Elsevier

The Lancet

Volume 391, Issue 10119, 3–9 February 2018, Pages 441-450
The Lancet

Articles
Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial

https://doi.org/10.1016/S0140-6736(17)32406-6Get rights and content

Summary

Background

Women with unexplained infertility are often offered intrauterine insemination (IUI) with ovarian stimulation as an alternative to in-vitro fertilisation (IVF). However, little evidence exists that IUI is an effective treatment. In 2013, the UK National Institute for Health and Care Excellence recommended that IUI should not be routinely offered for couples with unexplained infertility.

Methods

For this pragmatic, open-label, randomised, controlled, two-centre study, we enrolled women attending two fertility clinics in New Zealand with unexplained infertility and an unfavourable prognosis of natural conception. Participants were randomly assigned (1:1) using a computer-generated randomisation sequence, prepared by an independent statistician, to either three cycles of IUI with ovarian stimulation (with either oral clomifene citrate [50–150 mg, days 2–6] or oral letrozole [2·5–7·5 mg, days 2–6], with choice of ovarian stimulation made by the clinic) or three cycles of expectant management (couples advised to be sexually active around the likely time of ovulation and provided with a diary to record the first day of each menstrual cycle and dates of sexual activity) in blocks of four, six, and ten, without stratification. The participating couple and the clinicians were informed of treatment allocation. The primary outcome was cumulative livebirth rate in the intention-to-treat population. The safety analyses were done in the intention-to-treat population. This study was prospectively registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612001025820.

Findings

Between March 12, 2013, and May 12, 2016, we randomly assigned 101 women to IUI with ovarian stimulation and 100 to expectant management, all of whom were included in the primary efficacy analysis and safety analyses. Women assigned to IUI had a higher cumulative livebirth rate than women assigned to expectant management (31 [31%] livebirths among 101 women vs nine [9%] livebirths among 100 women; risk ratio [RR] 3·41, 95% CI 1·71–6·79; p=0·0003). Of 31 livebirths in the IUI group, 23 resulted from IUI cycles and eight were conceived without assistance before or between IUI cycles. Of nine livebirths in the expectant management group, one patient was pregnant from IUI with ovarian stimulation at study entry and one had received off-protocol treatment (IVF). Two sets of twins were born, both in the IUI group (one from a cancelled cycle for over-response).

Interpretation

IUI with ovarian stimulation is a safe and effective treatment for women with unexplained infertility and an unfavourable prognosis for natural conception.

Funding

Auckland Medical Research Foundation, Evelyn Bond Fund of Auckland District Health Board, Mercia Barnes Trust of Royal Australian and New Zealand College of Obstetricians and Gynaecologists, Maurice and Phyllis Paykel Trust, and The Nurture Foundation for Reproductive Research.

Introduction

Intrauterine insemination (IUI) is widely used in the USA, the UK, and Europe as a low-cost, less-invasive alternative to in-vitro fertilisation (IVF) for couples with unexplained infertility.1, 2 IUI of sperm suspension is done at the estimated time of ovulation in a natural cycle or after ovarian stimulation.1

Several randomised controlled trials of IUI have been done,3, 4, 5, 6, 7, 8, 9 but only two have considered the question of whether IUI is superior to expectant management (EM), and neither have provided evidence of effectiveness.5, 6, 7 One trial5 of IUI versus EM did not include ovarian stimulation and did not report evidence of benefit after 6 months, with livebirth rates of 23% versus 17%. In the other trial,6 women with intermediate prognosis for natural conception had six cycles of IUI with ovarian stimulation versus EM and the ongoing pregnancy rate was 23% versus 27%.

The UK National Institute for Health and Care Excellence (NICE) recommended in 2013 that intrauterine insemination, with or without ovarian stimulation, should not be routinely offered to couples with unexplained infertility and that IVF could be considered after 2 years of EM.10 However, a 2015 survey of UK fertility clinicians reported that 96% continued to offer IUI.11

Research in context

Evidence before this study

Before starting this study, we searched the Cochrane Library and PubMed for relevant studies published in English from database inception up to Dec 3, 2012. We used the following search terms: “unexplained infertility”, “unexplained subfertility”, “intrauterine insemination”, “intrautero tuboperitoneal insemination”, “IUI”, “artificial insemination by partner”, and “artificial insemination”. We identified one high quality Cochrane systematic review and no additional trials. The Cochrane systematic review reported two randomised controlled trials comparing intrauterine insemination (IUI) with expectant management. Neither study reported benefit. One randomised controlled trial compared IUI with gonadotropin therapy versus expectant management in women with intermediate prognosis for natural conception. The relative risk for livebirth was 0·86 (95% CI 0·54–1·4). The second study compared six cycles of IUI only versus expectant management; however, only 37 (19%) of 193 women in the IUI group completed all six cycles and 26 (13%) received none. Compared with expectant management, the odds ratio for a livebirth was 1·46 (95% CI 0·88–2·43) after unstimulated IUI. The 2013 National Institute for Health and Care Excellence guidelines for people with fertility problems recommend “that intrauterine insemination with or without ovarian stimulation should not be routinely offered to couples with unexplained infertility”.

