{"paper_id":"1693319b-a88e-4765-ace3-ef8ff25859a1","body_text":"IUI as first line treatment option is highly desirable for couples, easily accessible\nand practised worldwide. The procedure is also well accepted on account of its\nsimplicity ( Bahadur  et al .,\n2016a ). Questions over the efficacy, risks and cost effectiveness of IUI\nare occasionally raised in reviews and guidelines based on the analysis of evidence,\nas in the case of the controversial and much disputed National Institute for\nClinical Excellence  (NICE) 2013  guidelines on\nIUI. Overuse of expensive IVF procedures becomes a contentious issue with regards to\npublic funding when most public bodies around the world face budgetary limitations\n( Bahadur  et al .,\n2016b ).\nFor the 12 th  consecutive year, European data on IUI using husband/partner\nsemen (175,467 cycles) from 27 countries including France, Italy, Spain, Belgium and\nPoland, revealed that in 24 countries the mean live birth rate (LBR) per cycle was\n8.6%, while twin and triplet birth rates associated with IUI were 9.5% and 0.6%,\nrespectively. When all IVF cycles were considered, the clinical pregnancy rates (PR)\nper aspiration and per transfer were 29.6% and 34.5%, with a total multiple LBR of\n18.0%. The proportions of singleton, twin and triplet deliveries after IVF and ICSI\n(added together) were 82%, 17.5% and 0.5%, respectively ( European IVF-monitoring Consortium, 2017 ). In contrast to the\nextensive cross analyses on outcomes for IVF/ICSI cycles, the report places little\nemphasis on IUI cycles ( European IVF-monitoring\nConsortium, 2017 ) despite its benefits and against the ill-constructed\nNICE guidelines excluding IUI as a treatment modality ( Bahadur  et al ., 2017 ), which only considered\nIUI/CC (25mg). The method of reporting varied between countries. Some contained\nsevere limitations and should therefore be interpreted with caution. The data were\nincomplete and collected using different methods. A number of countries were unable\nto provide relevant data such as number of initiated cycles and deliveries.\nThe Cochrane review on IUI for unexplained subfertility ( Veltman-Verhulst  et al ., 2016 ) identified\nthree relevant RCTs ( Deaton  et al .,\n1990 ;  Steures  et al .,\n2006 ;  Bhattacharya  et\nal ., 2008 ) involving a total of 690 couples (mean female age of\n33 years) trying to conceive for an average of 2 to 4 years. One study compared IUI\nto timed SI with cycle monitoring ( Deaton  et\nal ., 1990 ), while the other two compared IUI with SI without\nany medical co-interventions ( Steures  et\nal ., 2006 ;  Bhattacharya\n et al ., 2008 ). The odds ratio (OR) of clinical\npregnancy for IUI without COS compared to SI was 1.53 (95% CI: 0.88-2.64), while the\npooled OR of clinical pregnancy for IUI with COS compared to SI was 1.00 (95% CI:\n0.59-1.67). The OR for multiple pregnancy was 0.50 (95% CI: 0.04-5.53) for IUI\nwithout COS compared to SI and 2.00 (95% CI: 0.18-22.34) for IUI with COS compared\nto SI. One RCT with 102 women offered same-dose FSH stimulation and who developed\ntwo or three follicles were randomised 3:1 to IUI (n=33) or IVF (n=10) ( Elzeiny  et al ., 2014 ). IUI or\nIVF was performed 36h after hCG administration with single or double embryo transfer\non day two yielded clinical pregnancy rates (40% vs. 12%,  p =0.04)\nand live birth rates (40% vs. 6%,  p =0.01) favouring IVF over IUI.\nThe data appears to suggest there is a disproportionate loss of pregnancies in the\nIUI group compared to the IVF group. While IUI outcomes resided towards the low end\nof what most practitioners experience, it is difficult to comprehend how they could\njustify dismissing IUI.