{"paper_id":"fca6c019-1365-4107-b827-34241e7863cb","body_text":"Subfertility is defined as not conceiving within 1 year of regular unprotected intercourse\nand this affects approximately one in nine heterosexual couples ( Datta  et al. , 2016 ). Following standard\ninvestigations, no cause can be identified in one-third of these couples who are said to\nhave unexplained subfertility. IVF with or without ICSI, is a commonly used treatment for\ncouples with prolonged unresolved subfertility and over 470 000 treatment cycles were\nrecorded in Europe in 2013 ( Calhaz-Jorge  et\nal. , 2017 ). IVF is a burden to couples in terms of mental and physical\nstress, is associated with high expectations and considerable investment in terms of\nemotions, finances and time ( Rooney and Domar,\n2016 ). The number of IVF cycles conducted increases annually, posing an increasing\nburden on health services in countries where IVF is publicly funded ( HFEA, 2004 ;  Andersen  et\nal. , 2007 ;  NVOG, 2010 ;  NICE, 2013 ;  Kamphuis\n et al. , 2014 ;  Calhaz-Jorge\n et al. , 2017 ; HFEA, 2018). This increase is generally considered\nto be the consequence of the increasingly liberal utilization of IVF for a variety of\nindications, including unexplained subfertility (HFEA, 2004;  Kamphuis  et al. , 2014 ; HFEA, 2015). Yet, there is\nlittle robust evidence supporting the effectiveness of IVF in couples with unexplained\nsubfertility compared to a wait-and-see approach i.e. expectant management ( Pandian  et al. , 2015 ;  Tjon-Kon-Fat  et al. , 2016 ).\nThere is a single trial evaluating the effectiveness of IVF versus expectant management for\ncouples with unexplained subfertility in terms of live birth which reported the chance of\nlive birth following IVF (11 out of 24 couples) to be12 times that of expectant management\n(1 out of 27 couples) ( Hughes  et al. ,\n2004 ). Although the results seem to support IVF, there is considerable uncertainty\naround this result based on very small numbers of participants and it is inappropriate for\nclinical practice across the globe to be based on this quality of evidence ( Tjon-Kon-Fat  et al. , 2016 ).\nObservational studies have separately quantified the predicted chances of conception after\nIVF and after a period of expectant management ( Leushuis\n et al. , 2009 ;  McLernon\n et al. , 2016 ;  van Eekelen\n et al. , 2017a ). There are two problems that hamper the\ncomparability of these predictions, which currently limit their clinical utility. First, the\nprognoses were derived from separate studies with dissimilar patient characteristics. For\ninstance, women with unexplained subfertility who received IVF are generally older than\nwomen who pursued expectant management. Second, the prognosis after IVF is expressed per\nembryo transfer or per complete IVF cycle while the prognosis associated with expectant\nmanagement is expressed in terms of calendar time, commonly over 1 year ( Daya, 2005 ).\nWe can address these problems by adjusting for differences between couples who were treated\nwith IVF and couples who pursued expectant management and expressing predicted chances over\na uniform time horizon. To this end, we opted for a pragmatic approach by analysing data\nfrom three observational cohorts: the UK national IVF registry and two groups of couples\n(from the Netherlands and Scotland, respectively) who embarked on a variable period of\nexpectant management.\nOur aim was threefold. First, to use individual patient data from these three cohorts to\ncompare the average absolute unadjusted 1-year chance of conception after IVF or expectant\nmanagement. Second, to compare the adjusted 1-year chance of conception after IVF or\nexpectant management and third, to estimate the effectiveness of IVF in individual patients\nbased on their clinical characteristics.\n\nThe population comprised couples with unexplained subfertility seen in fertility clinics.\nThe exposure was all IVF cycles and subsequent embryo transfers performed within 1 year\nafter the start of ovarian stimulation. The comparator in the unexposed group was expectant\nmanagement for 1 year after completion of the fertility workup. The outcome of interest was\nconception leading to ongoing pregnancy.\nData on couples treated with IVF between 1999 and 2011 were obtained from the Human\nFertilisation and Embryology Authority (HFEA) registry which collects data from all\nlicensed clinics in the UK ( McLernon  et\nal. , 2016 ). From 2009 onwards, the number of women included was\nlimited because explicit consent was required for the use of their data for research\npurposes ( McLernon  et al. ,\n2016 ).\nWe combined data from two separate cohorts comprising couples with unexplained\nsubfertility who underwent expectant management. The first was a prospective cohort\nassembled across 38 hospitals in The Netherlands between January 2002 and February 2004.