The stepwise development of an interactive web-based sex education programme for subfertile couples: the Pleasure & Pregnancy programme.

STUDY QUESTION: Can we develop a web-based sex education programme (programme running in a web browser) that addresses the needs of subfertile couples who are advised expectant management for at least 6 months? SUMMARY ANSWER: The 'Pleasure & Pregnancy' programme addresses couples' needs, is likely to improve couples' sexual functioning, and is subsequently hypothesised to improve the chance of natural pregnancy. WHAT IS KNOWN ALREADY: According to professional guidelines (e.g. the Netherlands and UK) couples with unexplained subfertility and a good chance of natural pregnancy, should be advised at least 6 months of expectant management. Adherence to expectant management is challenging as couples and gynaecologist prefer a more active approach. Targeting sexuality may be useful as subfertility is a risk factor for decreased sexual functioning. STUDY DESIGN, SIZE, DURATION: A novel programme was developed according to the three steps of the Medical Research Councils' (MRC) framework. First, relevant literature was explored. Second, an interdisciplinary expert panel developed a theory (based on a systematic literature review and patient interviews) on how the chance of natural conception can be improved. Third, the expected process and outcomes were modelled. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two licenced clinical sexologists, two gynaecologists, a clinical embryologist and two midwife-researchers, all from Belgium and the Netherlands, proposed components for the sex education programme. PubMed was searched systematically for randomised controlled trials (RCTs) evaluating the proposed components in different patient populations. The needs of 12 heterosexual Dutch or Belgian couples who were advised expectant management were explored with in-depth interviews. The content and delivery characteristics of the novel programme were described in detail with the aid of 'Intervention Taxonomy'. To model the outcomes, a protocol for an RCT was designed, registered and submitted for publication. MAIN RESULTS AND THE ROLE OF CHANCE: To help maintain or improve sexual functioning, mainly pleasure, and hence increase pregnancy rates, the web-based Pleasure & Pregnancy programme contains a combination of psychosexual education and couple communication, mindfulness and sensate focus exercises. Information on the biology of conception and interaction with fertility clinic staff and peers were added based on couples' needs to increase potential acceptability. LIMITATIONS AND REASON FOR CAUTION: This paper outlines the development phase of a sex education programme according to the MRC-framework. Whether the Pleasure & Pregnancy programme actually is acceptable, improves sexual functioning, increases pregnancy rates and is cost-effective remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: No previous interactive web-based sex education programme has aimed to increase the natural pregnancy rate of subfertile couples by targeting their sexual pleasure. The Pleasure & Pregnancy programme addresses couples' needs and its effect on sexual functioning and pregnancy rate is plausible but remains to be demonstrated by an RCT which is currently ongoing. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by The Netherlands Organisation for Health Research and Development (ZonMw), Flanders Research Foundation and the University of Amsterdam. C.B.L. is editor-in-chief of Human Reproductionbut was blinded to all parts of the peer review process. The remaining authors have no conflict of interest to report. TRIAL REGISTRATION NUMBER: Not applicable.

Stakeholders views on the ethical aspects of oocyte banking for third-party assisted reproduction: a qualitative interview study with donors, recipients and professionals.

STUDY QUESTION: What are the moral considerations held by donors, recipients and professionals towards the ethical aspects of the intake and distribution of donor bank oocytes for third-party assisted reproduction? SUMMARY ANSWER: Interviews with oocyte donors, oocyte recipients and professionals demonstrate a protective attitude towards the welfare of the donor and the future child. WHAT IS KNOWN ALREADY: The scarcity of donor oocytes challenges the approach towards the many ethical aspects that arise in establishing and operating an oocyte bank for third-party assisted reproduction. Including experiences and moral considerations originating from practice provides useful insight on how to overcome these challenges. STUDY DESIGN, SIZE, DURATION: The project was set-up as a qualitative interview study and took place between October 2016 and August 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: We conducted 25 semi-structured interviews with professionals engaged in the practice of oocyte banking (n = 10), recipients of donor oocytes (n = 7) and oocyte donors (n = 8). Key themes were formulated by means of a thematic analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the interviews, we formulated four main themes describing stakeholders' views regarding the ethical aspects of the intake and distribution of donor bank oocytes. First, respondents articulated that when selecting donors and recipients, healthcare workers should prevent donors from making a wrong decision and safeguard the future child's well-being by minimizing health risks and selecting recipients based on their parental capabilities. Second, they proposed to provide a reasonable compensation and to increase societal awareness on the scarcity of donor oocytes to diminish barriers for donors. Third, respondents considered the prioritization of recipients in case of scarcity a difficult choice, because they are all dependent on donor oocytes to fulfil their wish for a child. They emphasized that treatment attempts should be limited, but at least include one embryo transfer. Fourth and finally, the importance of good governance of oocyte banks was mentioned, including a homogenous policy and the facilitation of exchange of experiences between oocyte banks. LIMITATIONS, REASONS FOR CAUTION: The possibility of selection bias exists, because we interviewed donors and recipients who were selected according to the criteria currently employed in the clinics. WIDER IMPLICATIONS OF THE FINDINGS: Respondents' moral considerations regarding the ethical aspects of the intake and distribution of donor oocytes demonstrate a protective attitude towards the welfare of the donor and the future child. At the same time, respondents also questioned whether such a (highly) protective attitude was justified. This finding may indicate there is room for reconsidering strategies for the collection and distribution of donor bank oocytes. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMw: The Dutch Organization for Health Research and Development (Grant number 70-73000-98-200). A.M.E.B. and B.C.J.M.F. are the initiators of the UMC Utrecht oocyte bank. J.J.P.M.P. is the director of the MCK Fertility Centre. IMC is working as a gynaecologist at the AMC Amsterdam oocyte bank. During the most recent 5-year period, BCJM Fauser has received fees or grant support from the following organizations (in alphabetic order): Actavis/Watson/Uteron, Controversies in Obstetrics & Gynaecologist (COGI), Dutch Heart Foundation, Dutch Medical Research Counsel (ZonMW), Euroscreen/Ogeda, Ferring, London Womens Clinic (LWC), Merck Serono (GFI), Myovant, Netherland Genomic Initiative (NGI), OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter/Finox, Reproductive Biomedicine Online (RBMO), Roche, Teva and World Health Organization (WHO). The authors have no further competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

