Assisted reproduction (ART) is now an established therapy for the treatment of infertility in a multitude of clinical conditions. It embraces a wide scope of techniques of which intrauterine insemination (IUI), in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI) are most popular.
Contrary to IVF/ICSI methods, IUI is easy to perform, inexpensive and offers particular advantages such as the minimal equipment required, an easy technique to learn, being less invasive with a reduced psychological burden on the couple when compared to IVF/ICSI. Subsequently IUI has a good couple compliancy (low drop-out rate), a low risk for OHSS (ovarian hyperstimulation syndrome) and a low multiple pregnancy rate in natural cycles and clomiphene citrate or low-dose HMG (human menopausal gonadotrophins) ovarian stimulation protocols.
The rationale behind intrauterine insemination (IUI) is increasing the gamete density at the site of fertilization. Despite the extensive literature on the subject of artificial insemination with the husband’s semen, controversy remains about the effectiveness of this very popular treatment procedure, particularly in relation to IVF and ICSI.Nevertheless, artificial insemination with husband’s semen remains a widely used treatment option for many couples with unexplained infertility, cervical factor subfertility, physiologic or psychological sexual dysfunction and mild to moderate male subfertility.
Indications for IUI
2.1. Cervical factor
In the case of an isolated cervical factor, defined as a repeated negative post-coital test despite a normal semen quality and adequate timing, IUI in natural cycles significantly increases the probability of conception, In a prospective randomized study subfertile couples with an isolated cervical factor were treated with either IUI or expectant management for 6 months. 26 women in the IUI group conceived (51%) versus 16 women (33%) in the control group.
2.2. Male factor subfertility
In a Cochrane review it was clearly shown that there is insufficient evidence to conclude whether IUI is effective or not in moderate and mild male infertility. Older evidence, often from cross-over trials, found a significant beneficial effect of IUI. Nowadays it is generally accepted that results should be expressed as live birth rates per couple. Up to date such studies are lacking and should be performed as soon as possible. Nevertheless the evidence from older trials indicates that there might be a place for IUI in the case of a moderate male factor.
2.3. Unexplained subfertility
In a meta-analysis of various trials natural cycle IUI has no significant beneficial effect over expectant management in the case of unexplained infertility.On the other hand, this meta-analysis also shows that the combination of ovarian stimulation and IUI significantly improves live birth rates in couples with unexplained infertility, but we have to take into account that the ovarian stimulation regimen in a lot of these studies was rather aggressive resulting in high multiple pregnancy rates. Whether mild ovarian stimulation protocols significantly improves live birth rates has not been proven yet.
2.4. Sexual disorders
In the case of hypospadias, vaginismus, retrograde ejaculation and impotence there is often no need for intra-uterine insemination as semen might be placed intra-vaginally or intra-cervically. When semen parameters are low, as often is the case in men with retrograde ejaculation, semen preparation followed by IUI can be used as a first-line treatment option.
3.Semen quality and IUI
Although a literature search does not reveal level 1 evidence on the relation between sperm quality and IUI success, a large number of prospective observational studies and well organized retrospective analyses can be found. The four sperm parameters that are most frequently examined were the following: (a) the IMC (inseminating motile count after washing), (b) sperm morphology using strict criteria, (c) the TMSC (total motile sperm count in the native sperm sample) and (d) the TM (total motility in the native sperm sample).
It was clearly shown that a score of more than 4% normal morphology using strict criteria is needed to result in a significantly higher pregnancy rate per cycle. In a meta-analysis Van Weert suggested a cut-off value for the IMC between 0.8 and 5 million motile spermatozoa to reach a substantial discriminative performance while according to Ombelet et al an IMC of 1 million can be used as a reasonable threshold level above which IUI can be performed with acceptable pregnancy rates. For the TMSC and the TM a cut-off value of 5–10 million and 30% was most frequently reported, respectively.
It’s obvious that we urgently need more prospective cohort trials investigating the predicting value of semen parameters on IUI outcome by using ROC-curves and multivariate analyses to find out which are the cut-off levels of semen parameters above which IUI is an excellent first-line treatment.
4.Prevention of infections in an IUI program
Various viral agents such as cytomegalovirus (CMV), hepatitis B, C, D (HBV, HCV, HDV), herpes simplex virus type 2 (HSV-2), human T-lymphotrophic virus (HTLV), and human immunodeficiency virus (HIV) can be transmitted through semen and vaginal secretions. In general patients are routinely screened for HIV, HBV/HCV as well as other predominantly prevalent sexual transmitted infections (STIs) and the laboratory staff have to be notified of the test results before processing or cryopreservation of any biological specimen.
Although no sero-conversions of female partners were reported in the literature after inseminations with washed sperm from HIV-positive men, couples should be informed that sperm preparation techniques do not guarantee that HIV is 100% removed from the post-processed sperm sample of HIV-positive males. According to the WHO laboratory manual leukocytospermia may indicate the presence of an infection in the semen sample and can be associated with poor sperm quality.in these cases discontinuous density gradient centrifugation provides superior separation of highly motile spermatozoa from debris, leukocytes and other cell types.
