Discussion

These data add to previously published studies^{5-8, 15-17}showing better LBR following IVF than with IUI but this difference is much smaller than previously reported. Our study has also identified new data on the use of IVF and IUI in the UK which should have a direct impact in management strategies of couples presenting with infertility. Data summary provided by the HFEA has also allowed us to perform descriptive comparisons and trends, but limits the use of complex statistics. This is advantageous as alternative interpretations of the data become impossible, thereby removing interest biases. No sample size calculation was required to determine the power at a significance level of 0·05.

During the period of our study, IVF was associated with a significantly (p<0.001) higher risk of MGP than IUI. IVF is also associated with higher risks of OHSS and need for fetal reduction and pregnancy terminations which were not found after IUI. We found that from 2012 to 2016, there was 10.4-fold increase in the use of IVF over IUI with a significant (p<0.05) increase in IVF cycles and a corresponding decline in IUI cycles (table 1). This increased IVF activity cannot be justified on the basis of evidence-based data, since there are no comparative IVF versus IUI data.3 The increase in the number of IVF and decline in IUI cycles (table 1) coincide with the 2013 NICE guidelines3 recommendation against the use of IUI as the primary therapeutic line for infertile couples. This erroneous recommendation was based on poor IUI outcomes compared with expectant management with no data on IVF and yet recommended IVF practice instead of IUI.3 Our data show a small increased but significant (p<0.05) LBR following IVF from 25% to 27% during that period following the NICE recommendation.

The baseline IUI: IVF success rates (table 1) to deliver 1 LB was 2.35:1, which was much narrower than the RCT reported of 3:1 for IUI: IVF.5–8 15–17 Therefore, a small improvement in IUI LBR from 12.1% to 15.6% LBR narrows this difference to 1.73: 1, IUI: IVF cycles, with a highly favourable cost benefit for IUI over IVF. When considering IVF as a denominator it is important to emphasise that 3.7 IVF cycles are actually required to achieve a 100% theoretical LB. Overall, we found 8.69 IUI cycles at 12.1% LBR or 6.4 cycle for a 15.6% LBR IUI NMUH clinic are needed to theoretically achieve 100% LB. Despite the focus on IUI against IVF, the relationship between ordinary and high success IVF clinics seems curiously avoided. Mean-IVF clinics (27% LBR, MGP 15%) against as high performing IVF clinic (55% LBR, MGP 30%) have a 2.04:1 relationship but higher IVF clinics have riskier (2.2:1) outcomes for mother and baby.

Factoring tariffs alone, IUI is cheaper than IVF while also delivering lesser risks and perinatal complications for both mothers and babies. Higher IVF success clinics lose any benefits through increased tariffs and doubled MGP levels against IUI and against standard performing IVF clinics. The actual cost benefits are displayed in figures 1 and 2 which study the ICER to deliver 1 LB at various success rates and tariffs. Against prevailing tariffs IUI always has lower overall costs than IVF in commissioning treatment to achieve 1 LB. Patients should be informed that IUI success is closer to IVF but without the added risks to mothers and babies, the cost burden to the healthcare system of which are excessive for IVF.

A recent RCT shows that after 3–4 years unexplained infertility randomised for three cycles of IUI (CC) or expectant management5 a three-fold improvement in outcome in LBR from 31% and 9% is seen. IUI LB/cycle probabilities ranged from 21.4% to 5.1% dependent on age, cycle number and previous parity, with a MGP of 5.4%.18 IUI was also effective on LBR (OR 1.95 (1.10 to 3.44) (95% CI)) when compared with intercourse or expectant management in a stimulated cycle.19 Currently in most clinics, IUI suited cases are now receiving IVF treatments or are further aided with non-evidenced based add-on techniques.19 IUI success rates appear to face downward pressures from IVF clinics by managing difficult cases through IUI.20

So far no reliable national figures exist for the levels of different risks for patients undergoing IVF and IUI to help them towards a journey of making informed decisions or to help clinicians counsel their patients. With this large database, the MGP rate as a proportion of all births was significantly higher following IVF than following IUI (RR: 1.45 (1.31 to 1.60), p<0.001). This fact contradicts popular belief that IUI being the source of uncontrolled MGP. The rate of twins was also significantly higher following IVF (RR: 1.58, p<0.001). There was 0.2% fetal reductions performed for IVF and none for IUI. Moderate to severe OHSS risk of 0.9%/birth or 0.25% per cycle was related to IVF only and not IUI (table 1). No maternal deaths were reported due to any complications but it can be argued the HFEA may not be fully informed as the death registry is not linked to the HFEA database. Terminations accounted for 0.81% of all total births (clinical pregnancy rates unavailable) in IVF and none in IUI. From 2012 to 2016 there were a total of 698 terminations evenly spread across this period. Medical reasons accounted for 73.6% of terminations with 22.4% of these being for Down’s syndrome, and for the first time a 2.3% level of terminations for psychological and social reasons is revealed, while a further 24.1% of terminations were for undisclosed reasons. For the first time, direct information on level of terminations after IVF (but no terminations in IUI) conception is indicated for social and psychological reasons adding a new dimension of debate in ART. It serves to underline the vital role for support and counselling before, during and after fertility treatment.

