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This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.

STUDY QUESTION Which couples with unexplained subfertility can expect increased chances of ongoing pregnancy with IVF compared to expectant management? SUMMARY ANSWER For couples in which the woman is under 40 years of age, IVF is associated with higher chances of conception than expectant management. WHAT IS KNOWN ALREADY The clinical indications for IVF have expanded over time from bilateral tubal blockage to include unexplained subfertility in which there is no identifiable barrier to conception. Yet, there is little evidence from randomized controlled trials that IVF is effective in these couples. STUDY DESIGN, SIZE, DURATION We compared outcomes in British couples with unexplained subfertility undergoing IVF (n = 40 921) from registry data to couples with the same type of subfertility on expectant management. Those couples on expectant management (defined as no intervention aside from the advice to have intercourse) comprised a prospective nation-wide Dutch cohort (n = 4875) and a retrospective regional cohort from Aberdeen, Scotland (n = 975). We excluded couples who had tried for <1 year to conceive and also those with anovulation, uni- or bilateral tubal occlusion, mild or severe endometriosis or male subfertility i.e. impaired semen quality according to World Health Organization criteria. PARTICIPANTS/MATERIALS, SETTING, METHODS We matched couples who received IVF and couples on expectant management based on their characteristics to control for confounding. We fitted a Cox proportional hazards model including patient characteristics, IVF treatment and their interactions to estimate the individualized chance of conception over 1 year—either following IVF or expectant management for all combinations of patient characteristics. The endpoint was conception leading to ongoing pregnancy, defined as a foetus reaching a gestational age of at least 12 weeks. MAIN RESULTS AND THE ROLE OF CHANCE The adjusted 1-year chance of conception was 47.9% (95% CI: 45.0–50.9) after IVF and 26.1% (95% CI: 24.2–28.0) after expectant management. The absolute difference in the average adjusted 1-year chances of conception was 21.8% (95%CI: 18.3–25.3) in favour of IVF. The effectiveness of IVF was influenced by female age, duration of subfertility and previous pregnancy. IVF was effective in women under 40 years, but the 1-year chance of an IVF conception declined sharply in women over 34 years. In contrast, in woman over 40 years of age, IVF was less effective, with an absolute difference in chance compared to expectant management of 10% or lower. Regardless of female age, IVF was also less effective in couples with a short period of secondary subfertility (1 year) who had chances of natural conception of 30% or above. LIMITATIONS, REASONS FOR CAUTION The 1-year chances of conception were based on three cohorts with different sampling mechanisms. Despite adjustment for the three most important prognostic patient characteristics, namely female age, duration of subfertility and primary or secondary subfertility, our estimates might not be free from residual confounding. WIDER IMPLICATIONS OF THE FINDINGS IVF should be used selectively based on judgements on gain compared to continuing expectant management for a given couple. Our results can be used by clinicians to counsel couples with unexplained subfertility, to inform their expectations and facilitate evidence-based, shared decision making. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Tenovus Scotland [grant G17.04]. Travel for RvE was supported by the Amsterdam Reproduction & Development Research Group [grant V.000296]. SB reports acting as editor-in-chief of HROpen. Other authors have no conflicts.

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STUDY QUESTION What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6–12 months for infertile women of age ≥35 years? SUMMARY ANSWER Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses. WHAT IS KNOWN ALREADY In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age. STUDY DESIGN, SIZE, DURATION A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms ‘fertility service’, ‘waiting list’, ‘treatment-independent’ and ‘spontaneous conception’. Language restrictions were not imposed. PARTICIPANTS/MATERIALS, SETTING, METHODS Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle–Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs). MAIN RESULTS AND THE ROLE OF CHANCE We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5–8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35–42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11–0.19) after 6 months and 0.24 (95% CI 0.17–0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04–0.11) after 6 months and 0.13 (95% CI 0.07–0.18) after 12 months. LIMITATIONS, REASONS FOR CAUTION In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years. WIDER IMPLICATIONS OF THE FINDINGS Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility. STUDY FUNDING/COMPETING INTEREST(S) S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet. PROSPERO REGISTRATION NUMBER CRD42018096552.