\nPrevious ESHRE workshop reports presented generalised, albeit bleak IUI guidance,\nstating that IUI treatment requires ovarian stimulation to achieve modest\nresults, but the high multiple pregnancy rates meant that it is no more than a\npoor substitute for IVF treatment. Further statements included;”  IUI in\nstimulated cycles was effective only in patients with more than 3 years\nduration of infertility but is associated with a significant rate of\nhigher-order multiple births; although IUI treatment is cheaper and less\ndemanding on the patient, IVF is the most effective treatment for\ninfertility; IUI/ovarian stimulation: modest effect and risks of multiple\npregnancy and OHSS whereas IVF offered a 7-fold higher likelihood of\npregnancy ” ( ESHRE Capri Workshop\nGroup, 2009 ). These recommendations, however, were made in the\nabsence of proper management trials and almost absent IUI live birth data. This\nraises profound questions on the bias allied to IVF practices, and whether fair\nand ethical first line treatment options are offered to patients ( Bahadur  et al ., 2016a ).\nA later Cochrane and Capri review ( Pandian\n et al . 2012 ;  ESHRE Capri Workshop Group, 2015 ) identified three trials comparing\novarian stimulation plus IUI with IVF. Due to different protocols with\nsignificant heterogeneity, the data from only two of these (small) studies,\ncomparing three cycles of ovarian stimulation plus IUI with one cycle of IVF,\ncould be aggregated. The pooled odds ratio for IUI was 1.09 (95% CI 0.74-1.59),\nsuggesting no clear benefit associated with either treatment.\nRecent evidence dispels the prevailing prejudices surrounding IUI treatment. Two\nrandomised controlled trials reported at  ESHRE\n2017  ( Brown, 2017 ) further\nprompt a change in the NICE guidelines (although these are only applicable to UK\nNHS centres). The first RCT with 201 couples with 3-4 years unexplained\ninfertility randomised towards three cycles of IUI (CC) or expectant management\n( Farquhar  et al .,\n2017 ;  2018 ) revealed a\nthree-fold improvement in outcome in live birth rate from 31% and 9%. Another\nRCT supported IUI as first line treatment using CC over low dose FSH ( Danhof  et al ., 2017a ; b ). The second RCT involved 24 centres in\nthe Netherlands ( Brown, 2017 ), 369 women\nhaving IUI stimulated with FSH and 369 women with CC; 31% (n=113) were pregnant\nwith IUI-FSH; 26% (n=97) became pregnant with IUI-CC; 3 women (1%) had multiple\npregnancy following IUI-FSH; 8 (2%) women had multiple pregnancy following\nIUI-CC (NS). They also reported 48 of 210 pregnancies (23%) by natural\nconception (in line with the natural conception rate) suggesting ‘expectant\nmanagement’ might not be such a hopeless alternative. The findings are similar\nto an earlier RCT ( Nandi  et\nal ., 2017 ). The overall conclusion is that ‘ IUI with\nCC may be offered to couples with unexplained infertility as a safe and\neffective treatment .’ The NICE recommendations were based on just\ntwo trials in unexplained infertility, one of which included IUI without\nstimulation ( Brown, 2017 ). Similar\nconclusions were drawn about retracting the NICE guidelines on IUI ( Brown, 2017 ;  Bahadur  et al ., 2017 ). The PRISM consortium also\nsupported IUI over expectant management in unexplained subfertility where the\nfecundity ratio for conceiving after IUI compared to expectant management was\n1.56 (95% CI: 1.20-2.03). IUI provides higher pregnancy rates compared to\nexpectant management and thus must remain as a first-line treatment for couples\nwith unexplained subfertility.\nFew studies report success rates in fertility treatments across a couple’s\ncomplete fertility treatment history, across clinics, evaluating live births\nafter insemination, ART and natural conceptions. A study looked into the Danish\nART Registry and Medical Birth Registry for live births (2007-2010). Sub-fertile\ncouples were followed for 2 years (N=19 884), 3 years (N=14 445) and 5 years\n(N=5165), or until their first live birth. Cumulative live birth rates were\nestimated 2, 3 and 5 years from the first treatment cycle, in all women,\nincluding dropouts. In women starting treatment with IUI (N=3028), 35% delivered\nafter IUI within 5 years, 24% delivered after a shift to IVF/ICSI treatments and\n17% delivered after natural