Intra-uterine insemination for unexplained subfertility

Review question

Does treatment with intra-uterine insemination (IUI), with or without fertility drugs, compared to timed intercourse or expectant management (watchful waiting) with or without fertility drugs, or treatment with IUI with fertility drugs compared to IUI without fertility drugs improve live birth rates in couples with unexplained subfertility?

Background

IUI is a treatment often used for couples with unexplained subfertility. In an IUI cycle, the male partner's sperm is prepared and placed directly in the womb around the time of ovulation. IUI cycles can be used in combination with fertility drugs to increase the number of available eggs. However, these drugs can have side effects, and also increase the risk of multiple pregnancies. Expectant management and timed intercourse have also been shown to increase pregnancy rates, resulting in live births. With this review, we would like to enhance decision-making for couples starting treatment for unexplained subfertility.

Study characteristics

Cochrane authors identified 15 randomised controlled trials which included 2068 women. Women who were treated with IUI, with or without fertility drugs, were compared to those who were assigned timed intercourse or expectant management with or without fertility drugs, or women who received IUI with fertility drugs were compared to those who were treated with IUI without fertility drugs. The main outcomes of interest were live birth rates and multiple pregnancy rates. Other outcomes included pregnancy rate, miscarriage rate and other adverse events. The evidence is current to October 2019.

Key results

For most treatment groups, it is uncertain whether treatment with one IUI treatment type improves cumulative live birth rates (i.e. rates at the end of a course of treatment) with acceptable multiple pregnancy rates when compared to another treatment type. However, there is moderate-quality evidence that, in couples with a low chance of natural conception, treatment with IUI combined with fertility drugs probably improves cumulative live birth rates compared to treatment with expectant management. Similarly, there is moderate-quality evidence that treatment with IUI alone probably improves cumulative live birth rates compared to treatment with expectant management combined with fertility drugs.

Quality of the evidence

The evidence was of low to moderate quality for cumulative live birth and of low quality for multiple pregnancy. The main limitation of the evidence was a lack of precision in the findings, due to the inclusion of few studies with small sample sizes.

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.

Read the full 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 strategy: 

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).

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