Rui Wang1,2, Wentao Li2, Esmée M Bordewijk3, Richard S Legro4, Heping Zhang5, Xiaoke Wu6, Jingshu Gao6, Laure Morin-Papunen7, Roy Homburg8, Tamar E König9, Etelka Moll10, Sujata Kar11, Wei Huang12, Neil P Johnson1,13, Saad A Amer14, Walter Vegetti15, Stefano Palomba16, Angela Falbo17, Ülkü Özmen18, Hakan Nazik19, Christopher D Williams20, Grasso Federica21, Jonathan Lord22, Yilmaz Sahin23, Siladitya Bhattacharya24, Robert J Norman1,25, Madelon van Wely3, Ben Willem Mol1,2. 1. Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia. 2. Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia. 3. Centre for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. 4. Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA, USA. 5. Department of Biostatistics, Yale University School of Public Health, New Haven, CO, USA. 6. Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China. 7. Department of Obstetrics and Gynecology, Medical Research Center, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland. 8. Homerton Fertility Centre, Homerton University Hospital, London, UK. 9. Department of Obstetrics and Gynecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 10. Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis (OLVG) West, Amsterdam, the Netherlands. 11. Department of Obstetrics and Gynaecology, Kar Clinic and Hospital, Bhubaneswar, India. 12. Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China. 13. Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. 14. Department of Obstetrics and Gynaecology, University of Nottingham, Royal Derby Hospital, Derby, UK. 15. Infertility Unit, Fondazione I.R.C.C.S. Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 16. Department of Obstetrics and Gynecology, Grande Ospedale Metropolitano of Reggio Calabria, Reggio Calabria, Italy. 17. Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, Italy. 18. Department of Obstetrics and Gynecology, School of Medicine, Zonguldak Bulent Ecevit University, Kozlu, Zonguldak, Turkey. 19. Department of Obstetrics and Gynaecology, Adana City Training and Research Hospital, Adana, Turkey. 20. Reproductive Medicine and Surgery Center of Virginia, Charlottesville, VA, USA. 21. Department of Surgery Obstetrics and Gynecology, University of Catania, Catania, Italy. 22. Department of Obstetrics and Gynaecology, Royal Cornwall Hospital, University of Exeter Medical School, Truro, UK. 23. Department of Obstetrics and Gynecology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 24. Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, UK. 25. Fertility SA, Adelaide, SA, Australia.
Abstract
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.
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.
Authors: E M Bordewijk; N S Weiss; M J Nahuis; J Kwee; A F Lambeek; G A van Unnik; F P J Vrouenraets; B J Cohlen; T A M van de Laar-van Asseldonk; C B Lambalk; M Goddijn; P G Hompes; F van der Veen; B W J Mol; M van Wely Journal: Hum Reprod Date: 2020-06-01 Impact factor: 6.918