Couples in whom the results of an initial fertility workup fail to identify the presence of any obvious barriers to conception are diagnosed with unexplained subfertility. Couples who have tried to conceive for a relatively short time have a good chance of natural conception and thus may not benefit from immediate access to ART. As fertility decreases over time, the main dilemma that clinicians and couples face is when to abandon an expectant approach in favour of active treatment. Several prognostic or predictive models have been used to try to discriminate between couples with high and low chances of conception but have been unable to compare individualized chances of conception associated with ART relative to chances of natural conception at various time points. These models are also unable to recalculate the chances of pregnancy at subsequent time points in those who return after a period of unsuccessful expectant management. In this paper, we discuss currently available models. We conclude that in order to provide accurate, individualized and dynamic fertility prognoses associated with and without treatment at different points in time, we need to develop, validate and update clinical prediction models which are fit for purpose. We suggest several steps to move the field forwards.

STUDY QUESTION Can we use prediction modelling to estimate the impact of coronavirus disease 2019 (COVID 19) related delay in starting IVF or ICSI in different groups of women? SUMMARY ANSWER Yes, using a combination of three different models we can predict the impact of delaying access to treatment by 6 and 12 months on the probability of conception leading to live birth in women of different age groups with different categories of infertility. WHAT IS KNOWN ALREADY Increased age and duration of infertility can prejudice the chances of success following IVF, but couples with unexplained infertility have a chance of conceiving naturally without treatment whilst waiting for IVF. The worldwide suspension of IVF could lead to worse outcomes in couples awaiting treatment, but it is unclear to what extent this could affect individual couples based on age and cause of infertility. STUDY DESIGN, SIZE, DURATION A population based cohort study based on national data from all licensed clinics in the UK obtained from the Human Fertilisation and Embryology Authority Register. Linked data from 9589 women who underwent their first IVF or ICSI treatment in 2017 and consented to the use of their data for research were used to predict livebirth numbers. PARTICIPANTS/MATERIALS, SETTING, METHODS Three prediction models were used to estimate the chances of livebirth associated with immediate treatment versus a delay of 6 and 12 months in couples about to embark on IVF or ICSI. MAIN RESULTS AND THE ROLE OF CHANCE We estimated that a 6-month delay would reduce livebirths by 0.4%, 2.4%, 5.7%, 9.5% and 11.8% in women aged &lt;30, 30-35, 36-37, 38-39 and 40-42 years, respectively, while corresponding values associated with a delay of 12 months were 0.9%, 4.9%, 11.9%, 18.8% and 22.4%, respectively. In women with known causes of infertility, worst case (best case) predicted chances of livebirth after a delay of 6 months in women aged &lt;30, 30-35, 36-37, 38-39 and 40-42 years varied between 31.6% (35.0%), 29.0% (31.6%), 23.1% (25.2%), 17.2% (19.4%) and 10.3% (12.3%) for tubal infertility and 34.3% (39.2%), 31.6% (35.3%) 25.2%(28.5%) 18.3% (21.3%), and 11.3% (14.1%) for male factor infertility. The corresponding values in those treated immediately were 31.7%, 29.8%, 24.5%, 19.0% and 11.7% for tubal factor and 34.4%, 32.4%, 26.7%, 20.2% and 12.8% in male factor infertility. In women with unexplained infertility the predicted chances of livebirth after a delay of 6 months followed by one complete IVF cycle were 41.0%, 36.6%, 29.4%, 22.4% and 15.1% in women aged &lt;30, 30-35, 36-37, 38-39 and 40-42 years, respectively, compared to 34.9%, 32.5%, 26.9%, 20.7% and 13.2% in similar groups of women treated without any delay. The additional waiting period, which provided more time for spontaneous conception, was predicted to increase the relative number of babies born by 17.5%, 12.6%, 9.1%, 8.4% and 13.8%, in women aged &lt;30, 30-35, 36-37, 38-39 and 40-42 years, respectively. A 12-month delay showed a similar pattern in all subgroups. LIMITATIONS, REASONS FOR CAUTION Major sources of uncertainty include the use of prediction models generated in different populations and the need for a number of assumptions. Although the models are validated and the bases for the assumptions are robust, it is impossible to eliminate the possibility of imprecision in our predictions. Therefore, our predicted live birth rates need to be validated in prospective studies to confirm their accuracy. WIDER IMPLICATIONS OF THE FINDINGS A delay in starting IVF reduces success rates in all couples. For the first time, we have shown that while this results in fewer babies in older women and those with a known cause of infertility, it has a less detrimental effect on couples with unexplained infertility, some of whom conceive naturally whilst waiting for treatment. Post COVID 19, clinics planning a phased return to normal clinical services should prioritise older women and those with a known cause of infertility. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received for this study. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, Merck KGaA, Guerbet and iGenomics. SB is Editor-in-Chief of Human Reproduction Open. None of the other authors declare any conflicts of interest.