\nCouples were followed for natural conception from the completion of the fertility workup\nonwards. The detailed protocol for this has been described elsewhere ( van der Steeg  et al. , 2007 ). The\nsecond was a retrospective population-based cohort from the Grampian region of Scotland\ncomprising subfertile couples who registered at Aberdeen Fertility Clinic. Using a unique,\npseudonomized identifier, we linked patient records, including demographic and diagnostic\ninformation, from the fertility clinic to treatment records from Aberdeen Assisted\nReproduction Unit Database and to pregnancy outcomes from the Aberdeen Maternity and\nNeonatal Databank ( van Eekelen  et al. ,\n2018 ). This process was carried out according to the Standard Operating\nProcedures of the Data Management Team, University of Aberdeen. We selected couples living\nin the Aberdeen City District whose births occurred at Aberdeen Fertility Clinic.\nPregnancy outcomes from natural conceptions were identified by linkage with the Aberdeen\nMaternity and Neonatal Databank, which captures all birth outcomes in this region ( Ayorinde  et al. , 2016 ).\nCouples who had been trying for a pregnancy for <1 year, those with anovulation, uni-\nor bilateral tubal occlusion, mild or severe endometriosis and male subfertility i.e.\nimpaired semen quality according to World Health Organization criteria were excluded from\nthe UK IVF and Scottish cohorts ( WHO, 1999 ;  WHO, 2010 ). For the Dutch cohort, the same exclusion\ncriteria were applied, except that mild endometriosis was considered as a part of\nunexplained subfertility and male subfertility was defined as a total motile count below 1\nmillion ( van Eekelen  et al. ,\n2017a ).\nDecisions regarding treatment were based on local and national protocols. In short, the\nUK IVF registry comprises every IVF cycle, with guidelines changing over time ( NICE, 2013 ). Treatment decisions for the Dutch cohort\nwere left to the discretion of physicians in agreement with their patients ( NVOG, 2004 ;  van der\nSteeg  et al. , 2007 ) and in the Scottish cohort by the local\nprotocol and national guideline ( NICE, 2013 ).\nExpectant management was defined as no intervention aside from the advice to have\nintercourse.\nOur outcome of interest was conception leading to an ongoing pregnancy, defined as a\nfoetus reaching a gestational age of at <12 weeks vizualised by ultrasound. The date of\nconception was defined as the first day of the last menstruation period prior to\nconception. We analysed data up to a maximum of 1 year of follow up.\nFollow up for couples on expectant management started at completion of the fertility\nworkup and ended, for those who did not conceive, at 1 year after the workup, on the date\nof last contact or the date of starting ovarian stimulation for IUI or IVF treatment\n(whichever came first) i.e. we censored their time-to-pregnancy. We assumed that couples\nwho continued with expectant management were no different, in terms of their clinical\ncharacteristics and resulting prognosis, to those who were censored (non-informative\ncensoring).\nCouples who received IVF were followed from the start of ovarian stimulation in the first\ncycle up until their last embryo transfer. Since the IVF registry contained all UK IVF\ncycles from 1999 to 2011, all ongoing IVF pregnancies within 1 year of initiating the\nfirst cycle (i.e. all fresh and frozen cycles) were recorded and we thus had complete\n1-year follow up during which couples received 1.5 embryo transfers on average. This\nassumes that couples who discontinued treatment had zero chance of conception after IVF\nafterwards, for instance for reasons related to an insufficient number of oocytes\ncollected during follicle aspiration, a low fertilization rate or financial reasons ( Daya, 2005 ).\nTo align with our assumption of pursuing one full year of expectant management, we also\nconsidered the hypothetical scenario in which couples continued their IVF attempts for a\nfull year of follow up during which they underwent three to four embryo transfers on\naverage. In the supplementary analysis following this scenario, we censored\ntime-to-pregnancy in couples receiving IVF after their last unsuccessful IVF transfer,\ndefined as the first day of menstruation before the last embryo transfer. We thus also\nassumed non-informative censoring in IVF i.e. that couples who continued IVF were similar\nto couples who dropped out of IVF.