First-line ovulation induction for polycystic ovary syndrome: An individual participant data meta-analysis

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS. © 2019 The Author(s). Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved

Research misconduct tests: putting patients' interests first

Abstract not available.Madelon van Wely, Esmee M Bordewijk, Rik van Eekelen, Rui Wang, Marian Showell, Ben W Mol, Wentao L

Data integrity of 35 randomised controlled trials in women’ health

While updating a systematic review on the topic of ovulation of induction, we observed unusual similarities in a number of randomised controlled trials (RCTs) published by two authors from the same institute in the same disease spectrum in a short period of time. We therefore undertook a focused analysis of the data integrity of all RCTs published by the two authors. We made pairwise comparisons to find identical or similar values in baseline characteristics and outcome tables between trials. We also assessed whether baseline characteristics were compatible with chance, using Monte Carlo simulations and Kolmogorov-Smirnov test. For 35 trials published between September 2006 and January 2016, we found a large number of similarities in both the baseline characteristics and outcomes of 26. Analysis of the baseline characteristics of the trials indicated that their distribution was unlikely to be the result of proper randomisation. The procedures demonstrated in this paper may help to assess data integrity in future attempts to verify the authenticity of published RCTs.Esmée M Bordewijk, Rui Wang, Lisa M.Askie, Lyle C.Gurrin, Jim G.Thornton ... Ben W.Mol ... et al

To share or not to share data: how valid are trials evaluating first-line ovulation induction for polycystic ovary syndrome?

BACKGROUND In our recent individual participant data (IPD) meta-analysis evaluating the effectiveness of first-line ovulation induction for polycystic ovary syndrome (PCOS), IPD were only available from 20 studies of 53 randomized controlled trials (RCTs). We noticed that the summary effect sizes of meta-analyses of RCTs without IPD sharing were different from those of RCTs with IPD sharing. Granting access to IPD for secondary analysis has implications for promoting fair and transparent conduct of RCTs. It is, however, still common for authors to choose to withhold IPD, limiting the impact of and confidence in the results of RCTs and systematic reviews based on aggregate data. OBJECTIVE AND RATIONALE We performed a meta-epidemiologic study to elucidate if RCTs without IPD sharing have lower quality and more methodological issues than those with IPD sharing in an IPD meta-analysis evaluating first-line ovulation induction for PCOS. SEARCH METHODS We included RCTs identified for the IPD meta-analysis. We dichotomized RCTs according to whether they provided IPD (shared group) or not (non-shared group) in the IPD meta-analysis. We restricted RCTs to full-text published trials written in English. We assessed and compared RCTs in the shared and non-shared groups on the following criteria: Risk of Bias (RoB 2.0), GRADE approach, adequacy of trial registration; description of statistical methods and reproducibility of univariable statistical analysis; excessive similarity or difference in baseline characteristics that is not compatible with chance; and other miscellaneous methodological issues. OUTCOMES In total, 45 trials (8697 women) were included in this study. IPD were available from 17 RCTs and 28 trials were categorized as the non-shared IPD group. Pooled risk rates obtained from the shared and non-shared groups were different. Overall low risk of bias was associated with 13/17 (76%) of shared RCTs versus 7/28 (25%) of non-shared RCTs. For RCTs that started recruitment after 1 July 2005, adequate trial registration was found in 3/9 (33%) of shared IPD RCTs versus 0/16 (0%) in non-shared RCTs. In total, 7/17 (41%) of shared RCTs and 19/28 (68%) of non-shared RCTs had issues with the statistical methods described. The median (range) of inconsistency rate per study, between reported and reproduced analyses for baseline variables, was 0% (0–92%) (6 RCTs applicable) in the shared group and 54% (0–100%) (13 RCTs applicable) in the non-shared group. The median (range) of inconsistency rate of univariable statistical results for the outcome(s) per study was 0% (0–63%) (14 RCTs applicable) in the shared group and 44% (0–100%) (24 RCTs applicable) in the non-shared group. The distributions of simulation-generated P-values from comparisons of baseline continuous variables between intervention and control arms suggested that RCTs in the shared group are likely to be consistent with properly conducted randomization (P = 0.163), whereas this was not the case for the RCTs in the non-shared group (P = 4.535 × 10−8). WIDER IMPLICATIONS IPD meta-analysis on evaluating first-line ovulation induction for PCOS preserves validity and generates more accurate estimates of risk than meta-analyses using aggregate data, which enables more transparent assessments of benefits and risks. The availability of IPD and the willingness to share these data may be a good indicator of quality, methodological soundness and integrity of RCTs when they are being considered for inclusion in systematic reviews and meta-analyses.Esmee M Bordewijk, Rui Wang, Madelon van Wely, Michael F Costello, Robert J Norman, Helena Teede, Lyle C Gurrin, Ben W Mol, Wentao L

