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Inhibidores de la aromatasa para pacientes con subfertilidad con síndrome de ovario poliquístico

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Referencias

Abdellah 2011 {published data only}

Abdellah MS. Reproductive outcome after letrozole versus laparoscopic ovarian drilling for clomiphene‐resistant polycystic ovary syndrome. International Journal of Gynecology and Obstetrics 2011;113(3):218‐21. CENTRAL

Abu Hashim 2010a {published data only}

Abu Hashim H, Mashaly AM, Badawy A. Letrozole versus laparoscopic ovarian diathermy for ovulation induction in clomiphene‐resistant women with polycystic ovary syndrome: a randomized controlled trial. Archives of Gynecology and Obstetrics 2010;282(5):567‐71. CENTRAL

Abu Hashim 2010b {published data only}

Abu Hashim H, Shokeir T, Badawy A. Letrozole versus combined metformin and clomiphene citrate for ovulation induction in clomiphene‐resistant women with polycystic ovary syndrome: a randomized controlled trial. Fertility and Sterility 2010;94(4):1405‐9. CENTRAL

Al‐Omari 2004 {published data only}

Al‐Omari WR, Sulaiman WR, Al‐Hadithi N. Comparison of two aromatase inhibitors in women with clomiphene‐resistant polycystic ovary syndrome. International Journal of Gynecology & Obstetrics 2004;85(3):289‐91. CENTRAL

Amer 2017 {published data only}

Amer SA, Smith J, Mahran A, Fox P, Fakis A. Double‐blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome. Human Reproduction 2017;32(8):1631‐8. [CENTRAL: 01405506]CENTRAL

Atay 2006 {published data only}

Atay V, Cam C, Muhcu M, Cam M, Karateke A. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation. Journal of International Medical Research 2006;34(1):73‐6. CENTRAL

Badawy 2008 {published data only}

Badawy A, Mosbah A, Shady M. Anastrozole or letrozole for ovulation induction in clomiphene‐resistant women with polycystic ovarian syndrome: a prospective randomized trial. Fertility and Sterility 2008;89(5):1209‐12. CENTRAL

Badawy 2009a {published data only}

Badawy A, Mosbah A, Tharwat A, Eid M. Extended letrozole therapy for ovulation induction in clomiphene‐resistant women with polycystic ovary syndrome: a novel protocol. Fertility and Sterility 2009;92(1):236‐9. CENTRAL

Badawy 2009b {published and unpublished data}

Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertility and Sterility 2009;92(3):849‐52. CENTRAL

Bayar 2006 {published data only}

Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial. Fertility and Sterility 2006;86(5):1447‐51. CENTRAL

Begum 2009 {published and unpublished data}

Begum MR, Ferdous J, Begum A, Quadir E. Comparison of efficacy of aromatase inhibitor and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. Fertility and Sterility 2009;92(3):853‐7. CENTRAL

Chen 2016 {published data only}

Chen Z, Zhang M, Qiao Y, Yang J. Effects of letrozole in combination with low‐dose intramuscularinjection of human menopausal gonadotropin on ovulationand pregnancy of 156 patients with polycystic ovary syndrome. Pakistanian Journal of Medical Sciences 2016;32(6):1434‐8. CENTRAL

Davar 2011 {published data only}

Davar R, Javedani M, Fallahzadeh MH. Metformin‐letrozole in comparison with metformin‐clomiphene citrate in clomiphene‐resistance PCOS patients undergoing IUI. Iranian Journal of Reproductive Medicine 2011;9(1):31‐6. CENTRAL

Dehbashi 2009 {published data only}

Dehbashi S, Kazerooni T, Robati M, Alborzi S, Parsanezhad ME, Shadman A. Comparison of the effects of letrozole and clomiphene citrate on ovulation and pregnancy rate in patients with polycystic ovary syndrome. Iranian Journal of Medical Sciences 2009;34:23‐8. CENTRAL

Elgafor 2013 {published data only}

Elgafor IA. Efficacy of combined metformin–letrozole in comparison with bilateral ovarian drilling in clomiphene‐resistant infertile women with polycystic ovarian syndrome. Archives of Gynecology and Obstetrics 2013;288(1):119‐23. [DOI: 10.1007/s00404‐013‐2714‐2]CENTRAL

El‐Gharib 2015 {published data only}

EL‐Gharib MN, Mahfouz AE, Farahat MA. Comparison of letrozole versus tamoxifen effects in clomiphene citrate resistant women with polycystic ovarian syndrome. Journal of Reproduction and Infertility 2015;16(1):30‐5. CENTRAL

El‐Khayat 2016 {published data only}

El‐Khayat W, Abdel Moety G, Mohammady MA, Hamed D. A randomized controlled trial of clomifene citrate, metformin, and pioglitazone versus letrozole, metformin, and pioglitazone for clomifene‐citrate resistant polycystic ovary syndrome. International Journal of Gynaecology and Obstetrics 2016;132(2):206‐9. CENTRAL

Foroozanfard 2011 {published data only}

Foroozanfard F, Mahdian M, Mousavi Gl, Pejmanmanesh M, Soleimani A. Use of letrozole versus clomiphene citrate combined with gonadotropins in patients with clomiphene resistant polycystic ovarian syndrome: A comparative study. Pakistan Journal of Medical Sciences 2011;27(5):967‐70. CENTRAL

Ganesh 2009 {published data only}

Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B. Comparison of letrozole with continuous gonadotropins and clomiphene‐gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. Journal of Assisted Reproduction and Genetics 2009;26(1):19‐24. CENTRAL

Ghahiri 2016 {published data only}

Ghahiri A, Mogharehabed N, Mamourian M. Letrozole as the first‐line treatment of infertile women with poly cystic ovarian syndrome (PCOS) copared with clomiphene citrate: a clinical trial. Advanced Biomedical Research 2016;5(6):1‐4. CENTRAL

Ghomian 2015 {published data only}

Ghomian N, Khosravi A, Mousavifar N. A randomized clinical trial on comparing the cycle characteristics of two different initiation days of letrozole treatment in clomiphene citrate resistant PCOS patients in IUI cycles. International Journal of Fertility and Sterility 2015;9(1):17‐26. CENTRAL

Hassan 2017 {published data only}

Hassan A, Shehata N, Wahba A. Cost effectiveness of letrozole and purified urinary FSH in treating women with clomiphene citrate‐resistant polycystic ovarian syndrome: a randomized controlled trial. Human Fertility 2017;20(1):37‐42. CENTRAL

Hendawy 2011 {published data only}

Hendawy SF, Samaha HE, Elkholy MF. Letrozole versus clomiphene citrate for induction of ovulation in patients with polycystic ovarian syndrome undergoing intratuerine insemination. Clinical Medicine Insights: Reproductive Health 2011;5:11‐6. CENTRAL

Ibrahim 2017 {published data only}

Ibrahim MH, Tawfic M, Hassan MM, Sedky OH. Letrozole versus laparoscopic ovarian drilling in infertile women with PCOS resistant to clomiphene citrate. Middle East Fertility Society Journal 2017;22(4):251‐4. CENTRAL

Kamath 2010 {published and unpublished data}

Kamath MS, Aleyamma TK, Chandy A, George K. Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double‐blind, placebo‐controlled trial. Fertility and Sterility 2010;94(7):2857‐9. CENTRAL

Kar 2012 {published data only}

Kar S. Clomiphene citrate or letrozole as first‐line ovulation induction drug in infertile PCOS women: a prospective randomized trial. Journal of Human Reproductive Sciences 2012;5(3):262‐5. [DOI: 10.4103/0974‐1208.106338]CENTRAL

Legro 2014 {published and unpublished data}

Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al. NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycycstic ovary syndrome. New England Journal of Medicine 2014;371(2):119‐29. CENTRAL
Legro RS, Kunselman AR, Brzyski RG, Casson PR, Diamond MP, Schlaff WD, et al. Effect of letrozole versus clomiphene on live birth in women with anovulatory infertility due to polycystic ovary syndrome (PCOS): A randomized double‐blind multi‐center trial. Fertility and Sterility2013; Vol. 100, issue 3:S51. CENTRAL

Liu 2015 {published data only}

Liu W, Dong S, Li Y, Shi L, Zhou W, Liu Y, et al. Randomized controlled trial comparing letrozole with laparoscopic ovarian drilling in women with clomiphene citrate‐resistant polycstic ovary syndrome. Experimental and Therapeutic Medicine 2015;10(4):1297‐302. CENTRAL

Liu 2017 {published data only}

Liu C, Feng G, Huang W, Wang Q, Yang S, Tan J, et al. Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary sndrome: a prospective randomized trial. Gynecological Endocrinology 2017;33(11):872‐6. CENTRAL

Moussa 2016 {published data only}

Moussa AA, Torky H, Dief O, Elwahed AA, Senna HA. The effect of clomiphene citrate versus tamoxifen versus letrozol on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries. Acta Medica International 2016;3(2):88‐92. CENTRAL

Nazik 2012 {published data only}

Nazik H, Kumtepe Y. Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction for women with polycystic ovarian syndrome. HealthMED Journal 2012;6(3):879‐83. CENTRAL

Ramezanzadeh 2011 {published data only}

Ramezanzadeh F, Nasiri R, Yazdi MS, Baghrei M. A randomized trial of ovulation induction with two different doses of Letrozole in women with PCOS. Archives of Gynecology and Obstetrics 2011;284(4):1029‐34. CENTRAL

Ray 2012 {published data only}

Ray PB, Ray A, Chakraborti PS. Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction in Indian women with polycystic ovarian syndrome. Archives of Gynecology and Obstetrics 2012;285(3):873‐7. CENTRAL

Roy 2012 {published data only}

Roy K, Baruah J, Singla S, Sharma JB, Singh N, Jain SK, et al. A prospective randomized trial comparing the efficacy of letrozole and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. Journal of Human Reproductive Sciences 2012;5(1):20‐5. CENTRAL

Selim 2012 {published data only}

Selim MF, Borg TF. Letrozole and clomiphene citrate effect on endometrial and subendometrial vascularity in treating infertilityin women with polycystic ovary syndrome. Journal of Gynaecologic Surgery 2012;28(6):405‐10. [DOI: 10.1089/gyn.2012.0033]CENTRAL

Seyedoshohadaei 2016 {published data only}

Seyedoshohadaei F, Tangestani L, Zandvakili F, Rashadmanesh N. Comparison of the effect of clomiphene‐ estradiol valerate vs letrozole on endometrial thickness, abortion and pregnancy rate in infertile women with polycystic ovarian syndrome. Journal of Clinical and Diagnostic Research 2016;10(8):QC10‐3. CENTRAL

Sharief 2015 {published data only}

Sharief M, Nafee NR. Comparison of letrazole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation. Journal of Pakistani Medical Association 2015;65(11):1149‐1152. CENTRAL

Sh‐El‐Arab Elsedeek 2011 {published data only}

Sheikh‐El‐Arab Elsedeek M, Elmaghraby HA. Predictors and characteristics of letrozole induced ovulation in comparison with clomiphene induced ovulation in anovulatory PCOS women. Middle East Fertility Society Journal 2011;16(2):125‐30. CENTRAL

Sohrabvand 2006 {published data only}

Sohrabvand F, Ansari SH, Bagheri M. Efficacy of combined metformin‐letrozole in comparison with metformin‐clomiphene citrate in clomiphene‐resistant infertile women with polycystic ovarian disease. Human Reproduction 2006;21(6):1432‐5. CENTRAL

Wu 2016 {published data only}

Wu X, Wang Y, Liu J, Liang R, Xue H, Ma H, et al. Randomized controlled trial of letrozole, berberine, or a combination for infertility in the polycystic ovary syndrome. Fertility and Sterility 2016;106(3):757‐66. CENTRAL

Zarei 2015 {published data only}

Zarei A, Shabahrami TB, Dadras N. Effects of letrozole in prevention of premature luteinizing hormone (LH) surge in infertile women with clomiphene citrate resistant polycystic ovary syndrome (PCOS) undergoing intrauterine insemination. Galen Medical Journal 2015;4(3):104‐11. CENTRAL

Zeinalzadeh 2010 {published data only}

Zeinalzadeh M, Basirat Z, Esmailpour M. Efficacy of letrozole in ovulation induction compared to that of clomiphene citrate in patients with polycystic ovarian syndrome. Journal of Reproductive Medicine 2010;55(1‐2):36‐40. CENTRAL

References to studies excluded from this review

Akbari 2012 {published data only}

Akbari S, Ayazi Roozbahani M, Ayazi Roozbahani F. Comparing of letrozole versus clomiphene citrate combined with gonadotropins in intrauterine insemation cycles. Iranian Journal of Reproductive Medicine 2012;10(1):29‐32. CENTRAL

Al‐Hussaini 2014 {published data only}

Al‐Hussaini T, Mohammed S, Abdellah M, Abdel Aleem A. Letrozole versus combined clomiphene citrate and metformin as a first line treatment in women with polycystic ovarian syndrome. British Journal of Obstetrics and Gynaecology 2014;E‐Posters:EP6.13. CENTRAL

Al‐Shaikh 2017 {published data only}

Al‐Shaikh SF, Al‐Mukhatar EJ, Al‐Zubaid AA, Al‐Rubaie BJ, Al‐Khuzaee L. Use of clomiphene or letrozole for treating women with polycystic ovary syndrome related subfertility in Hilla city. Middle East Fertility Society Journal 2017;22:105‐10. CENTRAL

Angel 2014 {published data only}

Angel M, Ghose S, Gowda M. A randomized trial comparing the ovulation induction efficacy of clomiphene citrate and letrozole. Journal of Natural Science Biology & Medicine 2014;5(2):450‐2. CENTRAL

Anwary 2012 {published data only}

Anwary SA, Alfazzaman M, Bar, N, Islam MR. Outcome of metformin treatment in polycystic ovary syndrome. Mymensingh Medical Journal 2012;21(1):60‐5. CENTRAL

Azargoon 2012 {published data only}

Azargoon A, Toussy JA, Darbanan FF. Pregnancies following the use of sequential treatment of metformin and incremental doses of letrozole in clomiphene‐resistant women with polycystic ovary syndrome. Iranian Journal of Reproductive Medicine 2012;10(1):33‐40. CENTRAL

Azmoodeh 2015 {published data only}

Azmoodeh A, Pejman Manesh M, Akbari Asbagh F, Ghaseminejad A, Hamzehgardeshi Z. Effects of letrozole‐HMG and clomiphene‐HMG on incidence of luteinized unruptured follicle syndrome in infertile women undergoing induction ovulation and intrauterine insemination: a randomised trial. Global Journal of Health Science 2015;8(4):244‐52. CENTRAL

Badawy 2009c {published data only}

Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or anastrozole for ovulation induction in women with polycystic ovary syndrome? A prospective controlled trial. Fertility and Sterility 2009;92:860‐3. CENTRAL

Baruah 2009 {published data only}

Baruah J, Roy KK, Rahman SM, Kumar S, Sharma JB, Karmakar D. Endometrial effects of letrozole and clomiphene citrate in women with polycystic ovary syndrome using spiral artery Doppler. Archives of Gynecology & Obstetrics 2009;279(3):311‐4. CENTRAL

El Bigawy 2008 {published data only}

El Bigawy AF, Fouda UMF, Wahab HAE. A randomized trial of letrozole versus clomiphene citrate in induction of ovulation in patients with polycystic ovary syndrome (PCOS). Middle East Fertility Society Journal 2008;13(1):52‐6. CENTRAL

Foroozanfard 2013 {published data only}

Foroozanfard F, Saberi H, Moravvegi A, Kazemi M. Pregnancy rate following luteal phase support in polycystic ovarian syndrome using combination therapies for ovulation induction: A randomized clinical trial.. Human Reproduction 2013;28(Suppl 1):i311‐56. CENTRAL

Khanna 2013 {published data only}

Khanna SC, Kumar A, Joy SG, Tanwar R, Sharma S, Prasad S. Is letrozole superior to clomiphene for ovarian stimulation priorto intrauterine insemination?. Archives of Gynaecology and Obstetrics 2013;287(3):571‐5. CENTRAL

Li 2016 {published data only}

Li J, Ng EH, Stener‐Victorin E, Hu Z, Wu W, Ai M, et al. Comparison of acupuncture pre‐treatment followed by letrozole versus letrozole alone on live birth in anovulatory infertile women with polycystic ovary syndrome:a study protocol for a randomised controlled trial. BMJ Open 2016;6(10):e010955. CENTRAL

Mittal 2004 {published data only}

Mittal S, Kamthane VP, Goswami SK, Ghosh S, Chakravarty BN. Comparative evaluation of different stimulation protocols in CC resistant P.C.O women undergoing IUI. 20th Annual Meeting of the ESHRE, Berlin, Germany, 2004 06 27‐30. 2004:i122. CENTRAL

Nahid 2012 {published data only}

Nahid L, Sirous K. Comparison of the effects of letrozole and clomiphene citrate for ovulation induction in infertile women with polycystic ovary syndrome. Minerva Ginecologica 2012;64(3):253‐8. CENTRAL

NCT00610077 {published data only}

NCT00610077. An open, randomized, parallel‐group, multicentric, comparative study of letrozole with clomiphene citrate for induction of ovulation in anovulatory infertility.. clinicaltrials.gov/ct2/show/NCT00610077 (first posted 07 February 2008). [NCT00610077]CENTRAL

NCT01315912 {published data only}

NCT01315912. Dosage optimization for letrozole treatment. clinicaltrials.gov/ct2/show/NCT01315912 (first posted 16 March 2011). [NCT01315912]CENTRAL

NCT01431352 {published data only}

NCT01431352. Letrozole versus chinese herbal medicine on polycystic ovary syndrome (PCOS). clinicaltrials.gov/ct2/show/NCT01431352(verified November 2013). [NCT01431352]CENTRAL

NCT01577017 {published data only}

NCT01577017. The effects of letrozole and clomiphene citrate for induction of ovulation in polycystic ovarian syndrome (PCOS). clinicaltrials.gov/ct2/show/NCT01577017 (first posted 13 April 2012). CENTRAL

NCT01679574 {published data only}

NCT01679574. Letrozole or combined clomiphene citrate metformin as a first line treatment in women with polycystic ovary syndrome. clinicaltrials.gov/ct2/show/NCT01679574 (first posted 96 September 2012). [NCT01679574]CENTRAL

NCT01793038 {published data only}

NCT01793038. Clomiphene citrate plus uFSH versus aromatase inhibitor plus uFSH in clomiphene resistant infertile PCOS women. clinicaltrials.gov/ct2/show/NCT01793038(verified March 2013). [NCT01793038]CENTRAL

Ozdemir 2013 {published data only}

Ozdemir U, Ozaksit G, Cakir Gungor AN, Aydogan M. Letrozole usage adjuvant to gonadotropins for ovulation induction for patients with clomiphene citrate failure. Archives of Gynecology and Obstetrics 2013;288(2):445‐8. CENTRAL

Pakrashi 2014 {published data only}

Pakrashi T, Baydoun H, Bocca S, Oehninger S, Stadtmauer L. Luteral phase supplementation with vaginal progesterone in women with Polycystic ovary syndrome and ovulatory Dysfunction undergoing ovulation induction with letrozole: a randomized controlled trial.. Fertility and Sterility 2014;102(3):Supplement, e237. CENTRAL

Palihawadana 2015 {published data only}

Palihawadana TS, Wijesinghe PS, Seneviratne HR. A comparison of endometrial thickness following augmentation of ovulation with clomifene citrate or letrozole in women with ovulatory infertility. Ceylon Medical Journal 2015;60(2):48‐52. CENTRAL

Pourali 2017 {published data only}

Pourali L, Ayati S, Tavakolizadeh S, Soleimani H, Sani FT. Clomiphene citrate versus letrozole with gonadotropins in intrauterine insemination cycles: a randomized trial. International Journal of Reproductive Biomedicine 2017;15(1):49‐54. CENTRAL

Sarvi 2010 {published data only}

Sarvi F. The effect of metformin in different phenotypes of poly cystic ovary syndrome according to Rotterdam criteria criteria. Iranian Registry of Clinical Trials2010. [IRCT201103146063N1]CENTRAL

Sharma 2010 {published data only}

Sharma S, Goswami SK, Rajani S, et al. Efficacy of letrozole‐gonadotropin, clomiphene‐gonadotropin and only gonadotropin in clomiphene and letrozole resistant PCOS women undergoing IUI. Human Reproduction 2010;25(Suppl 1):i46. CENTRAL

Xi 2015 {published data only}

Xi W, Liu S, Mao H, Yang Y, Xue X, Lu X. Use of letrozole and clomiphene citrate combined with gonadotropins in clomiphene‐resistant infertile women with polycystic ovary syndrome: a prospective study. Drug Design, Development and Therapy 2015;9:6001‐8. CENTRAL

Yang 2008 {published data only}

Yang M, Quan S, Li H, Song Y, Xing F. Effect of two different doses of letrozole in promoting ovulation in infertile women with polycystic ovarian syndrome. Journal of Southern Medical University 2008;28(11):2060‐2. CENTRAL

Yun 2015 {published data only}

Yun BH, Chon SJ, Park JH, Seo SK, Cho S, Choi YS, et al. Minimal stimulation using gonadotropin combined with clomiphene citrate or letrozole for intrauterine insemination. Yonsei Medical Journal 2015;56:490‐6. CENTRAL

References to studies awaiting assessment

Aygen 2007 {published data only}

Aygen EM, Guzel Z, Ozgun T, Atakul T, Sahin Y. The use of letrozole for ovulation induction in infertile women with polycystic ovarian syndrome. Erciyes Tip Dergisi 2007;29:195‐200. CENTRAL

Lorzadeh 2011 {published data only}

Lorzadeh N, Kazemirad S, Mohammadi Z. Comparison of effects letrozole and clomiphene citrate for ovulation induction in women with polycystic ovary syndrome. Iranian Journal of Obstetrics, Gynecology and Infertility 2011;14(3):13‐9. CENTRAL

NCT02551367 {published data only}

NCT02551367. Letrozole versus clomiphene citrate for ovulation induction in women with polycystic ovary syndrome ( PCOS). clinicaltrials.gov/ct2/show/NCT02551367(verified September 2015). [NCT02551367]CENTRAL

Safdarian 2012 {published data only}

Safdarian L, Dibazar NS, Ahmadzadeh A, Yekta BG. Comparing two ovulation induction methods by brachial artery ultrasonography in infertile women with polycystic ovary syndrome. Tehran University Medical Journal 2012;70:242‐9. CENTRAL

Shirin 2009 {published data only}

Shirin G, Mehran A, Maryam B, Maryam G, Masoumeh M. Comparing the effects of clomiphene‐HMG and letrozole‐HMG on ovulation Induction in infertile women. Journal of Reproduction and Infertility 2009;10(2):109‐14. CENTRAL

NCT03009838 {published data only}

NCT03009838. Letrozole versus laparoscopic ovarian drilling in polycystic ovary syndrome. clinicaltrials.gov/ct2/show/NCT03009838 (first posted 04 January 2017). CENTRAL

Abu 2012

Abu Hashim H. Clomiphene citrate alternatives for the initial management of polycystic ovary syndrome: an evidence‐based approach. Archives of Gynecology and Obstetrics 2012;285(6):1737‐45.

Azziz 2006

Azziz R, Carmina E, Dewailly D, Diamanti‐Kandarakis E, Escobar‐Morreale HF, Futterweit W, et al. Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. Journal of Clinical Endocrinology and Metabolism 2006;91(11):4237‐45.