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

STUDY QUESTION: Does 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 ANSWER: IUI-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 ALREADY: IUI-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, DURATION: A 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, METHODS: The 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 CHANCE: Data 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 CAUTION: The 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 FINDINGS: These 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.

Long-term follow up of couples initially randomized between immobilization and immediate mobilization subsequent to IUI.

A previous randomized clinical trial compared immobilization for 15 min with immediate mobilization subsequent to intrauterine insemination (IUI) and showed higher ongoing pregnancy rates in couples immobilizing subsequent to IUI. The current study compared the long-term effectiveness of immobilization subsequent to IUI. All couples (n = 391) included in the trial were followed for 3 years after randomization and pregnancies and treatments were recorded. After the initial trial period, couples in both groups were offered treatment according to local protocol. The primary outcome was an ongoing pregnancy during the 3 years after the initial trial. In this time period, there were 143 ongoing pregnancies in the immobilization group (n = 199 couples) and 112 ongoing pregnancies in the immediate mobilization group (n = 192). The ongoing pregnancy rates were 72% and 58%, respectively (relative risk 1.2, 95% CI 1.1-1.4). The persistent significant difference in ongoing pregnancy rates underpins the importance of immobilization after IUI. There is no valid reason to withhold women from immobilizing for 15 min after IUI.

Prognostic profiles and the effectiveness of assisted conception: secondary analyses of individual patient data.

BACKGROUND: At present, it is unclear which treatment strategy is best for couples with unexplained or mild male subfertility. We hypothesized that the prognostic profile influences the effectiveness of assisted conception. We addressed this issue by analysing individual patient data (IPD) from randomized controlled trials (RCTs). METHODS: We performed an IPD analysis of published RCTs on treatment strategies for subfertile couples. Eligible studies were identified from Cochrane systematic reviews and we also searched Medline and EMBASE. The authors of RCTs that compared expectant management (EM), intracervical insemination (ICI), intrauterine insemination (IUI), all three with or without controlled ovarian stimulation (COS) and IVF in couples with unexplained or male subfertility, and had reported live birth or ongoing pregnancy as an outcome measure, were invited to share their data. For each individual patient the chance of natural conception was calculated with a validated prognostic model. We constructed prognosis-by-treatment curves and tested whether there was a significant interaction between treatment and prognosis. RESULTS: We acquired data from 8 RCTs, including 2550 couples. In three studies (n = 954) the more invasive treatment strategies tended to be less effective in couples with a high chance of natural conception but this difference did not reach statistical significance (P-value for interaction between prognosis and treatment outcome were 0.71, 0.31 and 0.19). In one study (n = 932 couples) the strategies with COS (ICI and IUI) led to higher pregnancy rates than unstimulated strategies (ICI 8% versus 15%, IUI 13% versus 22%), regardless of prognosis (P-value for interaction in all comparisons >0.5), but at the expense of a high twin rate in the COS strategies (ICI 6% versus 23% and IUI 3% versus 30%, respectively). In two studies (n = 373 couples), the more invasive treatment strategies tended to be more effective in couples with a good prognosis but this difference did not reach statistical significance (P-value for interaction: 0.38 and 0.68). In one study (n = 253 couples) the differential effect of prognosis on treatment effect was limited (P-value for interaction 0.52), perhaps because prognosis was incorporated in the inclusion criteria. The only study that compared EM with IVF included 38 couples, too small for a precise estimate. CONCLUSIONS: In this IPD analysis of couples with unexplained or male subfertility, we did not find a large differential effect of prognosis on the effectiveness of fertility treatment with IUI, COS or IVF.