conception. Overall, more than 50% of the women\nstarting IUI did not need demanding IVF. Within 5 years from starting treatments\nwith ART (N=2137), 53% delivered after ART, 11% delivered after natural\nconception, and 0.6% delivered after IUI ( Malchau  et al ., 2017 ). While most of the deliveries\noccurred within 2 years, the data also confirmed that 52% of women entering\nfertility treatment did not require IVF procedures ( Malchau  et al ., 2017 ). The lack of IUI\npregnancy rate optimisation has been of concern especially when non-evidence\nbased expensive add-on techniques are applied for IVF. Curiously, utilising a\ndouble IUI within a cycle had been dismissed ( Cantineau  et al ., 2003 ). However, this Cochrane\nreview actually stated that there was a significant benefit to using double IUI\nwithin a cycle (OR: 2.0; 95% CI: 1.07-3.75;  p <0.03).\nLikewise, significantly positive pregnancy outcomes were seen with endometrial\nscratching within the follicular phase of 1,871 IUI cycles (OR: 2.27;\n p <.00001).\nThe overuse of IVF procedures is increasingly seen as a major risk factor in\npublicly funded fertility treatments ( Bahadur\n et al ., 2016b ). Although current data does not\nreveal a multiple birth problem with IUI, well-managed IUI with strict\ncancellation policies would obviate the risk for multiple births. A major\npractical innovation in IUI has been applied for overcoming severe male factor\ninfertility by using consecutive ejaculation to boost the total motile sperm\nnumbers, effectively cancelling out the oligozoospermic effect and thereby\nimproving IUI pregnancy outcomes ( Bahadur\n et al ., 2016c ). It means that males with severe\nmale factor must be explored for their potential to gain more motile sperm\nthrough consecutive ejaculates before embarking on IVF procedures. Overcoming\nmale factor infertility in IUI has also been observed when performing double\ninseminations within a cycle ( Ghanem  et\nal ., 2011 ).\nIn a RCT, ovarian stimulation with low-dose hMG was superior to CC in IUI cycles\nwith respect to clinical pregnancy rate. Ovarian stimulation with hMG yielded a\nhigher clinical pregnancy rate (hMG 48/334 (14.4%) versus CC29/323 (9.0%),\nrelative risk (RR) 1.6 (95% confidence interval (CI) 1.1-2.4)). The LBR was\nhigher (hMG46/334 (13.8%) versus CC28/323 (8.7%), RR1.6 (95% CI 1.0-2.4), low\nand comparable multiple live birth rate (hMG 3/46 (6.5%) versus CC 1/28 (3.6%),\n P . 0.99) ( Peeraer\n et al ., 2015 ). They recommended that IUI\ncombined with low-dose gonadotropins is the treatment of choice for patients\nwith indication for IUI treatment. In another RCT, after treatment with\ngonadotropin, clomiphene or letrozole, clinical pregnancies occurred in 35.5%,\n28.3%, and 22.4% of the cycles, and live births in 32.2%, 23.3%, and 18.7%,\nrespectively; pregnancy rates with letrozole were significantly lower than the\nrates with standard therapy (gonadotropin or clomiphene)\n( p =0.003) or gonadotropin alone ( p <0.001),\nbut not with clomiphene alone ( p =0.10) ( Diamond  et al ., 2015 ). In a RCT with 602\ncouples on IVF-SET, IVF-modified natural cycle (194) and IUI-COH (207), the\nbirth of a healthy child occurred in 104 (52%) couples in the IVF-SET group, 83\n(43%) in the IVF-modified natural cycle group, and 97 (47%) in the IUI-COH. This\ncorresponds to a risk, relative to IUI-COH, of 1.10 (95% confidence interval\n0.91 to 1.34) for IVF-SET and 0.91 (0.73 to 1.14) for IVF-modified natural\ncycle. All groups had similar outcomes, with low multiple pregnancy rates ( Bensdorp  et al ., 2015 ). The\nHFEA IUI data on pregnancy rate per cycle in the <35 age group in 2010 to\n2015 improved from 9.12% to 15.17%. This contrasts sharply against the\n4-7%/cycle considered for the weakly evidenced based NICE guidelines ( Bahadur  et al ., 2016a ;\n 2017 ). The Centre for Evidence-Based\nMedicine in Oxford independently provided evidence that IUI was effective on LBR\n(odds ratio was 1.95 (1.10 to 3.44) (95% CI)) when compared