Azziz 2009

Azziz R, Carmina E, Dewailly D, Diamanti‐Kandarakis E, Escobar‐Morreale HF, Futterweit W, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and Sterility 2009;91(2):456. [PUBMED: 18950759]

Biljan 2005

Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertility and Sterility 2005;84(Supplement 1):s95.

Brown 2016

Brown J, Farquhar C. Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome. Cochrane Database of Systematic Reviews 2016, Issue 12. [DOI: 10.1002/14651858.CD002249.pub5]

Casper 2006

Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation induction. Journal of Clinical Endocrinology and Metabolism 2006;91(3):760‐71.

Casper 2011

Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clinical Obstetrics and Gynaecology 2011;54(4):685‐95.

Cole 1990

Cole PA, Robinson CH. Mechanism and inhibition of cytochrome P‐450 aromatase. Journal of Medical Chemistry 1990;33(11):2933‐44.

Farquhar 2002

Farquhar CM, Williamson K, Gudex G, Johnson NP, Garland J, Sadler L. A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate‐resistant polycystic ovary syndrome. Fertility and Sterility 2002;78(2):404.

Farquhar 2012

Farquhar C, Brown J, Marjoribanks J. Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2012, Issue 6. [DOI: 10.1002/14651858.CD001122.pub4]

Forman 2007

Forman R, Gill S, Moretti M, Tulandi T, Koren G, Casper R. Fetal safety of letrozole and clomiphene citrate for ovulation induction. Journal of Obstetrics and Gynaecology Canada 2007;29(8):668.

Higgins 2011

Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.

Homburg 2011

Homburg R, Hendriks ML, König TE, Anderson RA, Balen AH, Brincat M, et al. Clomifene citrate or low‐dose FSH for the first‐line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study. Human Reproduction 2011;27(2):468‐73.

Jirge 2010

Jirge PR, Patil RS. Comparison of endocrine and ultrasound profiles during ovulation induction with clomiphene citrate and letrozole in ovulatory volunteer women. Fertility and Sterility 2010;93(1):174‐83.

Lee 2011

Lee VC, Ledger W. Aromatase inhibitors for ovulation induction and ovarian stimulation. Clinical Endocrinology 2011;74(5):537‐46.

Lunenfeld 2004

Lunenfeld B. Historical perspectives in gonadotrophin therapy. Human Reproduction Update 2004;10(6):453‐67.

Misso 2012

Misso ML, Wong JL, Teede HJ, Hart R, Rombauts L, Melder AM, et al. Aromatase inhibitors for PCOS: a systematic review and meta‐analysis. Human Reproduction Update 2012;18(3):301‐12.

Mitwally 2001

Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertility and Sterility 2001;75(2):305‐9.

Nahuis 2011

Nahuis MJ, Kose N, Bayram N, Van Dessel HJ, Braat DD, Hamilton CJ, et al. Long‐term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins. Human Reproduction 2011;26(7):1889‐904.

Reproductive Medicine Network 2013

Reproductive Medicine Network. Letrozole versus clomiphene citrate in anovulatory PCOS women: A cost‐effectiveness analysis. Fertility and Sterility2013; Vol. 100, issue 3:S128.

Roque 2015

Roque M, Tostes AC, Valle M, Sampaio M, Geber S. Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic review and meta‐analysis. Gynaecological Endocrinology 2015;31(12):917‐21. [DOI: 10.3109/09513590.2015.1096337]

Rotterdam 2003

Rotterdam ESHRE/ASRM‐Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction 2004;19(1):41.

Samani 2009

Samani FG, Farzadi L, Nezami N, Tarzamni MK, Soleimani F. Endometrial and follicular development following letrozole intervention in unexplained infertile patients failed to get pregnant with clomiphene citrate. Archives of Gynecology and Obstetrics 2009;280(2):201‐5.

Tulandi 2006

Tulandi T, Martin J, Al‐Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertility and Sterility 2006;85(6):1761‐5.

Velázquez 1997

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Von Hofe 2015

Von Hofe J, Wright Bates G. Ovulation Induction. Obstetrics and Gynecoly Clinics of North America 2015;42:27‐37.

White 1996

White DM, Polson DW, Kiddy D, Sagle P, Watson H, Gilling‐Smith C, et al. Induction of ovulation with low‐dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. Journal of Clinical Endocrinology and Metabolism 1996;81(11):3821‐4.

Zawadski 1992

Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. Boston: Blackwell Scientific Publications1992:377‐384.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abdellah 2011

Methods

Randomised controlled trial

Duration and location of the trial: quote: "The present study was conducted from July 15, 2007, to February 28, 2010, at the Women's Health Center, Assiut University, Assiut, Egypt, after approval was received from the Ethics Committee of Assiut University.“

Participants

Inclusion criteria: all participants met the Rotterdam consensus criteria for the diagnosis of PCOS. Other inclusion criteria included primary or secondary infertility because of anovulation for at least 1 year and clomiphene resistance. Clomiphene resistance was defined as lack of ovulation after 6 consecutive induction cycles with 50 mg of CC, then with 150 mg of CC each day for 5 days in each cycle. The male partner of each participant was required to have a normal result on semen analysis and each woman was required to have patent tubes on hysterosalpingography or on a diagnostic laparoscopy.

Exclusion criteria: exclusion criteria included age below 20 years or above 35 years; hormonal treatment within 3 months prior to the study; hyperprolactinaemia (morning plasma prolactin concentration 30 ng/ml or more); any other endocrine, hepatic, or renal disorder; presence of an organic pelvic mass; and a history of abdominal surgery that might have caused pelvic factor infertility.

Number of women randomised: 147, 74 in the letrozole group and 73 in the LOD group

Number of women analysed: 70 in the letrozole group and 70 in the LOD group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 7 women were lost to follow‐up.

Number of centres: 1, Women’s Health Center, Assiut University, Assiut

Age (y): group A letrozole: 23.9 ± 3.2, group B LOD: 23.6 ± 3.2

BMI (kg/m²): group A letrozole: 27.3 ± 2.6, group B LOD: 27.1 ± 2.6

Duration of infertility (y): group A letrozole: 4.2 ± 1.7, group B LOD: 4.2 ± 1.7

Country: Egypt

Interventions

Group A: letrozole, 5 mg/day given orally for 5 days during cycle days 3 ‐ 7 for up to 6 cycles

Group B: LOD, triple‐puncture laparoscopy, monopolar diathermy, needle electrode set at 40 W pressed against border of ovary for 4 sec to achieve penetration depths of 7 ‐ 8 mm, punctured at 4 ‐ 6 points

Outcomes

Primary outcomes: ovulation rate

Secondary outcomes: endometrial thickness on the day of hCG injection, rates of clinical pregnancy, spontaneous abortion, live birth and multiple pregnancies

Notes

Ethical approval: yes, the study was approved by Mansoura University Hospital Research Ethics Committee.

Informed consent: yes, all participants gave informed consent before inclusion in the trial.

Source of funding: not stated

Conflicts of interest: quote:“Conflict of interest statement: We declare that we have no conflict of interest”

Authors contacted about information on OHSS

Power calculation: quote: "the sample size required to detect a 25% difference between the 2 groups with a power of 80% was estimated to be 68 patients per group."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed using a computer‐generated random numbers table.

Allocation concealment (selection bias)

Low risk

Allocation concealment was achieved using serially‐numbered opaque envelopes that were only opened once the interventions were assigned.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not mentioned

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not mentioned

Incomplete outcome data (attrition bias)
All outcomes

Low risk

7 women lost to follow‐up, but similar (3 vs 4) in both groups; losses due to noncompliance

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Abu Hashim 2010a

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "The study comprised of 260 women with CC‐resistant PCOS among those attending the Outpatient Clinic in Mansoura University Hospitals, and a private practice setting in the period from August 2006 to March 2009.“

Participants

Inclusion criteria: infertile women with CC resistance and PCOS based on the Rotterdam criteria 2003. Patent fallopian tubes proved by hysterosalpingography and normal semen analysis for their partners according to the modified criteria of WHO.

Exclusion criteria: other causes of infertility, age over 40 years, BMI > 35, contraindication to general anaesthetic, previous history of LOD and women who had received metformin, gonadotropin, oral contraceptives or other hormonal drugs during the preceding 6 months. Women who intended to start a diet or a specific programme of physical activity were also excluded.

Number of centres: 2, outpatient clinic in Mansoura University hospitals and a private practice setting

Number of women randomised: 260, 128 in the letrozole group and 132 in the LOD group

Number of women analysed: 128 in the letrozole group and 132 in the LOD group

Number of withdrawals/exclusions/loss to follow‐up and reasons: none

Age (y): group A letrozole: 27.3 ± 2.6, group B LOD: 26.4 ± 2.4

BMI (kg/m²): group A letrozole: 26.4 ± 3.3, group B LOD: 26.6 ± 3.6

Duration of infertility (y): group A letrozole: 4.3 ± 1.11, group B LOD: 4.5 ± 1.24

Country: Egypt

Interventions

Group A: letrozole, 2.5 mg/day orally given for 5 days starting from day 3 of the cycle

Group B: LOD, laparoscopy was performed using 3‐puncture technique. Each ovary was cauterised at 4 points, each for 4 s at 40 W for a depth of 4 mm with a mixed current, using a monopolar electrosurgical needle.

Outcomes

Primary outcome: ovulation rate

Secondary outcomes: midcycle endometrial thickness (mm), biochemical pregnancy/cycle, clinical pregnancy/participant, biochemical miscarriage/cycle, clinical miscarriage/participant and live birth rates

Notes

Ethical approval: yes, the study was approved by Mansoura University Hospital Research Ethics Committee.

Informed consent: yes, all participants gave informed consent before inclusion in the trial.

Source of funding: not stated

Conflicts of interest: quote:“Conflict of interest statement: We declare that we have no conflict of interest”

Power calculation: quote: "Sample size was calculated based on the fact that with an expected rate of ovulation of 70% in the LOD group we needed 244 women to show an absolute increase of 15% in ovulation rate in the letrozole group, with a power of 80% at confidence interval of 95% using a two tailed chi‐square test with a 5% significance level (type alfa error)."

We had contact with Prof. Abu Hashim, and all questions were answered in detail.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were randomised according to a computer‐generated random‐numeric table prepared by an independent statistician.

Allocation concealment (selection bias)

Low risk

Concealment of treatment allocation was done by using sealed opaque envelopes that were given to a third party (nurse) who assigned participants to study arms.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Once allocated, the treatment was revealed to both the investigator and the patient."

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Once allocated, the treatment was revealed to both the investigator and the patient."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Abu Hashim 2010b

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "The study comprised of 260 women with CC‐resistant PCOS among those attending the Outpatient Clinic in Mansoura University Hospitals, and a private practice setting in the period from August 2006 to March 2009.“

Participants

Inclusion criteria: infertile women with PCOS based on the Rotterdam 2003 criteria. Additionally, diagnosed as CC‐resistant, patent fallopian tubes proved by hysterosalpingography and normal semen analysis for their partners according to the modified criteria of WHO 1999

Exclusion criteria: none stated

Number of centres: 2, Outpatient clinic in Mansoura University hospitals and a private practice setting

Number of women randomised: 250, 123 in the letrozole group and 127 in the CC + metformin (met) group

Number of women analysed: 123 in the letrozole group and 127 in the CC + met group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 28.3 ± 2.7, group B CC + met: 26.2 ± 2.2

BMI (kg/m²): group A letrozole: 29.1 ± 3.2, group B CC + met: 30.1 ± 2.3

Duration of infertility (y): not stated

Country: Egypt

Interventions

Group A: letrozole 2.5 mg/day for 5 days from cycle days 3 to 7

Group B: metformin HCl, 500 mg thrice daily for 6 ‐ 8 weeks, followed by 150 mg of CC orally given for 5 days starting on day 3 of menstruation

Participants continued treatment for 3 successive cycles using the same protocol.

Outcomes

Primary outcomes: ovulation rate, number of growing and mature follicles, serum oestrogen, serum progesterone and endometrial thickness

Secondary outcomes: pregnancy and miscarriage rates, multiple pregnancies and cases of OHSS

Notes

Ethical approval: yes, the study was approved by the local research ethics committee.

Informed consent: yes, all participants gave informed consent before inclusion in the trial.

Source of funding: not stated

Conflicts of interest: quote: "All authors have nothing to disclose"

Power calculation: quote: "the sample size was based on the fact that for an expected rate of ovulation of 70% in the combined metformin‐CC group we needed 244 women to show an absolute increase of 15% in ovulation rate in the letrozole group, with a power of 80% at confidence interval of 95% using a two‐tailed x² test with a 5% significance level."

We had contact with Prof. Abu Hashim, and all questions were answered in detail.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random table

Allocation concealment (selection bias)

Low risk

Quote: "Dark, sealed envelopes containing the intervention and taken from a computer‐generated random numeric table were prepared by a third party (independent statistician) not involved in the allocation process."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "patients were not blinded because of the difference in shape, colour and size of letrozole, CC and metformin tablets" (Email with Prof. Abu Hashim)

Blinding of outcome assessment (detection bias)
All outcomes

High risk

It is not plausible that outcome assessors were blinded if participants were not.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Al‐Omari 2004

Methods

Randomised double blind clinical trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: non‐fertile clomiphene‐resistant women with PCOS

Exclusion criteria: tubal, peritoneal and uterine causes of infertility were excluded by laparoscopic hysterosalpingogram or by ultrasonography. Specific endocrine abnormalities and male‐factor causes for infertility were also excluded. Participants had to end clomiphene treatment at least 2 months before enrolment.

Number of centres: quote: "The study was done in the Baghdad teaching hospital/ Medical city which is a tertiary ref. hospital affiliated with Baghdad Med college/ University of Baghdad." (Email)

Number of women randomised: 22 in the letrozole group and 18 in the anastrozole group

Number of women analysed: 22 in the letrozole group and 18 in the anastrozole group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 28.4 ± 5.18, group B anastrozole: 25.56 ± 6.26

BMI (kg/m²): group A letrozole: 29.95 ± 3.73, group B anastrozole: 27.90 ± 5.29

Duration of infertility (y): group A letrozole: 3.95 ± 2.70, group B anastrozole: 4.50 ± 3.61

Country: Iraq

Interventions

Group A: letrozole 2.5 mg/day orally given for 5 days during cycle days 3 ‐ 7

Group B: anastrozole 1 mg/day orally given for 5 days during cycle days 3 ‐ 7

Treatment was continued for 3 months. When ovulation or pregnancy did not occur, the same treatment protocol was used with the doubling of the first dose for a maximum of 2 treatment cycles.

Outcomes

Primary outcomes: ovulation rate/cycle, endometrial thickness (mm) measured on day of hCG administration

Secondary outcomes: multiple pregnancy rate, pregnancy rate/cycle, E2 (pmol/l), progesterone (nmol/l), LH (U/l), number and size of follicles, pulsatility index, day of hCG administration

Notes

Ethical approval: quote: "Ethical approval was obtained from the Iraqi Board for medical specialization/ Scientific committee" (email contact)

Informed consent: quote: "written consent was obtained from all patients" (email contact)

Source of funding: quote: "The study was partially funded by the Iraqi Board for medical specialization as well as the Drug Scientific Office of the Iraqi Ministry of Health."

Power calculation: not reported

We had email contact with Dr. Al‐Omari, but there was no further information available about the outcomes.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Actually, we just put all envelopes in a box, mixing them then the patient herself selected one." (email with Dr. Al‐Omari)

Allocation concealment (selection bias)

Unclear risk

Quote: "My associate informed me that for randomisation we distributed blank envelops containing the medications at our Gyn.clinic on twice weekly basis." (email with Dr. Al‐Omari)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants were not blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

It is not plausible that outcome assessors were blinded if participants were not

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Amer 2017

Methods

Randomised double‐blind controlled clinical trial

Duration and location of the trial: quote: "This study was conducted at the Fertility Unit, Derby Teaching Hospitals NHS Foundation Trust between April 2007 and June 2014.“

Participants

Inclusion criteria: quote: "eligible participants were women aged 18 – 39 years with BMI ≤ 35 kg/m2, anovulatory infertility, and a diagnosis of PCOS based on Rotterdam consensus (two of three criteria: oligo‐/anovulation, hyperandrogaenemia and sonographic appearance of polycystic ovaries) (Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group, 2004). Diagnosis of oligo‐/anovulation was based on a menstrual pattern of oligo‐/amenorrhoea (cycle > 35 days) and/or a low mid‐luteal serum progesterone concentration. Hyperandrogenaemia was diagnosed either clinically (acne/hirsutism) or biochemically (testosterone ≥ 2.5 nmol/l or free androgen index [FAI] ≥ 5). Ultrasound criteria included ≥ 12 follicles (2 – 9 mm) and/or an ovarian volume of > 10 ml (Jonard et al., 2003). All participants had proven patency of at least one fallopian tube and normal semen analysis of their male partners (WHO, 1999)."

Exclusion criteria: quote: "We excluded patients who have received OI within 6 months and those with uncontrolled thyroid disease or hyperprolactinaemia. Patients with marked hyperandrogaenemia were screened for adult onset congenital adrenal hyperplasia (by measuring serum 17‐ α ‐hydroxyl‐progesterone concentration) and Cushing syndrome (by measuring urinary free cortisol)."

Number of women randomised: 159 women were randomised in total; 79 to CC, 80 to letrozole

Number of women analysed: all women randomised were also analysed in the ITT analysis.

Number of withdrawals/exclusions/loss to follow‐up and reasons: 3 women in the CC group discontinued treatment due to failing to attend; also 3 women discontinued treatment in the letrozole arm (1 due to social reasons, 1 failed to attend, 1 withdrew consent).

Number of centres: this was a single centre, 2‐arm double‐blind RCT.

Age (y): letrozole: 28.3 (4.4) vs CC: 28.1 (4.2)

BMI (kg/m²): letrozole: 27.5 (23.4 ‐ 32.2) vs CC: 27.7 (23.0 ‐ 31.0)

Duration of infertility (y): 1.5 (1.0 ‐ 2.0) for both groups

Country: United Kingdom

Interventions

Group A: letrozole was prescribed (by the senior investigator, SA) orally daily for 5 days starting on Days 2 – 4 of a menstrual period or a progestogen‐induced bleed (medroxy‐progesterone acetate 10 mg twice daily for 5 days). The starting dose was 1 tablet/day (letrozole 2.5 mg) and if ovulation was not achieved, the dose would be doubled in the second cycle.

Group B: CC was prescribed daily for 5 days starting on days 2 – 4 of a menstrual period or a progestogen‐induced bleed (medroxy‐progesterone acetate 10mg twice daily for 5 days). The starting dose was 1 tablet/day (50 mg) and if ovulation was not achieved, the dose would be doubled in the second cycle. Participants who failed to ovulate on the maximum dose (2 tablets) or to conceive after 6 ovulatory cycles were crossed over to the other drug (after a 6‐week wash‐out period) following the same procedures as with the first drug.

Outcomes

Primary outcomes: clinical pregnancy (diagnosed by ultrasonographic visualisation of a gestational sac) rate per participant on primary treatment (before the cross‐over).

Secondary outcomes: secondary outcomes included ovulation, live birth, pregnancy by ovulating participant, pregnancy by strata, mono‐ovulation, endometrial development (thickness and grades), pregnancy outcome and pregnancy complications. Other outcomes included pregnancy and live birth rates on secondary and overall (primary and secondary) treatments.

Notes

Ethical approval: the trial was approved by West Midlands Research Ethics Committee (Reference: 07/MRE07/5) and by the Medicines and Healthcare Products Regulatory Agency (MHRA).

Informed consent: all participants gave written informed consent and the trial was monitored by the sponsor.

Source of funding: it was sponsored by the University of Nottingham.

Power calculation: quote: "to detect a clinically significant difference of 20% between the previously reported pregnancy rate of CC (˜35%) and letrozole with a two‐sided 5% significance level and power of 80%, a sample size of 212 participants (106 per arm) was required (Dickey and Holtkamp, 1996;Kousta et al., 1997; Imani et al., 2002)."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "An independent pharmacist randomly allocated participants to letrozole or CC, in 1:1 ratio according to a randomisation list created by the trial statistician using NQuery Advisor v6.0 software. Randomization was stratified by patients’ BMI (non‐obese < 30 kg/m2 and obese 30 – 35 kg/m2) using mixed block sizes."

Allocation concealment (selection bias)

Low risk

Quote: "An independent pharmacist randomly allocated participants to letrozole or CC, in 1:1 ratio."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Investigators, patients, outcome assessors and the statistician were blinded to the allocation of participants."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Investigators, patients, outcome assessors and the statistician were blinded to the allocation of participants."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Intention‐to‐treat (ITT) analysis included all randomised subjects, regardless of whether or not they received the study drug. Per protocol (PP) analysis included all randomised subjects who received the study drug and were not lost to follow‐up. Participants who were lost to follow‐up were assumed neither to be pregnant nor to have given LB in the ITT analysis."

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Atay 2006

Methods

Randomised controlled clinical trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: women with primary infertility and PCOS with no other known cause of infertility were enrolled into the study. All participants had a history of oligo‐ or amenorrhoea and ovaries with at least 10 subcapsular cysts 2 ‐ 10 mm in diameter and hyperechogenic stroma.

Exclusion criteria: none declared

Number of centres: setting unknown, tried to contact authors via email

Number of women randomised: 51 in the letrozole group and 55 in the CC group

Number of women analysed: 51 in the letrozole group and 55 in the CC group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 27.1 ± 0.9, group B CC: 26.2 ± 1.1

BMI (kg/m²): group A letrozole: 26.1 ± 1.9, group B CC: 25.8 ± 1.8

Duration of infertility (y): group A letrozole: 2.2 ± 0.7, group B CC: 2.4 ± 0.9

Country: Turkey

Interventions

Group A: letrozole, 2.5 mg/day orally given for 5 days starting on cycle day 3

Group B: clomiphene citrate, 100 mg/day orally given for 5 days starting on cycle day 3

Outcomes

Outcomes: number of mature follicles, endometrial thickness (mm), day of hCG administration, ovulation rate, pregnancy rate, multiple pregnancies

Notes

Ethical approval: yes, the study protocol was approved by the institutional ethics committee

Informed consent: yes, informed consent was obtained from all study participants

Source of funding: not stated

Conflicts of interest: quote:“Conflicts of interest: No conflicts of interest were declared in relation to this article”

Power calculation: not stated

We contacted Dr. V Atay via email about the study setting, about how randomisation and allocation were done, blinding and if data are available on OHSS, miscarriage rate and live birth rate, but no response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Unclear how it was done

Allocation concealment (selection bias)

Unclear risk

Unclear how it was done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Unclear risk

Protocol of the study was not available

Other bias

Low risk

None

Badawy 2008

Methods

Randomised controlled trial

Duration and location of the trial: quote: "The study comprised of 220 women (574 cycles) with CCresistant PCOS among those attending the Fertility Outpatient Clinic in Mansoura University Hospitals, Mansoura University, Egypt, and a private practice setting in the period from May 2005 to January 2007.“

Participants

Inclusion criteria: diagnosis of PCOS based on the revised 2003 consensus on diagnostic criteria and long‐term health risks related to PCOS. All women were previously treated with 100 mg of CC daily for 5 days each cycle, for 2 ‐ 3 cycles with persistent anovulation or ovulate with very thin endometrium < 5 mm at the time of hCG administration. They had patent fallopian tubes proved by hysterosalpingography and normal semen analysis for their partners according to the modified criteria of WHO.

