Should couples with unexplained infertility have three to six cycles of intrauterine insemination with ovarian stimulation or in vitro fertilization as first-line treatment?

The most acceptable definition of “unexplained infertility” is 1 to 3 years of attempting conception unsuccessfully when routine tests for tubal patency, ovulatory disorders, and sperm quality are normal. According to the literature, between 15% to 30% of all couples presenting with infertility after 1 year receive a diagnosis of unexplained infertility. Possible interventions in case of unexplained infertility consist of three options: expectant management, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) or intrauterine insemination (IUI) with mild gonadotropin, letrozole, or clomiphene citrate (CC) ovarian stimulation. Increasing success rates after IVF-ICSI with better implantation rates per embryo have been reported in recent years, partly because of better air quality and quality control programs in IVF laboratories and technical changes in the procedures itself, such as the use of soft catheters and ultrasound-guided embryo transfers (1Khoudja R.Y. Xu Y. Li T. Zhou C. Better IVF outcomes following improvements in laboratory air quality.J Assist Reprod Genet. 2013; 30: 69-76Crossref PubMed Scopus (31) Google Scholar, 2Mains L. Van Voorhis B.J. Optimizing the technique of embryo transfer.Fertil Steril. 2010; 94: 785-790Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). High-order multiple births, the main complication associated with IVF, have declined substantially in many countries because fewer embryos are transferred. These changes have made conventional IVF a more attractive option from a cost-effective point of view when compared with IUI. The rationale behind IUI with or without ovarian stimulation (OS) is to increase the gamete density at the site of fertilization. Compared with IVF, IUI can be done without expensive infrastructure and is less invasive, is less expensive, and requires only limited training. Moreover, IUI can be performed with minimal risks and monitoring, resulting in a high couple compliance (3Homburg R. The case for initial treatment with intrauterine insemination as opposed to in vitro fertilization for idiopathic infertility.Hum Fertil (Camb). 2003; 6: 122-124Crossref PubMed Scopus (10) Google Scholar). Three to six cycles of IUI have become common practice worldwide and at least three consecutive IUI cycles are recommended before resorting to IVF (4Cohlen B. Bijkerk A. Van der Poel S. Ombelet W. IUI: review and systematic assessment of the evidence that supports global recommendations.Hum Reprod Update. 2018; 24: 300-319Crossref PubMed Scopus (31) Google Scholar). Compared with IVF, a similar increase in pregnancy rates with IUI has not been reported. For IUI to remain the best first-line option in unexplained infertility, we need to increase the delivery rate per cycle without increasing the multiple pregnancy rate. Different strategies to increase IUI success rates—such as different ovarian stimulation protocols, better timing of IUI, and various sperm processing techniques—have been investigated, with limited success. Previous reports had shown that a slow-release IUI might improve the pregnancy rate compared with bolus IUI (5Muharib N.S. Abdel Gadir A. Shaw R.W. Slow release intrauterine insemination versus the bolus technique in the treatment of women with cervical mucus hostility.Hum Reprod. 1992; 7: 227-229Crossref PubMed Scopus (6) Google Scholar, 6Marschalek J. Egarter C. Vytiska-Binsdorfer E. Obruca A. Campbell J. Harris P. et al.Pregnancy rates after slow-release insemination (SRI) and standard bolus intrauterine insemination (IUI): a multicentre randomised, controlled trial.Sci Rep. 2020; 10: 7719Crossref Scopus (1) Google Scholar). We compared ongoing pregnancy rates after bolus IUI versus patient-friendly slow-release IUI. By using cluster-weighted generalized estimating equations we found a statistically significant increase (4.5%) in ongoing pregnancy rates in the slow-release group (7Bijnens H. Thijssen A. Jacobs P. Theys S. Pascale C. Vandewal V. et al.Patient-friendly insemination with homologous and donor sperm positively influences clinical pregnancy rates (Abstract).Hum Reprod. 