Abstract: We included five trials involving 639 clomiphene-resistant women with PCOS. Three studies compared UTND with LOD, and two compared UTND combined with gonadotropins with gonadotropins alone. The evidence was of low to very low quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency resulting from heterogeneity, imprecision induced by limited sample size, and lack of reporting of clinically relevant outcomes such as live birth and surgical complications. UTND versus LOD No studies reported on the main outcome live birth. One study reported on surgical complications; however, the evidence for this outcome was of very low quality because it was based on one study with small sample size and there were no events in either arm. Thus, we are uncertain whether there is any difference in surgical complications between UTND and LOD. We are also uncertain whether there is any difference in pregnancy rate when comparing UTND with LOD (OR 0.54, 95% CI 0.28 to 1.03; I2 = 56%; 3 RCTs, n = 473; very-low quality evidence). UTND may lead to a slight decrease in ovulation rate when compared to LOD (OR 0.66, 95% CI 0.45 to 0.97; I2 = 0%; 3 RCTs, n = 473; low-quality evidence). This suggests that among clomiphene-resistant women with PCOS using LOD with an expected ovulation rate of 69.5%, the ovulation rate among women using UTND may be between 50.6% and 68.8% No studies reported on the outcomes OHSS and multiple pregnancy. There was also insufficient evidence to reach a conclusion regarding miscarriage as there was only one study of very low quality. UTND combined with gonadotropins versus gonadotropins alone No studies reported on the main outcomes live birth and incidence of surgical complications. The evidence for the outcomes OHSS, pregnancy, ovulation, miscarriage, and multiple pregnancy in this comparison was of very low quality. Thus, we are uncertain whether there is any difference in these outcomes for women with clomiphene-resistant PCOS using UTND combined with gonadotropins as compared with gonadotropins. Based on very low-quality evidence, It is uncertain whether there is any difference in pregnancy rate, incidence of surgical complications, and miscarriage rate between UTND and LOD in women with clomiphene-resistant PCOS. UTND may lead to a slight decrease in ovulation rate when compared to LOD. No studies reported on the outcomes live birth rate, incidence of OHSS, and multiple pregnancy rate. No studies reported on the main outcomes live birth and surgical complications for the comparison UTND combined with gonadotrophins versus gonadotrophins alone. The evidence for the outcomes OHSS, pregnancy, ovulation, miscarriage, and multiple pregnancy in this comparison was of very low quality. Thus, it is unclear if there is a difference in any of the outcomes between UTND combined with gonadotrophins versus gonadotrophins alone.

Plain-language summary: Five randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) with 639 women were included in the review. Three compared UTND to LOD, and two compared UTND combined with gonadotropins to gonadotropins. UTND versus LOD The quality of the three studies was low to very low. None of the studies reported on the main outcome of live birth. Based on currently available evidence, we are uncertain whether pregnancy rate of women using UTND is different from that of LOD. UTND may lead to a small decrease in ovulation rate when compared to LOD. Thus, low-quality evidence suggests that among clomiphene-resistant women with PCOS using LOD with an expected ovulation rate of 69.5%, the rate among women using UTND may be between 50.6% and 68.8%. There is insufficient evidence to reach conclusions regarding surgical complications and miscarriage, as we found only one very low-quality study. None of the studies reported OHSS or multiple pregnancy rate. UTND combined with gonadotropins versus gonadotropins alone We were unable to assess the benefit or harm of applying UTND combined with gonadotropins for women with clomiphene-resistant PCOS, as we identified only two very low-quality trials that used different doses of gonadotropins. We assessed the quality of the evidence as low to very low due to poor explanations of study methodology and the limited number of included trials. Also, reporting on clinically relevant issues that are important for subfertile couples, such as live birth, was lacking.