Exclusion criteria: no exclusion criteria stated

Number of centres: 2, outpatient clinic in Mansoura University Hospitals and a private practice setting

Number of women randomised: 111 in the letrozole group and 109 in the anastrozole group

Number of women analysed: 111 in the letrozole group and 109 in the anastrozole group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 28.2 ± 2.8, group B anastrozole: 26.3 ± 2.5

BMI (kg/m²): group A letrozole: 29.1 ± 3.1, group B anastrozole: 30.1 ± 2.1

Duration of infertility (y): not stated

Country: Egypt

Interventions

Group A: letrozole 2.5 mg/day orally given for 5 days during cycle days 3 ‐ 7

Group B: anastrozole 1 mg/day orally given for 5 days during cycle days 3 ‐ 7

Treatment was continued for 3 months.

Outcomes

Primary Outcomes: number of growing and mature follicles, serum E2 (pg/ml), serum progesterone (ng/mL), and endometrial thickness (mm).

Secondary Outcomes: pregnancy rate, miscarriage rate, multiple pregnancy rate, ovarian hyperstimulation syndrome rate

Notes

Ethical approval: yes, the study was approved by the hospital ethics research committee.

Informed consent: yes, all participants gave informed consent before inclusion in the trial

Source of funding: not stated

Power calculation: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated using a computer‐generated random table into 2 treatment groups

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Badawy 2009a

Methods

Randomised controlled study

Duration and location of the trial: quote: "The study comprised 438 women (1063 cycles) with PCOS among those attending the Fertility Outpatient Clinic in Mansoura University Hospitals, Mansoura University, Egypt, and private practices in the period from January 2004 and September 2006.“

Participants

Inclusion criteria: infertile women with clomiphene‐resistant PCOS, diagnosis of PCOS based on the 2003 Rotterdam criteria. Normal serum PRl, TSH and 17OH‐P.

Exclusion criteria: infertility caused by fallopian tube problems, infertility problems caused by male partner

Number of centres: 2, outpatient clinic in Mansoura University Hospitals and a private practice setting

Number of women randomised: 110 in the short letrozole group and 108 in the long letrozole group

Number of women analysed: 110 in the short letrozole group and 108 in the long letrozole group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A short letrozole: 25.1 ± 3.2, group B long letrozole: 25.3 ± 3.0

BMI (kg/m²): group A short letrozole: 33.9 ± 3.1, group B long letrozole: 34.2 ± 2.6

Duration of infertility (y): not stated

Country: Egypt

Interventions

Group A: letrozole orally given, 5 mg/day for 5 days, from cycle days 3 ‐ 7

Group B: letrozole orally given, 2.5 mg/day for 10 days, from cycle days 3 ‐ 12

Outcomes

Primary Outcomes: number of growing and mature follicles, serum E2 (pg/mL), serum progesterone (ng/mL), and endometrial thickness (mm)

Secondary Outcomes: pregnancy rate, miscarriage rate, multiple pregnancies, OHSS

Notes

Ethical approval: yes, the study was approved by the hospital ethics research committee.

Informed consent: yes, all participants gave informed consent before inclusion in the trial

Source of funding: not stated

Conflicts of interest: quote:"All authors have nothing to disclose"

Power calculation: quote: "Sample size calculation, using StatCalc 3.02 computer package 8Acastat software, Leesburg, VA), showed that each arm should contain at least 103 patients to have 80% power of the study at 95% confidence interval (CI)."

We contacted the authors, but information on live birth was not collected.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly allocated into two treatment groups using a computer‐generated random table: short letrozole group and long letrozole group."

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All stated outcomes were reported

Other bias

Low risk

None

Badawy 2009b

Methods

Prospective randomised trial

Duration and location of the trial: quote: "The study comprised 218 women (444 cycles) with clomiphene‐resistant PCOS among those attending the gynecology outpatient clinic in Mansoura University Hospitals, Egypt, and a private practice setting in the period from December 2005 to December 2007.“

Participants

Inclusion criteria: diagnosis of PCOS based on the 2003 Rotterdam criteria. All women had patent fallopian tubes proved by hysterosalpingography and their partners had normal semen analysis parameters according to the modified criteria of the WHO. All participants had normal serum prolactin, TSH and 17‐OH progesterone.

Exclusion criteria: not stated

Number of centres: multiple, University teaching hospital and private practices

Number of women randomised: 218 in the letrozole group and 220 in the CC group

Number of women analysed: 218 in the letrozole group and 220 in the CC group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 27.1 ± 3.2, Group B clomiphene citrate: 29.3 ± 2.9

BMI (kg/m²): group A letrozole: 28.1 ± 3.2, group B CC: 27.1 ± 3.1

Duration of infertility (y): not reported

Country: Egypt

Interventions

Group A: letrozole orally given 5 mg/day for 5 days from cycle days 3 ‐ 7

Group B: clomiphene citrate orally given 100 mg/day for 5 days from cycle days 3 ‐ 7

Outcomes

Primary Outcomes: number of growing and mature follicles, the concentrations of serum E2 (pg/mL) and progesterone (ng/mL), and the endometrial thickness (mm)

Secondary Outcomes: ovulation rate, ovarian hyperstimulation rate, pregnancy rate, miscarriage rate, multiple pregnancy rate

Notes

Ethical approval: yes, the study was approved by the hospital research ethics committee.

Informed consent: yes, all participants gave informed consent before inclusion in the trial

Source of funding: the study was self‐funded

Power calculation: not stated

Authors were contacted via email and gave all information, but they did not measure the live birth.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated using a computer‐generated random table into 2 groups

Allocation concealment (selection bias)

Low risk

Quote: "Allocation concealment was done by sequentially numbered opaque sealed envelopes opened by the chief nurse" (by email contact with authors)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded, email with Prof. Badawy

Blinding of outcome assessment (detection bias)
All outcomes

High risk

It is not plausible that outcome assessors were blinded if participants were not

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported, Live birth was not measured

Other bias

Low risk

None

Bayar 2006

Methods

Randomised controlled study

Duration and location of the trial: quote: "During the study period of 2004 through 2005, 80 patients with PCOS who attended the outpatient clinics of the Infertility and Reproductive Medicine Unit of the Zonguldak Karaelmas University Hospital (Zonguldak, Turkey) participated in this study.“

Participants

Inclusion criteria: women with anovulatory PCOS diagnosed by using 2003 Rotterdam criteria

Exclusion criteria: tubal, peritoneal and uterine cause of infertility. Male‐factor infertility. Specific endocrine abnormalities (Cushings disease/syndrome, hypothyroidism, hyperthyroidism, prolactinoma)

Number of centres: 1, outpatient clinics of the Infertility and Reproductive Medicine Unit of the Zonguldak Karaelmas University Hospital (Zonguldak, Turkey)

Number of women randomised: 80, 40 in group A letrozole and 40 in group B CC

Number of women analysed: 38 in group A letrozole and 36 in group B CC

Number of withdrawals/exclusions/loss to follow‐up and reasons: 6 lost to follow‐up, no reasons given

Age (y): group A letrozole: 32.2 ± 3.9, group B CC: 30.6 ± 4.0

BMI (kg/m²): not stated

Duration of infertility (y): group A letrozole: 5 (1 ‐ 10), group B CC: 3 (3 ‐ 11)

Country: Turkey

Interventions

Group A: letrozole, 5 mg/day orally given for 5 days during cycle days 3 ‐ 7

Group B: clomiphene citrate, 100 mg/day orally given for 5 days during cycle days 3 ‐ 7

Outcomes

Outcomes: ovulation rate by cycle, pregnancy rate by cycle, delivery rate by cycle, miscarriage rate, multiple pregnancy rate, endometrial thickness on the day of hCG (mm), N of follicles sized > 15 mm in diameter on the day of hCG, E2 level on the day of hCG (pg/mL), E2 per follicle sized > 15 mm in diameter on the day of hCG (pg/mL)

Notes

Ethical approval: yes, the study was approved by the institutional ethics committee of Karelmal university.

Informed consent: not stated

Source of funding: no funding source or conflicts of interest stated

Power calculation: Sample‐size determination was based on the difference between the median number of follicles sized > 15 mm and E2 concentration on hCG day. A sample size of 60 participants (30 in each group) was targeted to be able to detect a difference of at least one follicle or of 200 pmol/L between the 2 groups, with alfa (type I error) set at 0.05 and 80% power.

We contacted Dr. Bayar by email for additional information, but he did not respond.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Simple randomisation performed by a computer

Allocation concealment (selection bias)

Unclear risk

Allocation concealment was achieved by using central consultation for treatment of eligible participants.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Stated as double‐blind but it is not clear who was actually blinded and how this was achieved

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Stated as double‐blind but it is not clear who was actually blinded and how this was achieved

Incomplete outcome data (attrition bias)
All outcomes

Low risk

6 participants lost to follow‐up, 4 and 2 respectively

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Begum 2009

Methods

Randomised non‐blinded controlled trial

Duration and location of the trial: quote: "The study was conducted in a private infertility care setting as a randomized controlled trial between August 2004 and December 2005.“

Participants

Inclusion criteria: infertile women with PCOS diagnosed by the Rotterdam criteria 2003 who failed to ovulate by taking 100 mg of CC/day for 5 days in 2 consecutive cycles

Exclusion criteria: women with hyperprolactinaemia, thyroid disorder, male‐factor infertility, known or suspicious tubal factor infertility (endometriosis and pelvic inflammatory disease), and unexplained infertility were excluded from the study.

Number of centres: 1, private infertility care setting

Number of women randomised: 32 in each group

Number of women analysed: 32 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 25.5 ± 4.0, group B clomiphene citrate: 26.1 ± 3.6

BMI (kg/m²): group A letrozole: 22.7 ± 2.8, group B clomiphene citrate: 23.6 ± 3.2

Duration of infertility (y): group A letrozole: 2.7 ± 1.1, group B clomiphene citrate: 2.6 ± 1.1

Country: India

Interventions

Group A: letrozole, 7.5 mg/day orally given for 5 days from cycle days 3 ‐ 7

Group B: clomiphene citrate, 150 mg/day orally given for 5 days from cycle days 3 ‐ 7

Outcomes

Primary Outcomes: ovulation and pregnancy rate

Secondary Outcomes: follicular development by day 16 (mm), serum E2 on day of hCG (pg/mL), endometrial development by day 16 (mm), serum progesterone on day 21 (ng/mL), multiple pregnancies, OHSS cases. Live birth rate was provided by email contact.

Notes

Ethical approval: yes, the study protocol was approved by the institutional review board (IRB) of Dhaka medical college.

Informed consent: yes, participants were counselled and informed consent was obtained before recruitment.

Source of funding: the study was self‐funded.

Power calculation: a study population of 57 women was calculated, considering an average of 60% of PCOS women are associated with insulin resistance, allowing an alfa value of 0.05.

Authors were contacted by email, and additional information was provided.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was done by lottery method. They put the name of letrozole and CC in a sealed opaque envelope. By calculating sample size they made 64 pieces of paper, 32 for letrozole and 32 for CC.

Allocation concealment (selection bias)

Unclear risk

Quote: "All unleveled envelop were put together and the patients drew one piece of envelop from them. Then we opened the envelop to see the name of the drug." (by email contact with Prof. Rashida)

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "There was no blinding" (by email contact with Prof. Rashida)

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "There was no blinding" (email with Prof. Rashida)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

None

Chen 2016

Methods

Randomised controlled study

Duration and location of the trial: quote: "All patients were admitted in our hospital between January 2013 and January 2015, who were not pregnant without contraception for over one year.“

Participants

Inclusion criteria: quote: "all the cases were PCOS infertility patients in line with the PCOS diagnostic criteria of the 2003 Rotterdam Conference, i.e. at least two of the following three were met: 1) ovulation abnormality (sporadic ovulation or no ovulation) occurred after continuous monitoring for two or more natural cycles; 2) the results of B ultrasound showed polycystic ovary; 3) patients had hyperandrogenism or showed clinical manifestations of androgen excess. Through salpingography or hydrotubation under transvaginal B ultrasound and other examinations, all cases were confirmed to have tubal patency on at least one side. The semen of male was normal."

Exclusion criteria: quote:"Those with androgen excess caused by other diseases such as adrenal hyperplasia Cushing’s syndrome and androgen‐secreting tumours were excluded. Exclusion criteria: 1) Infertility patients caused by non‐PCOS ovulatory disorder or other factors; 2) patients with history of ovarian surgery or complication with endometriosis or pelvic adhesion; 3) patients complicated with liver, kidney or thyroid dysfunction; 4) patients who did not receive treatment after enrolment according to the established regimen or gave up in the midst of treatment."

Number of women randomised: 156 patients, 52 in each group

Number of women analysed: 156 patients, 52 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: none reported

Number of centres: single‐centre trial

Age (y): letrozole group 26.4 ± 4.2; CC group 27.1 ± 4.7; letrozole + HMG group 27.7 ± 5.2 years

BMI (kg/m²): letrozole group 22.4 ± 4.5; CC group 23.4 ± 1.5; letrozole + HMG group 22.6 ± 2.6 years

Duration of infertility (y): letrozole group 3.4 ± 1.1; CC group 3.2 ± 0.7; letrozole + HMG group 3.3 ± 1.3 years

Country: China

Interventions

Group A (letrozole): the participants orally took 2.5 ‐ 5.0 mg/d‐1 LE (trade name: Fu Rui, Jiangsu Hengrui Medicine Co., Ltd.) on the 3rd ‐ 5th days of menstrual cycle for 5 consecutive days.

Group B (CC group): the participants were orally administered with 50 ‐ 100 mg/d‐1 CC (trade name: Fertilan, Codal Synto Pharmaceutical Co., Ltd.) on the 3rd ‐ 5th days of menstrual cycle for 5 consecutive days.

Group C (letrozole + HMG group): the participants orally took 2.5 ‐ 5.0 mg/d‐1 LE on the 3rd ‐ 5th days of menstrual cycle for 5 consecutive days. Starting from the day of oral administration of CC, 75 IU HMG (trade name: Lebaode, Livzon Group Livzon Pharmaceutical Co. Ltd.) was intramuscularly injected every other day for 5 consecutive days.

Outcomes

Primary outcomes: clinical pregnancy, defined as a fetal heart beat visible via transvaginal ultrasound on 30th day after ovulation

Secondary outcomes: OHSS, miscarriage, multiple pregnancy

Notes

Ethical approval: this study has been approved by the ethics committee of our hospital.

Informed consent: written consent has been obtained from all patients.

Source of funding: quote: “None”

Power calculation: no power calculation was reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “ the patients were randomly divided into an LE group, a CC group and an LE + HMG group”

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants randomised were also analysed.

Selective reporting (reporting bias)

Low risk

No study protocol was found, but all outcomes reported were also analysed.

Other bias

Low risk

None

Davar 2011

Methods

Single‐blind randomised clinical trial

Duration and location of the trial: quote: "In this single blind randomized trial, 148 ovarian cycles were studied in 100 clomiphene‐ resistance patients with PCOS who were chosen among 250 PCOS patients attending the Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran during the years 2007‐2008.“

Participants

Inclusion criteria: women who received 150 mg CC daily for 3 cycles and failed to become pregnant, and were diagnosed with anovulatory PCOS based on Rotterdam 2003.

Exclusion criteria: quote: “We excluded patients with liver and kidney dysfunction, cardiovascular disease, diabetics, and those who use metformin or drugs affecting insulin secretion and clomiphene citrate in recent 2 cycles.”

Number of centres: 1, research and clinical centre for infertility, Shahid Sadoughi University of Medical Sciences, Yazd

Number of women randomised: 100 women, 50 in group A met‐letrozole, 50 in group B met‐CC

Number of women analysed: 48 in group A met‐letrozole, 50 in group B met‐CC

Number of withdrawals/exclusions/loss to follow‐up and reasons: 2, experienced side effects with metformin before letrozole was started

Age (y): group A metformin‐letrozole: 28.5 ± 3.1, group B metformin‐clomiphene citrate: 29.6 ± 3.5

BMI (kg/m²): group A met‐letrozole: 29.0 ± 3.8, group B met‐CC: 29.2 ± 2.9

Duration of infertility (y): group A met‐letrozole: 3.8, group B met‐CC: 3.8

Country: Iran

Interventions

Group A: metformin 1500 mg daily for 6 ‐ 8 weeks, followed by 5 mg letrozole daily orally given for 5 days during cycle days 3 ‐ 7 if pregnancy did not occur

Group B: metformin 1500 mg daily for 6 ‐ 8 weeks, followed by 100 mg CC daily orally given for 5 days during cycle days 3 ‐ 7 if pregnancy did not occur

Outcomes

E2 (pg/mL) on day of hCG administration, number of follicles > 18 mm in diameter, endometrial thickness on day of hCG administration (mm), clinical pregnancy rate, miscarriage rate

Notes

SEthical approval: yes, the study was approved by ethical board of Shahid Sagoughi University of Medical Sciences, Yazd.

Informed consent: no, at least nothing written about it – authors contacted

Source of funding: quote: “the study was fully supported and funded by Shahid Sadoughi University of Medical Sciences, Yazd, Iran”

Power calculation: quote: "In this study, 50 cases were needed in each group so as to gain a significant difference of 22% in pregnancy rate at a significant level of 5% and a power of 80%"

We contacted Dr Davar by email to get additional information, but we did not get a response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was done using a random‐numbers table

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated who was blinded in this single‐blinded trial

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated who was blinded in this single‐blinded trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2 participants lost to follow‐up due to side effects experienced with metformin before letrozole was started.

Selective reporting (reporting bias)

Low risk

All outcomes reported stated in the protocol

Other bias

Low risk

None

Dehbashi 2009

Methods

Double‐blind randomised study

Duration and location of the trial: quote: "During the period of February 2004 through November 2006, 100 patients with PCOS who attended the outpatient infertility clinics at Shiraz University of Medical Sciences participated in the present study.“

Participants

Inclusion criteria: infertility for at least 1 year, diagnosis of PCOS by the Rotterdam criteria 2003, having patent tubes on hysterosalpingogram, and normal semen analysis of the husband

Exclusion criteria: participants must not have received any other medication for ovulation induction before enrolment into the study.

Number of centres: 1, outpatient infertility clinics at Shiraz University of Medical Sciences

Number of women randomised: 100 women, 50 in each group

Number of women analysed: 100 women, 50 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 23.6 ± 2.9, group B CC: 24.3 ± 3.4

BMI (kg/m²): group A letrozole: 27.5 ± 4.6, group B CC: 27.1 ± 3.6

Duration of infertility (y): group A letrozole: 2.0 ± 1.3, group B CC: 2.3 ± 1.9

Country: Iran

Interventions

Group A: letrozole, 5 mg/day orally given for 5 days during cycle days 3 ‐ 7

Group B: clomiphene citrate, 100 mg/day orally given for 5 days during cycle days 3 ‐ 7

Outcomes

Total number of follicles with diameter ≥ 14 mm, endometrial thickness on the day of hCG injection, pregnancy rate, miscarriage rate, multiple pregnancy rate, live birth rate

Notes

Ethical approval: yes, quote: “The study was approved by the Institutional Ethics Committee of the University.”

Informed consent: yes, quote: “An informed written consent was obtained from each patient”

Source of funding: not stated

Conflicts of interest: quote: "Conflicts of interest: None declared"

Power calculation: not stated

Authors contacted about randomisation, allocation, and information about OHSS

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not stated how it was done

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Only the pharmacist knew the name of the medication that had been taken by the participants.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Only the pharmacist knew the name of the medication that had been taken by the participants.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No participants excluded or lost to follow‐up

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

El‐Gharib 2015

Methods

Randomised controlled trial

Duration and location of the trial: quote: "This prospective intervention study was performed during the period from January 2010 till August 2012 at the outpatient clinic of Tanta University Hospital.“

Participants

Inclusion criteria: the most important inclusion criteria were fulfilment of at least 2 of Rotterdam criteria of PCOS, negative history of medical problems that can affect fertility such as diabetes mellitus, thyroid dysfunction, hyperprolactinaemia, congenital adrenal hyperplasia, normal hysterosalpingography and BMI between 20 and 30.

Exclusion criteria: history of medical problems which affect fertility, history of recent hormonal therapy, having pelvic infections and/or having abnormal laboratory findings other than PCOS findings. Women whose husbands had defective semen were also excluded.

Number of women randomised: 60 participants, 30 in each group

Number of women analysed: 60 participants analysed

Number of withdrawals/exclusions/loss to follow‐up and reasons: no participants were lost to follow‐up.

Number of centres: 1, single‐centre trial

Age (y): letrozole 26.2 ± 0.9; tamoxifen 26.9 ± 1.1

BMI (kg/m²): letrozole 27.7 ± 4.1; tamoxifen 28.4 ± 3.8

Duration of infertility (y): letrozole 3.2 ± 2.7; tamoxifen 3.0 ± 2.1

Country: Egypt

Interventions

Group A: letrozole (Femara; Novartis) 2.5 mg/day given from day 5 ‐ 9 of the menstrual cycle, for 3 successive cycles

Group B: TMX 20 mg/day given from day 5 ‐ 9 of the menstrual cycle, for 3 successive cycles

Outcomes

Pregnancy rate, follicular growth, endometrial thickness, cumulative ovulation

Notes

Ethical approval: the study was approved by the institutional ethics committee of Tanta Faculty of Medicine.

Informed consent: all women subjected to history taking, physical examination, counselling and signing a written consent

Source of funding: not reported

Power calculation: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Methods of randomisation were not sufficiently described: quote: "arranged at random, by sealed envelopes"

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

60 participants were randomised and analysed.

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

El‐Khayat 2016

Methods

Randomised double‐blind controlled trial

Duration and location of the trial: quote: "A prospective double‐blind randomized controlled trial was conducted at the Teaching University Hospital of Cairo University, Cairo, Egypt, between August 1, 2013, and December 31, 2014.“

Participants

Inclusion criteria: quote: "eligible women were younger than 40 years, had primary or secondary infertility associated with PCOS, and had not ovulated in response to three cycles of 150 mg clomiphene citrate every day for 5 days from day 3 of the menstrual cycle. PCOS diagnoses were based on the revised 2003 Rotterdam consensus criteria. The presence of at least two of the following characteristics was considered diagnostic of PCOS: oligo ovulation or anovulation; hyperandrogenism; and polycystic ovaries detected using vaginal ultrasonography."

Exclusion criteria: quote: "exclusion criteria were other factors of infertility, diabetes mellitus, hypertension, liver or kidney malfunction, heart disease, urinary symptoms, persistent hyperprolactinaemia, thyroid dysfunction, gonadotropin induction, and previous ovarian drilling. Male factor infertility was defined as a sperm count of less than 15 × 10^6/mL, a total motility of less than 40%, or normal morphology of less than 4%. Tubal factor infertility was confirmed by hysterosalpingography."

Number of women randomised: 100 women were randomised.

Number of women analysed: 100 women were analysed, 50 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: none

Number of centres: single centre

Age (y): CC 26.6 ± 2.9; letrozole 25.8 ± 3.6

BMI (kg/m²): CC 26.6 ± 2.7; letrozole 26.5 ± 2.8

Duration of infertility (y): CC 3.1 ± 1.4; letrozole 2.7 ± 1.6

Country: Egypt

Interventions

Group A: (control group) received 100 mg clomiphene citrate, given as 2 x 50 mg tablets daily for 5 days from the third day of the menstrual cycle.

Group B: 5 mg letrozole, given as 2 x 2.5 mg tablets daily for 5 days from the third day of the menstrual cycle.

Participants in both groups also received metformin and pioglitazone, which was taken daily as 1 tablet containing 850 mg metformin and 15 mg pioglitazone, for 10 days starting from the first day of the menstrual cycle.

