Male infertility has become a global health issue. It has been reported that there had been a decline in semen counts over the previous 50 years (16). According to the results from Agarwal A’s research (17), at least 30 million men worldwide are infertile with the highest rates in Africa and Eastern Europe. For a long time, IUI has been considered as the first-line treatment for male infertility. And the published pregnancy rates with IUI in NC cycles vary from 0-20.5%; while in stimulated cycles vary from 3.9–13.6% per cycle (4). In our study, the pregnancy rate and live birth rate per cycle in the NC-IUI group were 10.6% and 9.6%, respectively, while in the COS-IUI group were 12.8% and 11.4%, respectively, which was slightly higher than the former, but no statistically significant differences were observed. When only the first cycle were included and were further divided into two subgroups: the year before 2014 and the year after 2014, to eliminate the potential influence of repeated cycle data and different diagnostic criteria (WHO 4th version and WHO 5th version) on the results, similar results were shown. Besides, the cumulative live birth rate was also compared between those who used NC always and those who use NC or COS randomly (19.9% vs. 19.3%, P = 1.000, data were not shown). Therefore, we advocate that for male infertility, IUI with COS did not significantly increase the pregnancy rate and live birth rate regardless of the diagnostic criteria for male infertility, which is consistent with other studies (4, 13–15, 18). Furthermore, two recent systematic reviews (10, 19) also suggested that IUI with or without COS for male infertility has no significant differences in pregnancy rate and live birth rate. However, in the study of Guzick DS. et al. (20), discordant results were shown. Their results showed that for unexplained infertility or male infertility, the pregnancy rate was nearly twice in IUI with superovulation as high as that in IUI without superovulation (33% vs. 18%). This might be explained by their intense stimulation with 150 IU HMG as an initiated dose.
As it has also been suggested that COS could overcome subtle ovulation disorders that cannot be detected by routine testing (15, 21), and to some extent, multifollicular growth is associated with increased pregnancy rates, IUI with COS is always preferred. However, of note, when undertaking IUI with COS, unlike in vitro fertilization, which can choose single embryo transfer, the number of oocytes released and fertilized in vivo can be controlled only to a limited extent, therefore, increased incidence of multiple pregnancies was an inherent drawback of this treatment strategy.
Compared with singleton pregnancy, multiple pregnancy is related to a lot of pregnancy complications, including increased risks of miscarriage, pre-eclampsia, growth retardation, and preterm delivery (22). In addition, the rates of caesarean section and perinatal mortality rates were also higher in the multiple pregnancy. These are unacceptable. Therefore, the aim of fertility treatment is shifting from focusing on pregnancy rate to the birth of healthy singletons (23). A meta-analysis from van Rumste et al. (24)showed that the absolute pregnancy rate increased from 8.4–15% in IUI with COS when multifollicular growth was achieved as compared to monofollicular stimulation, while the multiple pregnancy rates increased from 3.7–17% per conceived cycle. They advocated that IUI with COS should not aim for more than two follicles, one stimulated follicle should be the goal if safety is the primary concern, whereas two follicles may be accepted after careful patient counseling.
In our study, two patients who received IUI with COS (both with HMG protocol, 2 follicles were generated) resulted in multiple pregnancies (one twin and one heterotopic pregnancy). A trend toward higher multiple pregnancy rate was observed in the COS-IUI group, when compared to that in the NC-IUI group (10.5% (2/19) vs. 0 (0/42)), but the difference did not reach statistical significance (P = 0.093). However, when we further compared the multiple pregnancy rates between NC-IUI group and ≥ 2 follicles group, a significant difference was found (0 vs. 20%, P = 0.034). Besides, no differences were found between 1 follicle group and ≥ 2 follicles group, which was also 0 vs. 20%, and we contributed this to the small sample size. Few literatures report on multiple pregnancy of IUI with or without COS in male infertility.