The economics of the fertility industry provides important insights as to how financial considerations are overriding evidence-based medicine while suppressing the availability of low cost IUI. With regard to the financial information which can serve as important steers for patients and stakeholders in commissioning services emerge. The HFEA confirms the size of the IVF industry for 2016 to be worth around £320 000 000 in 2016, with a 61% growth in activity since 2007/2008, revealing a mean tariff of £4699/cycle for IVF.13 The wider annual estimate of the fertility industry is £500 million which includes other activities such as cryopreservation of gametes and embryos, and add-on techniques. The main real tariffs paid by NHS commissioning groups for IUI were £800 and £1300 whereas for IVF £3500–5000 per cycle at the NHS level. The maternal and neonatal IVF risk burden of £115 082 017 representing 33%–50% of the 2016 IVF market value is passed on to the NHS. The level of NHS IVF funding from 2012 to 2016 was at 42.5%, which is much higher than generally accepted, while a further 14.8% of IVF cycles were commissioned through private IVF practices. Private clinics are not public bodies and therefore are not accountable under the FOI Act. NHS funding for IUI in the UK was removed following the non-evidenced-based NICE guidelines2 although some commissioning groups continue funding IUI. This clearly needs to be reversed with immediate effect.

The unique algorithm (figures 1 and 2) reveals points of efficiencies and inefficiencies for IUI and IVF treatments and describes a spectrum of financial, economic and success relationships with each other. At baseline success rates for IUI (12.1% LBR) and IVF (27.3% LBR) (figure 1), ICER favoured IUI over IVF by at least £13 663 to deliver 1 LB against the cheapest IVF tariff. When the realistic mean IVF tariff of £4699/cycle was considered mean IUI clinics could deliver a cost-effective benefit per LB of £42 558 (figure 1). Better performing IUI clinic at 15.6% LBR clinic (NMUH) could extend the cost savings to £76 257 per LB over mean IVF success of 27.3% LB and tariff of £4699. The cost savings to achieve 1 LB through improved IUI success over IVF are regarded as particularly high and beneficial to society. The algorithm defines the cost neutral point against mean IUI at 12.1% LBR, when IVF success reaches 32.58% (figure 2) which can be extended to 42% LBR for IVF with IUI at 15.6% LBR using the same algorithm. This threshold can also be much higher for higher IVF tariff. For every 1% LB improvement of IUI, IVF success needs to improve by 2.7% LBR to achieve the same incremental cost benefit as IUI. In other words, IVF needs to work much harder than IUI to achieve benefits and suggests the need to invest in improving IUI success rates. These ICER cost efficiency values should persuade stakeholders and patients to choose IUI before IVF. IVF success rates have improved by 2% only to 27.3% LBR from 2012 to 2016 despite expensive non-evidenced-based add-on techniques and treating potential IUI cases through IVF.

On the reverse scale, cost-effectiveness of IUI against lowest tariff IVF is maintained until the IUI success reaches 10.14% LBR (figure 1). Below 10.14% LB, IUI loses its cost-effectiveness against the lowest tariff IVF cycle. However, this lower IUI limit of 10.14% LBR will be even lower when considering higher tariff IVF (figure 1) and which can be extrapolated from figure 1. Below these IUI low points practitioners need to re-evaluate their management, protocols or stop performing IUI.

Higher IVF success rate clinics are also associated with increased tariffs and MGP levels. A clinic with a 55% LBR success has around 28% MGP,10 and twice the normal UK MGP rate lose all benefits through increased tariffs ranging from £7000 to 15 000 per cycle against mean IVF clinics. On tariff consideration alone, high-performing IUI clinic is more cost-effective than high-performing IVF clinics where tariff factors alone erode any benefits. Based on success and tariffs only, IUI at 15.6% (tariff £800) versus IVF at 27.3% (£4699) versus IVF at 55% (£15 000) LBR would cost the patients £5,128, £17 404 and £27 273, respectively, to achieve 1 LB, notwithstanding the increasing risks for mother and babies along this sequence. The algorithm (figures 1 and 2) also advises that the most expensive high-performing IVF clinic at 55% LBR can match the mean IVF clinics at 27.3% LBR by dropping the tariff to £9572/cycle, provided these clinics can also reduce their MGP from 28% to 13.8% level. The financial analyses exclude the cost of OHSS, terminations and complication mainly for IVF, while there will be additional cost for drugs. Excluded also are the fees paid by IVF patients to cryopreserve embryos, back-up sperm or purchase add-on procedures.