Outcomes

Primary outcome measure: cumulative ovulation rate (proportion of cycles in which ovulation occurred in the whole follow‐up period).
Other outcome measures: number of follicles ≥ 18 mm in size, endometrial thickness and serum estradiol levels on the day of hCG administration, serum progesterone level on day 21, and rate of clinical pregnancy (at least 1 intrauterine gestational sac detected)

Notes

Ethical approval: approved by the research ethics committee of the teaching University Hospital of Cairo University

Informed consent: all participants signed a written informed consent form.

Source of funding: Cairo University

Power calculation: Previous data indicated that the ovulation rate in group A would be 62%. If the ovulation rate for the letrozole, metformin, and pioglitazone (experimental) group was 87% (previous unpublished data from the study unit), a total of 47 women would have to be recruited to each group to ensure a sufficiently powered study. Assuming an attrition of 10%, the total number of patients to be recruited was 50 per group. Intention‐to‐treat analyses were planned.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Enrolled women were randomly allocated using computer‐generated random number tables (block size four)"

Allocation concealment (selection bias)

Low risk

Quote: "Opaque sealed envelopes containing group allocations were prepared at a separate location every 24 hours. These envelopes were sent to an assigned nurse, who opened them before commencing ovulation induction"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Participants, the staff who conducted follow‐up, and data analysts were masked to the allocation to avoid bias"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Participants, the staff who conducted follow‐up, and data analysts were masked to the allocation to avoid bias"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No participants were lost to follow‐up

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

None

Elgafor 2013

Methods

Randomised controlled trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: clomiphene citrate‐resistant women with infertility due to PCOS, diagnosed according to the Rotterdam 2003 criteria. Clomiphene citrate resistance was defined as failure to achieve adequate follicular maturation after 3 consecutive induction cycles with CC at 150 mg/day for 5 days.

Exclusion criteria: exclusion criteria include women with other causes of infertility such as male factor or tubal factor, those with endocrine disorders such as thyroid dysfunction and hyperprolactinaemia, women who received hormonal treatment or ovulation induction drugs 3 months before the study

Number of centres: 1, Zagazig University Hospital, Egypt

Number of women randomised: 146 women, 73 in each group

Number of women analysed: 146 women, 73 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A metformin + letrozole: 24.7 ± 1.8, group B LOD: 25.1 ± 2.1

BMI (kg/m²): group A metformin + letrozole: 31.5 ± 3.3, group B LOD: 32.4 ± 4.4

Duration of infertility (y): group A metformin + letrozole: 3.4 ± 0.9, group B LOD: 3.9 ± 1.1

Country: Egypt

Interventions

Group A: metformin 850 to 1700 mg daily for 6 ‐ 8 weeks, followed by 5 mg letrozole daily orally given for 5 days during cycle days 3 ‐ 7 if pregnancy did not occur

Group B: LOD, laparoscopy was performed using 3‐puncture technique.

Outcomes

Cycle regularity, ovulation rate, clinical pregnancy rate, miscarriage rate

Notes

Ethical approval: yes, quote: “Ethics Committee of Zagazig University approved the study"

Informed consent: yes, quote: “written informed consent was obtained from each patient at the start of the study”

Source of funding: not stated

Conflicts of interest: quote: "conflicts of interest: none"

Power calculation: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The participant women were randomised according to a computer‐generated random numeric table."

Allocation concealment (selection bias)

Low risk

The random allocation sequence was concealed in sealed dark envelopes, then participants assigned randomly into group 1 (n = 73) received metformin plus letrozole, and group 2 (n = 73) underwent LOD.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Foroozanfard 2011

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "This clinical trial was performed on 120 infertile women with PCOS who attended in the outpatient infertility clinic in Kashan, Iran during 2008.“

Participants

Inclusion criteria: quote: "Our inclusion criteria were age 20‐35 years, infertility for at least one year and resistance to Clomiphene (at least 3 cycles Clomiphene usage, 150 mg/day with no ovulatory response)"

Exclusion criteria: exclusion criteria were BMI > 27, endocrine disorders such as hypothyroidism, hyperprolactinaemia, infertility due to male factors, uterine factors and adhesive diseases due to pelvic surgery.

Number of centres: 1, outpatient infertility clinic in Kashan

Number of women randomised: 60 in each group

Number of women analysed: 60 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole + hMG: 25.8 ± 3.8, group B CC + hMG: 25.3 ± 4.1

BMI (kg/m²): group A letrozole + hMG: 24.1 ± 2.3, group B CC + hMG: 24.9 ± 2.0

Duration of infertility (y): group A letrozole + hMG: 2.8 ± 2.3, group B CC + hMG: 2.6 ± 2.1

Country: Iran

Interventions

Group A: letrozole, 5 mg/day orally given for 5 days from cycle days 3 ‐ 7 + 150 IU hMG intramuscularly during cycle days 5 ‐ 8

Group B: clomiphene citrate, 100 mg/day orally given for 5 days from cycle days 3 ‐ 7 + 150 IU hMG intramuscularly during cycle days 5 ‐ 8

Outcomes

Live birth rate, OHSS rate, pregnancy rate, miscarriage rate, multiple birth rate, number of dominant follicles, endometrial thickness (mm), ectopic pregnancies

Notes

Ethical approval: Yes, quote: ”approval was obtained from the Institute Research Board to perform this study.“

Informed consent: Yes, quote: “All patients were informed about possible side effects ad also off label use of letrozole for the purpose of inducing ovulation and written consent were obtained for all participants.”

Source of funding: Yes, quote: “Authors acknowledge the research deputy of Kashan University of Medical Sciences for providing the financial support.”

Power calculation: Not stated

Authors contacted by email, all information provided

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Simple randomisation was performed by a computer

Allocation concealment (selection bias)

Low risk

By sequentially‐numbered opaque sealed envelopes (email with authors)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Before commence of the study all patients were informed of the study and were told about this issue that it is possible to be enrolled in letrozole or clomiphene group but none of them knew which group she allocated to and the researcher was blinded also to patients' treatment approach."  (email contact with authors)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

See above

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Ganesh 2009

Methods

Randomised controlled trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: 1387 women with PCOS diagnosed by the Rotterdam criteria who had previously failed to conceive or ovulate with CC treatment and undergoing IUI. Specific inclusion criteria for the study were normal TSH and prolactin levels and normozoospermic male partners as per WHO guidelines.

Exclusion criteria: women with pre‐existing ovarian cyst on day 3 and previous history of ovarian drilling were excluded.

Number of centres: 1, a tertiary infertility care unit, Institute of Reproductive Medicine, Kolkata, India

Number of women randomised: 1378

Number of women analysed: 1378

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 30.3 ± 4.9, group B CC: 30.4 ± 5.2, group C rFSH: 30.8 ± 4.6

BMI (kg/m²): group A letrozole: 24.5 ± 3.8, group B CC: 24.8 ± 4.1, group C rFSH: 24.1 ± 3.4

Duration of infertility (y): Not reported

Country: India

Interventions

Group A: letrozole, 5 mg/day orally given for 5 days from cycle days 3 ‐ 7

Group B: clomiphene citrate, 100 mg/day orally given for 5 days from cycle days 3 ‐ 7 + 75 or 100 IU rFSH during cycle days 3 and 8.

Group C: rFSH 75IU/100IU from day 2 until the day of hCG administration

Outcomes

Primary outcome measures: ovulation rate, cancellation rate, miscarriage rate and pregnancy rate
Secondary outcomes: OHSS rate and multiple pregnancy rate.

Notes

Ethical approval: yes, approval was obtained from the institutional Research Ethics Board.

Informed consent: yes, quote: “Written informed consent was taken from all women included in this study.”

Source of funding: quote: "This study was not funded by any funding agency.”

Power calculation: not stated

Authors contacted by email, all information provided

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The subjects recruited for the study were randomly and blindly assigned to one of the treatment protocols. The procedure was carried out by requesting the patient to pick up randomly an opaque, sealed envelope. Each envelope contained a piece of paper with one of the three protocols written on it. Many such sealed envelopes were prepared and placed randomly. Once the patient picked the envelope, the seal was opened in front of the patient and the coordinator, the content showed and the protocol allocated." (Information by email from the author)

Allocation concealment (selection bias)

Low risk

Quote: "the allocation was done using sealed envelopes where the person allocating was blinded to the type of protocol received by the patients."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Only researcher was blinded and the patient aware of the protocol followed since the route of administration was different in all the three groups."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Only researcher was blinded and the patient aware of the protocol followed since the route of administration was different in all the three groups."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Ghahiri 2016

Methods

Randomised controlled clinical trial

Duration of the trial: quote: "This was a randomized prospective clinical trial, including consecutive women with primary or secondary infertility due to PCOS from Jan 2009 to Sept 2011.“

Participants

Inclusion criteria: the major criteria for diagnosis of PCOS were oligo‐ and/or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries, in accord with the revised 2003 Rotterdam criteria of PCOS. Thyroid function, prolactin level, and husband’s sperm analysis were checked for normal values.

Exclusion criteria: women with other causes of infertility, infertility < 1 year, and those who got previous treatment(s) for infertility were not included in the study.

Number of women randomised: 103; 51 to group A (CC), 52 to group B (letrozole)

Number of women analysed: 50 participants in group A, 51 in group B

Number of withdrawals/exclusions/loss to follow‐up and reasons: 2 participants, 1 from each group lost to follow‐up due to no show

Number of centres: single‐centre study

Age (y): no mean age reported for the treatment groups

BMI (kg/m²): group A 27.1 ± 4.9; group B 28.2 ± 5.2

Duration of infertility (y): no means reported

Country: Iran

Interventions

Group A: clomiphene citrate 100 mg for 5 days starting from day 3 of their menstrual cycle

Group B: 5 mg letrozole for 5 days from day 3 of their menstrual cycle

Both groups were advised to have intercourse on days 11, 13, and 15 of their menstrual cycles.

Outcomes

Pregnancy rate, miscarriage rate, multiple pregnancies, ectopic pregnancies, OHSS rate

Notes

Ethical approval: the protocol was approved by the ethical investigation committee of the institution

Informed consent: informed consent was obtained from all the participants after full informative session.

Source of funding: not reported

Power calculation: quote: "based on our statistical data, the fair needed number for performing this study was 50 per group (the sample size was calculated by considering z, p, and d as 1.96, 0.15, and 0.1, respectively)."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

All candidates were randomised based on envelope method into either clomiphene citrate group (group A, n = 51) or letrozole group (group B, n = 50)

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2 of 103 participants were lost to follow‐up

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

None

Ghomian 2015

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "The study was performed from March to November 2010 at the Mashhad IVF center, a university based infertility center.“

Participants

Inclusion criteria: based on Rotterdam criteria, 70 women with PCOS were enrolled in this randomised clinical trial. The diagnosis of PCOS was made when 2 of the following 3 criteria existed: oligomenorrhoea or amenorrhoea, clinical hyperandrogenism, and polycystic ovaries on ultrasonography. The inclusion criteria were as follows: i. Previous diagnosis of PCOS according to Rotterdam criteria, ii. Age between 20 and 30 years, iii. No previous history of ovarian surgery, and iv. lack of ovulation with CC in at least 3 previous cycles (lack of follicle ≥ 18 mm on ultrasound scan). The woman’s age, her partner’s age, duration of infertility, type of infertility (primary and secondary), history of previous intrauterine insemination (IUI) cycles, pattern of ovary (PCO and non‐PCO), pattern of menstruation (regular, oligomenorrhoea and amenorrhoea), BMI and basal LH/FSH ratio were recorded for each participant.

Exclusion criteria: the exclusion criteria were as follows: i. No other infertility factors, ii. Exposure to cytotoxic drugs and iii. Pelvic radiation therapy.

Number of women randomised: 70

Number of women analysed: 69

Number of withdrawals/exclusions/loss to follow‐up and reasons: 1 patient discontinued treatment in group B

Number of centres: single‐centre study

Age (y): group A: 25.3 ± 4.4, group B: 25.6 ± 3.5

BMI (kg/m²): group A: 27.0 ± 3.8, group B: 26.4 ± 4.8

Duration of infertility (y): number of previous treatment cycles (CC): group A: 1.1 ± 0.4, group B: 1.3 ± 0.5

Country: Mashhad, Iran

Interventions

Group A: group A (n = 35) receiving 5 mg letrozole (Letrofem; Iran Hormone, Iran) on cycle days 3 ‐ 7

Group B: group B (n = 35) receiving the same amount on cycle days 5 ‐ 9.

Outcomes

The cycle characteristics, the ovulation and pregnancy rate

Notes

Ethical approval: this study was approved by Ethical Committee of Mashhad University of Medical Sciences.

Informed consent: a written informed consent was taken from all women participating in this study.

Source of funding: not reported

Power calculation: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 participant was excluded from analysis due to discontinuation of treatment.

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported.

Other bias

Low risk

None

Hassan 2017

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "This was a balanced, randomized (allocation ratio 1:1), parallel group study conducted in Cairo and Beni‐Suef University Hospitals from May 2013 to January 2015.“

Participants

Inclusion criteria: women included in the study had CC‐resistant PCOS, and were aged 20 – 40 years. PCOS was diagnosed according to the Rotterdam 2003 criteria. CC resistance was defined as failure of ovulation despite receiving 150 mg of CC for 5 days during successive menstrual cycles for 3 months.

Exclusion criteria: other causes of infertility, BMI> 35 kg/m², hyperprolactinaemia, allergy to FSH, and previous use of FSH or letrozole therapies.

Number of women randomised: 140, 70 to each group

Number of women analysed: 140, 70 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 3 women in the letrozole group and 2 women in the uFSH group were lost to follow‐up; intention‐to‐treat analysis was adopted in which these participants were considered anovulatory in the 3 cycles.

Number of centres: 2‐centre trial

Age (y): letrozole group 28.7 ± 6.2, uFSH group 30.0 ± 5.6

BMI (kg/m²): letrozole group 27.6 ± 4.1, uFSH group 27.2 ± 3.8

Duration of infertility (y): letrozole group 87.0 ± 2.1, uFSH group 5.2 ± 2.2

Country: Cairo University and Beni‐Suef University Hospitals, Egypt

Interventions

Group A: quote: "group 1 received letrozole (Femara VR, Novartis, Basel, Switzerland) 2.5 mg twice daily for five days starting from the third day of menstruation or progesterone withdrawal bleeding."

Group B: quote: "group 2 received uFSH (Fostimon VR IBSA, Geneva, Switzerland). To minimize the risk of multiple pregnancy and OHSS, we used a low‐dose FSH setup regimen. The starting daily dose of uFSH was 75 IU for seven days starting from the third day of menstruation or progesterone withdrawal bleeding. If the follicular diameter did not exceed 9 mm, the daily dose was increased by 37.5 IU every seven days. The cycle was cancelled if no follicles exceeded 9 mm by four weeks after starting FSH."

Outcomes

Cumulative clinical pregnancy, defined as the presence of an intrauterine gestational sac 5 weeks after timed intercourse

Secondary outcomes were ovulation, miscarriage and possible drug side effects, i.e. OHSS, headache, dizziness, hot flushes, nausea, vomiting or constipation

Notes

Ethical approval: the study was approved by the research ethics committees of both institutions.

Informed consent: written informed consent was obtained

Source of funding: quote: "The study was self‐funded"

Power calculation: quote: "The required sample size was estimated using PS Power and Sample Size Calculations software, version 3.0.11 for Microsoft Windows. We needed to study 64 women receiving letrozole and 64 women receiving uFSH for three cycles to be able to reject the null hypothesis that the pregnancy rates for letrozole and uFSH in CC‐resistant women were equal, with a probability (power) of 0.9."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

An independent individual generated the allocation sequence using computer‐generated random numbers

Allocation concealment (selection bias)

Low risk

Allocation was concealed using sequentially‐numbered opaque sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants randomised were also analysed

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

None

Hendawy 2011

Methods

Randomised controlled clinical trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: quote: "infertile patients (defined as one year of unprotected coitus without conception in patients who have never conceived before) with PCOS, aged younger than 35 years, and attending the infertility out‐ patient clinic at Ain Shams University Hospital and/or a local private outpatient setting. Diagnosis of PCOS was based on the Rotterdam criteria (2003 ESHRE/ ASRM consensus), whereby patients diagnosed with PCOS require the presence of two of three criteria, i.e., oligomenorrhoea and/or anovulation, clinical and/ or biochemical signs of hyperandrogenism, and/or polycystic ovaries on ultrasound. All patients had a history of failed induction of ovulation with appropriately timed intercourse at least 4–6 times."

Exclusion criteria: women with infertility due to uterine and tubal pathologies or male factor

Number of women randomised: 60 women with primary infertility

Number of women analysed: 54 women were analysed, 28 in group 1 (letrozole) and 26 in group 2 (clomiphene citrate)

Number of withdrawals/exclusions/loss to follow‐up and reasons: during folliculometry, 2 participants in Group 1 and 4 participants in Group 2 showed no follicular response and were excluded from the study.

Number of centres: 2‐centre trial

Age (y): group 1 included 30 women aged 21 – 34 (mean ± SD, 27.2 ± 5.18) years, group 2 included 30 women aged 20 – 33

BMI (kg/m²): group 1 included 30 women with a BMI of 24 – 31 (26.2 ± 1.8). Group 2 included 30 women with a BMI of 23 – 32 (29.1 ± 2.3)

Duration of infertility (y): mean duration of infertility not reported

Country: Egypt

Interventions

Group A: group 1 included 30 women who were given letrozole (Femara®, Novartis, Basel, Switzerland) orally at a dose of 2.5 mg once daily on days 3 – 7 of the menstrual cycle.

Group B: group 2 included 30 women who were given clomiphene citrate (Clomid®, Sano Aventis, France) 50 mg orally twice daily on days 3 – 7 of the menstrual cycle.

Outcomes

Pregnancy rate, multiple pregnancy rate, number of follicles on hCG administration day, endometrial thickness

Notes

Ethical approval: the study was approved by the medical ethics committee of Ain Shams University Hospital.

Informed consent: Informed consent was obtained from all participants

Source of funding: not reported

Power calculation: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomised using a computer‐generated programme

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

double‐blind randomised, but not reported how blinding was achieved

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

double‐blind randomised, but not reported how blinding was achieved

Incomplete outcome data (attrition bias)
All outcomes

Low risk

6/60 participants were lost to follow‐up

Selective reporting (reporting bias)

Unclear risk

No study protocol was found

Other bias

Unclear risk

None

Ibrahim 2017

Methods

Randomised controlled trial

Duration of the trial: quote: "The study was conducted during the period from 1st August 2015 to 30th March 2016.“

Participants

Inclusion criteria: quote: "age >20 and <35 years old, patients were diagnosed to have PCOS criteria of diagnosis of PCO. Normal HSG and their partners had normal semen analysis according to WHO criteria (WHO, 2010) and CC‐resistant. If patients fail to respond to 150 mg/day for 5 days for 3 consecutive cycles, they are considered as CC‐resistant."

Exclusion criteria: quote: "Age less than 20 yr or more than 35 yr, non‐PCOS, and those Patients with poor ovarian reserve i.e. hyperprolactinaemia, hypo and hyperthyroidism, diabetic patients and Cushing’s syndrome were excluded, non‐classical congenital adrenal hyperplasia, current or previous (within the last 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, antidiabetic or antiobesity drugs, or other hormonal drugs, any subject was affected by either neoplastic, metabolic, hepatic, or cardiovascular disorder or other concurrent medical illness (i.e. diabetes, renal disease, or malabsorptive disorders) were excluded, pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility, tubal infertility and male factor infertility were excluded with a hysterosalpingogram and with semen analysis, respectively."

Number of women randomised: 80 women, 40 within each group

Number of women analysed: 80 women, 40 within each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: none

Number of centres: single‐centre trial

Age (y): LOD group 28.8 ± 3.1 vs let group 29.7 ± 3.7

BMI (kg/m²): LOD group 29.1 ± 1.6, letrozole group 29.2 ± 1.7

Duration of infertility (y): no mean ± SD reported

Country: Egypt

Interventions

Group A: quote: "In group A, laparoscopy was performed under intravenous general anaesthesia with the patient in a supine position. A 5 mm incision was made in the navel, through which a long sheath punctured into the abdominal cavity, and the inflatable pneumoperitoneum was placed. Another two 5‐mm incisions were made on the right and left lower abdomen and the surgical instruments were inserted into the abdominal cavity. The patient was adjusted into a position with the head high up, the pelvic organs were exposed and a comprehensive exploration of the pelvic organs was made, focusing on the structure and position of the adjacent organs of the bilateral ovaries. Once immobilized, each ovary was cauterized at 4–6 points, using a monopolar electrosurgical needle, according to the size of each ovary. Following cauterization, a bilateral tubal hydrotubation with methylene blue was performed. During the procedure. The pelvis was irrigated using physiological saline. Ringer’s solution plus dexamethasone was added into the abdominal cavity to avoid adhesion. The total duration of the procedure, as well as any intra‐operative or post‐operative complications, was noted."

Group B: quote: "In group B, 2.5 mg twice daily LE oral tablets were administered on the 3rd day of menses and then every day for 5 days.

Treatment was repeated for up to six cycles if the patient failed to ovulate, the patients were followed‐up for 6 months after the treatment in both groups."

Outcomes

Pregnancy rate, abortion rate, ovulation, regular cycles, ovarian volume, antral follicle count (AFC)

Notes

Ethical approval: This study was approved by Minia University Ethical Committee

Informed consent: quote: “Informed consent was obtained from all participating women after the nature and purpose of the study had been explained to them and were fully understood”

Source of funding: quote: “We have not received any funding from any corporate body or pharmaceutical company. “

Power calculation: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was achieved via the use of a randomisation number allocated prior to dosing, once eligibility had been determined, and a randomisation schedule was produced by an interactive voice response system vendor."

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants were not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Once the patients had been allocated to one of the two groups, the treatment was revealed to the investigator; however, the doctor responsible for performing the transvaginal ultrasound follow up assessment was blinded to the treatment groups."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women randomised were also analysed.

Selective reporting (reporting bias)

Unclear risk

We found no reporting of outcomes in a study protocol or Methods section

Other bias

Low risk

None

Kamath 2010

Methods

Randomised double‐blind placebo‐controlled trial

Duration and location of the trial: quote: "This trial was conducted in a university teaching hospital between 2007 and 2009.“

Participants

Inclusion criteria: women with PCOS and clomiphene resistance who were being treated with ovulation induction. Additionally, women had to have a normal hormone profile and a male partner with normal semen parameters by WHO criteria. Normal hormone profile was defined as a FSH level of < 12 IU/L, serum prolactin level of < 25 ng/mL, and a thyroid‐stimulating hormone (TSH) value between 0.3 and 4.5 µIU/mL.

Exclusion criteria: women with other endocrine disorders such as Cushing syndrome, and congenital adrenal hyperplasia

Number of centres: 1, Reproductive Medicine Unit, Christian Medical College, Vellore, Tamil Nadu, India

Number of women randomised: 18 in each group

Number of women analysed: 17 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 2 lost to follow‐up before treatment started

Age (y): group A letrozole: 25.6 ± 3.6, group B placebo: 25.7 ± 3.7

BMI (kg/m²): group A letrozole: 26.1 ± 3.7, group B placebo: 24.7 ± 4.2

Duration of infertility (y): group A letrozole: 5.2 ± 3.2, group B placebo: 3.6 ± 2.2

Country: India

Interventions

Group A: letrozole, orally given 2.5 mg/day for 5 days from cycle days 2 ‐ 6

Group B: placebo, also given for 5 days from cycle days 2 ‐ 6

Outcomes

Primary Outcome: ovulation rate

Secondary Outcomes: live birth rate, OHSS rate, pregnancy rate, miscarriage rate, multiple pregnancy rate, endometrial thickness (mm), day 21 serum progesterone (nmol/L), number of participants with mature follicle (%)

Notes

Ethical approval: yes, the protocol of the study was approved by the institutional review board

Informed consent: yes, written informed consent was obtained from each participant

Source of funding: not stated

Conflicts of interest: quote: "The Authors have nothing to disclose"

Power calculation: quote: "Our literature pointed to a 75% ovulation rate when 2.5 mg of letrozole was used in women with PCOS who had clomiphene resistance. We hypothesized an ovulation rate of 60& with letrozole and 10% with placebo. On this basis, a sample size of 17 women in each arm (80% and alpha .05 for a two‐sided test) was calculated."

