Synchronised approach for intrauterine insemination in subfertile couples

RATIONALE: Intrauterine insemination (IUI) is widely used as a first-line treatment for subfertile couples with favourable prognostic factors, yet pregnancy rates vary considerably. The optimal method for timing IUI - whether through different monitoring strategies or ovulation triggering techniques in natural or stimulated cycles - remains uncertain. This review explores which timing approaches and methods of ovulation monitoring and triggering lead to the best outcomes, including live birth and clinical pregnancy. It updates a Cochrane review last published in 2014. OBJECTIVES: To evaluate the effectiveness of different methods of synchronisation of insemination with ovulation on live birth or ongoing pregnancy, in natural and stimulated cycles for IUI in subfertile couples. SEARCH METHODS: We used the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, and two other databases, along with reference checking, citation searching, handsearching of conference abstracts, and contact with study authors to identify the studies included in the review. The latest search date was October 2023. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) comparing timing methods in natural or stimulated cycles, and different ovulation triggering methods. These included: varying the time interval between ovulation triggering and insemination, luteinising hormone (LH) detection in urine, LH detection in blood, basal body temperature charts, ultrasound detection of ovulation, human chorionic gonadotropin (hCG) administration, a combination of LH detection and hCG administration, gonadotropin-releasing hormone (GnRH) agonist administration, and other trigger administrations. OUTCOMES: Critical outcome: live birth or ongoing pregnancy rate per couple. Important outcomes (all are rate per couple): clinical pregnancy; multiple pregnancy; miscarriage; ovarian hyperstimulation syndrome; tubal pregnancy. RISK OF BIAS: We used the Cochrane Collaboration's original tool to assess the risk of bias in the included RCTs. SYNTHESIS METHODS: After the search, we screened the trials, extracted the data, and assessed the risk of bias and trustworthiness of the included studies. We synthesised results for each outcome using meta-analysis where possible. We expressed results for each included study as Mantel-Haenszel odds ratios (OR) with 95% confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. INCLUDED STUDIES: This review update includes 42 studies: 18 from the 2014 version, plus 24 studies newly identified in the updated search. SYNTHESIS OF RESULTS: Of the 42 included studies (a total of 6603 couples), we included seven in the primary meta-analyses (1917 couples) and 12 in the sensitivity meta-analyses (2143 couples). The certainty of the evidence was low for most comparisons. The main limitation of the evidence was serious imprecision. Of the seven studies included in the primary analyses, two compared the optimum time interval from hCG injection to IUI for live birth or ongoing pregnancy rate, comparing different time frames ranging from 0 to 48 hours. We categorised the time frames into three groups: (i) 0 to 33 hours; (ii) 34 to 40 hours; and (iii) more than 40 hours. We compared 0 to 33 hours versus 34 to 40 hours, and 34 to 40 hours versus more than 40 hours. Results were too imprecise to be informative in both comparisons (0 to 33 hours versus 34 to 40 hours: OR 1.42, 95% CI 0.90 to 2.23; 1 study, 374 couples; 34 to 40 hours versus more than 40 hours: OR 0.45, 95% CI 0.15 to 1.33; 1 study, 107 couples). We included one study in the primary analysis for each of the following comparisons: hCG versus LH surge; recombinant hCG versus urinary hCG; and hCG alone versus hCG plus follicle-stimulating hormone (FSH). It is unclear whether there might be a difference in live birth or ongoing pregnancy rates in the first two comparisons: hCG versus LH surge: OR 1.08, 95% CI 0.50 to 2.37; 1 study, 392 couples; low-certainty evidence; recombinant hCG versus urinary hCG: OR 1.13, 95% CI 0.49 to 2.63; 1 study, 125 couples; low-certainty evidence. However, live birth or ongoing pregnancy rates may be lower with hCG alone compared to hCG plus FSH (OR 0.35, 95% CI 0.13 to 0.95; 1 study, 108 couples; low-certainty evidence). We found no clear evidence of a difference between any of the groups in clinical pregnancy rate or adverse events (multiple pregnancy rate, miscarriage rate, tubal pregnancy rate). However, all results were of low-certainty evidence. None of the studies included in the primary analyses reported on ovarian hyperstimulation syndrome. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether there is any difference in effectiveness between different methods of synchronisation of ovulation and insemination. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: First review update (2014): doi.org/10.1002/14651858.CD006942.pub3 Review (2010): doi.org/10.1002/14651858.CD006942.pub2 Protocol (2008): doi.org/10.1002/14651858.CD006942.