Review question. Cochrane authors reviewed the evidence about the effectiveness of different timing techniques for intrauterine insemination in subfertile couples.
Background. Couples that have not reached pregnancy after trying for at least a year are defined as subfertile. This affects approximately 10% of couples trying to have a baby. A procedure that may assist couples is intrauterine insemination (IUI). This is an assisted reproduction procedure where sperm are placed directly into the uterus at a specific time in the woman's menstrual cycle (as close to ovulation as possible). It remains unclear which technique of timing for IUI results in the best treatment outcome, a healthy live birth. Timing of IUI is most frequently performed with hormone (luteinising hormone (LH)) detection in urine or blood, or human chorionic gonadotropin (hCG) injection. The usefulness of urinary LH monitoring is hampered by the possibility of false-negative results which can cause inaccurate timing and significantly reduce pregnancy rates. On the other hand, the ease of performing a test at home, the lower costs and the non-invasiveness are advantages. Limitations of timing by ultrasound and hCG administration are frequent hospital visits and the occurrence of premature LH surges or the possibility of triggering ovulation in the presence of an immature follicle. The major advantage of this hCG method is the clinical predictability of the ovulation.
Study characteristics. We found 18 randomised controlled trials, all comparing different timing methods in one treatment cycle for IUI, with a total of 2279 couples. The evidence was current to October 2013.
Key results. We found no evidence of a difference in live birth rates between timing methods. We also found no evidence of a difference between any of the groups in rates of pregnancy or adverse events (multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS)).
Quality of the evidence. Most of the evidence was of low or very low quality. The main limitations were poor reporting of study methods, imprecision and losses to follow up. More research is needed.
There is insufficient evidence to determine whether there is any difference in safety and effectiveness between different methods of synchronization of ovulation and insemination. More research is needed.
In many countries intrauterine insemination (IUI) is the treatment of first choice for a subfertile couple when the infertility work up reveals an ovulatory cycle, at least one open Fallopian tube and sufficient spermatozoa. The final goal of this treatment is to achieve a pregnancy and deliver a healthy (singleton) live birth. The probability of conceiving with IUI depends on various factors including age of the couple, type of subfertility, ovarian stimulation and the timing of insemination. IUI should logically be performed around the moment of ovulation. Since spermatozoa and oocytes have only limited survival time correct timing of the insemination is essential. As it is not known which technique of timing for IUI results in the best treatment outcome, we compared different techniques for timing IUI and different time intervals.
To evaluate the effectiveness of different synchronisation methods in natural and stimulated cycles for IUI in subfertile couples.
We searched for all publications which described randomised controlled trials of the timing of IUI. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (1966 to October 2014), EMBASE (1974 to October 2014), MEDLINE (1966 to October 2014) and PsycINFO (inception to October 2014) electronic databases and prospective trial registers. Furthermore, we checked the reference lists of all obtained studies and performed a handsearch of conference abstracts.
Randomised controlled trials (RCTs) comparing different timing methods for IUI were included. The following interventions were evaluated: detection of luteinising hormone (LH) in urine or blood, single test; human chorionic gonadotropin (hCG) administration; combination of LH detection and hCG administration; basal body temperature chart; ultrasound detection of ovulation; gonadotropin-releasing hormone (GnRH) agonist administration; or other timing methods.
Two review authors independently selected the trials, extracted the data and assessed study risk of bias. We performed statistical analyses in accordance with the guidelines for statistical analysis developed by The Cochrane Collaboration. The overall quality of the evidence was assessed using GRADE methods.
Eighteen RCTs were included in the review, of which 14 were included in the meta-analyses (in total 2279 couples). The evidence was current to October 2013. The quality of the evidence was low or very low for most comparisons . The main limitations in the evidence were failure to describe study methods, serious imprecision and attrition bias.
Ten RCTs compared different methods of timing for IUI. We found no evidence of a difference in live birth rates between hCG injection versus LH surge (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.06 to 18, 1 RCT, 24 women, very low quality evidence), urinary hCG versus recombinant hCG (OR 1.17, 95% CI 0.68 to 2.03, 1 RCT, 284 women, low quality evidence) or hCG versus GnRH agonist (OR 1.04, 95% CI 0.42 to 2.6, 3 RCTS, 104 women, I2 = 0%, low quality evidence).
Two RCTs compared the optimum time interval from hCG injection to IUI, comparing different time frames that ranged from 24 hours to 48 hours. Only one of these studies reported live birth rates, and found no difference between the groups (OR 0.52, 95% CI 0.27 to 1.00, 1 RCT, 204 couples). One study compared early versus late hCG administration and one study compared different dosages of hCG, but neither reported the primary outcome of live birth.
We found no evidence of a difference between any of the groups in rates of pregnancy or adverse events (multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS)). However, most of these data were very low quality.