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Intrauterine insemination (IUI) is commonly recommended to couples with mild infertility problems or unexplained infertility before moving onto more expensive treatments such as in-vivo fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Unlike IVF or ICSI, IUI is a more variable procedure that can involve different ovarian stimulation and semen preparation protocols. As a result, the success rate can range from 2% to 22% per cycle depending a variety of factors:
- Number of follicles
- Ovarian stimulation protocols and medications used
- Cause and duration of infertility
- Semen characteristics
Among them, follicle characteristics and ovarian stimulation protocols are female factors that can be optimized for the best chance of IUI success.
- IUI success and follicle parameters
- IUI success with ovarian stimulation protocols
- When should you move on?
IUI success and follicle parameters
Controlled ovarian hyperstimulation is often used in IUI to increase the number of follicles. While more follicles generally improve the odds of pregnancy, they also increase the risk of multiple pregnancy. In the past, multiple pregnancies were common in assisted reproductive technologies, but there is now a consensus that they are associated with higher risks of preterm delivery, growth retardation and preeclampsia.
Multiple pregnancy rate increases with more than two follicles
According to a meta-analysis published on the Human Reproduction Update, multifollicular growth is associated with better pregnancy rates in IUI with ovarian stimulation, but at the expense of high risk of multiple pregnancy.1 Cycles with three or four follicles were associated with an increased multiple pregnancy rate without substantial gain in overall pregnancy rate. The authors concluded that IUI with ovarian hyperstimulation should use no more than two follicles.
IUI success rate with only one follicle
Two studies consisting of more than 60% monofollicular cycles reported high pregnancy rates of 16.6% and 10.4%.2,3 In addition, a study involving 300 couples found that induction of more than one follicle did not improve the ongoing pregnancy rate, but did increase the risk of multiple pregnancies.4 These results support the notion that IUI with only one follicle does not compromise success rate but provides safety.
Optimal follicle size
Apart from the number of follicles, the diameter of follicles also affects IUI success. One study reported that patients with a follicle size of 19-20 mm had much higher clinical pregnancy (30.2%), ongoing pregnancy (24%) and live birth rate (24%).5
IUI success with ovarian stimulation protocols
Ovarian stimulation in IUI usually involves using either clomiphene citrate or gonadotrophins. Compared to natural IUI, drug assisted IUI generally has a higher success rate. For example, one study reported a 9.8% pregnancy rate using clomiphene citrate, much higher than that of natural IUI cycles (3.3%).6
Gonadotrophin vs Clomiphene citrate
Several studies have reported a higher success rate when gonadotrophins are used for ovarian stimulation. In a study of patients with unexplained or mild male factor infertility who underwent IUI with recombinant gonadotrophin, the pregnancy rate per cycle was 16.6%.7 Live birth rate was 11.4% per cycle or 21.1% per patient. In another study, the success live birth rate of IUI with gonadotrophins was 13% as opposed to 8% using clomiphene.8 However, this difference only exists when there is only one follicle present. When there are two or more follicles, the two stimulation protocols are equally effective.
1. One or two follicles only
There is abundant evidence that suggested using one or two follicles in IUI is sufficient and safer than multiple follicles. Multiple follicles generally do not improve IUI success but increase the risk of multiple pregnancy and related pregnancy complications. Therefore, it is important to ensure low doses of ovarian stimulation medications with your treatment provider.
2. Gonadotrophin stimulation protocol
Controlled ovarian stimulation is an effective strategy of timing ovulation and improving IUI success. Among the different protocols, gonadotrophin stimulation appears to have the highest success rate. Therefore, it is worth checking with your clinic which stimulation protocol is used and why they think the choice is justified.
3. Progesterone luteal support following insemination
Progesterone luteal support is commonly used in the second half of an IVF cycle following controlled ovarian hyperstimulation. Patients undergoing IUI with controlled ovarian stimulation can also benefit from progesterone luteal support after insemination. In three independent studies, the use of progesterone luteal phase support led to a noticeable improvement in the IUI success rate, with 10%, 9% and 13.4% improvement respectively.9-11
4. Ultrasound guidance by an experienced physician
One study reported that the use of ultrasound guidance could improve IUI success rate from 13.9% to 23.4%.12 However, another study also concluded no significant difference with ultrasound guidance.13 It appears that ultrasound guidance is only beneficial when used by an experienced professional, but not when conducted by a junior provider.14
5. Doing two IUI per cycle (Double IUI)
A study reported that doing two IUIs 18 hours and 36 hours after the day of timed ovulation resulted in better clinical pregnancy rate (16.2%) as compared to a single IUI (11%).15 Similar benefits have also been shown in patients positive for anti-endometrial antibodies.16 Therefore, a double IUI may be beneficial for some patients. Nevertheless, there is also evidence suggesting that one well-timed IUI is sufficient for most patients.
