.94), preterm birth (aRR, 0.93; 95% CI, 0.88, 0.97), low birthweight (<2,500 g) (aRR, 0.72; 95% CI, 0.68, 0.77), small for gestational age (aRR, 0.66; 95% CI, 0.62, 0.70) and congenital anomaly (aRR, 0.85; 95% CI, 0.78, 0.94), but higher risk of high birthweight (>4,000 g) (aRR, 1.64; 95% CI, 1.58, 1.72) and large for gestational age (aRR, 1.62; 95% CI, 1.55, 1.70) in comparison with fresh ET. In twins, frozen ET was associated with lower risk of very preterm birth (aRR, 0.84; 95% CI, 0.73, 0.97), and low birthweight (aRR, 0.72; 95% CI, 0.68, 0.77), but with a higher chance of a healthy baby (aRR, 1.11; 95% CI, 1.06, 1.16) compared to fresh ET. Singletons conceived following frozen ET had a lower risk of low birthweight (aRR, 0.56; 95% CI, 0.44, 0.74) and being small for gestational age (aRR, 0.54; 95% CI, 0.42, 0.68) than a singleton sibling born after a fresh ET. Frozen ET also was associated with higher risk of high birthweight (aRR, 1.85; 95% CI, 1.54, 2.24) and being large for gestational age (aRR, 1.81; 95% CI, 1.50, 2.20), and also were less likely to be preterm (aRR, 0.81; 95% CI, 0.67, 0.99). CONCLUSION(S): Our key finding is that singletons born following a frozen ET are less likely to be small for gestational age than a singleton sibling born following fresh ET but are more likely to be large for gestational age.