Highlight
- Updated Cochrane review synthesises 42 randomised controlled trials (6603 couples) on timing strategies for intrauterine insemination (IUI).
- No clear evidence supports one optimal method for synchronising insemination with ovulation.
- Low-certainty evidence due to imprecision limits clinical guidance, highlighting urgent research needs.
- Pregnancy and adverse event rates remained similar across different ovulation monitoring and triggering approaches.
Background
Subfertility, defined as the failure to conceive after 12 months of unprotected intercourse, affects approximately 10–15% of couples globally. Intrauterine insemination (IUI) is often considered a first-line intervention in couples with favourable prognostic indicators, such as normal tubal patency and mild male factor infertility. A critical determinant of IUI success is the precise synchronisation of insemination with ovulation. However, clinical practice varies widely regarding timing methods, choice of ovulation monitoring, and triggering agents. This has led to heterogeneity in reported pregnancy rates and a lack of consensus on optimal protocols.
Study Design
This updated Cochrane systematic review assessed randomised controlled trials (RCTs) that compared various timing strategies for IUI in natural and stimulated cycles, as well as different ovulation triggering methods. Databases searched included the Cochrane Gynaecology and Fertility Group’s specialised register, CENTRAL, MEDLINE, and others, with the last search conducted in October 2023. Inclusion criteria required RCTs evaluating live birth or ongoing pregnancy rates as primary outcomes, with secondary endpoints including clinical pregnancy, multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), and tubal pregnancy.
Interventions studied were diverse, including ultrasound monitoring, luteinising hormone (LH) detection in urine or blood, basal body temperature charting, administration of human chorionic gonadotropin (hCG), recombinant hCG, gonadotropin-releasing hormone (GnRH) agonists, and combined trigger regimens such as hCG plus follicle-stimulating hormone (FSH).
Key Findings
A total of 42 studies spanning 6603 couples were included, with seven studies (1917 couples) contributing to primary meta-analyses. Twelve studies (2143 couples) informed sensitivity analyses. Certainty of evidence was generally low due to serious imprecision and methodological variability.
Timing from hCG Injection to IUI
Two trials assessed optimal intervals between hCG administration and insemination. Comparisons showed no significant nor precise differences:
- 0–33 hours vs 34–40 hours: OR 1.42, 95% CI 0.90 to 2.23 (1 study, 374 couples).
- 34–40 hours vs >40 hours: OR 0.45, 95% CI 0.15 to 1.33 (1 study, 107 couples).
Ovulation Trigger Strategies
Single-trial comparisons yielded low-certainty findings:
- hCG vs LH surge detection: OR 1.08, 95% CI 0.50 to 2.37 (392 couples).
- Recombinant hCG vs urinary hCG: OR 1.13, 95% CI 0.49 to 2.63 (125 couples).
- hCG alone vs hCG + FSH: OR 0.35, 95% CI 0.13 to 0.95 (108 couples), suggesting possible benefit with combined triggers.
Secondary Outcomes
No clear differences were identified across groups for clinical pregnancy rates or key adverse events, including multiple pregnancy, miscarriage, and tubal pregnancy. Notably, OHSS was not reported as an outcome in primary analyses.
Expert Commentary
Given current evidence limitations, clinicians should approach IUI timing protocols with flexibility, acknowledging that no single method has proven superiority. The consistent low-certainty evidence reflects small sample sizes, heterogeneity of study designs, and lack of standardisation in intervention delivery. While logic suggests that precise ovulation prediction could enhance IUI success, biological variability and inter-cycle differences may attenuate potential benefits.
Future trials must prioritise adequate sample sizes, consistent endpoint definitions, and clinically relevant outcome measures (live birth rather than biochemical pregnancy). Standardised use of monitoring modalities and trigger regimens would enhance comparability, and inclusion of safety endpoints such as OHSS is essential.
Conclusion
This updated Cochrane review underscores the absence of definitive evidence guiding optimal synchronisation of ovulation and insemination in IUI for subfertile couples. Clinicians may continue to use established local protocols, but should be aware that robust comparative data are lacking. Future well-designed trials could clarify whether nuanced timing adjustments translate into meaningful reproductive gains.
Funding and Registration
The review received no dedicated funding. Registration details: First review update (2014) – doi.org/10.1002/14651858.CD006942.pub3.
References
- Adesina M, Cantineau AE, Showell MG, Vail A, Wilkinson J. Synchronised approach for intrauterine insemination in subfertile couples. Cochrane Database Syst Rev. 2025 Sep 23;9(9):CD006942. doi: 10.1002/14651858.CD006942.pub4. PMID: 40985294; PMCID: PMC12455694.