\nTo be able to compare couples who received IVF and couples who underwent expectant\nmanagement, we had to make assumptions around the dates of ovarian stimulation and first\nday of menstruation in couples who had IVF. As couples start their IVF treatment with\novarian stimulation, we elected to follow couples from that date until conception (the\nfirst day of last menstruation before the final embryo transfer) to align with the general\ndefinition of time to natural conception. Since dates of initiation of ovarian stimulation\nwere not available in the UK IVF database and are not applicable to frozen/thawed cycles,\nwe assumed a period of 15 days before the date of embryo transfer ( Alport  et al. , 2011 ).\nIn the Dutch cohort, the date of workup completion could be derived and this date was\nused as the start of follow up ( van Eekelen  et\nal. , 2017a ). For the Scottish cohort, this date was not available and\nwas estimated at 6 weeks after the date of registration, which was the average time\nbetween registration and completion of the fertility workup in the Dutch cohort.\nThe prognostic patient characteristics that were recorded in all cohorts were female age,\nduration of subfertility and (female) primary or secondary subfertility. In the UK IVF\ncohort, data for primary or secondary subfertility from 2008 onwards\n( n  = 7532, 18%) were not systematically recorded and were considered as\nmissing. Because of these missing values, we applied multiple imputation including all\nrelevant prognostic characteristics and a covariate for the cumulative hazard of pregnancy\nto account for the aspect of time in the data, creating 10 imputation sets ( White and Royston, 2009 ). In the Dutch cohort, fewer\nthan 1% of data used for the present study were missing and were accounted for in a\nprevious study by multiple imputation, creating 10 imputation sets ( van Eekelen  et al. , 2017a ). In the Scottish cohort,\nfewer than 1% of data were missing and we applied multiple imputation identical to the\napproach in the UK IVF cohort. Ten imputation sets were thus created separately for the\nthree cohorts, then combined to derive 10 combined datasets and we pooled their results\nusing Rubin’s Rules ( Rubin, 2004 ).\nTo ensure that there was minimal confounding due to the three prognostic patient\ncharacteristics (female age, duration of subfertility and previous pregnancy), we applied\nmatching ( Austin, 2014 ). In this matching\nprocedure, we paired couples on expectant management to couples that received IVF that had\nthe same (rounded) female age, duration of subfertility and primary or secondary\nsubfertility status. We found all possible pairs with replacement, which allows each\npatient to be used as a match more than once. This yields higher quality matches than\nmatching without replacement due to data on all matches being used ( Abadie and Imbens, 2006 ). Then, we weighted couples such that the\nexpectant management group was the reference or ‘target population’. Thus, in the\nresulting complete ‘matched’ dataset, the average patient characteristics and sample size\nof couples on expectant management were now identical to couples who received IVF. Using\nthis matched data, we estimate what would happen if couples on expectant management would\ninstead start IVF (referred to as the average treatment effect in controls, or ATC) ( Austin, 2014 ).\nWe calculated the unadjusted 1-year chance of conception after IVF as the observed\nfraction of couples who conceived within 1 year of IVF on the original, unmatched\ndataset. We estimated the unadjusted 1-year chance of conception after expectant\nmanagement with the Kaplan–Meier method on the original, unmatched dataset. We\ncalculated the average unadjusted effect as the absolute difference of these two\nchances. To estimate the adjusted chances and the adjusted average effect, we repeated\nboth these analyses on the matched dataset.\nWe defined the individualized effectiveness of IVF as the absolute difference between\nthe estimated 1-year chance of conception after IVF and the 1-year chance when pursuing\nexpectant management for a couple based on female age, duration of subfertility and\nprimary/secondary subfertility status. To estimate these individual chances, we fitted a\nCox proportional hazards model on the original, unmatched dataset using treatment (IVF\nor expectant management), the patient characteristics and the interaction between\ntreatment and patient characteristics as covariates. This was done following three\nsteps.\nWe first determined how female age and duration of subfertility could best be entered\ninto our statistical model; we evaluated both linear and non-linear associations with\nthe log hazard of conception using linear terms or restricted cubic splines, then tested\nwhich fitted better using Wald tests and Akaike’s Information Criterion (AIC) ( Akaike, 1974 ; Harrell  et al. ,\n1996).