2017; 32: i25Google Scholar). Better patient selection is also important. In patients with mid-distal or distal unilateral tubal occlusion, a statistically significant decrease in IUI success rate has been found. These patients should be referred for laparoscopic assessment and IVF instead of IUI should be the first-choice treatment (8Berker B. Şükür Y.E. Kahraman K. Atabekoğlu C.S. Sönmezer M. Özmen B. et al.Impact of unilateral tubal blockage diagnosed by hysterosalpingography on the success rate of treatment with controlled ovarian stimulation and intrauterine insemination.J Obstet Gynaecol. 2014; 34: 127-130Crossref PubMed Scopus (11) Google Scholar). Recent reports have described a statistically significant negative effect of human papilloma virus (HPV) positivity in men and women on clinical pregnancy rates after IUI (9Depuydt C.E. Verstraete L. Berth M. Beert J. Bogers J.-P. Salembier G. et al.Human papillomavirus positivity in women undergoing intrauterine insemination has a negative effect on pregnancy rates.Gynecol Obstet Invest. 2016; 81: 41-46Crossref PubMed Scopus (24) Google Scholar, 10Depuydt C.E. Donders G.G.G. Verstraete L. Vanden Broeck D. Beert J.F.A. Salembier G. et al.Infectious human papillomavirus virions in semen reduce clinical pregnancy rates in women undergoing intrauterine insemination.Fertil Steril. 2019; 111: 1135-1144Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Therefore, HPV-positive women and men should not receive IUI as a first-line treatment although it is unknown yet whether HPV positivity has an effect on IVF-ICSI pregnancy rates. During the last 5 years, a number of well-organized studies in different patient populations have shown that IUI should be the first-line treatment option over IVF in selected cases of unexplained infertility (11Tjon-Kon-Fat R.I. Bensdorp A.J. Bossuyt P.M.M. Koks C. Oosterhuis G.J.E. Hoek A. et al.Is IVF-served two different ways-more cost-effective than IUI with controlled ovarian hyperstimulation?.Hum Reprod. 2015; 30: 2331-2339Crossref PubMed Scopus (35) Google Scholar, 12Danhof N.A. van Wely M. Repping S. Koks C. Verhoeve H.R. de Bruin J.P. et al.Follicle stimulating hormone versus clomiphene citrate in intrauterine insemination for unexplained subfertility: a randomized controlled trial.Hum Reprod. 2018; 33: 1866-1874Crossref PubMed Scopus (17) Google Scholar, 13Farquhar C.M. Liu E. Armstrong S. Arroll N. Lensen S. Brown J. Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open label, randomised, controlled, two-centre trial.Lancet. 2018; 93: 441-450Abstract Full Text Full Text PDF Scopus (37) Google Scholar). In a multicenter, randomized, noninferiority INeS trial, Bensdorp et al. (14Bensdorp A.J. Tjon-Kon-Fat R.I. Bossuyt P.M.M. Koks C.A.M. Oosterhuis G.J.E. Hoek A. et al.Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine inse.BMJ. 2015; 350: g7771Crossref PubMed Scopus (70) Google Scholar) showed that IUI-OS was noninferior compared with IVF with single-embryo transfer or IVF in a modified natural cycle, with a reasonably low multiple birth rate for couples with mild male factor or unexplained infertility and a poor prognosis of becoming pregnant naturally. Farquhar et al. (13Farquhar C.M. Liu E. Armstrong S. Arroll N. Lensen S. Brown J. Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open label, randomised, controlled, two-centre trial.Lancet. 2018; 93: 441-450Abstract Full Text Full Text PDF Scopus (37) Google Scholar) randomized 201 patients with unexplained infertility to IUI with CC or expectant management, showing that the former was associated with a threefold greater live-birth rate than the latter (31% vs. 9%). In a large randomized multicentre study in the Netherlands including 738 couples with an unfavorable prognosis, four cycles of IUI + FSH were not superior to four cycles of IUI + CC, with 31% and 26% ongoing pregnancies, respectively, and no difference in the multiple pregnancy rate (12Danhof N.A. van Wely M. Repping S. Koks C. Verhoeve H.R. de Bruin J.P. et al.Follicle stimulating hormone versus clomiphene citrate in intrauterine insemination for unexplained subfertility: a randomized controlled trial.Hum Reprod. 