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Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter? 
 
STUDY QUESTION
Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles?
 
SUMMARY ANSWER
Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after sixearlier failed ovulatory CC cycles.
 
WHAT IS ALREADY KNOWN
For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterineinsemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after sixfailed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC withsimilar live birth rates without the extra costs of gonadotropins.
 
STUDY DESIGN, SIZE, DURATION
Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change togonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome wasconception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CCcycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC.
 
PARTICIPANTS/MATERIALS, SETTING, METHODS
EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. Weperformed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the bestcut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMTvalues below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER).
 
MAIN RESULTS AND THE ROLE OF CHANCE
Mid-cycle EMT in the sixth cycle interacted with treatment effect (P  7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83women (34%) (RR 1.57, 95% CI 1.13–2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75–1.29).