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Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial

2017; Elsevier BV; Volume: 391; Issue: 10122 Linguagem: Inglês

10.1016/s0140-6736(17)33308-1

1474-547X

Nienke S Weiss, Marleen Nahuis, Esmée M Bordewijk, Jurjen E. Oosterhuis, J Smeenk, Annemieke Hoek, Frank J. Broekmans, Kathrin Fleischer, Jan Peter de Bruin, Eugenie M. Kaaijk, Joop S.E. Laven, Dave J. Hendriks, Marie H Gerards, Ilse AJ van Rooij, Petra Bourdrez, Judith Gianotten, Carolien A.M. Koks, Cornelis B. Lambalk, Peter G.A. Hompes, Fulco van der Veen, Ben W. Mol, Madelon van Wely,

Assisted Reproductive Technology and Twin Pregnancy

Background:Clomiphene citrate (CC) is in many countries the treatment of first choice in women with normogonadotropic anovulation.If these women ovulate but do not conceive after several cycles with CC, medication is usually switched to gonadotrophins, with or without intrauterine insemination (IUI).We aimed to assess whether switching to gonadotrophins is more effective than continuing CC, and whether IUI is more effective than intercourse. Methods:We performed a two-by-two factorial multicenter randomized clinical trial including women with normogonadotropic anovulation not pregnant after six ovulatory cycles with CC (NTR1449).Women were randomized using a central password protected internet-based randomization program to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse.CC dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously.Primary outcome was conception leading to live birth within eight months after randomization.Primary analysis was by intention to treat.We made two comparisons, one in which gonadotrophins was compared to CC and one in which IUI was compared to intercourse. Findings:Between December 8 th 2008 and December 16 th 2015 we randomized 666 women to gonadotrophins/IUI (N=166), gonadotrophins/intercourse (N=165), CC/IUI (N=163), or CC/intercourse (N=172).Women allocated to gonadotrophins had more live births than those allocated to CC (167 of 327 women [51•5%] vs. 138 of 334 [41•3%], (RR 1•24 (95% CI 1•05-1•46), p = 0•0124).Addition of IUI did not increase live births compared to intercourse (161 of 327 women [49•2%] vs. 144 of 334 [43•1%], RR 1•14 (95% CI 0•97-1•35), p = 0•1152).Multiple pregnancy rates for the two comparisons were low and not different.There were three adverse events: one child with congenital abnormalities, one immature delivery due to cervical insufficiency, and one stillbirth. Interpretation:In women with normogonadotropic anovulation and CC failure, a switch of treatment to gonadotrophins increases chances of live birth over treatment with CC, while we could not prove that addition of IUI does so.