JBRA Assist. Reprod. 2021;25(1):162-164
UPDATE OR OPINION ARTICLE
doi: 10.5935/1518-0557.20200066
1Reproductive Medicine Unit, North Middlesex University Hospital, Old Admin Block, London N18 1QX, UK
2X&Y Fertility, Leicester, UK
3Chelsea Westminster Hospital/West Middlesex Hospital University Trust, Twickenham Road, Isleworth TW7 6AF
4Ayrshire Fertility Unit, University Hospital Cross house, Kilmarnock, KA2 0BE, Scotland
5University College London Hospital, 250 Euston Road. London NW1 2PG
6Homerton Fertility Centre, Homerton University Hospital, London E9 6SR, UK
CONFLICT OF INTEREST
The author has no conflict of interest to declare.
ABSTRACT
Information supporting IVF at the expense of intrauterine insemination (IUI) has
become commonplace, but it lacks critical analyses. Data from poorly practiced
IUI, without an equivalent comparison to IVF, has been generalised to recommend
a total abandonment of IUI in favour of IVF treatment. Our intention with this
paper is to reappraise and balance arguments so that patients and stakeholders
can have an unbiased informed choice. We provide information that reveals IUI to
predominate over IVF in terms of integrated success, risks and cost to deliver
one live birth whilst obviating the maternal and neonatal costs. Exceptional
cost savings are demonstrated for IUI over IVF for fee-paying agencies and
patients with lowered risks of maternal and neonatal care along with other risks
including OHSS, fetal reduction and termination of pregnancies. This analysis
supports the view that patients and stakeholders can choose IUI instead of IVF
in most instances, except with bilateral tubal blockage and severe male factor
infertility. It is apparent that fertility clinics need to re-evaluate and
reconsider this field, and IUI can be of benefit to both subfertile patients and
the stakeholders.
Keywords: IVF, IUI, cost efficiency, public health, stakeholder
BACKGROUND
Questions on how RCTs and the potential selection bias compared to big data, are
particularly relevant for ART, where there is interest. Crucially, the UK’s National
Institute of Health and Care Excellence (NICE) recommended that IUI treatment should
be replaced by 3 cycles of IVF treatment, following appraisal of IUI studies with
very low doses of clomiphene citrate (CC) (25mg) and without comparative data (Bahadur et al., 2017; Wordsworth et al., 2011). The
FASST (Fast Track and Standard Treatment) trial had several weaknesses due to the
in-built biases omitting IUI/hMG cycles and suggesting the premature use of IVF
(Reindollar et al.,
2010). That IUI/hMG serves a potential ‘threat’ to IVF is encapsulated in a
further meta-analysis that focussed solely on high risk IUI/hMG studies, and then
concluded that IUI/hMG should not be practiced whatsoever (Hansen, 2020; Zolton et
al., 2020). In our opinion, almost all of the cases in this
meta-analysis would have warranted cancellation, and the paper (Hansen, 2020; Zolton et al., 2020) is biased in favour of IVF
treatment. Furthermore, none of the limitations was made clear to stakeholders and
this requires analyses that are more critical. Financial analyses on cost
effectiveness have so far been conducted crudely and seem overly concerned to
portray IUI treatment as cost-inefficient. However, such analyses select poorly
practised IUI cases, which are then utilized by Clinical Commissioning Groups (CCG)
as evidence for NICE (2014). The most recent
Cochrane analyses acknowledges that IUI in a stimulated cycle may result in a higher
cumulative live birth rate compared to natural cycle IUI (Ayeleke et al., 2020).
With the proliferation of meta-analyses in the medical literature, these have come
under considerable criticism for the level of arbitrary and selection biases (Page et al., 2014), raising
questions regarding the validity of the data. Of particular interest is the
systematic review and meta-analysis (Zolton et al., 2020) comparing live births and multiple
gestations in couples with unexplained infertility undergoing IUI, following ovarian
stimulation (OS-IUI) with oral medications versus gonadotropins. This study
concludes that gonadotropin-stimulated IUI cycles in unexplained infertility could
not be supported, and contrasts the largest comparative and integrated analyses
between IVF and IUI (Bahadur et al.,
2020). We express caution regarding the conclusions, which appear to
preclude less invasive fertility treatments than IVF (Bahadur et al., 2020).
Interestingly, the eight studies chosen after rigorous selection could all be
considered as ‘high risk’, since they include a decision to proceed to treatment,
thus exposing mothers and babies to potential harm (Zolton et al., 2020). In two studies, no cancellation
policy was presented, whilst the remaining studies permitted insemination with 3-7
follicles. Most practitioners would exercise caution with such high follicle
numbers. Furthermore, non-cancellation might even be considered to amount to poor
practice, unless there were a maximum of 3 follicles and where case-by-case
assessment was made. There is no clear information as to how many mature follicles
were present, which resulted in multiple births. The cases considered were not
purely unexplained, and up to 50% of the cases appear to be mixed male factor;
therefore, negating the authors’ claim that the strength of the study is in the
number of 2,989 unexplained infertile couples (Zolton et al., 2020).
