Reuben Olugbenga Ayeleke1, Joyce Danielle Asseler2, Ben J Cohlen3, Susanne M Veltman-Verhulst4. 1. University of Auckland, Department of Obstetrics and Gynaecology, Private Bag 92019, Auckland, New Zealand. 2. Academic Medical Center, Department of Obstetrics and Gynaecology, Meibergdreef 9, Amsterdam, Netherlands, 1105AZ. 3. Isala Clinics, Location Sophia, Department of Obstetrics and Gynaecology, Dr van Heesweg 2, Isala Zwolle, Netherlands. 4. Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Room F5.126, PO Box 85500,, Utrecht, Netherlands, 3508 GA.
Abstract
BACKGROUND: Intra-uterine insemination (IUI) is a widely-used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rates. OBJECTIVES: To determine whether, for couples with unexplained subfertility, the live birth rate is improved following IUI treatment with or without OH compared to timed intercourse (TI) or expectant management with or without OH, or following IUI treatment with OH compared to IUI in a natural cycle. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 17 October 2019, together with reference checking and contact with study authors for missing or unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IUI with TI or expectant management, both in stimulated or natural cycles, or IUI in stimulated cycles with IUI in natural cycles in couples with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, quality assessment and data extraction. Primary review outcomes were live birth rate and multiple pregnancy rate. MAIN RESULTS: We include 15 trials with 2068 women. The evidence was of very low to moderate quality. The main limitation was very serious imprecision. IUI in a natural cycle versus timed intercourse or expectant management in a natural cycle It is uncertain whether treatment with IUI in a natural cycle improves live birth rate compared to treatment with expectant management in a natural cycle (odds ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.78; 1 RCT, 334 women; low-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle to be 16%, that of IUI in a natural cycle would be between 15% and 34%. It is uncertain whether treatment with IUI in a natural cycle reduces multiple pregnancy rates compared to control (OR 0.50, 95% CI 0.04 to 5.53; 1 RCT, 334 women; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a stimulated cycle It is uncertain whether treatment with IUI in a stimulated cycle improves live birth rates compared to treatment with TI in a stimulated cycle (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs, 208 women; I2 = 72%; low-quality evidence). If we assume the chance of achieving a live birth with TI in a stimulated cycle was 26%, the chance with IUI in a stimulated cycle would be between 23% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle reduces multiple pregnancy rates compared to control (OR 1.46, 95% CI 0.55 to 3.87; 4 RCTs, 316 women; I2 = 0%; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a natural cycle In couples with a low prediction score of natural conception, treatment with IUI combined with clomiphene citrate or letrozole probably results in a higher live birth rate compared to treatment with expectant management in a natural cycle (OR 4.48, 95% CI 2.00 to 10.01; 1 RCT; 201 women; moderate-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle was 9%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle results in a lower multiple pregnancy rate compared to control (OR 3.01, 95% CI 0.47 to 19.28; 2 RCTs, 454 women; I2 = 0%; low-quality evidence). IUI in a natural cycle versus timed intercourse or expectant management in a stimulated cycle Treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, 342 women: moderate-quality evidence). If we assume the chance of a live birth with expectant management in a stimulated cycle was 13%, the chance of a live birth with IUI in a natural cycle would be between 14% and 34%. It is uncertain whether treatment with IUI in a natural cycle results in a lower multiple pregnancy rate compared to control (OR 1.05, 95% CI 0.07 to 16.90; 1 RCT, 342 women; low-quality evidence). IUI in a stimulated cycle versus IUI in a natural cycle Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle (OR 2.07, 95% CI 1.22 to 3.50; 4 RCTs, 396 women; I2 = 0%; low-quality evidence). If we assume the chance of a live birth with IUI in a natural cycle was 14%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 36%. It is uncertain whether treatment with IUI in a stimulated cycle results in a higher multiple pregnancy rate compared to control (OR 3.00, 95% CI 0.11 to 78.27; 2 RCTs, 65 women; low-quality evidence). AUTHORS' CONCLUSIONS: Due to insufficient data, it is uncertain whether treatment with IUI with or without OH compared to timed intercourse or expectant management with or without OH improves cumulative live birth rates with acceptable multiple pregnancy rates in couples with unexplained subfertility. However, treatment with IUI with OH probably results in a higher cumulative live birth rate compared to expectant management without OH in couples with a low prediction score of natural conception. Similarly, treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with timed intercourse with OH. Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle.