Contacted authors about OHSS rate and how randomisation and allocation concealment were done in detail. All information provided

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomly distributed using a computer‐generated randomisation sequence in blocks of 6, into 2 groups.

Allocation concealment (selection bias)

Low risk

Allocation concealment was done by using consecutively‐numbered sealed opaque envelopes containing the treatment packets.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The randomisation code was maintained by the pharmacy department, which revealed the group assignments at the end of the trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The code was revealed after the statistical analysis had been performed.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1 women in each group was lost to follow‐up, after randomisation and before treatment started.

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

None

Kar 2012

Methods

Randomised controlled trial

Duration of the trial: quote "The prospective randomized trial was conducted between July 2010 and July 2011.“

Participants

Inclusion criteria: quote: "PCOS was diagnosed according to Rotterdam criteria. All women were treatment‐naive i.e. had not undergone any significant treatment for infertility/ovulation induction earlier."

Exclusion criteria: quote: "Patients with hyperprolactinaemia, thyroid disorder, male factor, suspected tubal factor, endometriosis, unexplained infertility were not included in the study."

Number of centres: quote: "This study was conducted at a private hospital with a large gynaecological practice."

Number of women randomised: 103 women, 52 in the letrozole group and 51 in the CC group.

Number of women analysed: 103 women, 52 in the letrozole group and 51 in the CC group.

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 26.3 ± 2.4, group B CC: 26.3 ± 2.5

BMI (kg/m²): group A letrozole: 25.9 ±3.6, group B placebo: 26.0 ± 3.3

Duration of infertility (y): group A letrozole: 3.1 ± 1.9, group B CC: 3.1 ± 2.2

Country: India

Interventions

Group A: letrozole, 5 mg/day orally given for 5 days from cycle days 2 ‐ 6

Group B: clomiphene citrate, 100 mg/day orally given for 5 days from cycle days 2 ‐ 6

Outcomes

Primary outcomes: ovulation rate, endometrial thickness, mono vs. multi‐follicular rate, and days to ovulation.

Secondary outcomes: pregnancy and miscarriage rate

Notes

Ethical approval: yes, quote: "Study protocol was approved by the institutional ethics committee."

Informed consent: not stated.

Source of funding: quote: "Nil"

Power calculation: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomised by lottery"

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

None

Legro 2014

Methods

Randomised double‐blind multicentre trial

Duration of the trial: quote: "Enrollment began in February 2009 and was completed in January 2012.“

Participants

Inclusion criteria: women with PCOS defined by the Rotterdam criteria and at least 1 patent fallopian tube and normal uterine cavity, and a male partner with sperm concentration of > 14 million/mL

Exclusion criteria: quote: "We will exclude subjects with medical conditions that represent contraindications to CC,letrozole and/or pregnancy or who are unable to comply with the study procedures."

Number of centres: multicentre trial

Number of women randomised: 750, 374 in the letrozole group and 376 in the CC group

Number of women analysed: 750, 374 in the letrozole group and 376 in the CC group

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 29 ± 5, group B CC: 28 ± 4

BMI (kg/m²): group A letrozole: 35 ± 10, group B CC: 35 ± 9

Duration of infertility (y): not reported

Country: USA

Interventions

Group A: letrozole, orally given 2.5 mg/day for 5 days during cycle days 3 ‐ 7

Group B: clomiphene citrate, orally given 100 mg/day for 5 days during cycle days 3 ‐ 7

Outcomes

Live birth, ovulation rate, clinical pregnancy rate, miscarriage rate, multiple pregnancy rate

Notes

Ethical approval: quote:"The institutional review board at each centre approved the protocol, and all participants (women and their male partners) gave written informed consent."

Informed consent: quote: "The institutional review board at each centre approved the protocol, and all participants (women and their male partners) gave written informed consent."

Source of funding: quote: "The study is funded through a cooperative agreement by the Eunice Kennedy ShriverNational Institutes of Child Health and Human Development (NICHD)"

Power calculation: a sample size of 300 subjects in each arm of the randomisation yields 81% statistical power to prospectively demonstrate a 0.10 absolute difference in live birth proportions between treatment arms (0.20 for CC and 0.30 for letrozole) using the Pearson’s Chi2 test with a 2‐sided significance level of 0.05

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Almac statisticians will generate the randomisation scheme for the study."

Allocation concealment (selection bias)

Low risk

Third‐party allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "In order to maintain the double‐blind, CC and letrozole will be over encapsulated and packaged in identically appearing numbered study kits (using AlmacClinical Services, Durham NC) which will then be directly shipped to each clinical site."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "In order to maintain the double‐blind, CC and letrozole will be over encapsulated and packaged in identically appearing numbered study kits (using AlmacClinical Services, Durham NC) which will then be directly shipped to each clinical site. The randomisation scheme (including block size) will be disclosed to the DCC data manager, but not to any RMN investigators or staff, including the Protocol Lead Investigator."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts were reported

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

None

Liu 2015

Methods

Randomised controlled clinical trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: quote: "the women were diagnosed with PCOS based on the Revised 2003 Consensus Diagnostic Criteria for PCOS. Clomiphene resistance, i.e. failure to ovulate following 100 mg CC for 5 days for at least three cycles; patent fallopian tubes, confirmed by hysterosalpingography or hysteroscopic diagnosis; normal semen analysis parameters of the patients' spouses according to the modified criteria of the World Health Organization (14); normal serum prolactin, thyroid stimulating hormone and 17‑OH progesterone; no systemic disease; no gonadotropin or other hormonal drug treatment during the preceding 3 months; normal blood count and blood chemistry, including glutamic‑pyruvic transaminase, glutamic‑oxaloacetic transaminase, urea nitrogen, creatinine, glucose and urine analysis. The semen of the patients' spouses was tested to strengthen the comparability between the two groups. During the period of treatment, all patients were requested to follow a normal diet and rest regime and to avoid intense physical activities in any form and mental stress and fatigue."

Exclusion criteria: infertility induced by reasons other than PCOS; uterine cavity lesions or ovarian cyst; > 40 years old; BMI > 26 kg/m2; contraindications to general anaesthesia; history of pelvic surgery; other endocrine diseases; or a history of liver or kidney disease

Number of women randomised: 141 women were randomly assigned, 71 to group A (letrozole) and 70 to group B (LOD)

Number of women analysed: all women randomised were also analysed

Number of withdrawals/exclusions/loss to follow‐up and reasons: none

Number of centres: single‐centre trial

Age (y): letrozole group 29.5 ± 3.3, LOD group 28.1 ±3.6

BMI (kg/m²): letrozole group 22.5 ± 1.5, LOD group 22.4 ± 2.1

Duration of infertility (y): letrozole group 3.4 ± 0.4, LOD group 3.2 ± 0.7

Country: China

Interventions

Group A: quote: "In group A, 2.5 mg LE oral tablets (Adooq Bioscience, Nanjing, China) were administered on the fifth day of menses and then every day for 5 days. Treatment was repeated for up to six cycles if the patient failed to conceive."

Group B: quote: "In group B, laparoscopy was performed under intravenous general anaesthesia (Diprivan; AstraZeneca S.p.A., Rome, Italy) with the patient in a supine position. A 5‑mm incision was made in the navel, through which a long sheath punctured into the abdominal cavity, and the inflatable pneumoperitoneum (Guangxi University, Yuannan, China) was placed. Another two 5‑mm incisions were made on the right and left lower abdomen and the surgical instruments were inserted into the abdominal cavity. The patient was adjusted into a position with the head high up, the pelvic organs were exposed and a comprehensive exploration of the pelvic organs was made, focusing on the structure and position of the adjacent organs of the bilateral ovaries. Once immobilized, each ovary was cauterized at 4‑6 points, each for 4 sec at 40 W, at a depth of 7‑8 mm and a diameter of 3‑5 mm, using a monopolar electrosurgical needle (Kirgen Co., Shanghai, China), according to the size of each ovary. Following cauterization, a bilateral tubal hydrotubation with methylene blue was performed. During the procedure, small pieces of the ovaries were obtained for pathological analysis. The pelvis was irrigated using physiological saline. Ringer's solution (ZiQi Bioscience, Shanghai, China) plus dexamethasone was added into the abdominal cavity to avoid adhesion. The total duration of the procedure, as well as any intra‑operative or post‑operative complications, was noted. The patients were followed‑up for 6 months after the procedure."

Outcomes

Live birth rate, OHSS, clinical pregnancy was defined by a fetal heart beat monitored by ultrasound at 6 weeks of gestation.

Biochemical pregnancy was considered when hCG was > 2.5 mIU/ml in the absence of menstruation.

Ovulation rate, endometrial thickness in mm, synchronous cycles, mean follicular diameter, spontaneous abortion rate, multiple pregnancy rate

Notes

Ethical approval: this study was approved by Tongji Hospital Research Ethics Committee (Shanghai, China)

Informed consent: all participants provided informed consent prior to inclusion in the trial.

Source of funding: the present study was supported by the Shanghai Natural Science Foundation (grant no. 12ZR1434200).

Power calculation: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The women were randomly allocated into the either the letrozole or LOD group (groups A and B, respectively)."

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "Once the patients had been allocated to one of the two groups, the treatment was revealed to the investigator; however, the doctor responsible for performing the transvaginal ultrasound follow‑up assessment was blinded to the treatment groups."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Once the patients had been allocated to one of the two groups, the treatment was revealed to the investigator; however, the doctor responsible for performing the transvaginal ultrasound follow‑up assessment was blinded to the treatment groups."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women randomised were also analysed

Selective reporting (reporting bias)

Unclear risk

All expected outcomes were reported

Other bias

Unclear risk

None

Liu 2017

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "PCOS patients attending the outpatient department of the hospital between April 2012 and March 2014, who had a desire for childbearing and fulfilled the Rotterdam diagnostic criteria as well, were recruited for this study.“

Participants

Inclusion criteria: quote: "PCOS patients attending the outpatient department of the hospital between April 2012 and March 2014, who had a desire for childbearing and fulfilled the Rotterdam diagnostic criteria as well, were recruited for this study. The inclusion criteria for this study were as follows: (1) patency of at least one side of the fallopian tube and (2) normal spouse’s sperm."

Exclusion criteria: quote:"The exclusion criteria were as follows: (1) patients with gynaecologic tumours or genital tract malformations, (2) patients with severe systemic disease or acute and chronic urogenital tract infections, (3) patients with other endocrine diseases such as thyroid disease and adrenal disease, (4) body mass index (BMI)>30, and (5) age over 35 years or below 20 years."

Number of women randomised: 268 women

Number of women analysed: Unknown if all 268 or only 240 were analysed

Number of withdrawals/exclusions/loss to follow‐up and reasons: 28 women left the study; 13 in the CC groups, 15 in the LE groups; 5 in the CC + met and 7 in the LE + met group left the study due to complications; 3 participants were excluded (no reasons reported), the rest were lost to follow‐up

Number of centres: single‐centre trial

Age (y): group A (CC) 26.8 ± 3.1; group B (CC + met) 27.2 ± 2.8; group C (letrozole) 27.0 ± 3.0; group D (letrozole + met) 27.2 ± 3.3

BMI (kg/m²): group A (CC) 21.1 (19.9, 22.8); Group B (CC + met) 21.4 (19.8, 23.6); group C (letrozole) 20.8 (19.1, 22.3); group D (letrozole + met) 21.6 (19.2, 23.6)

Duration of infertility (y): group A (CC) 1 (0, 2); group B (CC + met) 1 (0, 3); group C (let) 1 (0, 2); group D (let + met) 1 (0, 3)

Country: China

Interventions

Group A: the oral administration of CC was started in the group CC or CC + met from day 3 to day 5 of the menstrual cycle at a daily dose of 50 mg for 5 days; and the daily dose gradually increased to 100 mg or 150 mg at maximum in the next cycle if the undeveloped follicle (< 16 mm) was present in the previous cycle.

Group B: The oral administration of letrozole started in the group letrozole or letrozole + met from day 3 to day 5 of the menstrual cycle at a daily dose of 5 mg for 5 days.

Additional met (1000 – 1500 mg/d) was orally administered to participants in the groups CC + met and letrozole + met.

Outcomes

Ovulation rate, pregnancy rate, live birth rate, miscarriage rate, premature delivery, OHSS, multiple pregnancy rate

Notes

Ethical approval: the study was approved by the ethics committee of the West China Second University Hospital, Sichuan University, China (approval No. Medical Research 2012 No. 004), and the study was registered in the Chinese Clinical Trial Registry Center (registration No. ChiCTR‐TRC‐11001821).

Informed consent: informed consent was obtained from each participant.

Source of funding: self‐supported by West China Women's and Children's Hospital S.C.U

Power calculation: ovulation rate as the main indicator, the sample size was calculated by introducing maximal and minimal ovulation rate retrieved in literatures into the formula

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation with computer‐generated blocks

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

28 of 268 women left the study (> 10%)

Unknown if all 268 or only 240 were analysed

Selective reporting (reporting bias)

Low risk

All outcomes expected were reported

Other bias

Low risk

None

Moussa 2016

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "Three hundred and thirty seven infertile women with anovulatory (PCOS) were recruited from the outpatient clinics of both 6th October and Bab Elshaaria University Hospitals from August 2014 and January 2015.“

Participants

Inclusion criteria: infertile women with anovulatory (PCOS), age between 20 and 35 years, BMI between 18 and 30 kg/m2, normal uterus and patent tubes by hysterosalpingography, normal semen analysis and normal serum prolactin

Exclusion criteria: women with endocrinal disturbance, active liver disease, local disease as hydro‐ or pyosalpinx, and history of previous ovarian surgery

Number of women randomised: 150 women

Number of women analysed: 150 women were analysed, 50 within each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: none

Number of centres: 2‐centre trial

Age (y): group A: 27.5 ± 4.1, group B: 27.2 ± 3.9, group C: 27.5 ± 4.1

BMI (kg/m²): group A: 26.9 ± 1.7, group B: 26.8 ± 1.7, group C: 26.7 ± 1.5

Duration of infertility (y): group A: 1.9 ± 0.7, group B: 1.9 ± 0.7,and group C: 2.2 ± 0.7

Country: Egypt

Interventions

Each of the 3 groups received 2 tablets for 5 days starting from day 3 ‐ day 7 of the cycle

Group A: 100 mg (50 mg/tablet) clomiphene citrate

Group B: 5 mg (2.5 mg/tablet) letrozole

Group C: 40 mg (20 mg/tablet) tamoxifen

Outcomes

Primary outcomes: endometrial thickness and endometrial blood flow (PI and RI)

Secondary outcomes: development and number of follicles, and the pregnancy rate

Notes

Ethical approval: the study was approved by the ethical committee of Al Azhar University.

Informed consent: not reported

Source of funding: authors declare that they have neither conflict of interest nor received financial support.

Power calculation: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The patients were prospectively randomised into three groups each containing fifty patients by computer"

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants randomised were also analysed

Selective reporting (reporting bias)

Unclear risk

We found no study protocol

Other bias

Low risk

None

Nazik 2012

Methods

A partly‐randomised controlled clinical trial.

Duration and location of the trial: not stated

Participants

Inclusion criteria: infertile women with PCOS,  diagnosis based on the 2003 Rotterdam criteria

Exclusion criteria: women with ovarian or adnexal surgery, hypothyroidism, hyperprolactinaemia, bilateral tubal occlusion diagnosed with hysterosalpingography and unexplained infertility, and those with follicles greater than 10 mm

Number of centres: 1, infertility polyclinic of Atatürk University Medical Faculty Erzurum

Number of women randomised: 31 in group A, 33 in group B

Number of women analysed: 31 in group A, 33 in group B

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 25.6 ± 4.5, group B CC: 27.8 ± 6.2

BMI (kg/m²): group A letrozole: 24.7 ± 3.6, group B CC: 24.9 ± 4.8

Duration of infertility (y): group A letrozole: 3.4 ± 3.0, group B CC: 4.4 ± 3.6

Country: Turkey

Interventions

Group A: letrozole, orally given 2.5 mg/day for 5 days during cycle days 3 ‐ 7

Group B: clomiphene citrate, orally given 100 mg/day for 5 days during cycle days 3 ‐ 7

Outcomes

Primary Outcomes: ovulation rate and pregnancy rate

Secondary Outcomes: ovarian hyperstimulation syndrome rate, miscarriage rate, multiple pregnancy rate, number of follicles on day of hCG (≥ 17 mm), E2 (pg/mL) on hCG day, endometrial thickness (mm), other side effects

Notes

Ethical approval: yes, quote: “Ethical approval was obtained from the institutional review board of Atatürk University Medical Faculty in order to conduct this study.”

Informed consent: quote: "Instead of written consent verbal approval was obtained from the patients prior to study begin and treatment" ‐ correspondence with Dr. Hakan Nazik

Source of funding: quote: "This study was done by researchers without any funding"

Power calculation: not stated

All questions were answered by Dr. Hakan Nazik

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “The patients were randomly allocated using a computer random list into first and second groups”

Allocation concealment (selection bias)

Unclear risk

Quote: “The patients were randomly allocated using a computer random list into first and second groups”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "There was no blinding in our study" (email with Dr. Hakan Nazik)

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "There was no blinding in our study" (email with Dr. Hakan Nazik)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

High risk

Participants in Group 2 letrozole were significantly younger and had a significantly shorter duration of infertility.

Ramezanzadeh 2011

Methods

Randomised controlled trial

Duration and location of the trial: quote: "The study was conducted in the infertility clinic of a tertiary referral centre (Vali‐E‐asr Hospital–Tehran University of Medical Sciences) as a randomized controlled trial, between March 2009 and February 2010.“

Participants

Inclusion criteria: women with PCOS with infertility who underwent ovulation induction and timed intercourse for the first time. PCOS was diagnosed by the Rotterdam 2003 criteria. Participants were < 35 years old with at least 1 year of infertility with no other infertility factor.

Exclusion criteria: ovarian cysts on cycle day 3 found by transvaginal ultrasound examination.

Number of centres: 1, an infertility clinic of a tertiary referral centre

Number of women randomised: 80; group A letrozole 5 mg: 40, group B letrozole 7.5 mg: 40

Number of women analysed: group A letrozole 5 mg: 30, group B letrozole 7.5 mg: 37

Number of withdrawals/exclusions/loss to follow‐up and reasons: 4 excluded in group A due to a cyst before treatment, 6 lost to follow‐up in group A and 3 lost to follow‐up in group B

Age (y): group A letrozole 5 mg: 28.3 ± 5.0, group B letrozole 7.5 mg: 28.2 ± 4.5

BMI (kg/m²): group A letrozole 5 mg: 25.9 ± 4.2, group B letrozole 7.5 mg: 26.7 ± 3.6

Duration of infertility (y): group A letrozole 5 mg: 3.6 ± 2.3, group B letrozole 7.5 mg: 4.7 ± 3.2

Country: Iran

Interventions

Group A: letrozole orally given, 5 mg/day for 5 days from cycle days 3 ‐ 7

Group B: letrozole orally given, 7.5 mg/day for 5 days from cycle days 3 ‐ 7

Outcomes

Number and size of follicles and endometrial thickness on days 12 ‐ 14, the number of days to reach mature follicle, day 7 testosterone level, day 21 progesterone level, ovulation rate, pregnancy rate, miscarriage rate, multiple pregnancy rate, ovarian hyperstimulation syndrome rate

Notes

Ethical approval: yes, the hospital research ethics board approved the study.

Informed consent: all participants gave informed consent before inclusion in trial.

Source of funding: not stated

Conflicts of interest: quote: “Conflict of interest: All of the authors do not have any conflict of interest”

Power calculation: quote: "Using PASS software and based on two previous studies, a sample size of 30 subjects in each group would provide 80% power to detect a significant difference in the number of mature follicles and duration of stimulation between two groups with a significant level of 0.05."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated using computer‐generated random table into 2 letrozole treatment groups.

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

High risk

4 participants excluded due to ovarian cyst on day 3 sonography. 9 participants lost to follow‐up, 6 from group A and 3 from group B, without reasons given

Selective reporting (reporting bias)

Low risk

All outcomes reported.

Other bias

Low risk

None

Ray 2012

Methods

Comparative randomised phase III open‐labelled trial

Duration and location of the trial: quote: "A comparative, prospective, phase III, open labelled trial study was conducted in the Eden Hospital, Medical College Kolkata between January 2008 and December 2009.“

Participants

Inclusion criteria: infertile women aged 20 ‐ 35 with PCOS diagnosis based on the Rotterdam criteria 2003

Exclusion criteria: women with hyperprolactinaemia, thyroid disorder, male‐factor infertility, known or suspicious tubal‐factor infertility (endometriosis and pelvic inflammatory disease). Also women with a history of liver and kidney failure, cardiovascular diseases, diabetes, or women who consumed metformin or drugs affecting insulin secretion or CC in the previous 2 months

Number of centres: 1, Eden Hopsital, Mecial College Kolkata

Number of women randomised: 147; group A letrozole: 69, group B CC: 78

Number of women analysed: group A letrozole: 69, group B CC: 78

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 28 (19 ‐ 35), group B CC: 29 (20 ‐ 35)

BMI (kg/m²): group A letrozole: 28.8 (23.2 ‐ 34.6), group B CC: 28.5 (24.2 ‐ 33.6)

Duration of infertility (y): group A letrozole: 2.2, group B CC: 2.4 (SD or range not given)

Country: India

Interventions

Group A: letrozole, 2.5 mg/day given orally for 5 days from cycle day 3 ‐ 7

Group B: clomiphene citrate, 100 mg/day given orally for 5 days from cycle day 3 ‐ 7

Outcomes

Primary Outcomes: ovulation rate, average follicular diameter on day 16, number of mature follicles produced by cycle, mean estradiol level on the day of hCG administration, mean endometrial thickness, pregnancy rate

Secondary Outcomes: miscarriage rate, live birth rate

Notes

Ethical approval: yes, the study protocol was approved by the ethical committee of Medical College Kolkata

Informed consent: yes, participants were counselled and informed consent was obtained before recruitment

Source of funding: quote: “Conflict of interest: the authors hereby declare that they have not received any financial support for this study and there is no conflict of interest.”

Power calculation: not stated

We contacted Dr. Ray by email about randomisation, allocation, blinding, MPR and OHSS, but he did not respond.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Unclear how randomisation was done

Allocation concealment (selection bias)

Unclear risk

Unclear how allocation was done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported if anyone was blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported if anyone was blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No participants stated as lost, but 147 participants is an odd number to start with, and so are the groups of 69 and 78 respectively; authors contacted for protocol

Selective reporting (reporting bias)

Unclear risk

All expected outcomes were reported, but contacted authors for protocol

Other bias

Low risk

None

Roy 2012

Methods

Randomised clinical trial

Duration and location of the trial: quote: "This prospective randomized controlled trial was performed at a tertiary care hospital from January 2005 to January 2010.“

Participants

Inclusion criteria: women aged 20 ‐ 35 years having infertility for > 1 year, BMI < 28, and with anovulatory PCOS based on the Rotterdam 2003 criteria

Exclusion criteria: quote: "in all patients, a comprehensive infertility work‐up was done. This included a tubal patency test, pelvic ultrasonography, husband semen analysis, and serum hormone measurements (FSH, LH, prolactin, estradiol, progesterone, and testosterone) on the 2nd to 5th day of the cycle. Patients having abnormality in any of these tests, which may be responsible for reproductive failure, were excluded from the study."