When should you move on?
Unfortunately, IUI is more variable than IVF and it is not always possible to figure out what went wrong. If IUI has failed for 3 times or there is low ovarian reserve, the chance of success with IUI is much lower than more precise treatments like IVF and ICSI. One study found that 7.4% of couples were pregnant after 1 cycle, 18% were pregnant after 3 cycles, 30% after for 6 cycles, and 41% after 9 cycles. By adding more cycles, the chance of success does increase, but at a reduced difference each time. For patients with more severe male infertility or low ovarian reserve, IVF should be considered earlier.
1 van Rumste, M. M. et al. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis. Hum Reprod Update 14, 563-570, doi:10.1093/humupd/dmn034 (2008).
2 Crosignani, P. G., Somigliana, E. & Intrauterine Insemination Study, G. Effect of GnRH antagonists in FSH mildly stimulated intrauterine insemination cycles: a multicentre randomized trial. Hum Reprod 22, 500-505, doi:10.1093/humrep/del416 (2007).
3 Ragni, G. et al. GnRH antagonists and mild ovarian stimulation for intrauterine insemination: a randomized study comparing different gonadotrophin dosages. Hum Reprod 19, 54-58, doi:10.1093/humrep/deh023 (2004).
4 van Rumste, M. M., den Hartog, J. E., Dumoulin, J. C., Evers, J. L. & Land, J. A. Is controlled ovarian stimulation in intrauterine insemination an acceptable therapy in couples with unexplained non-conception in the perspective of multiple pregnancies? Hum Reprod 21, 701-704, doi:10.1093/humrep/dei365 (2006).
5 Maher, M. A., Abdelaziz, A. & Shehata, Y. A. Effect of follicular diameter at the time of ovulation triggering on pregnancy outcomes during intrauterine insemination. Int J Gynaecol Obstet 139, 174-179, doi:10.1002/ijgo.12291 (2017).
6 Hannoun, A., Abu-Musa, A., Kaspar, H. & Khalil, A. Intrauterine insemination IUI: the effect of ovarian stimulation and infertility diagnosis on pregnancy outcome. Clin Exp Obstet Gynecol 25, 144-146 (1998).
7 Erdem, A., Erdem, M., Atmaca, S., Korucuoglu, U. & Karabacak, O. Factors affecting live birth rate in intrauterine insemination cycles with recombinant gonadotrophin stimulation. Reprod Biomed Online 17, 199-206, doi:10.1016/s1472-6483(10)60195-2 (2008).
8 Ghesquiere, S. L., Castelain, E. G., Spiessens, C., Meuleman, C. L. & D’Hooghe, T. M. Relationship between follicle number and (multiple) live birth rate after controlled ovarian hyperstimulation and intrauterine insemination. Am J Obstet Gynecol 197, 589 e581-585, doi:10.1016/j.ajog.2007.05.016 (2007).
9 Maher, M. A. Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles. Eur J Obstet Gynecol Reprod Biol 157, 57-62, doi:10.1016/j.ejogrb.2011.03.022 (2011).
10 Erdem, A., Erdem, M., Atmaca, S. & Guler, I. Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles: a prospective randomized study. Fertil Steril 91, 2508-2513, doi:10.1016/j.fertnstert.2008.04.029 (2009).
11 Agha-Hosseini, M., Rahmani, M., Alleyassin, A., Safdarian, L. & Sarvi, F. The effect of progesterone supplementation on pregnancy rates in controlled ovarian stimulation and intrauterine insemination cycles: a randomized prospective trial. Eur J Obstet Gynecol Reprod Biol 165, 249-253, doi:10.1016/j.ejogrb.2012.08.007 (2012).
12 Oztekin, D. et al. The use of ultrasound during intrauterine insemination in unexplained infertility may improve pregnancy outcomes. Med Princ Pract 22, 291-294, doi:10.1159/000345387 (2013).
13 Ramon, O. et al. Ultrasound-guided artificial insemination: a randomized controlled trial. Hum Reprod 24, 1080-1084, doi:10.1093/humrep/den498 (2009).
14 Oruc, A. S. et al. Influence of ultrasound-guided artificial insemination on pregnancy rates: a randomized study. Arch Gynecol Obstet 289, 207-212, doi:10.1007/s00404-013-2965-y (2014).
15 Randall, G. W. & Gantt, P. A. Double vs. single intrauterine insemination per cycle: use in gonadotropin cycles and in diagnostic categories of ovulatory dysfunction and male factor infertility. J Reprod Med 53, 196-202 (2008).
16 Subit, M., Gantt, P., Broce, M., Seybold, D. J. & Randall, G. Endometriosis-associated infertility: double intrauterine insemination improves fecundity in patients positive for antiendometrial antibodies. Am J Reprod Immunol 66, 100-107, doi:10.1111/j.1600-0897.2010.00973.x (2011).