Double versus single intrauterine insemination (IUI) in stimulated cycles for subfertile couples.

BACKGROUND: In subfertile couples, couples who have tried to conceive for at least one year, intrauterine insemination (IUI) with ovarian hyperstimulation (OH) is one of the treatment modalities that can be offered. When IUI is performed a second IUI in the same cycle might add to the chances of conceiving. In a previous update of this review in 2010 it was shown that double IUI increases pregnancy rates when compared to single IUI. Since 2010, different clinical trials have been published with differing conclusions about whether double IUI increases pregnancy rates compared to single IUI. OBJECTIVES: To determine the effectiveness and safety of double intrauterine insemination (IUI) compared to single IUI in stimulated cycles for subfertile couples. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase and CINAHL in July 2020 and LILACS, Google scholar and Epistemonikos in February 2021, together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled, parallel trials of double versus single IUIs in stimulated cycles in subfertile couples. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We identified in nine studies involving subfertile women. The evidence was of low quality; the main limitations were unclear risk of bias, inconsistent results for some outcomes and imprecision, due to small trials with imprecise results. We are uncertain whether double IUI improves live birth rate compared to single IUI (odds ratio (OR) 1.15, 95% confidence interval (CI) 0.71 to 1.88; I2 = 29%; studies = 3, participants = 468; low quality evidence). The evidence suggests that if the chance of live birth following single IUI is 16%, the chance of live birth following double IUI would be between 12% and 27%. Performing a sensitivity analysis restricted to only randomised controlled trials (RCTs) with low risk of selection bias showed similar results. We are uncertain whether double IUI reduces miscarriage rate compared to single IUI (OR 1.78, 95% CI 0.98 to 3.24; I2 = 0%; studies = 6, participants = 2363; low quality evidence). The evidence suggests that chance of miscarriage following single IUI is 1.5% and the chance following double IUI would be between 1.5% and 5%. The reported clinical pregnancy rate per woman randomised may increase with double IUI group (OR 1.51, 95% CI 1.23 to 1.86; I2 = 34%; studies = 9, participants = 2716; low quality evidence). This result should be interpreted with caution due to the low quality of the evidence and the moderate inconsistency. The evidence suggests that the chance of a pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%. We are uncertain whether double IUI affects multiple pregnancy rate compared to single IUI (OR 2.04, 95% CI 0.91 to 4.56; I2 = 8%; studies = 5; participants = 2203; low quality evidence). The evidence suggests that chance of multiple pregnancy following single IUI is 0.7% and the chance following double IUI would be between 0.85% and 3.7%. We are uncertain whether double IUI has an effect on ectopic pregnancy rate compared to single IUI (OR 1.22, 95% CI 0.35 to 4.28; I2 = 0%; studies = 4, participants = 1048; low quality evidence). The evidence suggests that the chance of an ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%. AUTHORS' CONCLUSIONS: Our main analysis, of which the evidence is low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. Our sensitivity analysis restricted to studies of low risk of selection bias for both outcomes is consistent with the main analysis. Clinical pregnancy rate may increase in the double IUI group, but this should be interpreted with caution due to the low quality evidence. We are uncertain whether double IUI has an effect on multiple pregnancy rate and ectopic pregnancy rate compared to single IUI.

Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions. OBJECTIVES: To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes. MAIN RESULTS: This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose. AUTHORS' CONCLUSIONS: Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.