2018; 33: 1866-1874Crossref PubMed Scopus (17) Google Scholar). Gonadotropins seem to improve live-birth/ongoing pregnancy rates compared with CC within a protocol adhering to strict cancellation criteria, not taking into account costs and patients preference (15Danhof N.A. Wang R. van Wely M. van der Veen F. Mol B.W.J. Mochtar M.H. IUI for unexplained infertility-a network meta-analysis.Hum Reprod Update. 2020; 26: 1-15Crossref PubMed Scopus (8) Google Scholar). Female age should also be considered as an important factor. According to the 2017 Belgian Register for Assisted Procreation (BELRAP) data the delivery rate per cycle for patients older than 40 years was 1.7% for IUI and 9.5 % for IVF-ICSI (16Belgian Register for Assisted Procreation (BELRAP) website.https://www.belrap.beGoogle Scholar). As costs linked to fertility care are not covered by government or insurance companies in most countries, the relative cost-effectiveness of fertility treatments is very important. In an investigation of direct health care costs in the cohort of patients of the INeS-trial, IUI-OS turned out to be the most cost-effective strategy and up to six cycles of IUI–OS was still cost-effective when compared with direct IVF (11Tjon-Kon-Fat R.I. Bensdorp A.J. Bossuyt P.M.M. Koks C. Oosterhuis G.J.E. Hoek A. et al.Is IVF-served two different ways-more cost-effective than IUI with controlled ovarian hyperstimulation?.Hum Reprod. 2015; 30: 2331-2339Crossref PubMed Scopus (35) Google Scholar). Making use of a computer-simulated cohort of infertile women, Moolenaar et al. (17Moolenaar L.M. Cissen M. de Bruin J.P. Hompes P.G.A. Repping S. van der Veen F. et al.Cost-effectiveness of assisted conception for male subfertility.Reprod Biomed Online. 2015; 30: 659-666Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar) showed that above a prewash total motile sperm count (TMSC) of 3 million, IUI is less costly than conventional IVF, but below 3 million IVF-ICSI is less costly. In a cost-effectiveness analysis alongside the randomized controlled trial of Danhof et al. (18Danhof N.A. van Wely M. Repping S. van der Ham D.P. Klijn N. Janssen I.C.A.H. et al.Gonadotrophins or clomiphene citrate in couples with unexplained infertility undergoing intrauterine insemination: a cost-effectiveness analysis.Reprod Biomed Online. 2020; 40: 99-104Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar), it was concluded that gonadotropin-IUI were more expensive compared with CC-IUI without being statistically significantly more effective. The U.K. data from a Human Fertilisation and Embryology Authority (HFEA) freedom of information request for 2012–2016 show that IUI is safer and more cost-effective than IVF treatment (19Bahadur G. Homburg R. Bosmans J.E. Huirne J.A.F. Hinstridge P. Jayaprakasan K. et al.Observational retrospective study of UK national success, risks and costs for 319,105 IVF/ICSI and 30,669 IUI treatment cycles.BMJ Open. 2020; 10e034566Crossref Scopus (10) Google Scholar). Intrauterine insemination is publicly funded in 14 out of 42 European countries (20Calhaz-Jorge C. De Geyter C.H. Kupka M.S. Wyns C. Mocanu E. Motrenko T. et al.Survey on ART and IUI: legislation, regulation, funding and registries in European countries: the European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE).Hum Reprod Open. 2020; 2020: hoz044Crossref Google Scholar), and this will surely increase the number of IUIs performed. On the other hand, IUI is the only available method for unexplained infertility in many resource-poor countries where IVF-ICSI is not accessible for the large majority of the population due to limited availability of IVF centers and high costs (21Ombelet W. Cooke I. Dyer S. Serour G. Devroey P. Infertility and the provision of infertility medical services in developing countries.Hum Reprod Update. 