with intercourse or\nexpectant management in a stimulated cycle ( Heneghan  et al ., 2016 ). This study performed\nindependently of fertility practitioners also highlighted how statistically\nsuperior IUI is when placed in the context of promoting expensive add-on IVF\ntechniques such as endometrial scratching or time lapse embryoscopy for which\nlittle evidence-based support exists ( Heneghan\n et al ., 2016 ). Better quality evidence to help\npatients make informed choices is necessary and it has been debated that desired\nresults might be obtained through bias in study selection ( Alikani  et al ., 2018 ).\nThe moral concerns against selectively promoting expensive IVF over IUI\nparticularly highlights invalid reasoning and unproven effectiveness, while\nexposing patients to risks and economic burdens ( Tjon-Kon-Fat  et al ., 2016 ).\nIn an early economic evaluation of IUI in which pregnancy rates were already\nsubstandard to UK ( Bahadur  et\nal ., 2016a ), outcomes showed costs for IUI of £98 per cycle,\ncompared to £0 for SI ( Wordsworth\n et al ., 2011 ). The authors unsurprisingly\nconcluded that IUI was an ineffective and costly treatment. This analysis was\nwidely regarded as poor, since pregnancy outcomes were typically half of the UK\naverage. However, current analyses characterised IUI as cost effective. IUI is\nless expensive than IVF, since the mean cost per live birth for IVF is 7187\nEuros versus 5070 Euros for IUI. The cost effective incremental ratio per live\nbirth for IVF-SET compared with IUI-COH was €43,375, reflecting the\nadditional costs necessary to achieve one additional healthy child in IVF-SET\nversus IUI-COH ( Tjon-Kon-Fat  et\nal ., 2015 ). Another strategy dictates that postponing\nIVF by 1 year might be a cost-effective measure forward, but this also depends\non prognosis. The cost-effective CE ratio, i.e. the incremental costs of\nimmediate versus delayed IVF per extra live birth, is the highest (range of\n€15 000 to >€60 000) for couples with unexplained infertility\nand for them it depends strongly on female age and duration of infertility,\nwhilst being lowest for endometriosis (range 8000-23 000) and, for such\npatients, only slightly dependent on female age and duration of infertility\n( Eijkemans  et al .,\n2017 ). While it is generally recognised that CC is a less expensive\ndrug than gonadotropins, it is actually more cost effective to achieve pregnancy\nwith gonadotropin ( Peeraer  et\nal ., 2018 ).\nMultiple birth is a well-known major risk of IVF procedures and hence a major\ndrive for SET procedures. The cost of fetal reduction has never been factored in\nfor IVF procedures. Importantly, the actual costs of multiple births and\nassociated problems have so far been omitted in IVF costing as has its impact on\nnational healthcare and human costs. Recent financial analysis shows a\nsignificantly higher total cost (ART treatment, pregnancy follow-up, delivery,\nchild cost until the age of 2 years) for multiple births (both children: mean\n€43,397) than for singleton births (mean: €17,866)\n( p <0.0001). A 50% reduction in multiple LBR resulted in\na significant 13% reduction in hospital care costs ( Peeraer  et al ., 2017 ). Financial analysis\nof fertility treatments and outcomes is clearly a complex endeavour with several\nlevels, on the impact cannot be assumed to be the same for IVF and IUI without\nhaving a measure of the size of the problem.\nIUI has been liberally blamed for multiple births although such data is usually\nabsent - in the UK, the HFEA does not collect live birth data for IUI. NICE\nassumed that IUI and IVF yield equal numbers of multiple births despite the\nabsence of LBR data for IUI. The UK NICE costing ( NICE, 2013 ) adopted a quality adjusted life years (QALYs)\nmodel to allow comparisons between infertile women and other clinical\nconditions. This approach is controversial because infertility care values\ncannot be easily captured in QALYs ( Devlin &\nParkin, 2003 ). The model fails to address the complexities faced by\nseveral stakeholders involved, as well as the size of the problem for society.