Gonadotrophins versus clomiphene citrate with or without IUI in women with normogonadotropic anovulation and clomiphene failure: a cost-effectiveness analysis

Study Question: Are six cycles of ovulation induction with gonadotrophins more cost-effective than six cycles of ovulation induction with clomiphene citrate (CC) with or without IUI in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC? Summary Answer: Both gonadotrophins and IUI are more expensive when compared with CC and intercourse, and gonadotrophins are more effective than CC. What is Known Already: In women with normogonadotropic anovulation who ovulate but do not conceive after six cycles with CC, medication is usually switched to gonadotrophins, with or without IUI. The cost-effectiveness of these changes in policy is unknown. Study Design, Size, Duration: We performed an economic evaluation of ovulation induction with gonadotrophins compared with CC with or without IUI in a two-by-two factorial multicentre randomized controlled trial in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC. Between December 2008 and December 2015 women were allocated to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse. The primary outcome was conception leading to a live birth achieved within 8 months of randomization. Participants/Materials, Setting, Methods: We performed a cost-effectiveness analysis on direct medical costs. We calculated the direct medical costs of ovulation induction with gonadotrophins versus CC and of IUI versus intercourse in six subsequent cycles. We included costs of medication, cycle monitoring, interventions, and pregnancy leading to live birth. Resource use was collected from the case report forms and unit costs were derived from various sources. We calculated incremental cost-effectiveness ratios (ICER) for gonadotrophins compared to CC and for IUI compared to intercourse. We used non-parametric bootstrap resampling to investigate the effect of uncertainty in our estimates. The analysis was performed according to the intention-to-treat principle. Main Results and the Role of Chance: We allocated 666 women in total to gonadotrophins and IUI (n = 166), gonadotrophins and intercourse (n = 165), CC and IUI (n = 163), or CC and intercourse (n = 172). Mean direct medical costs per woman receiving gonadotrophins or CC were €4495 versus €3006 (cost difference of €1475 (95% CI: €1457-€1493)). Live birth rates were 52% in women allocated to gonadotrophins and 41% in those allocated to CC (relative risk (RR) 1.24:95% CI: 1.05-1.46). The ICER was €15 258 (95% CI: €8721 to €63 654) per additional live birth with gonadotrophins. Mean direct medical costs per woman allocated to IUI or intercourse were €4497 versus €3005 (cost difference of €1510 (95% CI: €1492-€1529)). Live birth rates were 49% in women allocated to IUI and 43% in those allocated to intercourse (RR = 1.14:95% CI: 0.97-1.35). The ICER was €24 361 (95% CI: €-11 290 to €85 172) per additional live birth with IUI. Limitations, Reasons for Caution: We allowed participating hospitals to use their local protocols for ovulation induction and IUI, which may have led to variation in costs, but which increases generalizability. Indirect costs generated by transportation or productivity loss were not included. We did not evaluate letrozole, which is potentially more effective than CC. Wider Implications of the Findings: Gonadotrophins are more effective, but more expensive than CC, therefore, the use of gonadotrophins in women with normogonadotropic anovulation who have not conceived after six ovulatory CC cycles depends on society's willingness to pay for an additional child. In view of the uncertainty around the cost-effectiveness estimate of IUI, these data are not sufficient to make recommendations on the use of IUI in these women. In countries where ovulation induction regimens are reimbursed, policy makers and health care professionals may use our results in their guidelines.E.M. Bordewijk, N.S. Weiss, M.J. Nahuis, N. Bayram, M.H.A. van Hooff, D.E.S. Boks, D.A.M. Perquin, C.A.H. Janssen, R.J.T. van Golde, C.B. Lambalk, M. Goddijn, P.G. Hompes, F. van der Veen, B.W.J. Mol and M. van Wely, on behalf of the M-ovin study grou

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis

Background: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. Objective and Rationale: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. Search Methods: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. Outcomes: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). Wider Implications: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.Rui Wang, Wentao Li, Esmée M. Bordewijk, Richard S. Legro, Heping Zhang, Xiaoke Wu, Jingshu Gao, Laure Morin-Papunen, Roy Homburg, Tamar E. König, Etelka Moll, Sujata Kar, Wei Huang, Neil P. Johnson, Saad A. Amer, Walter Vegetti, Stefano Palomba, Angela Falbo, Ülkü Özmen, Hakan Nazik, Christopher D. Williams, Grasso Federica, Jonathan Lord, Yilmaz Sahin, Siladitya Bhattacharya, Robert J. Norman, Madelon van Wely, Ben Willem Mol, Reproductive Medicine Network, the International Ovulation Induction IPDMA Collaboratio