2008; 14: 605-621Crossref PubMed Scopus (289) Google Scholar, 22Ombelet W. Onofre J. IVF in Africa: what is it all about?.Facts Views Vis Obgyn. 2019; 11: 65-76PubMed Google Scholar). To conclude, for women younger than 40 years with unexplained infertility, three to six cycles of IUI with ovarian stimulation should be recommended as a first-line therapy, provided a strict cancellation strategy is followed to avoid multiple pregnancies. The results from IUI have to improve by optimizing patient selection and refining the techniques and treatment strategies. When I talk to laypeople about fertility, they are always surprised to discover how little we truly understand of conception and implantation. Perhaps the best example of this is unexplained infertility, the enigma of reproductive medicine. Why are these couples unable to conceive? We do not know. We do know that some of them are not diseased at all: conceiving is, after all, very much like throwing a die (23Evers J.L. Female subfertility.Lancet. 2002; 360: 151-159Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). Sometimes you throw a six, but you will not be surprised if you get anything else. Some patients will not throw a six many times in a row. These “unlucky” patients—who are perfectly healthy—are very likely to conceive naturally, despite their diagnosis after (at least) 1 year of trying. Approximately 30% of unexplained infertile couples conceive in the year following diagnosis (24Hunault C.C. Habbema J.D. Eijkemans M.J. Collins J.A. Evers J.L. te Velde E.R. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models.Hum Reprod. 2004; 19: 2019-2026Crossref PubMed Scopus (196) Google Scholar, 25Te Velde E.R. Eijkemans R. Habbema H.D. Variation in couple fecundity and time to pregnancy, an essential concept in human reproduction.Lancet. 2000; 355: 1928-1929Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 26Van Eekelen R. Scholten I. Tjon-Kon-Fat R.I. van der Steeg J.W. Steures P. Hompes P. et al.Natural conception: repeated predictions over time.Hum Reprod. 2017; 32: 346-353Crossref PubMed Scopus (29) Google Scholar). On the other side of the spectrum are the couples with unexplained infertility who seem to be unable to conceive no matter what we try, even after IVF. This can be considered sterility (27Gray E. Evans A. Anderson J. Kippen R. Using split-population models to examine predictors of the probability and timing of parity progression.Eur J Population. 2010; 26: 275-295Crossref Scopus (12) Google Scholar). With a perspective that covers many years—the entire reproductive life span of a woman—it will not matter what treatment options are presented to sterile couples. All other subtypes of unexplained infertility, with biological mechanisms we are currently unaware of, lie somewhere in between: lower than average fertility but not sterile. This can be referred to as subfertility, which includes age-related fertility decline (25Te Velde E.R. Eijkemans R. Habbema H.D. Variation in couple fecundity and time to pregnancy, an essential concept in human reproduction.Lancet. 2000; 355: 1928-1929Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 28ESHRE Capri Workshop GroupA prognosis-based approach to infertility: understanding the role of time.Hum Reprod. 2017; 32: 1556-1559Crossref PubMed Scopus (18) Google Scholar). Our current inability to accurately distinguish among these types of patients is the core of this dilemma. The logical conclusion is that we are dependent on the factor of time. As time passes, selection takes place, during which couples with the best prognoses conceive; this filters out the healthy-but-unlucky and subfertile patients who do not necessarily require IUI, let alone IVF (26Van Eekelen R. Scholten I. Tjon-Kon-Fat R.I. van der Steeg J.W. Steures P. Hompes P. et al.Natural conception: repeated predictions over time.Hum Reprod. 2017; 32: 346-353Crossref PubMed Scopus (29) Google Scholar, 29Van Eekelen R. van Geloven N. van Wely M. McLernon D.J. Eijkemans M.J. Repping S. et al.Constructing the crystal ball: how to get reliable prognostic information for the management of subfertile couples.Hum Reprod. 