\nOnce a suitable form for female age and duration of subfertility was determined, we\nincluded IVF treatment, female age, duration of subfertility, primary or secondary\nsubfertility and all interaction terms with IVF treatment in the model to assess if the\neffect of IVF depended on these characteristics. We then tested all interaction terms\nsimultaneously with an overall Wald test. If this test was significant, we performed\nbackwards selection on the full model using Wald tests per separate interaction and AIC\nto determine which interaction was informative and removed those that were not ( Akaike, 1974 ). We checked the proportional hazards\nassumption for all covariates in the model using scaled Schoenfeld residuals ( Grambsch and Therneau, 1994 ) and accounted for the\nnon-proportional hazard for IVF treatment versus expectant management by stratifying on\ntreatment group.\nAfter the final model fit, we visualized the association between patient\ncharacteristics which varied the effect of IVF by estimating the 1-year chances of\nconception for couples with different characteristics.\nIn addition, we estimated chances for all combinations of patient characteristics,\ntabulating the estimated chances, their corresponding 95% CIs, absolute differences,\nrelative differences and the number needed to treat (NNT).\nIn the first supplementary analysis, in order to estimate the outcome if couples would\ncontinue to have IVF over 1 full year, we used the Kaplan-Meier method both for couples\nreceiving IVF and for couples pursuing expectant management on the original and matched\ndatasets.\nIn the second supplementary analysis, we again estimated individualized chances after\nboth IVF and expectant management but now expressed over a period of 6 months. We\ntabulated these 6-month chances as well as their corresponding 95% CIs, absolute\ndifferences, relative differences and the NNT.\nThe study was approved by the North of Scotland Research Ethics Committee (17/NS/0122).\nData linkage and all statistical analyses were performed in the Data Safe Haven of the\nUniversity of Aberdeen using R version 3.4.3 (R Core Team (2017). R: A language and\nenvironment for statistical computing. R Foundation for Statistical Computing, Vienna,\nAustria.  http://www.R-project.org/ ) and\nRStudio using the  survival  package for the Kaplan–Meier method,\n mice  for multiple imputation of missing data,  rms \nfor functions for splines and fitting Cox models and  Matching  to\nconduct the matching by patient characteristics.\n\nData from a total of 46 771 couples were available for analysis ( Fig. 1 ). Out of 40 921 couples in the UK IVF cohort who received 61 019\nembryo transfers in total, 16 281 conceived (39.8% of couples, 26.7% per embryo transfer)\nwithin 1 year of starting IVF. In total, 32 396 (79%) couples received IVF and 8525 (21%)\nreceived ICSI. There were 4891 multiple gestations after IVF (12% of couples, 30% of\nconceptions). Out of 4875 couples in the Dutch cohort pursuing expectant management, 903\n(18.5%) couples conceived naturally within 1 year after completion of the fertility workup.\nThere were 11 multiple gestations (0.2% of couples, 1.2% of conceptions). Out of 975 couples\nin the Scottish cohort pursuing expectant management, 229 (23.5%) couples conceived\nnaturally within 1 year after completion of the fertility workup. There were no multiple\ngestations.\nFlowchart of recruitment and inclusion/exclusion in the three cohorts .\nBaseline characteristics at the start of follow up for the three cohorts included in\nthe analysis.\nOverlap of patient characteristics for couples who received IVF and couples who\nunderwent expectant management.  ( A ) Distribution of female age per\ntreatment group, depicted by relative frequency (density). ( B ) Distribution\nof duration of subfertility per treatment group, depicted as the proportion of couples\nper group who had a certain (rounded) duration.\nThe median duration of follow up for couples receiving IVF was one embryo transfer\n(25th–75th percentile: 0–7 months) as 29% of couples conceived after their first embryo\ntransfer and 21% discontinued IVF treatment after their first unsuccessful embryo transfer.\nThe median follow up for couples pursuing expectant management was 7 months (25th–75th\npercentile: 3–12 months).\nEstimated effects of patient characteristics on conception leading to ongoing\npregnancy.\n* Contrasts between values for female age and duration of subfertility were\nchosen to depict their non-linear estimated effects.\nResults are from the model including interaction (via stratification) with\ntreatment.\nAssociation between female age and the 1-year chance of conception after receiving\nIVF or pursuing expectant management for a primary subfertile couple who have been\ntrying to conceive for 2 years.  Grey bands are 95% confidence limits.