STUDY QUESTION What is the chance of a treatment-independent live birth following IVF (including ICSI) treatment? SUMMARY ANSWER Over 5 years of follow-up, the treatment-independent live birth rate was 17% in unsuccessfully treated women and 15% in those who had a live birth after IVF. WHAT IS KNOWN ALREADY A limited number of studies have investigated the chance of treatment-independent conception following completion of IVF, but most of them have been based on surveys with poor response rates and limited sample sizes. STUDY DESIGN, SIZE, DURATION This is a population-based, retrospective cohort study of 2133 women who received IVF treatment between 1998 and 2011 at a single regional IVF Unit and were followed for a minimum of 1 year and maximum of 15 years after their last IVF or ICSI treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included all women, residing in the north-east of the UK, who attended the Aberdeen Fertility Clinic and received IVF treatment between 1998 and 2011. Clinical and diagnostic information of all women was linked with treatment and pregnancy outcome data. A total of 2133 women were divided into two groups: (i) those who achieved a live birth following successful IVF or ICSI treatment (n = 1060) and (ii) those in whom treatment was unsuccessful i.e. resulted in either no pregnancy or pregnancy loss (n = 1073). The two groups were followed from the date of the last embryo transfer until the first treatment-independent live birth or 31 December 2012, whichever came first. The primary outcome was the treatment-independent live birth rate at 1, 2.5, 5 and 10 years of follow-up. Cox regression was used to determine factors associated with treatment-independent live birth in each group. MAIN RESULTS AND THE ROLE OF CHANCE Within 5 years of follow-up, the treatment-independent live birth rate was 17% (95% CI, 15–19%) among women whose IVF or ICSI treatment was unsuccessful and 15% (95% CI, 12–17%) among women whose treatment resulted in live birth. In both groups, shorter duration of infertility, younger female age and IVF as compared to ICSI were associated with a higher chance of achieving treatment-independent live birth. Among unsuccessfully treated women, the chance of post-IVF live birth was reduced in those with tubal factor infertility. Three or more previous IVF or ICSI embryo transfers were associated with a lower chance of treatment-independent live birth among successfully treated women. LIMITATIONS, REASONS FOR CAUTION The study was conducted in a single fertility centre, which could compromise the generalizability of the findings. Moreover, data were unavailable on the women’s use of contraception or active attempts to get pregnant, both of which could influence treatment-independent live birth rates. WIDER IMPLICATIONS OF THE FINDINGS This study provides a better understanding of the long-term prognosis for treatment-independent live birth after completion of IVF or ICSI treatment. The results will inform women of their chances of a treatment-independent live birth following failed or successful treatment and the factors that are associated with it. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. The authors have no competing interests. TRIAL REGISTRATION NUMBER Not applicable.