\nThe argument on multiple births lingers on a discourse suggesting eSET has\neradicated multiple births in IVF procedures. Evidence from a multicentre study\nhas shown that twin pregnancy rates can be very low in an IUI programme (much\nlower than in most IVF programmes worldwide) with a reasonable IUI pregnancy\noutcome ( Bensdorp  et al .,\n2015 ).\nOn average, 1 in 10 IVF pregnancies is a multiple pregnancy, compared to 1 in 80\nfor women who conceive naturally. With approximately 19,000 IVF babies born in\nthe UK in 2014, this contributes significantly to the rate of multiple births\n( NOS, 2017 ). In January 2009, the\nHFEA introduced a policy to minimise the risk of multiple births from IVF\ntreatment. This allowed centres to develop their own strategy - the aim was to\nreduce the UK IVF multiple pregnancy rate to 10% over a period of years.\nThe UK facts for multiple births where data is available is as follows; 1 in 80\nbirths following natural conception in the UK are multiples; 1 in 4 births after\nIVF in the UK result in either twins or triplets (incl. ICSI); 40% of IVF babies\nare twins. The number of multiple babies has risen significantly: in 1995 just\nover 2600 IVF babies were born as part of a multiple birth; in 2003 more than\n3700 IVF babies were born as part of a multiple birth - a rise of more than 41%;\n126 IVF babies die each year as a consequence of having been born in a multiple\nbirth. Of these 51 are stillbirths, 42 died within the first week of life, and\n33 died later in the first year of life. These figures do not include\nmiscarriages or fetal reduction procedures ( Oakley & Doyle, 2006 ;  NOS,\n2017 ). There is increased risk (ranging 2-18 times higher) for babies\nand mothers associated with twin and triplet births for being born prematurely,\ndeath in the first week of life, cerebral palsy, while mothers face similarly\nincreased risk of pre-eclampsia, diabetes, coronary heart disease, and death for\ncardiovascular causes ( Sattar & Greer,\n2002 ).\nAlthough fertility clinics market themselves on league table type success rates,\nthey are less clear about the issues derived from the multiple births produced\nin each clinic. More importantly, in the UK multiple births remain invisible to\nspecific IVF clinics. Fertility clinics remain unaccountable to multiple birth\ncontributions and do not have to make any financial contribution towards\nimmediate care with obstetric complications. Multiple births in IVF have,\ntherefore, been seriously overlooked in terms of the human and economic costs\nand one might question why financial analyses have never factored in the cost\neffectiveness of IVF or IUI procedures.\n\nAll recent high-quality evidence suggests old conclusions should be updated.\nPrejudices surrounding IUI and in favour of IVF as being substandard or fraught with\nrisks of multiple births is completely unfounded and needs to be reappraised on\nevidence. Costing analyses so far have failed to capture the serious health and\nhuman cost of higher order births stemming from IVF procedures. It raises questions\non conflict of interests, but also demands that we develop a moral and ethical\nperspective when offering first line treatment options to patients in a balanced and\nfair manner. Only the financial interest related to offering expensive IVF\nprocedures stand in the way of an exciting new era of growth for IUI procedures,\nwhich can be overcome by prudent government funding policies where funding exists.\nGreater use of low cost IUI treatment will also increase the chance to fund IVF\ntreatment when needed. Public bodies and IVF interest groups have a duty of care to\naccurately inform patients, the public, funding bodies and stakeholders of the\nbenefits, efficacy and cost-effectiveness of IUI before embarking on expensive IVF\nprocedures.","source_license":"CC-BY-4.0","license_restricted":false}