\nThe baseline characteristics of couples, stratified by cohort, are presented in  Table I . In comparison with women who were managed\nexpectantly, those who received IVF were older (mean 35.1 years in the UK IVF, 32.5 years\nin the Dutch and 33.2 years in the Scottish cohorts), had been trying to conceive for\nlonger (median 4.0 years in UK IVF, 1.6 years in the Dutch and 2.1 years in the Scottish\ncohorts) but were just as likely to have primary subfertility (60% in the UK IVF, 66% in\nthe Dutch and 59% in the Scottish cohorts).\nThe distributions of female age and duration of subfertility for couples who received IVF\nand couples who pursued expectant management are shown in  Fig. 2A  and  B .\nThe unadjusted 1-year chance of conception after starting IVF was 39.8% (95% CI:\n39.3–40.3) and after expectant management was 26.1% (95% CI: 24.7–27.5). The average\nabsolute difference in the unadjusted 1-year chance of conception was 13.6% (95% CI:\n11.6–15.7) in favour of IVF. The 1-year chances following expectant management in the\nDutch and Scottish cohorts were similar (26.9% and 23.8%, respectively).\nAssociation between duration of subfertility and the 1-year chance of conception\nreceiving IVF or pursuing expectant management for a primary subfertile couple of\nwhich the woman is 35 years old.  Grey bands are 95% confidence limits.\nA total of 5818 out of 5850 (99%) couples pursuing expectant management were matched with\n31 867 out of 40 921 (78%) counterparts who received IVF and had the same characteristics.\nThe adjusted 1-year chance of conception was 47.9% (95% CI: 45.0–50.9) after starting IVF\nand 26.1% (95% CI: 24.2–28.0) after expectant management. The average absolute difference\nin the adjusted 1-year chance of conception was 21.8% (95% CI: 18.3–25.3) in favour of\nIVF.\nBoth female age and duration of subfertility were non-linearly associated with conception\n(Wald tests for non-linearity both  P  < 0.001, splines with five and\nthree knots, respectively).\nThere were statistically significant interactions between all three patient\ncharacteristics and IVF treatment (overall  P  < 0.001, individual\ninteractions all  P  < 0.001) .\nThe estimated effects of couple characteristics on conception in terms of hazard ratios\n(HRs) are presented in  Table II . In general, as\nfemale age increased, the chance of conception decreased both after expectant management\nand after IVF, but the detrimental effect of female age above 34 years on the chance of\nconception was stronger in the latter (HR of 40 versus 35 years: 0.43 after IVF and 0.64\nafter expectant management). As duration of subfertility increased, the chance of\nconception decreased in both groups, but this effect was stronger for those on expectant\nmanagement (HR of 6 versus 2 years: 0.86 after IVF and 0.39 after expectant management).\nCouples with primary subfertility on expectant management had a lower chance of conception\ncompared to couples with secondary subfertility (HR of primary versus secondary: 0.71) but\nthere was no noticeable difference in the IVF group (HR: 0.98).\nThe predicted 1-year chance of conception in couples with primary subfertility of 2 years\nduration and female age ranging between 26 and 42 years are shown in  Fig. 3 . The effectiveness of IVF decreased in women over 34 years.\nThe predicted 1-year chances of conception in couples with primary subfertility where\nfemale age is 35 years and the duration of subfertility ranges from 1 to 8 years are\nvisualized in  Fig. 4 . The effectiveness of IVF\nincreased as the duration of subfertility increased.\nThe predicted 1-year chances of conception for couples with 2 year duration where female\nage is 35 years stratified for primary and secondary subfertility are presented in  Table III . IVF was more effective for couples with\nprimary subfertility than for couples with secondary subfertility.\nAssociation between primary or secondary subfertility and the 1-year chance of\nconception after receiving IVF or pursuing expectant management for a couple of which\nthe woman is 35 years old who have been trying to conceive for 2 years.\nIn  Supplementary Tables , we\npresent full tables containing the predicted 1-year chance of conception after IVF and\nafter starting expectant management for all combinations of patient characteristics. Also\nprovided are the absolute differences between these chances, the relative differences and\nthe NNT to achieve one additional conception. Predictions are presented separately for\nprimary ( Supplementary Table SI )\nand secondary ( Supplementary Table\nSII ) subfertility for ranges of female age from 26 to 42 years and duration of\nsubfertility from 1 to 8 years. For instance, a typical couple undergoing IVF, where the\nwoman is 35 years old with 4 years duration of primary subfertility, has an estimated\n1-year chance of conception of 46% (95% CI: 44–48) after IVF compared to 12% (95% CI:\n9–14) after expectant management, with an absolute difference of 34% and a NNT of 2.9.