Key messages
• There is not enough evidence to know whether different ways of timing ovulation and insemination are safer or more effective than others.
• We also can't say if any one method for monitoring or triggering ovulation is better, because the results are either too uncertain or come from just one small study.
• Future studies should use better methods and measure the success of treatments in terms of live births or ongoing pregnancies.
What is subfertility?
Subfertility is usually defined as the inability of a couple to achieve pregnancy after 12 months of regular, unprotected sexual intercourse, or after six months in women aged 35 years and older. Subfertility affects roughly 10% of couples trying to have a baby.
How is subfertility treated?
Treatment options for subfertile couples vary, and depend on the cause of subfertility, the couple’s age, how long they’ve been trying, and other factors.
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.
The timing of insemination is usually planned using either a hormone injection (human chorionic gonadotropin (hCG)) or by detecting a natural hormone surge (luteinising hormone (LH)) in a woman's urine or blood. Other methods are also used. However, it is still not clear which timing method gives the best chance of having a healthy baby or a pregnancy that continues beyond the early stages.
What did we want to find out?
We wanted to find out which of the different timing techniques is most effective for achieving a live birth.
What did we do?
We searched for studies that compared different methods of timing intrauterine insemination (IUI) in subfertile couples. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study sizes and methods.
What did we find?
We found 42 studies that involved 6603 couples. We mainly drew on evidence from only seven studies involving 1917 couples. The other 35 studies had inadequate methods or did not provide enough information to allow us to analyse their results.
Main results
• Three studies compared different timings between hormone injection (hCG) and insemination. We analysed results for different time intervals: 0 to 33 hours versus 34 to 40 hours between injection and insemination, and 34 to 40 hours versus more than 40 hours. The results did not show clear evidence of a difference in ongoing pregnancy or live birth rates between the groups.
• One study compared hCG injection to luteinising hormone surge to determine insemination timing. It is uncertain whether there is a difference in live birth or ongoing pregnancy rates between the groups.
• One study compared two types of ovulation-triggering hormone injection: recombinant hCG versus urinary hCG. It is unclear whether there is a difference in live birth or ongoing pregnancy rates between the groups.
• One study explored whether adding an extra hormone (FSH, which stimulates the ovaries to grow more eggs) to the standard hCG ovulation trigger improves the chances of getting pregnant, compared to using hCG alone. This comparison showed there may be fewer live births or ongoing pregnancies in the hCG group compared to the hCG plus FSH group. However, our confidence in this result is low; larger studies are needed to confirm this finding.
What are the limitations of the evidence?
We have little confidence in the evidence for all comparisons because the studies included too few women to provide clear results for the most important outcome (namely, live birth or ongoing pregnancy).
How current is this evidence?
The evidence is current to October 2023.
Read the full abstract
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.
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 strategy
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.
Selection criteria
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.
Data collection and analysis
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.
Main results
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.
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