Number of centres: 1, a tertiary care hospital in India

Number of women randomised: 212 women; group A let: 104, group B CC: 108

Number of women analysed: letrozole group: 98, clomiphene group: 106

Number of withdrawals/exclusions/loss to follow‐up and reasons: 8 lost to follow‐up

Age (y): group A letrozole: 26.1 ± 1.8, group B CC: 26.5 ± 1.3

BMI (kg/m²): group A letrozole: 25.8 ± 2.1, group B CC: 25.4 ± 1.6

Duration of infertility (y): group A letrozole: 6.4 ± 3.8, group B CC: 5.8 ± 3.1

Country: India

Interventions

Group A: letrozole, orally given in doses of 2.5 mg/day and 5 mg/day for 5 days during cycle days 3 ‐ 7

Group B: clomiphene citrate, orally given in doses of 50 mg/day and 100 mg/day for 5 days during cycle days 3 ‐ 7

Treatment was continued for 3 months.

Outcomes

The mean number of follicles, endometrial thickness, ovulatory cycle rate, conception rate, pregnancy outcome, miscarriage rate, multiple pregnancies and OHSS rate

Notes

Ethical approval: yes, the necessary ethical approval was taken from Institutional Review Board to conduct this study.

Informed consent: yes, the participants were counselled, and informed consent was taken before randomisation.

Source of funding: quote: “Source of support: Nil, Conflict of interest: None declared.”

Power calculation: quote: "On basis of previous studies, to achieve a statistically valid comparison of pregnancy rates in the two groups, with a type I error of 0.05 and a power of 80%, a sample size of at least 40 women in each arm was required."

We contacted Dr. Roy by email to get additional information, but he did not respond.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Online software was used to generate a random number table (www.randomization.com).

Allocation concealment (selection bias)

Unclear risk

Quote: "Randomisation codes (A, B) were packed into sealed opaque envelopes by an individual not involved in enrolment, treatment and follow‐up of subjects to ensure concealment of allocation. One resident had the responsibility for dispensing the trial drugs to the patient based on the unique randomisation code. At the end of allocation, the resident provided us with a randomisation list."

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

8 losses to follow‐up of 112 participants

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

None

Selim 2012

Methods

Randomised controlled trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: diagnosis of PCOS based on Rotterdam criteria provided that anovulation is 1 of the 2 required criteria

Exclusion criteria: quote: "exclusion criteria included hyperprolactinaemia, congenital adrenal hyperplasia, thyroid disease, other causes of amenorrhoea such as premature ovarian failure, and clinically suspected Cushing’s syndrome or androgen‐secreting neoplasm. Exclusion criteria also included all women who had received metformin or ovarian drilling in the previous 6 months. Other causes of infertility were excluded by documentation of a normal uterine cavity and at least one patent fallopian tube, and each woman’s current partner had a semen concentration of at least 2 · 107/mL."

Number of centres: not reported

Number of women randomised: 220; group A letrozole: 110, group B CC: 110

Number of women analysed: group A letrozole: 102, group B CC: 99

Number of withdrawals/exclusions/loss to follow‐up and reasons: quote: "In the letrozole group, eight women were excluded because of missed follow‐up visits (three women), treatment suspension (two women), and homogenous not triple‐line endometrial pattern (three women). In the CC group, 11 women were excluded because of missed follow‐up visits (four women), treatment suspension (two women), and homogenous not triple‐line endometrial pattern (five women)."

Age (y): group A letrozole: 26.0 ± 2.7, group B CC: 25.1 ± 3.1

BMI (kg/m²): group A letrozole: 24.4 ± 4.3, group B CC: 23.8 ± 3.7

Duration of infertility (y): group A letrozole: 2.9 ± 0.6, group B CC: 2.6 ± 0.7

Country: Saudi Arabia

Interventions

Group A: 110 participants treated with 5 mg/day of letrozole (Femara; Novartis, Switzerland) in 2 divided doses from cycle day 3 ‐ 7

Group B: 110 participants treated with 100 mg/day of CC (Clomid; Sanofi Aventis, France) in 2 divided doses from cycle day 3 ‐ 7

Outcomes

quote: "The mean number of follicles, endometrial thickness, the Doppler study of endometrial and sub endometrial vasculatures, ovulation rate, and pregnancy rate were compared in both groups."

Notes

Ethical approval: quote: "approval was obtained from the Institutional Review Board of Jeddah Clinic Hospital, Jeddah, Saudi Arabia."

Informed consent: yes, quote: "all participants gave verbal and written informed consent."

Source of funding: not stated

Conflicts of interest: quote: “No competing financial interests exist.”

Power calculation: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were randomly allocated to the letrozole group or CC group by means of a series of blind envelopes numbered from 1 to 220.

Allocation concealment (selection bias)

Low risk

Each participant was invited to choose an envelope and was placed by the clinic secretary in either the letrozole group or the CC group.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The patients were not blinded about the treating drug in either group."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

To remove any inter‐observational bias, ultrasound on all participants was demonstrated by a single observer (MF Selim) who was blinded to the treating drug.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All dropouts were reported, reasons given.

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported.

Other bias

Low risk

None

Seyedoshohadaei 2016

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "This double blind clinical trial study was conducted on 100 PCOS infertile women who have not responded to initial treatment, referring to the Infertility Center of Sanandaj Besat Hospital from June 2014 to December 2015.“

Participants

Inclusion criteria: PCOS infertile women who have not responded to initial treatment. PCOS was confirmed by Rotterdam criteria (menstrual disturbances: oligomenorrhoea or amenorrhoea, clinical or biochemical hyperandrogenism and sonographic findings of polycystic ovaries). Women with 2 of the 3 PCOS criteria were included in the study.

Exclusion criteria: women with hyperprolactinaemia, thyroid problems and anatomical problem in uterus cavity and fallopian tubes confirmed by hysterosalpangiography, sonohysterography or laparoscopy were excluded from the study.

Number of women randomised: 100 women, 50 to each group

Number of women analysed: 100 women, 50 in each group

Number of withdrawals/exclusions/loss to follow‐up and reasons: none

Number of centres: single centre

Age (y): group A (CC + EV) 30.3 ± 3.1; group B (letrozole) 29.6 ± 5.1

BMI (kg/m²): not reported

Duration of infertility (y): group A (CC + EV) 3.4 ± 2.8; group B (letrozole) 3.9 ± 2.4

Country: Iran

Interventions

Group A: 100 mg clomiphene citrate (Iran Hormone Pharmaceutical Company) from day 3 ‐ day 7 of menstruation and 4 mg estradiol valerate (Aburaihan Pharmacy Company) after the 8th day of menstruation until 14th day

Group B: 5 mg letrozole (Iran Hormone Pharmaceutical Company) from day 3 ‐ 7 of menstruation with placebo from 8th ‐ 14th day of menstruation

Outcomes

Pregnancy rate, outcome of pregnancy, live birth, miscarriage rate, endometrial thickness

Notes

Ethical approval: quote: "This study was approved by the Ethics Committee of Kurdistan University of Medical Sciences and has been registered in the Iranian Registry of Clinical Trials with registration number IRCT2015052612789N11."

Informed consent: quote: "Written consent was taken before the intervention."

Source of funding: quote: "Authors would like to thank Vice Chancellor for Research of Kurdistan University of Medical Sciences to support the study financially. "

Power calculation: quote: "The sample size was calculated based on previous studies. Considering the mean of endometrial thickness, 5% type I error and 20% type II error, 45 patients were required in each group. To compensate for possible loss and increase the power of the study, 50 patients were studied in each group."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Women were block‐randomised and divided in 2 groups

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "To blind the study, transvaginal sonography was performed by a fellow of infertility, the medication was prescribed by a gynaecologist and the patients in group B received placebo."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "To blind the study, transvaginal sonography was performed by a fellow of infertility, the medication was prescribed by a gynaecologist and the patients in group B received placebo."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All women randomised were also analysed

Selective reporting (reporting bias)

Unclear risk

No study protocol was found

Other bias

Low risk

None

Sh‐El‐Arab Elsedeek 2011

Methods

Randomised controlled double‐blind trial

Duration and location of the trial: not stated

Participants

Inclusion criteria: diagnosis of PCOS based on Rotterdam criteria provided that anovulation is 1 of the 2 required criteria

Exclusion criteria: exclusion criteria were BMI > 35, presence of other causes of infertility, > 5 years infertility duration and known poor response to either drugs in previous cycles. Cases found to have baseline ovarian cysts or endometrial pathology were also excluded.

Number of centres: 1, an infertility unit of a university hospital

Number of women randomised: 124; group A letrozole: 62, group B CC: 62

Number of women analysed: group A letrozole: 59, group B CC: 57

Number of withdrawals/exclusions/loss to follow‐up and reasons: 3 in the letrozole and 5 in the CC group were reported as lost to follow‐up, but no further explanation given

Age (y): group A letrozole: 25.0 ± 3.1, group B CC: 25.0 ± 3.6

BMI (kg/m²): group A letrozole: 27.7 ± 3.5, group B CC: 29.2 ± 3.5

Duration of infertility (y): Not reported

Country: India

Interventions

Group A: letrozole, 5 mg/day orally given for 5 days, cycle days not given

Group B: clomiphene citrate, 100 mg/day orally given for 5 days, cycle days not given

Outcomes

Pregnancy rate, ovulation rate, endometrial thickness (mm), mid‐luteal progesterone level (ng/mL), number of follicles ≥ 12 mm

Notes

Ethical approval: yes, institutional review board (IRB) approval was obtained for the study.

Informed consent: yes, informed consent was taken from all included cases

Source of funding: not reported, also no conflicts of interest given.

Power calculation: not stated

We contacted Dr. Sheik‐el‐Arab Elsedeek by email about allocation concealment, blinding of outcome assessors, information on live birth, miscarriage rate, OHSS, multiple pregnancies and funding/COI, but he did not respond.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomised using computer generated tables to undergo one cycle of CC or let induction."

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated if personnel were blinded and how the participants were blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "Both patients and sonographers were blinded to this allocation." ‐ Unclear if the other outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

8 participants lost to follow‐up, reasons unknown

Selective reporting (reporting bias)

Unclear risk

Only pregnancy was reported; we contacted the authors to get study protocol.

Other bias

Low risk

None

Sharief 2015

Methods

Randomised controlled clinical trial

Duration and location of the trial: quote: "The prospective clinical trial was conducted at Basrah Maternity and Child Hospital, Basrah, Iraq, between January 2012 and April 2013, and comprised women with PCOS and primary infertility.“

Participants

Inclusion criteria: quote: "Women with PCOS and primary infertility. The subjects were selected from among those who were attending the infertility centre with primary infertility, which was defined as inability of a couple to obtain pregnancy after 1‐2 years of unprotected intercourse. All subjects were diagnosed as having anovulation due to PCOS. PCOS was diagnosed when the ultrasonographic (USG) findings of the ovaries were >10 follicles 2‐8 mm in diameter scattered either around or through an echodense thickened central stroma. In addition, there had to be one or more of the following: oligomenorrhoea, positive progesterone, withdrawal bleeding, hirsutism/acne, obesity, and Luteinizing hormone/Follicle‐stimulating hormone (LH/FSH) ratio >2 or raised circulating androgen, normal thyroid stimulating hormone (TSH). Those included were aged between 18 and 36 years, period of infertility was more than 2 years, serum prolactin level was normal, serum FSH <12u/L, normal thyroid function, and hirsutism, which was diagnosed when the Ferriman and Gallwey score was >8.9 Besides, the male partners had to have a normal seminal analysis by World Health Organisation (WHO) criterion."

Exclusion criteria: all women having had patent tubes by either hysterosalpingogram or laparoscopy, history of pelvic surgery with tubal blockage were excluded from the study.

Number of women randomised: not stated how many participants were randomised

Number of women analysed: 75 women were analysed, 40 in group A, 35 in group B

Number of withdrawals/exclusions/loss to follow‐up and reasons: not stated

Number of centres: single centre

Age (y): group A 25.3 ± 2.1 years, group B 26.1 ± 1.3 years

BMI (kg/m²): group A 27.8 ± 1.7, group B 28.1 ± 1.9

Duration of infertility (y): group A 2.3 ± 0.4, group B 2.4 ± 0.6

Country: Iraq

Interventions

Group A: clomiphene citrate for 6 months with a dose between 100 ‐ 200 mg for 5 days beginning on day 3 of the menstrual cycle

Group B: letrozole 2.5 ‐ 5 mg daily for 5 days starting from the 3rd day of a spontaneous or progesterone‐induced menstrual bleeding

Outcomes

Pregnancy rate, multiple pregnancies, follicular development,N of follicles, serum E2 on day of HCG, endometrial thickness, ovulation rate

Notes

Ethical approval: approval was obtained from the ethical committee of the College of Medicine, University of Basrah, Iraq.

Informed consent: not reported if informed consent was obtained

Source of funding: not reported

Power calculation: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The patients were randomised into two groups."

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not reported how many women were randomised in first instance

Selective reporting (reporting bias)

Unclear risk

No study protocol was found

Other bias

Low risk

None

Sohrabvand 2006

Methods

Single‐blinded randomised clinical trial

Duration and location of the trial: quote: "In this single‐blind randomized clinical trial, 120 ovarian cycles were studied in 60 clomiphene‐resistant patients with PCOS, who were chosen among 115 PCOS patients attending the infertility clinic of Vali‐e‐Asr Hospital (Tehran, Iran) during the years 2003–2004.“

Participants

Inclusion criteria: women with PCOS who had failed to become pregnant after 3 courses of 150 mg clomiphene citrate (considered as clomiphene‐resistant), whereas the values of hormonal tests were normal. Tests: thyroid function, prolactin level, hysterosalpingography and husband’s sperm analysis

Exclusion criteria: women with a history of liver and kidney failure, cardiovascular disease, diabetes (based on criteria set by the American Diabetic Association) or women who consumed metformin or drugs affecting insulin secretion or clomiphene citrate in the previous 2 months

Number of centres: 1, infertility clinic of Vali‐e‐Asr Hospital, Tehran

Number of women randomised: 60; group A met‐letrozole: 30, group B met‐CC: 30

Number of women analysed: group A met‐letrozole: 29, group B met‐CC: 30

Number of withdrawals/exclusions/loss to follow‐up and reasons: 1 because she got pregnant after met treatment before letrozole was started

Age (y): group A met‐letrozole: 28.2 ± 3.1 , group B met‐CC: 29.6 ± 3.5

BMI (kg/m²): group A met‐letrozole: 30.0 ± 4.8, group B met‐CC: 30.2 ± 3.9

Duration of infertility (y): group A met‐letrozole: 3.8, group B met‐CC: 3.8

Country: Iran

Interventions

Group A: metformin 500 mg x 3/d for 6 ‐ 8 weeks. If pregnancy did not occur, 2.5 mg letrozole from cycle days 3 ‐ 7 was given orally.

Group B: metformin 500 mg x 3/d for 6 ‐ 8 weeks. If pregnancy did not occur, 100 mg CC from cycle days 3 ‐ 7 was given orally.

Treatment was continued for 2 cycles.

Outcomes

Endometrial thickness on day of hCG administration (cm), N of follicles > 18 mm in diameter, Mean total estradiol level on day of hCG administration (pM/L), mean estradiol level by mature follicle (pM/l), regular menses after metformin, adverse effects of metformin, live birth rate, pregnancy rate, miscarriage rate

Notes

Ethical approval: yes, consent from the deputy of research and the medical ethics committee of Tehran University of Medical Sciences

Informed consent: not obtained because quote: “it was the routine treatment protocol and it was just put in the frame of a structured study” (email with Dr Farnaz Sohrabvand)

Source of funding: quote: "No funding was necessary" (email with Dr Farnaz Sohrabvand)

Power calculation: not stated

Authors were contacted about live birth, multiple pregnancies, OHSS per woman randomised, informed consent, funding. No data available on live birth, multiple pregnancies and OHSS. Information retrieved about informed consent and funding (email with Dr Farnaz Sohrabvand)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A series of blind envelopes numbered from 1 to 60 had been prepared. Each patient was invited to pull out an envelope and was placed by the clinic secretary in either the metformin‐letrozole group (number 1‐30) or in the metformin‐CC group (31‐60)."

Allocation concealment (selection bias)

Unclear risk

Quote: "A series of blind envelopes numbered from 1 to 60 had been prepared. Each patient was invited to pull out an envelope and was placed by the clinic secretary in either the metformin‐letrozole group (number 1‐30) or in the metformin‐CC group (31‐60)."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants were not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

It is not plausible that outcome assessors were blinded if participants were not

Incomplete outcome data (attrition bias)
All outcomes

Low risk

One participant was excluded due to pregnancy after start of metformin treatment

Selective reporting (reporting bias)

Low risk

All outcomes were reported

Other bias

Low risk

None

Wu 2016

Methods

Randomised clinical trial

Duration of the trial: quote: "The trial was started on October 2009. Owing to the expiration of the study drug (berberine and matching placebo), the data safety and monitoring board decided to stop enrollment in November 2013“

Participants

Inclusion criteria: quote: "Chinese women with PCOS attempting to get pregnant were eligible if they fulfilled the following criteria: 1) age 20–40 years; 2) diagnosis of PCOS according to two of the three Rotterdam 2003 criteria, including oligo‐ovulation or anovulation, clinical and/or biochemical signs of hyperandrogenism, and/or polycystic ovaries; 3) at least one open fallopian tube and normal uterine cavity documented by hysterosalpingography, sonohysterography, or diagnostic laparoscopy within the past 3 years; 4) a male partner with sperm concentration of 15 million/mL and motility of 40% in at least one ejaculate; and 5) at least 1 year of infertility."

Exclusion criteria: quote: "Subjects were excluded if they used hormonal drugs or other medications, including Chinese herbal prescriptions, in the past 3 months; had known severe organ dysfunction or mental illness; were pregnant, post‐miscarriage, postpartum, or breastfeeding within the past 6 weeks; or had congenital adrenal hyperplasia, clinically suspected Cushing syndrome, or an androgen‐secreting neoplasm."

Number of women randomised: 644 women

Number of women analysed: 644 women were analysed, 215 in group A, 214 in group B, 215 in group C.

Number of withdrawals/exclusions/loss to follow‐up and reasons: 16/215 (7.4%) in the letrozole group, 25/214 (11.7%) in the berberine group, and 15/215 (7.0%) in the combination group (P = 0.16). Reasons for withdrawal were similar among the 3 groups (P = 0.16 for the 3 groups; P = 0.19 for lost to follow‐up; P = 0.88 for dropout; P = 1.0 for protocol violations; and P = 0.33 for adverse events).

Number of centres: multicentre trial, 19 hospitals

Age (y): group A 27.8 ± 3.6; group B 27.8 ± 3.7; group C 27.8 ± 3.6

BMI (kg/m²): group A 24.8 ± 4.5; group B 24.5 ± 4.1; group C 25.1 ± 5.0

Duration of infertility (months): group A 32.7 ± 24.0; group B 28.5 ± 21.6; group C 29.8 ± 21.3

Country: China

Interventions

Group A: 2.5 mg (1 tablet) of letrozole on days 3 – 7 of the first 3 treatment cycles. This dose was increased to 5 mg letrozole (2 tablets) or 2 tablets of letrozole placebo on days 3 – 7 of the last 3 treatment cycles if not pregnant

Group B: berberine was administered orally at a daily dose of 1.5 g for 6 months.

Group C: letrozole and berberine were administered in the same doses as reported above.

Outcomes

Cumulative live births, ovulation rate, conception rate, clinical pregnancy rate, multiple pregnancy rate, abortion rate, pregnancy complications, adverse events from study medications

Notes

Ethical approval: the Institutional Review Boards at participating hospitals approved the protocol.

Informed consent: every participant gave written informed consent.

Source of funding: supported by National Public Welfare Projects for Chinese Medicine (200807021) of China, National Key Discipline of Chinese Medicine in Gynecolog, 2009–14, Heilongjiang Province Foundation for Outstanding Youths (JC200804), Intervention for Polycystic Ovary Syndrome Based on Traditional Chinese Medicine Theory–‘‘TianGui Shi Xu’’ (2011TD006), and National Clinical Research Base in Chinese Medicine, 2009–14, at First Affiliated Hospital, Heilongjiang University of Chinese Medicine. The funding sources had no involvement in the study design, the collection, analysis, and interpretation of data, the writing of the report, or in the decision to submit the article for publication.

Power calculation: the sample size calculation was based on anticipated live birth rate.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomisation was performed through a web‐based computer program (http://210.76.97.192:8080/cjbyj) operated by an independent data coordinating centre, the Institute of Basic Clinical Medicine of the China Academy of Chinese Medical Sciences. The randomisation was stratified by the participating sites."

Allocation concealment (selection bias)

Low risk

Randomisation was operated by an independent data co‐ordinating centre

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, investigators, physicians taking care of the participants, laboratory technicians, and data analysers were blinded to the assignments.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Participants, investigators, physicians taking care of the participants, laboratory technicians, and data analysers were blinded to the assignments.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

7% – 12% were lost to follow‐up, had protocol violations or adverse events. ITT analysis was performed.

Selective reporting (reporting bias)

Low risk

None, study protocol was published prior to participant enrolment in the study

Other bias

Low risk

None

Zarei 2015

Methods

Randomised controlled clinical trial

Duration of the trial: quote: "They underwent intra uterine insemination (IUI) between August 2011 and December 2012.“

Participants

Inclusion criteria: quote: "patients with CC‐resistant PCOS. According to Rotterdam criteria, patients with at least 2 out of 3 of below criteria were included as a PCOS: 1‐ Chronic anovulation, 2‐ Clinical and/or biochemical evidence of hyperandrogenism and 3‐ polycystic appearance of ovaries in Transvaginal Ultrasound (TVS) Moreover, infertility was defined as failure to conceive despite having unprotected and frequent intercourse for at least 1 year. CC‐resistance was considered as absence of ultrasound evidence regarding ovarian response consumption of 150mg of CC between the 5th and the 9th day of menstruation cycle for three consecutive cycles. All participants had a documented normal blood test, renal function test, liver function test, hysterosalpingography (HSG) and negative pregnancy test before the study. The partners should have at least two semen analyses. According to WHO, a normal semen analysis should have these properties: Sperm concentration ≥15 million/ml, total sperm count ≥39 million, mobility rate >40%, progressive motility ≥32% and normal morphology ≥ 4% ."

Exclusion criteria: women with breast cancer, renal and liver diseases, autoimmune problems and endocrinological problems such as diabetes, hyperprolactinaemia, thyroid diseases, Cushing’s syndrome and smokers were excluded from the study.

Number of women randomised: 140 women

Number of women analysed: 131 women were analysed, 67 patients in control group and 64 cases in letrozole group.

Number of withdrawals/exclusions/loss to follow‐up and reasons: quote: "during this study, we eliminated 6 patients from the control group, 4 fell out of the study and 2 were finally diagnosed for OHSS. Three patients were also eliminated from the letrozole group; one fell out of the study protocol and 2 due to OHSS."