\nOn the other hand, a typical couple pursuing expectant management, where the woman is\n33 years old with 2 years of primary subfertility, has an estimated 1-year chance of\nconception of 53% (95% CI: 50–55) after IVF compared to 23% (95% CI: 20–25) after\nexpectant management, with an absolute difference of 30% and a NNT of 3.3.\nIn couples where the woman is under 40 years, IVF was effective compared to expectant\nmanagement. In contrast, in couples where the woman is over 40 years, IVF was less\neffective as the absolute difference between chances was ~10% or lower. In couples with\n1-year duration of secondary subfertility, regardless of the age of the woman, IVF was\nalso less effective since their chances of natural conception remained relatively high at\n30% or above.\nIn the supplementary analysis where we estimated outcomes in couples who continued with\nIVF for a full year, the unadjusted 1-year chance of conception after IVF was estimated at\n51.6% (95% CI: 50.9–52.2). The average absolute difference in the unadjusted 1-year chance\nof conception became 25.4% (95% CI: 23.1–27.7) in favour of IVF.\nThe adjusted 1-year chance of conception after receiving IVF for one full year was\nestimated at 59.7% (95% CI: 55.3–64.0). The average absolute difference in the adjusted\n1-year chance of conception became 33.6% (95% CI: 28.8–38.3) in favour of IVF.\nIn  Supplementary Tables SIII and\nSIV , we present the same individualized predictions as in  Supplementary Tables SI and SII  but\nnow expressed over 6 months instead of 1 year.\n\nIn couples with unexplained subfertility, we found that IVF increased the average 1-year\nchance of conception compared to expectant management. Factors affecting the effectiveness\nof IVF were female age, duration of subfertility and primary/secondary subfertility.\nAlthough couples who received IVF had, on average, a higher female age and a higher\nduration of subfertility compared to couples who continued expectant management, the large\nsample size of treated and untreated couples resulted in sufficient overlap of case-mix to\nenable us to accurately estimate all the separate interactions between patient\ncharacteristics and treatment. A second strength was our ability to control for confounding\nin the average adjusted chance by matching on female age, duration of subfertility and\nprimary versus secondary subfertility.\nWe were able to predict individualized chances of conception following either IVF or\nexpectant management on the same time axis representing 1 year of ‘real’ calendar time. This\nis intuitive, allows for a straightforward comparison, allows for most couples to complete\nat least one full IVF cycle and is easier to communicate to patients compared to chances per\nembryo transfer or per IVF cycle. A longer follow up might increase the rates after both IVF\nand expectant management but may be more difficult for decision making, as the longer the\nfollow up period becomes, the less likely couples are to continue IVF.\nAside from calculating the observed fraction of couples who conceived within 1 year in the\nmatched data (~48%), we also estimated the adjusted chance of conception when receiving IVF\nfor one full year i.e. when continuing IVF (~60%). The latter might be an optimistic\nestimate, as not all couples can continue with additional IVF cycles, for instance because\nof an insufficient number of oocytes or financial reasons.\nLimitations of this study include the availability of only three important patient\ncharacteristics in all data sources, the missing date of completion of the fertility workup\nin the Scottish data and the possibility of residual confounding due to the observational\nnature of the data. We had to make an assumption on the time between registration and\ncompletion of the fertility workup in the Scottish cohort. In the Dutch cohort, this was on\naverage 6 weeks ( van Eekelen  et al .,\n2018 ). In a previously conducted validation study, we found similar chances of\nongoing pregnancy in the Scottish and Dutch cohort when assuming 6 weeks between\nregistration and completion of the fertility workup; hence, this assumption was deemed\nreasonable ( van Eekelen  et al .,\n2018 ). The dropout rate after the first embryo transfer of 21% is >12% reported\nin a recent Dutch validation study, but the difference can be explained by the geographical\nvariation in reimbursement for the UK IVF cohort compared to full reimbursement up to three\ncycles at the time of the Dutch study ( Leijdekkers\n et al ., 2018 ).