5.Semen preparation techniques (SPT)
Density gradient centrifugation (DGC) showed to be superior to the swim-up and simple wash technique: a clear improvement of morphological normal spermatozoa with grade A motility and normal DNA integrity are obtained in the prepared sample. The DGC selects spermatozoa according to their density and gravity. In a Cochrane Review there was no clear evidence which sperm washing technique is superior when clinical outcomes after IUI are investigated. The meta-analysis did not show evidence of a difference in the effectiveness of a swim-up versus DGC on pregnancy rates per couple (30.5% versus 21.5% Swim-up technique versus wash and centrifugation also showed no significant difference in pregnancy rates (22.2% versus 38.1% resp. Two studies compared gradient versus wash and centrifugation technique with pregnancy rates reaching 23.5% and 13.3%, respectively .Although DGC showed to be superior to swim-up and wash technique concerning laboratory outcomes (e.g. semen parameters) there is insufficient evidence to recommend any specific SPT when speaking about clinical outcome after IUI. Nevertheless, it is clear that quality control and quality management in semen preparation for IUI are mandatory.
6.Ovarian stimulation and prevention of multiple pregnancies
IUI in combination with mild ovarian stimulation is effective in couples with unexplained subfertility, minimal to mild endometriosis and mild male subfertility. According to a risk analysis by van Rumste et al. one should aim for a maximum of two dominant follicles in order to avoid high-order multiple pregnancies.
Ovarian stimulation should be mild and clomiphene citrate (CC, 50–100 mg per day for 5 days) remains the first-choice drug to use although CC might have a negative effect on the endometrium. Contrary to gonadotrophins, CC is easily available, easy to use and less costly. If needed HMG or recombinant FSH can be used in dosages of 50–75 IU per day. Strict ultrasound monitoring of each stimulated cycle is mandatory. One should strive after two dominant follicles larger than 15 mm but all follicles larger than 10 mm should be measured and taken into account when defining cancelation criteria. According to the literature and looking at cost-effectiveness there seems no place for aromatase inhibitors, GnRH agonist or antagonists in IUI programmes (18,19).
It is recommended that secondary preventive measures to prevent multiple pregnancies are needed when four or more follicles ⩾14 mm are present at the time of HCG injection, although evidence-based data are lacking. These measures include cancelation of the cycle, the aspiration of supernumerary follicles and/or escape IVF.
7 . Timing and number of IUIs per cycle, bedrest after IUI
It is well known that oocytes and spermatozoa have a limited period of survival. Therefore adequate timing of the insemination seems to be essential. It was generally accepted that the insemination should be performed just before or maximally 10 h after ovulation. According to the current available evidence a wider time frame can be followed, from 12 to 36 h after HCG injection. Timing of IUI can be performed with LH surge detection or HCG injection.
Most reports recommend a single well timed IUI in couples suffering from unexplained subfertility. Only one study reported a positive effect of double insemination in couples suffering from male subfertility. Double IUI should only be advised when proven effective, since a second IUI will increase the costs and psychological burden. Whether double insemination should be recommended will depend on the results of randomized controlled trials which are urgently needed. Six randomized trials including 829 patients were combined (Table 2). After double IUI, 54 (13.6%) clinical pregnancies were observed; however, after single IUI, there were 62 (14.4%) clinical pregnancies. Both random and fixed effects model yielded similar results (OR, 0.92; 95% CI, 0.59–1.45; P¼0.715 for random effects model; OR, 0.93; 95% CI, 0.62–1.40, P¼0.723 for fixed effects model; Fig. 2). There was no significant difference in the probability to have a pregnancy in women after double IUI as compared to women with single IUI.
According to two prospective randomized trials 10–15 min immobilization subsequent to intra uterine insemination, with or without ovarian stimulation, significantly improves cumulative ongoing pregnancy rates and live birth rates.
Treatment by artificial insemination with husband’s sperm remains a valuable first choice treatment before starting more invasive and more expensive techniques of assisted reproduction in many cases of human subfertility, at least if tubal patency is proven. It is a simple and non-invasive technique which can be performed without expensive infrastructure.
Considering daily practice evidence-based data indicate that the success rate of IUI is improved with an IMC above 1 million, a morphology score of more than 4% normal forms, a TMCS of more than 5 million and an initial total motility of more than 30%. In couples with cervical factor subfertility IUI in natural cycles significantly increases the probability of conception while the combination of ovarian stimulation and IUI is recommended in couples with unexplained subfertility. The goal of ovarian stimulation should be the development of a maximum of two dominant follicles. Sperm washing techniques are used to prevent partner-to-partner transmission during an AIH procedure but do not guarantee that infections are 100% removed from the post-processed sperm sample and no sperm washing technique is superior to another considering IUI outcome. Double IUI results in higher pregnancy rates compared with single IUI in couples with male factor subfertility, but not in unexplained infertility cases. The optimal time-interval between HCG injection and IUI seems between 12 and 36 h and at least 10–15 min of immobilization should be applied after every insemination attempt.