Whilst elective single embryo transfer (eSET) has been shown to be an effective
strategy in reducing the number of multiple births after IVF cycles, it is
inappropriate to compare this to high risk IUI practices if no comparative multiple
birth data is presented in well managed IUI/hMG cycles. The authors allude to a
cancellation of around 6.9% in their high risk IUI category, leaving the readers to
imagine such a cancellation level would apply to all IUI gonadotropin well-managed
cycles and that high multiple birth rates remains unavoidable.
More significant is the fact that the success rate for gonadotrophin-stimulated IUI
cycles was 31.8%, which was much higher than the most recent IVF mean UK national
figures from Human Fertilisation & Embryology Authority (HFEA), where even the
best rates in women under the age of 35 years is 29% for IVF and 18% for OS-IUI
(HFEA, 2020a; b). This point needs to be positively harnessed and worked in
ways to minimise multiple births. IVF remains the single most important factor for
multiple births and comparisons with high-risk IUI cycles serves an unnecessary
distraction (Bahadur et al.,
2020). Numerous well-constructed evidence-based studies support IUI
(Bensdorp et al., 2015; Nandi et al., 2017; Tjon-Kon-Fat et al., 2017).
The recent Cochrane review acknowledges IUI in a stimulated cycle may result in a
higher cumulative live birth rate when compared to treatment with IUI in a natural
cycle review (Ayeleke et al.,
2020).
The USA does not classify IUI as an ART procedure. However, if it were included, this
could potentially highlight to patients and funding agencies the option of a low
risk, cost-effective treatment option. The largest integrated and comparative study
undertaken on this topic places IUI in the context of IVF without the biases seen in
numerous papers (Bahadur et al.,
2020). This concludes that patients and stakeholders would well be
advised to undergo IUI before IVF in most cases. The baseline IUI: IVF success rates
to deliver a live birth (LB) was 2.35:1, which was much narrower than the RCT
reported of 3:1. A small improvement in IUI LBR from 12.1% to 15.6% LBR narrows this
difference to 1.73:1. The paper informs patients and stakeholders that 3.7 IVF
cycles or 8.69 IUI cycles at 12.1% LBR or 6.4 cycle for a 15.6% LBR IUI are required
to achieve a 100% theoretical LB. Despite creative ways of presenting IVF success
rates, 70% of the women will never achieve an IVF baby. The multiple births for IVF
were significantly greater than for IUI, despite the increasing eSET practice. IVF
pregnancies were also associated with a 0.2% fetal reduction as a way to lessen
multiple births. The paper reveals other risks for IVF, such as terminations for
medical and a small number due to personal and social reasons. The knock-on effect
for maternal and neonatal cost per year to the UK from IVF babies was £115 million,
a cost burden not picked up by IVF clinics. The unique algorithms developed reveal
that IUI clinics could deliver a cost-effective benefit per LB of £42 558, while
extending this benefit to £76 257 for 15.6% LB IUI against IVF 27.3% LB. IVF clinics
providing `add-on’ techniques simply increase the cost, thereby eroding any cost
benefit IVF can deliver per LB, while increasing the cost efficiency of IUI LB. On
an economic and scientific basis, it is worthwhile investing in IUI LB improvement,
when considering non-evidenced based add-ons with no proven worth. By its own
financial guidelines, NICE is compelled to inform UK CCGs to fund IUI before IVF,
given the cost efficiencies deliverable from IUI procedures (Bahadur et al., 2020; NICE, 2014). For the first time this unfettered unique analysis
provides fee-paying stakeholders, patients and governments crafting policies
detailed information to make informed choices away from IVF clinics.
To conclude, the politics of influencing crucial bodies to construct treatment
policies and funding criteria require interest groups to provide evidence through
peer reviewed papers. Such bodies dismiss large grey data unpublished in peer
reviewed journals. It has been all too easy to exploit these loopholes for those
motivated to generate evidence on a variety of levels and in favour of more
profitable IVF treatments despite weak to very weak evidence. It is therefore
imperative to gain a balanced view of the field of ART dealing with highly sensitive
and vulnerable patients. For the first time, a sizable and a bird’s eye view
analyses make a compelling case for IUI treatment before embarking on IVF treatment,
based on outcomes, risks and cost effectiveness. We recommend that fertility
treatment policies are constructed to use the new information away from IVF clinic
pressures.
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