\nIn addition, the three different data sources used different sampling mechanisms, which\ncould potentially compromise the comparability of study populations. Couples pursuing\nexpectant management were recruited at completion of the fertility workup (Dutch cohort) or\nidentified retrospectively (Scottish cohort). In contrast, couples who received IVF were\nregistered in the UK IVF database with no prior data other than diagnosis. Therefore, we\nwere unable to assess or adjust for any selection bias that might occur between completion\nof the fertility workup and the start of treatment, as only couples that did not conceive\nnaturally during that period will have ended up in the UK IVF registry, a selection which\nmight not be fully captured by the duration of subfertility ( van Eekelen  et al ., 2017b ).\nAs the UK IVF data were only available up to 2011 and treatment success rates were found to\nincrease over time, our estimates for the 1-year chance after IVF might be conservative for\ntoday’s practice. However, IVF rates in the UK in 2016 were found to plateau in 2013 to\n25%–26% per cycle (HFEA, 2016, 2018). A recent external validation of the outcome prediction\nin subfertility model developed on UK IVF data up to 2008 showed good performance in Dutch\ndata collected up to 2014, meaning that our data might reasonably reflect today’s practice\nand pregnancy outcomes ( McLernon  et al. ,\n2016 ;  Leijdekkers  et al. ,\n2018 ). The decade has witnessed changes in embryo transfer protocols in the UK from\npredominantly double embryo transfer (DET) to increasing numbers of elective single embryo\ntransfer (eSET) resulting in a decline in multiple pregnancy rates from 27% in 2008 to16% in\n2014 ( Harbottle  et al. , 2015 ;\nHFEA, 2015). Nevertheless, the impact of this change in IVF policy on our estimated chances\nof conception might be minor as the cumulative chances of IVF success are comparable\nfollowing DET and eSET combined with subsequent transfers of frozen/thawed embryos ( Lukassen  et al. , 2005 ;  McLernon  et al. , 2010 ;  Harbottle  et al. , 2015 ).\nThe primary outcome was ongoing pregnancy because the increased logistical efforts and\nassociated costs involved in following couples to delivery were not possible in the Dutch\ncohort. Ongoing pregnancy is generally considered an appropriate proxy for live birth in\nclinical research; ~95% of ongoing pregnancies lead to live birth ( Clarke  et al. , 2010 ;  Braakhekke  et al. , 2014 ).\nA large randomized controlled trial (RCT) would be the ideal study design to assess the\neffectiveness of IVF compared to expectant management. Conducting such a trial now would be\nchallenging as IVF has become an established treatment for unexplained subfertility and many\ncouples are unconfident about the value of expectant management, overestimate IVF success\nand push for early active treatment ( van den Boogaard\n et al. , 2011 ;  Kersten\n et al. , 2015 ). In addition, many clinicians fail to take into\naccount couples’ chances of natural conception in their consultations and believe that it\nwould be unethical to withhold early access to IVF ( Kersten  et al. , 2015 ). This has created a genuine lack of\nequipoise without which no trial can be conducted. We therefore felt that the best and most\npragmatic option was to compare observational data from cohorts on expectant management and\nIVF ( van Eekelen  et al. ,\n2017b ).\nA key benefit of the present study is the provision of the adjusted average effectiveness\nof IVF compared to expectant management and, in addition, individualized estimates, which\nare easy to interpret and allow for direct comparisons.\nOur results may be used by clinicians to counsel couples with unexplained subfertility to\ninform their expectations and to avoid unnecessary treatment for some while allowing timely\naccess to IVF for others. They can also be used to allow funders and commissioners to make\ndecisions on access to publicly funded IVF.\nOur results need to be validated in other datasets or, ideally, in RCTs involving couples\nwith characteristics in whom the effectiveness of IVF is unclear and some equipoise remains.\nIn addition, data on long-term follow up after the first live birth is necessary to counsel\ncouples who wish to have multiple children.\n\nThe effectiveness of IVF over expectant management in unexplained subfertility depends on\nthe characteristics of the couple and thus, IVF should be used selectively based on\njudgements on gain for a given couple. Our results can be used by clinicians to counsel\ncouples with unexplained subfertility, to inform their expectations and facilitate\nevidence-based, shared decision making.\n\nClick here for additional data file.\nClick here for additional data file.\nClick here for additional data file.\nClick here for additional data file.","source_license":"CC0","license_restricted":false}