Double versus single IUI for unexplained infertility

Polyzos, etal. Fertil Steril 94:1261-66, 2010.

This study gathered information from six randomized trials involving 829 women.  The clinical pregnancy rate for treatment with double IUI was 13.6% and was 14.4% with a single IUI.  There was no statistical difference between these groups suggesting that a double IUI offers no clear benefit in the overall clinical pregnancy rate in couples with unexplained infertility.

Comparison of the effectiveness of single versus double intrauterine insemination with three different timing regimens.  Tonguc etal.  Fertil Steril 94:1267-70.

This study examines not only one versus two IUIs, but also when to do the IUIs.  All of their patients where on gonadotropin superovulation with hCG triggering of ovulation.  This type of superovulation is a cycle during which a woman recieves injections for several days to stimulate her ovaries to produce more than the customary one egg per cycle.  The authors compared one IUI at 24hrs vs. one at 36hrs vs. two IUIs at 12 and 36hrs.  The pregnancy rates were 11.3%, 17.2% and 14.0% respectively for the three groups.  Statistically these numbers were not different.

Dr. Albrecht’s Comments:

Since the first description of intrauterine inseminations using washed sperm by Dr. John Kerin in 1982, there has been no consensus on how, when and how many to do.  Because correct timing of IUI depends on the timing of ovulation, increasing the frequency of IUI around the anticipated time of ovulation should logically improve success.  However, although some past studies have suggested that two IUIs are better than one, many studies have shown no difference.

The first study is an attempt to combine the results of six randomized studies to give us yet one more opinion.  Of the six studies, three recommend doing one IUI and only one recommend doing two; the remaining 2 saw no difference.  When combined to do the meta-analysis, the results suggest that a double IUI offers no clear benefit over a single IUI.

The second study is hampered by small numbers and non-homogeneous infertility diagnoses.   Given the small numbers of patients the numerical differences observed in the pregnancy rates could not be proven to be statistically different.  Perhaps if the study had been properly powered (had more patients in each arm of the study) a statistical difference would have been seen.  Nevertheless, looking at the numerical differences it suggests that there might be a difference in early IUI (24hrs) versus 36hrs in the other two arms.

We began doing IUIs in 1982 shortly after the initial study came out.  Dr. Kerin performed a single insemination and we set up our protocol to do the same but became interested in the optimal timing of the insemination.  We performed urine LH testing and vaginal pelvic ultrasounds to evaluate the timing.  On the first morning following the LH surge the follicle was generally still present (ie. preovulation).  On the second morning the follicle generally had collapsed (ie. immediately postovulation).  We found that the best chances for pregnancy were with the first insemination; however, we had patients that requested two inseminations and we noticed that they had a better pregnancy rate than the other two groups.  I have to state that this was not a randomized clinical trial but only a clinical observation that we serendipitously made.  Nevertheless, because of this personal experience, I have generally recommended that couples consider two inseminations per cycle.  This obviously costs twice as much and has twice the inconvenience and stress but it does not result in twice as many pregnancies.  However, we observed an improvement in the pregnancy rate by approximately 25% which is similar to improvement in the pregnancy results seen in the second study (23.8%).

Is it worth it???

Maybe not for those patients who are new to the treatment process.  A couple who has already performed inseminations using only a single IUI per cycle might have a better chance for pregnancy if they perform two IUIs in their subsequent attempts.  The reason for this is that twice as many sperm are being introduced to the female reproductive tract and if the longevity of the sperm is compromised, we are spreading out the effective time within which fertilization of the egg can occur.

It also needs to be pointed out that these studies address the results of patients with unexplained infertility.  Would the conclusions be different for patients with cervical factor or male factor?  Two previous studies (not included in the current study because they were not unexplained infertility) showed a very clear benefit for patients with these diagnoses using two versus one IUI.

The other controversial subject is how many cycles of IUIs are enough.  This is not as simple a question as it appears.  If the ovulation during a cycle was not good or one of the fallopian tubes is compromised, it is important to count only the months with optimal ovulation on the side with a normal/patent fallopian tube.  Assuming that these factors are optimal, studies still vary with the number of cycles recommended.  The range is 3 to 6 cycles.  Certainly the majority of successful cycles will be in the first 3 and only very rare successes are recorded after cycle 6.

We generally encourage patients to consider 3 cycles and then to decide about moving to more complex (and hence more expensive and stressful) treatments versus continuing with another 3 cycles.  In couples where the diagnosis is male factor or cervical factor our experience and that in the literature suggests that two IUIs are indicated.  In unexplained infertility, one IUI should be sufficient.  An excellent compromise approach would be to do 2 or 3 cycles with just one IUI per cycle and if not successful but the decision is to continue with IUI treatments to transition to two IUIs for the next 2 or 3 cycles.  This approach gives the easier single IUI treatment an opportunity to work but then gets more aggressive and exhausts IUIs as an effective treatment regimen.