Separate ICER calculations for high-performing IUI (15.6% LBR, £800 tariff) against high-performing IVF (55% LBR, £15 000) show that it is £56 204 cheaper to gain 1 LB by IUI. Likewise, separate ICER calculations for mid-performing IVF (27% LBR, £4699) against high-performing IVF (55% LBR, £15 000) show that it is £35 246 cheaper to gain 1 LB through mid-IVF clinics compared with high-performing IVF clinics.

The algorithms allow detailed cross analyses of the practices and confirm IUI is superior to IVF to derive the best possible cost benefit to gain a child while minimising the risk to mother and babies if applicable. The second line option is for patients to choose a mid-performing IVF clinic paying attention to MGP levels. Evidenced-based bodies have a duty of care to explicitly inform stakeholders when ICER is favourable, and in this case IUI is dominant over IVF.21 Previous cost-effective studies have been performed against extremely poor IUI results, while relying on optimal IVF in local settings to persuade purchasers to fund more IVF cycles instead of IUI.22 23

The second major cost analyses relate to the MGP maternal/neonatal-related cost burden which has remained invisible to date. For 2016, the IVF cost burden to the NHS was £115 million (£532 million over 2012–2016), against the IVF clinics turnover estimated between £340 and 538 million depending on the tariffs range £3500–5000/per cycle cost considered. The HFEA mean cost estimate per cycle treatment for 2016 was £4699/cycle and a market worth of £320 million. In contrast the IUI market worth was £3.24–5.3 million using tariffs of £800–1300, against the negative cost impact of £2.94 million for 2016. It is prudent to fund only essential IVF such as bilateral tubal blockages and severe male factor infertility as a priority before considering IUI failed cases through modified eSET (elective single embryo transfer) in order to control costs while minimising MGP.24

There are some critical limitations to the current study and the main one being it was an observational and retrospective in nature, with the main concern being selection bias of data collection. However, due to the unique nature of having gained the treatment cycles data under FOI from the UK regulatory body, the potential for selection bias is minimised. The data do not reveal the baseline characteristics and treatment details of patients such as age, cause, type and duration of subfertility, prognostic indicators like ovarian reserve status, stimulation protocols, fresh or frozen IVF cycles, the distinction between IVF or ICSI or the number of cycles of treatment each patient has undergone to be able to comment on the cumulative success rates. Further limitation of this study relates to non-random selection of IUI or IVF treatment in this study with good prognosis patients may have been selected for IUI or IVF as first choice. Contrastingly, some poor prognosis patients may have chosen lesser invasive IUI treatment as the only option and some have had IVF cycle cancellation with subsequent rescue IUI cycles, both of which may potentially bias IUI and IVF success rates. Specific patient pathologies such as severe male factor infertility or bilateral tubal blockages will obviously necessitate IVF procedures creating a degree of selection bias but this cannot be revealed from our data analyses. However, it is important to recognise that by analysing aggregate national UK data for the entire subfertile population rather than a sample of the population, the risks of selection and treatment biases are somewhat mitigated and potentially allowing a high degree of data generalisability. Stakeholders in other countries should review their practices, risks and costs of assisted reproductive procedures based on our UK experience.

Patients and stakeholders also need to consider intervention-related risks and long-term risks before making choices. IUI and IVF both have common underlying risks relating to the general health pathologies of subfertile couples and due to ovarian stimulation protocols. However, there appear long-term added risks for babies from IVF, ICSI, embryo culture and freezing procedures. The added risks have been reported for singleton IVF babies and singletons after fetal reduction having pre-term weights, and large sized babies from frozen embryo procedures. Late onset diseases relating to increased risk of some cancers are being reported.25 26 In vitro embryo cultures and exposures may affect later life developments along with any (epi) genetic modifications provide added risks27 or lead to higher imprinting disorders such as Beckwith-Wiedemann syndrome28–30 ³⁰ compared with naturally conceived children. This is a dynamic and evolving area of research.

In conclusion, IUI LBRs are much closer to IVF than previously described. IUI is associated with lesser risks to mothers and babies and more cost-effective than IVF in delivering 1 LB against current tariffs. IUI always has lower overall costs than IVF in commissioning treatment to achieve 1 LB. The cost burden to the healthcare system is excessive for IVF. Some selection bias cannot be excluded to the retrospective design and the data should be interpreted with caution. However, this unfettered, uniquely integrated analysis of success, risks and cost provides important information to healthcare stakeholders and governments to develop effective fertility treatment policies.