2017; 32: 2153-2158Crossref Scopus (14) Google Scholar). I believe that, from this principle, it follows that several cycles of IUI (ideally in combination with ovarian stimulation) should be the first-line treatment for couples with unexplained infertility. There are four reasons to choose IUI. The most important argument is invasiveness: IVF is generally considered a stressful and painful procedure, and IUI much less so. Especially for women with unexplained infertility of whom many do not require IVF, the primum non nocere oath should be adhered to. A second argument concerns improving the mental health of patients: they may feel their issue is acknowledged when their trajectory now involves active treatment, without resorting to the most invasive and stressful option. A third argument is that the effectiveness of IVF versus IUI in terms of increasing the chance of a live birth has a poor evidence base; there are no trials that compare IVF with both IUI and expectant management (30Kamphuis E.I. Bhattacharya S. van der Veen F. Mol B.W. Templeton A. Are we overusing IVF?.BMJ. 2014; 348: g252Crossref PubMed Scopus (86) Google Scholar, 31Tjon-Kon-Fat R.I. Bensdorp A.J. Scholten I. Repping S. van Wely M. Mol B.W. et al.IUI and IVF for unexplained subfertility: where did we go wrong?.Hum Reprod. 2016; 31: 2665-2667Crossref PubMed Scopus (12) Google Scholar, 32Wang R. Danhof N.A. Tjon-Kon-Fat R.I. Eijkemans M.J. Bossuyt P.M. Mochtar M.H. et al.Interventions for unexplained infertility: a systematic review and network meta-analysis.Cochrane Database Syst Rev. 2019; 9CD012692Google Scholar). Even if observational data suggest that the per-cycle chance of IVF is the highest, it is much less clear if this is the case over a longer period of follow up, or when receiving IUI first and then IVF (14Bensdorp A.J. Tjon-Kon-Fat R.I. Bossuyt P.M.M. Koks C.A.M. Oosterhuis G.J.E. Hoek A. et al.Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine inse.BMJ. 2015; 350: g7771Crossref PubMed Scopus (70) Google Scholar, 33Van Eekelen R. Eijkemans M.J. Mochtar M.H. Mol F. Mol B.W. Groen H. et al.Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?.Human Reprod. 2020; 35: 2137-2146Crossref Scopus (3) Google Scholar). The fourth and last argument is stalling for time allows selection to take place: couples rarely receive consecutive IUI cycles, such that their IUI trajectory also serves as a postponement of IVF during which they might even conceive naturally. Again, this selection could filter out the last healthy-but-unlucky or subfertile patients in particular, without harming the sterile patients. As for not offering IUI as a first-line treatment, there are a couple of exceptions to consider. Shorter time to pregnancy is a more important argument for couples that wish to have multiple children, although the clinician should prepare the couple for the fact that this might be unattainable. This is especially true when the woman is of a more advanced age (i.e., 38 years or above), although the higher the female age, the less certain it is that IVF offers much benefit compared with expectant management (34Chua S.J. Danhof N.A. Mochtar M.H. van Wely M. McLernon D.J. Custers I. et al.Age-related natural fertility outcomes in subfertile women over 35: an individual participant data meta-analysis.Hum Reprod. 2020; 35: 1808-1820Crossref Scopus (6) Google Scholar, 35Van Eekelen R. van Geloven N. van Wely M. Bhattacharya S. van der Veen F. Eijkemans M.J. et al.IVF for unexplained subfertility; whom should we treat?.Hum Reprod. 2019; 34: 1249-1259Crossref Scopus (3) Google Scholar). If a multiple pregnancy has to be avoided at all costs (e.g., due to a high risk of complications), this can be achieved with IUI without ovarian stimulation or, generally considered more effective, IVF using single-embryo transfer (SET). Albeit costs depend on the country and reimbursement system, the general consensus (with current limited evidence) is as follows: IUI-OS seems more expensive and more effective than expectant management, and IVF seems more expensive and more effective than IUI-OS (32Wang R. Danhof N.A. Tjon-Kon-Fat R.I. Eijkemans M.J. Bossuyt P.M. Mochtar M.H. et al.Interventions for unexplained infertility: a systematic review and network meta-analysis.Cochrane Database Syst Rev. 2019; 9CD012692Google Scholar, 33Van Eekelen R. Eijkemans M.J. Mochtar M.H. Mol F. Mol B.W. Groen H. et al.Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?.Human Reprod. 2020; 35: 2137-2146Crossref Scopus (3) Google Scholar). When multiple options are available to solve the same problem, the major decision-making problem is which to give first (36Briggs A. Claxton K. Sculpher M. Decision modelling for health economic evaluation. Oxford University Press, Oxford2006Google Scholar). If the couple must pay for their own treatment, depending on their budget, IVF might be chosen to avoid incurring costs for two treatment trajectories. The evidence so far supports that treating later—allowing selection to take place over time, be it via expectant management or an IUI trajectory—avoids costly and invasive IVF treatment without decreasing the cumulative chance of live birth. Not only has this been shown in a recent cost-effectiveness analysis that combined the current body of evidence on unexplained infertility (32Wang R. Danhof N.A. Tjon-Kon-Fat R.I. Eijkemans M.J. Bossuyt P.M. Mochtar M.H. et al.Interventions for unexplained infertility: a systematic review and network meta-analysis.Cochrane Database Syst Rev. 2019; 9CD012692Google Scholar, 33Van Eekelen R. Eijkemans M.J. Mochtar M.H. Mol F. Mol B.W. Groen H. et al.Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?.Human Reprod. 2020; 35: 2137-2146Crossref Scopus (3) Google Scholar), this was also shown in the most recent trial that compared IUI-OS with IVF, the Dutch INeS trial (14Bensdorp A.J. Tjon-Kon-Fat R.I. Bossuyt P.M.M. Koks C.A.M. Oosterhuis G.J.E. Hoek A. et al.Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine inse.BMJ. 2015; 350: g7771Crossref PubMed Scopus (70) Google Scholar). In this trial, the primary analysis followed the intention-to-treat principle, meaning that patients allocated to IUI-OS were analyzed as IUI-OS regardless of what they actually received. The investigators showed that a considerable fraction of the couples allocated to IUI-OS who did not conceive at first then switched to IVF SET. This yielded a less expensive strategy, in which the cumulative chance of live birth was similar to the strategy in which everyone started with IVF SET. To summarize, IUI as first-line treatment spares many women with unexplained infertility from an invasive, stressful treatment. This approach also seems to be cost-effective without decreasing the cumulative chance of a live birth. William Ledger, M.D.View Large Image Figure ViewerDownload Hi-res image Download (PPT) For many years, IVF has been viewed as the last resort for couples presenting with infertility, rather than as the first-line treatment. Although some conditions present a clear indication for first-line IVF—for example, severe male factor infertility or tubal disease—for those couples with unexplained or mild male factor infertility, IUI has often been favored as a more tolerable and cost effective option. However, this concept has been challenged in recent years because the increasing success rates and decreasing complications recorded for IVF have closed the gap. With the U.K. National Institute for Health and Care Excellence (NICE) guidelines (37National Institute for Health and Care Excellence (NICE)Fertility problems: assessment and treatment. Clinical Guideline CG156.https://www.guidelines.co.uk/sexual-health/nice-fertility-problems-guideline/454859.articleGoogle Scholar) now recommending IVF as the first-line treatment for couples with unexplained infertility, the debate continues on how to best serve these patients. In its infancy, the success rates for IVF were reported in single digits (38Edwards R.G. Steptoe P.C. Current status of in vitro fertilisation and implantation of human embryos.Lancet. 