Number of centres: single‐centre trial

Age (y): aged 18 ‐ 35: control group: 27.7 ± 1.8, letrozole group: 27.9 ± 1.9

BMI (kg/m²): control group: 25.6 ± 3.2, letrozole group: 25.1 ± 4.4

Duration of infertility (y): control group: 5.4 ± 1.9 , letrozole group: 5.0 ± 3.0

Country: Shiraz, Iran

Interventions

Group A: control group. 75 IU/day highly purified recombinant FSH (Gonal‐f, Serono, Hellas, Puregon, Greece) intramuscularly, from the 3rd day through the day of HCG injection

Group B: letrozole group additionally received 5 mg/day letrozole (Razak Drug Laboratory, Tehran, Iran) since the 8th day of cycle up to the day of HCG injection.

Outcomes

Premature LH surge, pregnancy rate, abortion rate, ongoing pregnancy rate, N of follicles > 18 mm, endometrial thickness (mm)

Notes

Ethical approval: not reported

Informed consent: not reported

Source of funding: not reported.

Power calculation: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

quote: "In this study, 140 cases with PCOS resistant to CC were enrolled and divided into two groups of control (n=70) and letrozole (n=70)."

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "During this study, we eliminated 6 patients from the control group, 4 fell out of the study and 2 were finally diagnosed for OHSS. Three patients were also eliminated from the letrozole group; one fell out of the study protocol and 2 due to OHSS. Thus, 67 patients (age ranges 18‐39 years) remained in control group and 64 cases (age ranges 21‐37 years) remained in letrozole group."

Selective reporting (reporting bias)

Unclear risk

Unclear; Quote: "This trial was registered in Islamic Republic Clinical Trials Database (IRCT2014010615102N2)."

We were unable to find the protocol, because the given trial registry number leads to a study protocol for pain medication after rhinoplastic surgery.

Other bias

High risk

Methods not very well described, Clinical trial registration number leads to wrong trial.

Zeinalzadeh 2010

Methods

Randomised controlled trial

Duration and location of the trial: quote: "This clinical trial was performed on 107 infertile patients with PCOS who were referred to Fatemeh Zahra Infertility Center, Babol, Iran, in 2006 and 2007.“

Participants

Inclusion criteria: women with primary infertility, documented PCOS, age < 35 years, < 5 years infertility and BMI between 19 and 26. PCOS was defined on the basis of ultrasonography findings, oligomenorrhoea and an increased luteinising hormone (LH)/follicle‐stimulating hormone (FSH) ratio (> 3).

Exclusion criteria: moderate or severe case of OHSS during trial, infertility resulting from male factors, tubular factors and endometriosis.

Number of centres: 1, Fatemeh Zahra Infertility Center, Babol

Number of women randomised: 107; group A letrozole: 50, group B CC: 57

Number of women analysed: 107; group A letrozole: 50, group B CC: 57

Number of withdrawals/exclusions/loss to follow‐up and reasons: 0

Age (y): group A letrozole: 23.8 ± 3.6, group B CC: 23.1 ± 3.6

BMI (kg/m²): not reported

Duration of infertility (y): group A letrozole: 2.4 ± 1, group B CC: 2.6 ± 1.2

Country: Iran

Interventions

Group A: 5 mg letrozole from cycle days 3 ‐ 7 was given orally.

Group B: 100 mg CC from cycle days 3 ‐ 7 was given orally.

Outcomes

Ovulation rate, pregnancy rate, number of follicles > 17mm, OHSS rate, multiple pregnancy rate, endometrial thickness.

Notes

Ethical approval: yes, "The study protocol was approved by the ethics committee of Babol Medical University."

Informed consent: yes, "All the patients signed a written consent form as to be enrolled in the study"

Source of funding: no, but "Financial disclosure: The authors have no connection to any companies or products mentioned in this article”

Power calculation: not stated

We contacted authors for additional information, but they did not respond.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The participants were assigned to two groups using systematic randomisation method"

Allocation concealment (selection bias)

Unclear risk

Not stated

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not stated

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts reported

Selective reporting (reporting bias)

Low risk

All expected outcomes were reported

Other bias

Low risk

None

BMI: body mass index; CC: clomiphene citrate; FSH: follicle‐stimulating hormone; hCG: human chorionic gonadotropin; hMG: human menopausal gonadotropin; LH: luteinising hormone; LOD: laparoscopic ovarian drilling; OHSS: ovarian hyperstimulation syndrome; PCOS: polycystic ovary syndrome; s: seconds; SD: standard deviation; TSH: thyroid‐stimulating hormone; W: watts; y: year

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Akbari 2012

No PCOS

Al‐Hussaini 2014

Only short conference abstract; we did not find a published study article. We were unable to retrieve any information from study authors.

Al‐Shaikh 2017

Not a RCT

Angel 2014

RCT, but not about women with PCOS

Anwary 2012

Not a RCT

Azargoon 2012

Not a RCT

Azmoodeh 2015

No PCOS

Badawy 2009c

Not a RCT

Baruah 2009

Quasi‐randomised trial (quote: "Based on attendance order, patients with odd numbers were given letrozole and those with even numbers were given CC")

El Bigawy 2008

Quasi‐randomised trial

Foroozanfard 2013

Not randomised for clomiphene or letrozole

Khanna 2013

Not a RCT, no PCOS

Li 2016

Not randomised for letrozole

Mittal 2004

Not a RCT

Nahid 2012

Suspected quasi‐randomisation based on attendance order

NCT00610077

No published data found, last updated on clinicaltrials.gov in 2008. No response from study authors.

NCT01315912

Not a RCT

NCT01431352

For the 2018 update, there was no update on clinicaltrials.gov. No study data available, and no response from authors.

NCT01577017

No study results found, unable to obtain more information from study authors

NCT01679574

Study should be finished. We contacted authors by email found through Google because no contact information was written in the study protocol: [email protected].

For the 2018 update, there was no update on clinicaltrials.gov and still no response from the author.

NCT01793038

Unable to obtain information from study authors. No study data found, no update on clinicaltrials.gov.

Ozdemir 2013

RCT, but not about women with PCOS

Pakrashi 2014

Not randomised for letrozole

Palihawadana 2015

Women with PCOS were excluded from the study

Pourali 2017

Women with PCOS were excluded from the study

Sarvi 2010

Not randomised for letrozole

Sharma 2010

Only conference abstract available, full article could not be found. Contact address of authors unknown

Xi 2015

Not a RCT

Yang 2008

Not a RCT (Quote: "the allocation depended on the patients' choice" ‐ translated by Prof Taixiang Wu)

Yun 2015

Not a RCT

Characteristics of studies awaiting assessment [ordered by study ID]

Aygen 2007

Methods

Randomised clinical study

Participants

15 infertile women with polycystic ovarian syndrome

Interventions

Women were randomised into 3 treatment groups:

In group 1, continuous metformin was used at the dose of 850 mg/tid/day for 6 months; afterwards, daily 2.5 mg letrozole between 3 and 7 days of the menstrual cycle was added to the metformin therapy.

Group 2 participants received only daily 2.5 mg letrozole between days 3 and 7 of the menstrual cycle.

Group 3 participants received daily 100 mg clomiphene citrate only between days 3 and 7 of the menstrual cycle.

Outcomes

Unclear

Notes

The article was written in Turkish, and we were not able to have it translated properly.

Lorzadeh 2011

Methods

Randomised clinical trial

Participants

100 infertile women with PCOS referred to Asali Hospital and private clinic in 2008

Interventions

The women were randomised into 2 groups of 50 that were treated with 5 mg letrozole or 100 mg clomiphene citrate from day 3 to 7 of the menstrual cycle.

Outcomes

Outcomes: Pregnancy rate

Notes

The article was written in Persian, but we were not able to have it translated properly.

NCT02551367

Methods

Randomised controlled trial

Participants

110 infertile women diagnosed as polycystic ovary syndrome (PCOS) aged 20 ‐ 35 distributed randomly

Interventions

55 women will receive letrozole 2.5 mg twice daily orally from the 2nd to the 6th day of the cycle for 3 successive cycles.

55 women will receive clomiphene citrate 50 mg twice daily orally from the 2nd to the 6th day of the cycle for 3 successive cycles.

Outcomes

  1. Rate of ovulation assessed by number of mature follicles produced per cycle.

  2. Serum progesterone level on day 21 ( assessed up to 24 weeks).

  3. Mean endometrial thickness ( assessed up to 24 weeks).

  4. Chemical pregnancy ( assessed up to 24 weeks).

  5. Ongoing pregnancy ( assessed up to 24 weeks).

Notes

We found no study data, although trial completed since 2016 on clinicaltrials.gov

Safdarian 2012

Methods

Double‐blind randomised clinical trial

Participants

59 infertile women who had the inclusion criteria for PCOS were evaluated in the Infertility Clinic of Shariati Hospital in Tehran, Iran in 2010 ‐ 2011.

Interventions

The participants were assigned to 2 letrozole and 1 letrozole‐plus‐HMG groups.

Outcomes

Reported no outcomes of interest to our review

Notes

The article was written in Persian, but we were not able to have it translated properly.

Shirin 2009

Methods

Randomised clinical trial, "Quote: The cases were assigned to two groups through simple random sampling"

Participants

100 infertile, 20 ‐ 35‐year‐old women with PCOS attending Vali‐e‐Asr Infertility Clinic from April 2003 to April 2007

Interventions

Group A received clomiphene citrate plus HMG, Group B received letrozole plus HMG

Outcomes

Outcomes: pregnancy, miscarriage and multiple pregnancy rates

Notes

The article was written in Persian, but we were not able to have it translated properly.

Characteristics of ongoing studies [ordered by study ID]

NCT03009838

Trial name or title

Letrozole versus laparoscopic ovarian drilling in polycystic ovary syndrome

Methods

Randomised, open‐label, clinical trial

Participants

Inclusion criteria:

  • History of at least 1 year of infertility, either primary or secondary

  • BMI: 25 ‐ 35

  • Normal fallopian tubes

  • Normal semen analysis of the husband

  • Women who will agree to participate in the study

Exclusion criteria:

  • BMI > 35

  • Contraindication to general anaesthesia

  • Previous laparoscopic drilling

  • Presence of other causes of infertility

  • Women who had received metformin, gonadotropin, oral contraceptives or other hormonal drugs during the preceding 6 months

  • Women who intended to start a diet programme

  • Women who refuse to participate in the study

Interventions

Group A: letrozole 2.5 mg

Group B: laparoscopic ovarian drilling

Outcomes

Ovulation rate

Starting date

January 2017

Contact information

Responsible party: Ahmed Mohamed Abbas, Assiut University

Notes

Estimated primary completion date: December 2018

Data and analyses

Open in table viewer
Comparison 1. Letrozole compared to placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

3.17 [0.12, 83.17]

Analysis 1.1

Comparison 1 Letrozole compared to placebo, Outcome 1 Live birth rate.

Comparison 1 Letrozole compared to placebo, Outcome 1 Live birth rate.

2 Ovarian hyperstimulation syndrome rate Show forest plot

2

167

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.05, 0.05]

Analysis 1.2

Comparison 1 Letrozole compared to placebo, Outcome 2 Ovarian hyperstimulation syndrome rate.

Comparison 1 Letrozole compared to placebo, Outcome 2 Ovarian hyperstimulation syndrome rate.

3 Clinical pregnancy rate Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

2.88 [1.08, 7.66]

Analysis 1.3

Comparison 1 Letrozole compared to placebo, Outcome 3 Clinical pregnancy rate.

Comparison 1 Letrozole compared to placebo, Outcome 3 Clinical pregnancy rate.

4 Miscarriage rate by woman randomised Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.26, 9.89]

Analysis 1.4

Comparison 1 Letrozole compared to placebo, Outcome 4 Miscarriage rate by woman randomised.

Comparison 1 Letrozole compared to placebo, Outcome 4 Miscarriage rate by woman randomised.

5 Miscarriage rate by pregnancies Show forest plot

1

20

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.07, 4.56]

Analysis 1.5

Comparison 1 Letrozole compared to placebo, Outcome 5 Miscarriage rate by pregnancies.

Comparison 1 Letrozole compared to placebo, Outcome 5 Miscarriage rate by pregnancies.

6 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 1.6

Comparison 1 Letrozole compared to placebo, Outcome 6 Multiple pregnancy rate.

Comparison 1 Letrozole compared to placebo, Outcome 6 Multiple pregnancy rate.

Open in table viewer
Comparison 2. Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

13

2954

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.42, 1.99]

Analysis 2.1

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 1 Live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 1 Live birth rate.

1.1 AIs versus clomiphene citrate

8

1646

Odds Ratio (M‐H, Fixed, 95% CI)

1.79 [1.42, 2.25]

1.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.60, 1.81]

1.3 Aromatase inhibitor + metformin compared to clomiphene + metformin

2

194

Odds Ratio (M‐H, Fixed, 95% CI)

1.70 [0.89, 3.23]

1.4 Aromatase inhibitor + FSH compared to clomiphene + FSH

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.53, 2.61]

1.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

1.48 [0.54, 4.06]

1.6 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

1.94 [1.33, 2.84]

2 Live birth rate by BMI Show forest plot

11

2774

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.42, 2.02]

Analysis 2.2

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 2 Live birth rate by BMI.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 2 Live birth rate by BMI.

2.1 BMI > 25

7

1678

Odds Ratio (M‐H, Fixed, 95% CI)

1.67 [1.34, 2.09]

2.2 BMI < 25

4

1096

Odds Ratio (M‐H, Fixed, 95% CI)

1.73 [1.31, 2.28]

3 Live birth rate by first‐ or second‐line treatment Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 2.3

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 3 Live birth rate by first‐ or second‐line treatment.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 3 Live birth rate by first‐ or second‐line treatment.

3.1 No previous ovulation induction

4

1089

Odds Ratio (M‐H, Fixed, 95% CI)

1.61 [1.22, 2.14]

3.2 CC‐resistant women

4

344

Odds Ratio (M‐H, Fixed, 95% CI)

1.78 [1.08, 2.93]

3.3 Unclear or mixed study cohort

5

1521

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.35, 2.16]

4 Impact of allocation bias for live birth rate Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 2.4

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 4 Impact of allocation bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 4 Impact of allocation bias for live birth rate.

4.1 Unclear risk of allocation

8

1031

Odds Ratio (M‐H, Fixed, 95% CI)

1.90 [1.42, 2.54]

4.2 Low risk of allocation

5

1923

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [1.29, 1.95]

5 Impact of detection bias for live birth rate Show forest plot

13

2954

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.42, 1.99]

Analysis 2.5

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 5 Impact of detection bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 5 Impact of detection bias for live birth rate.

5.1 High risk of detection

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

2.6 [0.83, 8.13]

5.2 Low risk of detection

7

2083

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [1.33, 1.99]

5.3 Unclear risk of detection

5

807

Odds Ratio (M‐H, Fixed, 95% CI)

1.76 [1.27, 2.44]

6 Impact of attrition bias for live birth rate Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 2.6

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 6 Impact of attrition bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 6 Impact of attrition bias for live birth rate.

6.1 Unclear risk of attrition

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

2.04 [0.93, 4.50]

6.2 Low risk of attrition

11

2539

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.41, 2.03]

6.3 High risk of attrition

1

268

Odds Ratio (M‐H, Fixed, 95% CI)

1.46 [0.85, 2.50]

7 Ovarian hyperstimulation syndrome rate Show forest plot

12

2536

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

Analysis 2.7

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 7 Ovarian hyperstimulation syndrome rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 7 Ovarian hyperstimulation syndrome rate.

7.1 AIs versus clomiphene citrate

9

2010

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

7.2 AI versus clomiphene + metformin

1

250

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.02, 0.02]

7.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.04, 0.04]

8 Ovarian hyperstimulation syndrome rate per BMI Show forest plot

11

Risk Difference (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 2.8

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 8 Ovarian hyperstimulation syndrome rate per BMI.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 8 Ovarian hyperstimulation syndrome rate per BMI.

8.1 BMI > 25

6

1851

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

8.2 BMI < 25

5

605

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.02, 0.02]

9 Clinical pregnancy rate Show forest plot

25

4629

Odds Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.78]

Analysis 2.9

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 9 Clinical pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 9 Clinical pregnancy rate.

9.1 AIs versus clomiphene citrate

17

2930

Odds Ratio (M‐H, Fixed, 95% CI)

1.50 [1.28, 1.76]

9.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.60, 1.71]

9.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.86 [1.05, 3.29]

9.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.82, 2.27]

9.5 AIs versus tamoxifen

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [0.64, 3.90]

9.6 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

2.47 [0.94, 6.46]

9.7 AIs ± berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

2.15 [1.48, 3.13]

10 Impact of allocation bias for clinical pregnancy rate Show forest plot

23

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 2.10

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 10 Impact of allocation bias for clinical pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 10 Impact of allocation bias for clinical pregnancy rate.

10.1 Unclear risk of allocation

16

1907

Odds Ratio (M‐H, Fixed, 95% CI)

1.77 [1.43, 2.18]

10.2 Low risk of allocation

7

1912

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [1.12, 1.65]

11 Miscarriage rate by woman randomised Show forest plot

18

3754

Odds Ratio (M‐H, Fixed, 95% CI)

1.39 [1.07, 1.81]

Analysis 2.11

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 11 Miscarriage rate by woman randomised.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 11 Miscarriage rate by woman randomised.

11.1 AIs versus clomiphene citrate

11

2190

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.97, 1.93]

11.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.25, 4.23]

11.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.52, 2.82]

11.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.31, 2.27]

11.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

12.21 [0.66, 226.97]

11.6 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [0.87, 3.04]

12 Miscarriage rate by pregnancies Show forest plot

18

1210

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.70, 1.26]

Analysis 2.12

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 12 Miscarriage rate by pregnancies.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 12 Miscarriage rate by pregnancies.

12.1 AIs versus clomiphene citrate

11

705

Odds Ratio (M‐H, Fixed, 95% CI)

0.96 [0.65, 1.42]

12.2 AI versus clomiphene + metformin

1

85

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.24, 4.40]

12.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.80 [0.32, 2.02]

12.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

104

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.23, 1.96]

12.5 AIs versus clomiphene + estradiol valerate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

8.13 [0.39, 167.90]

12.6 AIs +/‐ berberine versus berberine

1

213

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.43, 1.80]

13 Multiple pregnancy rate Show forest plot

17

3579

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.41, 1.16]

Analysis 2.13

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 13 Multiple pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 13 Multiple pregnancy rate.

13.1 AIs versus clomiphene citrate

13

2409

Odds Ratio (M‐H, Fixed, 95% CI)

0.61 [0.32, 1.16]

13.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 2.82]

13.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.29, 3.05]

13.4 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

4.53 [0.24, 84.46]

Open in table viewer
Comparison 3. Letrozole compared to clomiphene citrate, followed by IUI

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

2

1494

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

Analysis 3.1

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 1 Ovarian hyperstimulation syndrome rate.

1.1 AI versus Clomiphene

1

107

Risk Difference (M‐H, Fixed, 95% CI)

‐0.02 [‐0.07, 0.03]

1.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

2 Clinical pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.30, 2.25]

Analysis 3.2

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 2 Clinical pregnancy rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 2 Clinical pregnancy rate.

2.1 AI versus Clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

2.09 [0.97, 4.53]

2.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.23, 2.22]

3 Miscarriage rate by woman randomised Show forest plot

2

1490

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.62, 2.40]

Analysis 3.3

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 3 Miscarriage rate by woman randomised.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 3 Miscarriage rate by woman randomised.

3.1 AI versus Clomiphene

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.06]

3.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.66, 2.65]

4 Miscarriage rate by pregnancies Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.37, 1.57]

Analysis 3.4

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 4 Miscarriage rate by pregnancies.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 4 Miscarriage rate by pregnancies.

4.1 AI versus Clomiphene

1

15

Odds Ratio (M‐H, Fixed, 95% CI)

0.10 [0.00, 3.09]

4.2 AI versus Clomiphene +rFSH and rFSH only

1

245

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.40, 1.79]

5 Multiple pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.49, 2.13]

Analysis 3.5

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 5 Multiple pregnancy rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 5 Multiple pregnancy rate.

5.1 AI versus Clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

3.48 [0.14, 87.49]

5.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.44, 2.03]

Open in table viewer
Comparison 4. Letrozole compared to laparoscopic ovarian drilling

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

1.38 [0.95, 2.02]

Analysis 4.1

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 1 Live birth rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 1 Live birth rate.

2 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 4.2

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 2 Ovarian hyperstimulation syndrome rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 2 Ovarian hyperstimulation syndrome rate.

3 Clinical pregnancy rate Show forest plot

5

774

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.94, 1.74]

Analysis 4.3

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 3 Clinical pregnancy rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 3 Clinical pregnancy rate.

3.1 AI versus LOD

4

628

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.93, 1.83]

3.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.60, 2.39]

4 Miscarriage rate by woman randomised Show forest plot

5

774

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.38, 1.70]

Analysis 4.4

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 4 Miscarriage rate by woman randomised.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 4 Miscarriage rate by woman randomised.

4.1 AI versus LOD

4

628

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.29, 1.63]

4.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [0.29, 6.27]

5 Miscarriage rate by pregnancies Show forest plot

5

240

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.30, 1.43]

Analysis 4.5

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 5 Miscarriage rate by pregnancies.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 5 Miscarriage rate by pregnancies.

5.1 AI versus LOD

4

191

Odds Ratio (M‐H, Fixed, 95% CI)

0.54 [0.22, 1.33]

5.2 AI + metformin versus LOD

1

49

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.24, 6.09]

6 Multiple pregnancy rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

3.00 [0.12, 74.90]

Analysis 4.6

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 6 Multiple pregnancy rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 6 Multiple pregnancy rate.

Open in table viewer
Comparison 5. Letrozole compared to FSH

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 5.1

Comparison 5 Letrozole compared to FSH, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 5 Letrozole compared to FSH, Outcome 1 Ovarian hyperstimulation syndrome rate.

2 Clinical pregnancy rate Show forest plot

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.40, 1.67]

Analysis 5.2

Comparison 5 Letrozole compared to FSH, Outcome 2 Clinical pregnancy rate.

Comparison 5 Letrozole compared to FSH, Outcome 2 Clinical pregnancy rate.

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 5.3

Comparison 5 Letrozole compared to FSH, Outcome 3 Miscarriage rate by woman randomised.

Comparison 5 Letrozole compared to FSH, Outcome 3 Miscarriage rate by woman randomised.

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 5.4

Comparison 5 Letrozole compared to FSH, Outcome 4 Miscarriage rate by pregnancies.

Comparison 5 Letrozole compared to FSH, Outcome 4 Miscarriage rate by pregnancies.

5 Multiple pregnancy rate Show forest plot

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.12]

Analysis 5.5

Comparison 5 Letrozole compared to FSH, Outcome 5 Multiple pregnancy rate.

Comparison 5 Letrozole compared to FSH, Outcome 5 Multiple pregnancy rate.

Open in table viewer
Comparison 6. Letrozole compared to anastrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 6.1

Comparison 6 Letrozole compared to anastrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

2 Clinical pregnancy rate Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.51, 1.43]

Analysis 6.2

Comparison 6 Letrozole compared to anastrozole, Outcome 2 Clinical pregnancy rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 2 Clinical pregnancy rate.

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 6.3

Comparison 6 Letrozole compared to anastrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 6 Letrozole compared to anastrozole, Outcome 3 Miscarriage rate by woman randomised.

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 6.4

Comparison 6 Letrozole compared to anastrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 6 Letrozole compared to anastrozole, Outcome 4 Miscarriage rate by pregnancies.

5 Multiple pregnancy rate Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

5.0 [0.24, 105.35]

Analysis 6.5

Comparison 6 Letrozole compared to anastrozole, Outcome 5 Multiple pregnancy rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 5 Multiple pregnancy rate.

