Is IUI with ovarian stimulation effective in couples with unexplained subfertility?

R van Eekelen (Corresponding Author), N van Geloven, M van Wely, D J McLernon, F Mol, I M Custers, P Steures, S Bhattacharya, B W Mol, F van der Veen, M J Eijkemans

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STUDY QUESTIONDoes starting IUI with ovarian stimulation (IUI-OS) within 1.5 years after completion of the fertility workup increase ongoing pregnancy rates compared to expectant management in couples with unexplained subfertility?SUMMARY ANSWERIUI-OS is associated with higher chances of ongoing pregnancy compared to expectant management in unexplained subfertile couples, specifically those with poor prognoses of natural conception, i.e. <15% over 6 months or <25% over 1 year.WHAT IS KNOWN ALREADYIUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found conflicting results. A cohort of couples with unexplained subfertility exposed to expectant management and IUI-OS offers an opportunity to determine the chances of conception after both strategies and to evaluate whether the effect of IUI-OS depends on a couple’s prognosis of natural conception.STUDY DESIGN, SIZE, DURATIONA prospective cohort study on couples with unexplained or mild male subfertility who could start IUI-OS at any point after completion of the fertility workup, recruited in seven Dutch centres between January 2002 and February 2004. Decisions regarding treatment were subject to local protocols, the judgement of the clinician and the wishes of the couple. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. Follow up was censored at the start of IVF, after the last IUI cycle or at last contact and truncated at a maximum of 1.5 years after the fertility workup.PARTICIPANTS/MATERIALS, SETTING, METHODSThe endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.MAIN RESULTS AND THE ROLE OF CHANCEData from 1896 couples were available. There were 800 couples whom had at least one IUI-OS cycle within 1.5 years post fertility workup of whom 142 couples conceived (rate: 0.50 per couple per year, median follow up 4 months). The median period between fertility workup completion and starting IUI-OS was 6.5 months. Out of 1096 untreated couples, 386 conceived naturally (rate: 0.31 per couple per year, median follow up 7 months). Starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.96 (95% CI: 1.47–2.62) compared to expectant management. The effect of treatment was modified by a couple’s prognosis of achieving natural conception (P = 0.01), with poorer prognoses or additional failed natural cycles being associated with a stronger effect of treatment. The predicted 6-month ongoing pregnancy rate for a couple with a prognosis of 25% at completion of the fertility workup over the next six cycles (~40% over 1 year) was 25% (95% CI: 21–28%) for expectant management and 24% (95% CI: 9–36%) when starting IUI-OS directly. For a couple with a prognosis of 15% (25% over 1 year), these predicted rates were 17% (95% CI: 15–19%) for expectant management and 24% (95% CI: 15–32%) for starting IUI-OS.LIMITATIONS, REASONS FOR CAUTIONThe effect estimates are based on a prospective cohort followed up for 1.5 years after completion of the fertility workup. Although we balanced the known predictors of conception between treated and untreated couples using inverse probability weighting, observational data may be subject to residual confounding. The results need to be confirmed in external datasets.WIDER IMPLICATIONS OF THE FINDINGSThese results explain the discrepancies between previous trials that compared IUI-OS to expectant management, but further studies are required to establish the threshold at which IUI-OS is (cost-)effective.STUDY FUNDING/COMPETING INTEREST(S)This study was facilitated by (Grant 945/12/002) from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. S.B. reports acting as Editor-in-Chief of HROpen. The other authors have no conflicts of interest.
Original languageEnglish
Pages (from-to)84-91
Number of pages8
JournalHuman Reproduction
Issue number1
Early online date5 Nov 2018
Publication statusPublished - 1 Jan 2019

Bibliographical note

Data collection for this study was facilitated by grant 945/12/002 from ZonMw, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. BWM is supported by Practitioner Fellowship grant GNT1082548 from the Australian National Health and Medical Research Council (NHMRC)


  • IUI
  • prospective cohort
  • sequential Cox model
  • time-varying treatment
  • unexplained subfertility
  • IVF


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