Added value of this study

This study is a well powered, randomised controlled trial comparing IUI with clomifene citrate versus expectant management in women with poor prognosis for natural conception within the next 12 months. It differs from previous randomised controlled trials in this field in that the prognosis is less favourable and that ovulation induction with clomifene citrate was used. This is the first study to report benefit with IUI with ovarian stimulation compared with expectant management.

Implications of all the available evidence

Our study provides the first reliable evidence that IUI with ovarian stimulation can be offered to women with a poor prognosis for natural conception. However, further randomised controlled trials would be welcome to test our findings in other settings and provide additional evidence to support a change in the present recommendations. One such study (NTR5599) is currently recruiting in the Netherlands.

We aimed to compare the effectiveness of three cycles of IUI with ovarian stimulation (oral clomifene citrate or letrozole) versus three cycles of EM in women with unexplained infertility and an unfavourable prediction score for natural conception (<30%) in the next 12 months. We wished to test the hypothesis that livebirth rates would be higher in the IUI with ovarian stimulation group.

Section snippets

Study design and participants

The Uterine Insemination (TUI) study was a pragmatic, open-label, randomised, controlled, two-centre study of women with unexplained infertility and an unfavourable prognosis for natural conception. The New Zealand Ministry of Health Northern B Regional Ethics Committee approved the study protocol (12/NTB/41/AM03).

Women attending fertility clinics (Fertility Plus, Auckland District Health Board and Repromed Auckland) in Auckland, New Zealand, were invited to participate. A written patient

Results

We screened 473 women for eligibility. Of 341 eligible women invited to take part, 140 declined and 201 were randomly assigned to a group between March 12, 2013, and May 12, 2016: 101 to IUI with ovarian stimulation and 100 to EM (figure 1). The only significant difference between women agreeing or declining to participate was that women who declined had a shorter duration of infertility (median 24 months vs 44 months; p=0·03) and were more likely to be parous (38 [27%] of 142 vs 25 [12%] of

Discussion

In this randomised controlled trial, we have reported that, in women with unexplained infertility and an unfavourable prognosis for natural conception, three cycles of IUI with ovarian stimulation were associated with a three-fold improved CLBR compared with three cycles of EM. Two sets of twins were born, both in the IUI with ovarian stimulation group (6% multiple pregnancy rate).

Although an intention-to-treat analysis is the recommended approach for reporting clinical trials,16, 17 concerns

References (30)

  • P Steures et al.

    Intrauterine insemination with controlled ovarian hyperstimulation versus EM for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial

    Lancet

    (2006)
  • W Ombelet et al.

    Semen quality and prediction of IUI success in male subfertility: a systematic review

    Reprod Biomed Online

    (2014)
  • Effectiveness and treatment for unexplained infertility

    Fertil Steril

    (2006)
  • C Calhaz-Jorge et al.

    Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE

    Hum Reprod

    (2016)
  • DS Guzick et al.

    Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network

    N Engl J Med

    (1999)
  • RH Reindollar et al.

    A randomized clinical trial to evaluate optimal treatment for unexplained subfertility: the fast track and standard treatment (FASTT) trial

    Fertil Steril

    (2010)
  • S Bhattacharya et al.

    Clomifene citrate or unstimulated intrauterine insemination compared with EM for unexplained subfertility: pragmatic randomised controlled trial

    BMJ

    (2008)
  • SM Veltman-Verhulst et al.

    Intra-uterine insemination for unexplained subfertility

    Cochrane Database Syst Rev

    (2012)
  • AJ Bensdorp 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 insemination with controlled ovarian hyperstimulation

    BMJ

    (2015)
  • MP Diamond et al.

    Letrozole, gonadotropin, or clomiphene for unexplained Infertility

    N Engl J Med

    (2015)
  • Fertility: for people with fertility problems. NICE clinical guideline

  • D Kim et al.

    Intrauterine insemination: a UK survey on the adherence to NICE clinical guidelines by fertility clinics

    BMJ Open

    (2015)
  • CC Hunault et al.

    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)
  • Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome

    Fertil Steril

    (2004)
  • RS Legro et al.

    Improving the reporting of clinical trials of infertility treatments (IMPRINT): modifying the CONSORT statement

    Hum Reprod

    (2014)
  • Cited by (0)

    View full text