The prognostic profile of subfertile couples and treatment outcome after expectant management, intrauterine insemination and in vitro fertilisation: a study protocol for the meta-analysis of individual patient data.

OBJECTIVE: The current evidence concerning the best treatment option for couples with unexplained and male subfertility is inconclusive. Most studies that have evaluated the effectiveness of treatment options, such as expectant management (EM), intrauterine insemination (IUI), with or without controlled ovarian stimulation (COS), and in vitro fertilisation (IVF), have not taken the couples' prognosis into account. It is very likely that the individual prognosis of the couple influences the effect of treatment. Individual patient data analyses allow us to take these prognostic factors into account, and to evaluate their effect on treatment outcome. This study aims to use anonymised data from relevant published trials to perform an individual patient data meta-analysis, evaluating the effect of couples' prognosis on the effectiveness of EM, IUI, with or without COS, and IVF. METHODS: Based on earlier systematic reviews and an updated search, randomised controlled trials will be considered for inclusion. Untreated subfertile couples with unexplained or male subfertility included in trials comparing EM, IUI, with or without COS, and IVF are included. Authors of the included studies will be invited to share their original anonymised data. The data will be assessed on validity, quality and completeness. The prognosis of the individual couple will be calculated with existing prognostic models. The effect of the prognosis on treatment outcome will be analysed with marker-by-treatment predictiveness curves, illustrating the effect of prognosis on treatment outcome. This study is registered in PROSPERO (registration number CRD42011001832). CONCLUSION: Ultimately, this study may help to select the appropriate fertility treatment, tailored to the needs of an individual couple.

Timing oocyte collection in GnRH agonists down-regulated IVF and ICSI cycles: a randomized clinical trial.

BACKGROUND: The evidence underpinning the timing of an oocyte collection in IVF or ICSI is limited. The aim of this study was to assess the effect of the follicle diameter size of the dominant follicle on ongoing pregnancy rates. METHODS: We conducted a randomized controlled trial, including women aged between 18 and 43 years who were scheduled for GnRH agonist down-regulated IVF/ICSI treatment in four assisted conception units. Women were randomized between timing oocyte collection when the leading follicle had a diameter of 22 mm or when the leading follicle had a diameter of 18 mm. The primary end-point was ongoing pregnancy, defined as a viable pregnancy at 12 weeks of gestation. RESULTS: The trial had major problems with recruiting patients and after the planned 2 years of recruiting only half of the aimed 400 inclusions were obtained. We allocated 97 women to the 22-mm group and 93 women to the 18-mm group. In the 22-mm group more women reached an ongoing pregnancy (37 of 97 women, 38%) compared with the 18-mm group (22 of 93 women, 24%) resulting in a relative risk of 1.6 [95% confidence interval (CI): 1.03-2.5]. In a logistic regression analysis, the timing of oocyte collection, adjusted for female age, IVF/ICSI and centre, was still associated with ongoing pregnancy, although the association was no longer statistically significant (OR: 2.0; 95% CI: 0.96-4.2) CONCLUSIONS: This study suggests that delaying the timing of oocyte collection in IVF or ICSI results in better ongoing pregnancy rates, however, larger studies have to be performed to prove or refute these findings. TRIAL REGISTRATION: ISRCTN24724622.

The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis.

BACKGROUND: The influence of multifollicular growth on pregnancy rates in subfertile couples undergoing intrauterine insemination (IUI) with controlled ovarian hyperstimulation (COH) remained unclear. METHODS: Relevant papers were identified by searching MEDLINE, EMBASE and the Cochrane Library. A meta-analysis was performed and Mantel-Haenszel pooled odd ratios (ORs) and risk differences with 99% confidence intervals (CIs) were calculated to express the relation between the number of follicles and pregnancy rates. RESULTS: We included 14 studies reporting on 11 599 cycles. The absolute pregnancy rate was 8.4% for monofollicular and 15% for multifollicular growth. The pooled OR for pregnancy after two follicles as compared with monofollicular growth was 1.6 (99% CI 1.3-2.0), whereas for three and four follicles, this was 2.0 and 2.0, respectively. Compared with monofollicular growth, pregnancy rates increased by 5, 8 and 8% when stimulating two, three and four follicles. The pooled OR for multiple pregnancies after two follicles was 1.7 (99% CI 0.8-3.6), whereas for three and four follicles this was 2.8 and 2.3, respectively. The risk of multiple pregnancies after two, three and four follicles increased by 6, 14 and 10%. The absolute rate of multiple pregnancies was 0.3% after monofollicular and 2.8% after multifollicular growth. CONCLUSIONS: Multifollicular growth is associated with increased pregnancy rates in IUI with COH. Since in cycles with three or four follicles the multiple pregnancy rate increased without substantial gain in overall pregnancy rate, IUI with COH should not aim for more than two follicles. One stimulated follicle should be the goal if safety is the primary concern, whereas two follicles may be accepted after careful patient counselling.