Open in table viewer
Comparison 7. Different administration protocols of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.1

Comparison 7 Different administration protocols of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 7 Different administration protocols of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

1.1 Five days compared to 10 days administration protocol of letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Clinical pregnancy rate Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.2

Comparison 7 Different administration protocols of letrozole, Outcome 2 Clinical pregnancy rate.

Comparison 7 Different administration protocols of letrozole, Outcome 2 Clinical pregnancy rate.

2.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Letrozole day 3‐7 administratio versus day 5‐9 administration

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.3

Comparison 7 Different administration protocols of letrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 7 Different administration protocols of letrozole, Outcome 3 Miscarriage rate by woman randomised.

3.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.4

Comparison 7 Different administration protocols of letrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 7 Different administration protocols of letrozole, Outcome 4 Miscarriage rate by pregnancies.

4.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 7.5

Comparison 7 Different administration protocols of letrozole, Outcome 5 Multiple pregnancy rate.

Comparison 7 Different administration protocols of letrozole, Outcome 5 Multiple pregnancy rate.

5.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 8. Dosage studies of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 8.1

Comparison 8 Dosage studies of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 8 Dosage studies of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

1.1 5mg vs 7.5mg letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 8.2

Comparison 8 Dosage studies of letrozole, Outcome 2 Clinical pregnancy rate.

Comparison 8 Dosage studies of letrozole, Outcome 2 Clinical pregnancy rate.

2.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 8.3

Comparison 8 Dosage studies of letrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 8 Dosage studies of letrozole, Outcome 3 Miscarriage rate by woman randomised.

3.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 8.4

Comparison 8 Dosage studies of letrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 8 Dosage studies of letrozole, Outcome 4 Miscarriage rate by pregnancies.

4.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 8.5

Comparison 8 Dosage studies of letrozole, Outcome 5 Multiple pregnancy rate.

Comparison 8 Dosage studies of letrozole, Outcome 5 Multiple pregnancy rate.

5.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Study flow diagram for update 2018
Figuras y tablas -
Figure 1

Study flow diagram for update 2018

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.1 Live birth rate.
Figuras y tablas -
Figure 4

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.1 Live birth rate.

Funnel plot of comparison: 2 Aromatase inhibitors compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.
Figuras y tablas -
Figure 5

Funnel plot of comparison: 2 Aromatase inhibitors compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, outcome: 2.1 Live birth rate.

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.6 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Figure 6

Forest plot of comparison: 2 Aromatase inhibitors compared to other ovulation induction agents, outcome: 2.6 Ovarian hyperstimulation syndrome rate.

Comparison 1 Letrozole compared to placebo, Outcome 1 Live birth rate.
Figuras y tablas -
Analysis 1.1

Comparison 1 Letrozole compared to placebo, Outcome 1 Live birth rate.

Comparison 1 Letrozole compared to placebo, Outcome 2 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 1.2

Comparison 1 Letrozole compared to placebo, Outcome 2 Ovarian hyperstimulation syndrome rate.

Comparison 1 Letrozole compared to placebo, Outcome 3 Clinical pregnancy rate.
Figuras y tablas -
Analysis 1.3

Comparison 1 Letrozole compared to placebo, Outcome 3 Clinical pregnancy rate.

Comparison 1 Letrozole compared to placebo, Outcome 4 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 1.4

Comparison 1 Letrozole compared to placebo, Outcome 4 Miscarriage rate by woman randomised.

Comparison 1 Letrozole compared to placebo, Outcome 5 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 1.5

Comparison 1 Letrozole compared to placebo, Outcome 5 Miscarriage rate by pregnancies.

Comparison 1 Letrozole compared to placebo, Outcome 6 Multiple pregnancy rate.
Figuras y tablas -
Analysis 1.6

Comparison 1 Letrozole compared to placebo, Outcome 6 Multiple pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 1 Live birth rate.
Figuras y tablas -
Analysis 2.1

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 1 Live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 2 Live birth rate by BMI.
Figuras y tablas -
Analysis 2.2

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 2 Live birth rate by BMI.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 3 Live birth rate by first‐ or second‐line treatment.
Figuras y tablas -
Analysis 2.3

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 3 Live birth rate by first‐ or second‐line treatment.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 4 Impact of allocation bias for live birth rate.
Figuras y tablas -
Analysis 2.4

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 4 Impact of allocation bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 5 Impact of detection bias for live birth rate.
Figuras y tablas -
Analysis 2.5

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 5 Impact of detection bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 6 Impact of attrition bias for live birth rate.
Figuras y tablas -
Analysis 2.6

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 6 Impact of attrition bias for live birth rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 7 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 2.7

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 7 Ovarian hyperstimulation syndrome rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 8 Ovarian hyperstimulation syndrome rate per BMI.
Figuras y tablas -
Analysis 2.8

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 8 Ovarian hyperstimulation syndrome rate per BMI.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 9 Clinical pregnancy rate.
Figuras y tablas -
Analysis 2.9

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 9 Clinical pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 10 Impact of allocation bias for clinical pregnancy rate.
Figuras y tablas -
Analysis 2.10

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 10 Impact of allocation bias for clinical pregnancy rate.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 11 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 2.11

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 11 Miscarriage rate by woman randomised.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 12 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 2.12

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 12 Miscarriage rate by pregnancies.

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 13 Multiple pregnancy rate.
Figuras y tablas -
Analysis 2.13

Comparison 2 Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse, Outcome 13 Multiple pregnancy rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 3.1

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 3.2

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 2 Clinical pregnancy rate.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 3.3

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 3 Miscarriage rate by woman randomised.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 3.4

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 4 Miscarriage rate by pregnancies.

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 3.5

Comparison 3 Letrozole compared to clomiphene citrate, followed by IUI, Outcome 5 Multiple pregnancy rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 1 Live birth rate.
Figuras y tablas -
Analysis 4.1

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 1 Live birth rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 2 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 4.2

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 2 Ovarian hyperstimulation syndrome rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 3 Clinical pregnancy rate.
Figuras y tablas -
Analysis 4.3

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 3 Clinical pregnancy rate.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 4 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 4.4

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 4 Miscarriage rate by woman randomised.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 5 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 4.5

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 5 Miscarriage rate by pregnancies.

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 6 Multiple pregnancy rate.
Figuras y tablas -
Analysis 4.6

Comparison 4 Letrozole compared to laparoscopic ovarian drilling, Outcome 6 Multiple pregnancy rate.

Comparison 5 Letrozole compared to FSH, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 5.1

Comparison 5 Letrozole compared to FSH, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 5 Letrozole compared to FSH, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 5.2

Comparison 5 Letrozole compared to FSH, Outcome 2 Clinical pregnancy rate.

Comparison 5 Letrozole compared to FSH, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 5.3

Comparison 5 Letrozole compared to FSH, Outcome 3 Miscarriage rate by woman randomised.

Comparison 5 Letrozole compared to FSH, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 5.4

Comparison 5 Letrozole compared to FSH, Outcome 4 Miscarriage rate by pregnancies.

Comparison 5 Letrozole compared to FSH, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 5.5

Comparison 5 Letrozole compared to FSH, Outcome 5 Multiple pregnancy rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 6.1

Comparison 6 Letrozole compared to anastrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 6.2

Comparison 6 Letrozole compared to anastrozole, Outcome 2 Clinical pregnancy rate.

Comparison 6 Letrozole compared to anastrozole, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 6.3

Comparison 6 Letrozole compared to anastrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 6 Letrozole compared to anastrozole, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 6.4

Comparison 6 Letrozole compared to anastrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 6 Letrozole compared to anastrozole, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 6.5

Comparison 6 Letrozole compared to anastrozole, Outcome 5 Multiple pregnancy rate.

Comparison 7 Different administration protocols of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 7.1

Comparison 7 Different administration protocols of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 7 Different administration protocols of letrozole, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 7.2

Comparison 7 Different administration protocols of letrozole, Outcome 2 Clinical pregnancy rate.

Comparison 7 Different administration protocols of letrozole, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 7.3

Comparison 7 Different administration protocols of letrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 7 Different administration protocols of letrozole, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 7.4

Comparison 7 Different administration protocols of letrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 7 Different administration protocols of letrozole, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 7.5

Comparison 7 Different administration protocols of letrozole, Outcome 5 Multiple pregnancy rate.

Comparison 8 Dosage studies of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.
Figuras y tablas -
Analysis 8.1

Comparison 8 Dosage studies of letrozole, Outcome 1 Ovarian hyperstimulation syndrome rate.

Comparison 8 Dosage studies of letrozole, Outcome 2 Clinical pregnancy rate.
Figuras y tablas -
Analysis 8.2

Comparison 8 Dosage studies of letrozole, Outcome 2 Clinical pregnancy rate.

Comparison 8 Dosage studies of letrozole, Outcome 3 Miscarriage rate by woman randomised.
Figuras y tablas -
Analysis 8.3

Comparison 8 Dosage studies of letrozole, Outcome 3 Miscarriage rate by woman randomised.

Comparison 8 Dosage studies of letrozole, Outcome 4 Miscarriage rate by pregnancies.
Figuras y tablas -
Analysis 8.4

Comparison 8 Dosage studies of letrozole, Outcome 4 Miscarriage rate by pregnancies.

Comparison 8 Dosage studies of letrozole, Outcome 5 Multiple pregnancy rate.
Figuras y tablas -
Analysis 8.5

Comparison 8 Dosage studies of letrozole, Outcome 5 Multiple pregnancy rate.

Summary of findings for the main comparison. Letrozole with or without adjuncts compared to clomiphene citrate (CC) with or without adjuncts for subfertile women with polycystic ovary syndrome

Letrozole with or without adjuncts compared to clomiphene citrate (CC) with or without adjuncts for subfertile women with polycystic ovary syndrome

Patient or population: subfertile women with polycystic ovary syndrome
Setting: fertility clinics
Intervention: letrozole with or without adjuncts followed by timed intercourse
Comparison: CC with or without adjuncts followed by timed intercourse

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with CC with or without adjuncts

Risk with letrozole with or without adjuncts

Live birth rate

214 per 1000

314 per 1000
(279 to 352)

OR 1.68
(1.42 to 1.99)

2954
(13 RCTs)

⊕⊕⊕⊝
Moderate a

Ovarian hyperstimulation syndrome rate

5 per 1000

5 per 1000
(5 to 5)

RD 0.00
(−0.01 to 0.00)

2536
(12 RCTs)

⊕⊕⊕⊕
High

Clinical pregnancy rate

264 per 1000

359 per 1000
(330 to 390)

OR 1.56
(1.37 to 1.78)

4629
(25 RCTs)

⊕⊕⊕⊝
Moderate b

Miscarriage rate by pregnancies

201 per 1000

191 per 1000
(150 to 240)

OR 0.94
(0.70 to 1.26)

1210
(18 RCTs)

⊕⊕⊕⊕
High

Multiple pregnancy rate

17 per 1000

13 per 1000
(7 to 21)

OR 0.69
(0.41 to 1.16)

3579
(17 RCTs)

⊕⊕⊕⊕
High

*The risk in the intervention group (and its 95% confidence interval) is based on the mean risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RD: Risk difference: OR: Odds ratio;

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded one level for serious risk of bias associated with potential selective reporting: Studies that reported live birth tended to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be less favourable to letrozole if all studies reported live birth.
bDowngraded one level for serious risk of publication bias: a funnel plot analysis strongly suggests that there might be more publications without a significant effect which were not published.

Figuras y tablas -
Summary of findings for the main comparison. Letrozole with or without adjuncts compared to clomiphene citrate (CC) with or without adjuncts for subfertile women with polycystic ovary syndrome
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for subfertile women with polycystic ovary syndrome

Letrozole compared to laparoscopic ovarian drilling compared to placebo for subfertile women with polycystic ovary syndrome

Patient or population: Subfertile women with polycystic ovary syndrome
Setting: Fertility clinics
Intervention: Letrozole with or without adjuncts followed by timed intercourse
Comparison: Laparoscopic ovarian drilling (LOD) followed by timed intercourse

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with LOD

Risk with letrozole

Live birth rate

236 per 1000

299 per 1000
(227 to 385)

OR 1.38
(0.95 to 2.02)

548
(3 RCTs)

⊕⊕⊕⊝
Low a,b

Ovarian hyperstimulation syndrome rate

0 per 1000

0 per 1000
(0 to 0)

RD 0.00
(−0.01 to 0.01)

260
(1 RCT)

⊕⊕⊝⊝
Low c

Clinical pregnancy rate

284 per 1000

336 per 1000
(271 to 408)

OR 1.28
(0.94 to 1.74)

774
(5 RCTs)

⊕⊕⊕⊝
Low a,b

Miscarriage rate by pregnancies

145 per 1000

101 per 1000
(49 to 196)

OR 0.66
(0.30 to 1.43)

240
(5 RCTs)

⊕⊕⊕⊝
Moderate a

Multiple pregnancy rate

0 per 1000

0 per 1000
(0 to 0)

OR 3.00
(0.12 to 74.90)

548
(3 RCTs)

⊕⊕⊝⊝
Low a,b

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RD: Risk difference; OR: Odds ratio;

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aInsufficient data to allow judgement of risk of bias in some studies ‐ downgraded one level for serious risk of bias.
bThere is insufficient data to determine if there is a difference as opposed to no evidence of a difference ‐ downgraded one level for imprecision.
cEvidence is based on a single study and there were no events, which may increase the likelihood of imprecision ‐ downgraded two levels.

Figuras y tablas -
Summary of findings 2. Letrozole compared to laparoscopic ovarian drilling for subfertile women with polycystic ovary syndrome
Comparison 1. Letrozole compared to placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

3.17 [0.12, 83.17]

2 Ovarian hyperstimulation syndrome rate Show forest plot

2

167

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.05, 0.05]

3 Clinical pregnancy rate Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

2.88 [1.08, 7.66]

4 Miscarriage rate by woman randomised Show forest plot

2

167

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.26, 9.89]

5 Miscarriage rate by pregnancies Show forest plot

1

20

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.07, 4.56]

6 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 1. Letrozole compared to placebo
Comparison 2. Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

13

2954

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.42, 1.99]

1.1 AIs versus clomiphene citrate

8

1646

Odds Ratio (M‐H, Fixed, 95% CI)

1.79 [1.42, 2.25]

1.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.60, 1.81]

1.3 Aromatase inhibitor + metformin compared to clomiphene + metformin

2

194

Odds Ratio (M‐H, Fixed, 95% CI)

1.70 [0.89, 3.23]

1.4 Aromatase inhibitor + FSH compared to clomiphene + FSH

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.53, 2.61]

1.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

1.48 [0.54, 4.06]

1.6 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

1.94 [1.33, 2.84]

2 Live birth rate by BMI Show forest plot

11

2774

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.42, 2.02]

2.1 BMI > 25

7

1678

Odds Ratio (M‐H, Fixed, 95% CI)

1.67 [1.34, 2.09]

2.2 BMI < 25

4

1096

Odds Ratio (M‐H, Fixed, 95% CI)

1.73 [1.31, 2.28]

3 Live birth rate by first‐ or second‐line treatment Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 No previous ovulation induction

4

1089

Odds Ratio (M‐H, Fixed, 95% CI)

1.61 [1.22, 2.14]

3.2 CC‐resistant women

4

344

Odds Ratio (M‐H, Fixed, 95% CI)

1.78 [1.08, 2.93]

3.3 Unclear or mixed study cohort

5

1521

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.35, 2.16]

4 Impact of allocation bias for live birth rate Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Unclear risk of allocation

8

1031

Odds Ratio (M‐H, Fixed, 95% CI)

1.90 [1.42, 2.54]

4.2 Low risk of allocation

5

1923

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [1.29, 1.95]

5 Impact of detection bias for live birth rate Show forest plot

13

2954

Odds Ratio (M‐H, Fixed, 95% CI)

1.68 [1.42, 1.99]

5.1 High risk of detection

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

2.6 [0.83, 8.13]

5.2 Low risk of detection

7

2083

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [1.33, 1.99]

5.3 Unclear risk of detection

5

807

Odds Ratio (M‐H, Fixed, 95% CI)

1.76 [1.27, 2.44]

6 Impact of attrition bias for live birth rate Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Unclear risk of attrition

1

147

Odds Ratio (M‐H, Fixed, 95% CI)

2.04 [0.93, 4.50]

6.2 Low risk of attrition

11

2539

Odds Ratio (M‐H, Fixed, 95% CI)

1.69 [1.41, 2.03]

6.3 High risk of attrition

1

268

Odds Ratio (M‐H, Fixed, 95% CI)

1.46 [0.85, 2.50]

7 Ovarian hyperstimulation syndrome rate Show forest plot

12

2536

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

7.1 AIs versus clomiphene citrate

9

2010

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

7.2 AI versus clomiphene + metformin

1

250

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.02, 0.02]

7.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.04, 0.04]

8 Ovarian hyperstimulation syndrome rate per BMI Show forest plot

11

Risk Difference (M‐H, Fixed, 95% CI)

Subtotals only

8.1 BMI > 25

6

1851

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

8.2 BMI < 25

5

605

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [‐0.02, 0.02]

9 Clinical pregnancy rate Show forest plot

25

4629

Odds Ratio (M‐H, Fixed, 95% CI)

1.56 [1.37, 1.78]

9.1 AIs versus clomiphene citrate

17

2930

Odds Ratio (M‐H, Fixed, 95% CI)

1.50 [1.28, 1.76]

9.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.60, 1.71]

9.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.86 [1.05, 3.29]

9.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.82, 2.27]

9.5 AIs versus tamoxifen

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

1.58 [0.64, 3.90]

9.6 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

2.47 [0.94, 6.46]

9.7 AIs ± berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

2.15 [1.48, 3.13]

10 Impact of allocation bias for clinical pregnancy rate Show forest plot

23

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

10.1 Unclear risk of allocation

16

1907

Odds Ratio (M‐H, Fixed, 95% CI)

1.77 [1.43, 2.18]

10.2 Low risk of allocation

7

1912

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [1.12, 1.65]

11 Miscarriage rate by woman randomised Show forest plot

18

3754

Odds Ratio (M‐H, Fixed, 95% CI)

1.39 [1.07, 1.81]

11.1 AIs versus clomiphene citrate

11

2190

Odds Ratio (M‐H, Fixed, 95% CI)

1.37 [0.97, 1.93]

11.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.25, 4.23]

11.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

294

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.52, 2.82]

11.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.31, 2.27]

11.5 AIs versus clomiphene + estradiol valerate

1

100

Odds Ratio (M‐H, Fixed, 95% CI)

12.21 [0.66, 226.97]

11.6 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [0.87, 3.04]

12 Miscarriage rate by pregnancies Show forest plot

18

1210

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.70, 1.26]

12.1 AIs versus clomiphene citrate

11

705

Odds Ratio (M‐H, Fixed, 95% CI)

0.96 [0.65, 1.42]

12.2 AI versus clomiphene + metformin

1

85

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.24, 4.40]

12.3 Aromatase inhibitor + metformin versus clomiphene + metformin

3

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.80 [0.32, 2.02]

12.4 Aromatase inhibitor + hMG versus clomiphene + hMG

2

104

Odds Ratio (M‐H, Fixed, 95% CI)

0.67 [0.23, 1.96]

12.5 AIs versus clomiphene + estradiol valerate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

8.13 [0.39, 167.90]

12.6 AIs +/‐ berberine versus berberine

1

213

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.43, 1.80]

13 Multiple pregnancy rate Show forest plot

17

3579

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.41, 1.16]

13.1 AIs versus clomiphene citrate

13

2409

Odds Ratio (M‐H, Fixed, 95% CI)

0.61 [0.32, 1.16]

13.2 AI versus clomiphene + metformin

1

250

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 2.82]

13.3 Aromatase inhibitor + hMG versus clomiphene + hMG

2

276

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.29, 3.05]

13.4 AIs +/‐ berberine versus berberine

1

644

Odds Ratio (M‐H, Fixed, 95% CI)

4.53 [0.24, 84.46]

Figuras y tablas -
Comparison 2. Letrozole compared to selective estrogen receptor modulators with or without adjuncts, followed by timed intercourse
Comparison 3. Letrozole compared to clomiphene citrate, followed by IUI

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

2

1494

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

1.1 AI versus Clomiphene

1

107

Risk Difference (M‐H, Fixed, 95% CI)

‐0.02 [‐0.07, 0.03]

1.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Risk Difference (M‐H, Fixed, 95% CI)

‐0.00 [‐0.01, 0.00]

2 Clinical pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.30, 2.25]

2.1 AI versus Clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

2.09 [0.97, 4.53]

2.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.23, 2.22]

3 Miscarriage rate by woman randomised Show forest plot

2

1490

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [0.62, 2.40]

3.1 AI versus Clomiphene

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.06]

3.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.66, 2.65]

4 Miscarriage rate by pregnancies Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.37, 1.57]

4.1 AI versus Clomiphene

1

15

Odds Ratio (M‐H, Fixed, 95% CI)

0.10 [0.00, 3.09]

4.2 AI versus Clomiphene +rFSH and rFSH only

1

245

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.40, 1.79]

5 Multiple pregnancy rate Show forest plot

3

1597

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.49, 2.13]

5.1 AI versus Clomiphene

2

210

Odds Ratio (M‐H, Fixed, 95% CI)

3.48 [0.14, 87.49]

5.2 AI versus Clomiphene +rFSH and rFSH only

1

1387

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.44, 2.03]

Figuras y tablas -
Comparison 3. Letrozole compared to clomiphene citrate, followed by IUI
Comparison 4. Letrozole compared to laparoscopic ovarian drilling

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

1.38 [0.95, 2.02]

2 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

3 Clinical pregnancy rate Show forest plot

5

774

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.94, 1.74]

3.1 AI versus LOD

4

628

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.93, 1.83]

3.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.60, 2.39]

4 Miscarriage rate by woman randomised Show forest plot

5

774

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.38, 1.70]

4.1 AI versus LOD

4

628

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.29, 1.63]

4.2 AI + metformin versus LOD

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [0.29, 6.27]

5 Miscarriage rate by pregnancies Show forest plot

5

240

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.30, 1.43]

5.1 AI versus LOD

4

191

Odds Ratio (M‐H, Fixed, 95% CI)

0.54 [0.22, 1.33]

5.2 AI + metformin versus LOD

1

49

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.24, 6.09]

6 Multiple pregnancy rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

3.00 [0.12, 74.90]

Figuras y tablas -
Comparison 4. Letrozole compared to laparoscopic ovarian drilling
Comparison 5. Letrozole compared to FSH

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

2 Clinical pregnancy rate Show forest plot

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.40, 1.67]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5 Multiple pregnancy rate Show forest plot

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.12]

Figuras y tablas -
Comparison 5. Letrozole compared to FSH
Comparison 6. Letrozole compared to anastrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

2 Clinical pregnancy rate Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.51, 1.43]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5 Multiple pregnancy rate Show forest plot

2

260

Odds Ratio (M‐H, Fixed, 95% CI)

5.0 [0.24, 105.35]

Figuras y tablas -
Comparison 6. Letrozole compared to anastrozole
Comparison 7. Different administration protocols of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Five days compared to 10 days administration protocol of letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Clinical pregnancy rate Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Letrozole day 3‐7 administratio versus day 5‐9 administration

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.1 Five days compared to 10 days administration protocol of letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 7. Different administration protocols of letrozole
Comparison 8. Dosage studies of letrozole

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Ovarian hyperstimulation syndrome rate Show forest plot

1

Risk Difference (M‐H, Fixed, 95% CI)

Totals not selected

1.1 5mg vs 7.5mg letrozole

1

Risk Difference (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Clinical pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Miscarriage rate by woman randomised Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Miscarriage rate by pregnancies Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Multiple pregnancy rate Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.1 5mg vs 7.5mg letrozole

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 8. Dosage studies of letrozole