BACKGROUND: Intra-uterine insemination (IUI) is a widely-used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rates. OBJECTIVES: To determine whether, for couples with unexplained subfertility, the live birth rate is improved following IUI treatment with or without OH compared to timed intercourse (TI) or expectant management with or without OH, or following IUI treatment with OH compared to IUI in a natural cycle. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 17 October 2019, together with reference checking and contact with study authors for missing or unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IUI with TI or expectant management, both in stimulated or natural cycles, or IUI in stimulated cycles with IUI in natural cycles in couples with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, quality assessment and data extraction. Primary review outcomes were live birth rate and multiple pregnancy rate. MAIN RESULTS: We include 15 trials with 2068 women. The evidence was of very low to moderate quality. The main limitation was very serious imprecision. IUI in a natural cycle versus timed intercourse or expectant management in a natural cycle It is uncertain whether treatment with IUI in a natural cycle improves live birth rate compared to treatment with expectant management in a natural cycle (odds ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.78; 1 RCT, 334 women; low-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle to be 16%, that of IUI in a natural cycle would be between 15% and 34%. It is uncertain whether treatment with IUI in a natural cycle reduces multiple pregnancy rates compared to control (OR 0.50, 95% CI 0.04 to 5.53; 1 RCT, 334 women; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a stimulated cycle It is uncertain whether treatment with IUI in a stimulated cycle improves live birth rates compared to treatment with TI in a stimulated cycle (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs, 208 women; I2 = 72%; low-quality evidence). If we assume the chance of achieving a live birth with TI in a stimulated cycle was 26%, the chance with IUI in a stimulated cycle would be between 23% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle reduces multiple pregnancy rates compared to control (OR 1.46, 95% CI 0.55 to 3.87; 4 RCTs, 316 women; I2 = 0%; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a natural cycle In couples with a low prediction score of natural conception, treatment with IUI combined with clomiphene citrate or letrozole probably results in a higher live birth rate compared to treatment with expectant management in a natural cycle (OR 4.48, 95% CI 2.00 to 10.01; 1 RCT; 201 women; moderate-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle was 9%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle results in a lower multiple pregnancy rate compared to control (OR 3.01, 95% CI 0.47 to 19.28; 2 RCTs, 454 women; I2 = 0%; low-quality evidence). IUI in a natural cycle versus timed intercourse or expectant management in a stimulated cycle Treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, 342 women: moderate-quality evidence). If we assume the chance of a live birth with expectant management in a stimulated cycle was 13%, the chance of a live birth with IUI in a natural cycle would be between 14% and 34%. It is uncertain whether treatment with IUI in a natural cycle results in a lower multiple pregnancy rate compared to control (OR 1.05, 95% CI 0.07 to 16.90; 1 RCT, 342 women; low-quality evidence). IUI in a stimulated cycle versus IUI in a natural cycle Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle (OR 2.07, 95% CI 1.22 to 3.50; 4 RCTs, 396 women; I2 = 0%; low-quality evidence). If we assume the chance of a live birth with IUI in a natural cycle was 14%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 36%. It is uncertain whether treatment with IUI in a stimulated cycle results in a higher multiple pregnancy rate compared to control (OR 3.00, 95% CI 0.11 to 78.27; 2 RCTs, 65 women; low-quality evidence). AUTHORS' CONCLUSIONS: Due to insufficient data, it is uncertain whether treatment with IUI with or without OH compared to timed intercourse or expectant management with or without OH improves cumulative live birth rates with acceptable multiple pregnancy rates in couples with unexplained subfertility. However, treatment with IUI with OH probably results in a higher cumulative live birth rate compared to expectant management without OH in couples with a low prediction score of natural conception. Similarly, treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with timed intercourse with OH. Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle.
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