1983; 2: 1265-1269Abstract PubMed Scopus (169) Google Scholar). However, across the world we see consistently rising success rates year after year. For example, the Australia and New Zealand Assisted Reproduction Database (ANZARD) most recent report from 2017 quotes a 26.8% live-birth rate (LBR) per autologous embryo transfer (39Newman J.E. Fitzgerald O. Paul R.C. Chambers G.M. Assisted reproductive technology in Australia and New Zealand 2017. National Perinatal Epidemiology and Statistics Unit, the University of New South Wales Sydney, Sydney2019https://npesu.unsw.edu.au/sites/default/files/npesu/data_collection/Assisted%20Reproductive%20Technology%20in%20Australia%20and%20New%20Zealand%202017.pdfGoogle Scholar). The HFEA data from the same year in the United Kingdom quotes a 22% live-birth rate (40Human Fertility and Embryology AuthorityFertility treatment 2017: trends and figures.https://www.hfea.gov.uk/media/2894/fertility-treatment-2017-trends-and-figures-may-2019.pdfGoogle Scholar). Although pregnancy rates from IVF continue to improve, they remain relatively static with IUI (41Huang L. Tan J. Hitkari J. Dahan M. Should IVF be used as a firstling treatment or as a last resort. A debate presented at the 2013 Canadian Fertility and Andrology Society meeting.Reprod Biomed Online. 2015; 30: 128-136Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). A paucity of recent data concerning pregnancy and live-birth rates after IUI was acknowledged in a recent Cochrane review (42Ayeleke R.O. Asseler J.D. Cohlen B.J. Veltman-Verhulst S.M. Intra-uterine insemination for unexplained subfertility.Cochrane Database Syst Rev. 2020; 3CD001838PubMed Google Scholar), but pregnancy rates are commonly quoted as 10% to 20% (4Cohlen B. Bijkerk A. Van der Poel S. Ombelet W. IUI: review and systematic assessment of the evidence that supports global recommendations.Hum Reprod Update. 2018; 24: 300-319Crossref PubMed Scopus (31) Google Scholar, 43Chambers G. Sullivan E. Shanahan M. Ho M. Priester M. Chapman M.G. Is in vitro fertilisation more effective than stimulated intrauterine insemination as a first line therapy for subfertility? A cohort analysis.Aust NZ J Obstet Gynaecol. 2010; 50: 280-288Crossref PubMed Scopus (15) Google Scholar). A study by Chambers et al. (43Chambers G. Sullivan E. Shanahan M. Ho M. Priester M. Chapman M.G. Is in vitro fertilisation more effective than stimulated intrauterine insemination as a first line therapy for subfertility? A cohort analysis.Aust NZ J Obstet Gynaecol. 2010; 50: 280-288Crossref PubMed Scopus (15) Google Scholar) in 2010 reported a pregnancy rate for IUI at 15% for couples with unexplained infertility undergoing their first cycle of IUI, dropping to 7% with the second cycle. Chambers et al. (43Chambers G. Sullivan E. Shanahan M. Ho M. Priester M. Chapman M.G. Is in vitro fertilisation more effective than stimulated intrauterine insemination as a first line therapy for subfertility? A cohort analysis.Aust NZ J Obstet Gynaecol. 2010; 50: 280-288Crossref PubMed Scopus (15) Google Scholar) also showed that increasing IVF success rates translated into a shorter time to pregnancy. There are many studies that consistently show that women and men are waiting until later in life before starting their families. For example, the average age of women giving birth in the United Kingdom has increased from 26.4 years in 1975 to 30.5 in 2017 (44Office for National StatisticsBirth characteristics in England and Wales 2018: annual live births by sex, ethnicity and month, maternities by place of birth and with multiple births, and stillbirths by age of parents and calendar quarter.https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/bulletins/birthcharacteristicsinenglandandwales/2018Date: January 2019Google Scholar), and the average age of women using assisted reproduction technology (ART) in Australia is 35.9 years (39Newman J.E. Fitzgerald O. Paul R.C. Chambers G.M. Assisted reproductive technology in Australia and New Zealand 2017. National Perinatal Epidemiology and Statistics Unit, th