Live-Birth Rate Associated With Repeat In Vitro Fertilization Treatment Cycles.

In-vitro fertilization (IVF) is commonly stopped after three or four unsuccessful embryo transfers, 1 , 2 with three unsuccessful transfers labelled ‘repeat implantation failure’. 3 This practice has been influenced by a study of 1,328 embryo transfers undertaken twenty-years ago, without use of intra-cytoplasmic sperm injection (ICSI), which reported a decline in live-birth rates after the fourth cycle. 4 With one exception, 5 previous studies of cumulative pregnancy or live-birth rates have been relatively small, with limited ability to precisely estimate cumulative success beyond four transfers. 4 , 6 – 9 Previous studies have defined a cycle of IVF as an embryo transfer. 5 – 9 Thus, each initiation of IVF with ovarian stimulation has been treated as several separate cycles whenever there has been a series of repeated embryo transfers. Given the promotion of single embryo transfer and the effective freezing of embryos have increased markedly over the last 10-15 years, 10 – 15 it has been suggested that IVF success should be calculated as the live-birth rate per initiated ovarian stimulation, including all subsequent separate fresh and frozen embryo transfers. 5 , 10 – 13 The aim of this study was to determine the extent to which repeat IVF cycles continue to increase the likelihood of a live-birth, defining an IVF cycle as the initiation of treatment with ovarian stimulation and all resulting separate fresh or frozen embryo transfers; hereafter we use the term “cycle” for this. Specific objectives were to determine: (i) the live-birth rate within each cycle, and the cumulative rate across all cycles; (ii) how these varied by age and treatment types (use of donor oocyte, ICSI or sperm donation); and (iii) the association between oocyte yield in one cycle and live-birth rate in subsequent cycles.

Ethical approval for this study was provided by the UK Human Fertilisation and Embryology Authority (HFEA) who have statutory obligations to prospectively collect information on all assisted reproductive treatment (ART) in the UK. Women provided written consent for this information to be used in analyses, audit and publications. The HFEA provided us with data on all ART events occurring in the UK between 1st January 2003 and 30th June 2012, with linkage of cycles to individual women and data on birth outcomes. Because all UK clinics, whether private or public, must provide information on any patients treated with ART, together with the outcomes of that treatment, to the HFEA, they are able to link cycles to individual women for all UK ART. We chose the 2003 start date in order to obtain a large cohort representative of contemporary treatment, and June 2012 was the latest date for which the HFEA could provide validated data. Because the live-birth outcome data were incomplete for cycles commencing between January 2011 and June 2012 (as many of these cycles were still continuing and births from them could occur after June 2012) we limited our potentially eligible cohort to ovarian stimulation cycles initiated between 1st January 2003 and 31st December 2010, with live-birth outcome data collected up to June 2012. We excluded ART that was not IVF or was undertaken for the purpose of storage, donation or surrogacy. We excluded women who had started IVF before 2003. As in other studies, 5 – 9 once a live-birth occurred women were censored from further analysis. To reflect clinical practice and allow comparisons with other studies, 4 , 5 , 7 , 9 we included all embryo transfers, whether the individual transfer was of one or more embryos. Live-birth was defined as an infant born alive after 24 weeks gestation surviving more than one month. The World Health Organisation (WHO) define live-birth as a birth showing any sign of life irrespective of gestational age. As in other studies, 5 , 15 , 16 we modified this to capture births that were likely to be viable. We defined an IVF cycle as the initiation of ovarian stimulation and all resulting separate fresh or frozen embryo transfers. The live-birth rate within a cycle was defined as the probability of a live-birth from an ovarian stimulation encompassing all subsequent fresh and frozen embryo transfers from that stimulation. Thus, for those embarking on IVF the live-birth rate within one cycle answers the question ‘ What is my chance of a live-birth with one stimulation and retrieval of oocytes followed by as many subsequent separate embryo transfers as possible from that retrieval ?’ The cumulative live-birth rate at a given cycle was defined as the probability of a live-birth from all cycles up to and including that cycle. This answers the question ‘ What is my total chance of a live-birth with repeat ovarian stimulation and oocyte retrievals, together with the subsequent embryo transfers from each cycle, up to a given cycle number ?’. Information on age, types of treatment (oocyte donation, sperm donation and ICSI), oocyte yield and other couple characteristics were obtained from the HFEA dataset. We calculated the live-birth rates within the first and subsequent cycles up to the ninth, as the proportion of cycles resulting in a live-birth, using a normal approximation to construct confidence intervals. We calculated estimates of cumulative live-birth rates using different assumptions of women who discontinue IVF without a live birth (see below), up to the ninth cycle, using the Kaplan-Meier method with Greenwood’s approximation to calculate confidence intervals (see online supplementary material for full details). 17 , 18 We used a log-rank test 19 to compare the live-birth rate within each cycle and cumulatively across all cycles. The first set of comparisons was between woman’s age and oocyte source category and the second was between no male cause of infertility and male cause of infertility with and without treatment by ICSI or sperm donation. We assessed the relationship of oocyte yield in one cycle to live-birth rates in subsequent cycles in women younger than 40 years using their own oocytes, by calculating the within live-birth rate in the first, second, and third cycles by oocytes retrieved in the first cycle, and also calculating the within live-birth rate up to the fifth cycle by oocytes retrieved in the immediately preceding cycle. Infertile couples discontinue IVF for a number of reasons, with a systematic review of patient perceptions concluding that the commonest reasons were the physical and/or psychological burden of treatment, relationship or personal problems. 20 In any study estimating cumulative live-birth rates assumptions have to be made about what the rate in those who discontinue would have been had they continued. To account for this we calculated ‘optimal’ and ‘conservative’ estimates, which are the have been assessed in previous studies. In addition we calculated a prognostic-adjusted estimate. The optimal estimate, is based on the observed data, and whilst not always explicit in previous publications, this assumes that the cumulative live-birth rate in women who discontinue IVF without a live-birth, if they had continued would be equal to the rate in those who continue to have further cycles. 5 The conservative estimate assumes those who discontinue IVF would have had a subsequent live-birth rate of zero. 5 The true rate is thought to lie between these two. 7 The prognostic-adjusted estimate aims to obtain this more realistic value. It assumes a fixed proportion of those who discontinue do so because of poor prognosis and that the live-birth rate in that proportion would have been zero, whereas for those who discontinue for other reasons, such as inability to pay, emotional distress or (in our dataset) emigration from the UK, it would have been similar to those who continue with treatment. For the prognosis-adjusted estimate we considered the woman’s age at her first cycle and oocyte yield in the previous cycle to be the strongest prognostic factors, because these have been shown to be strongly related to live-birth success. 5 , 7 , 9 , 21 , 22 We checked that these were indicators of live-birth and of discontinuation of treatment in our own data, as well as comparing other available characteristics between those who discontinued and continued treatment after one unsuccessful cycle. To obtain age-adjusted and oocyte yield-adjusted estimates we calculated results for each age strata (18-34, 35-37, 38-39, 40-42, 43-44, 45-50, 50+ years) and for each possible oocyte-yield in the previous cycle and then obtained an average, weighted by the numbers within each category in the first cycle. It was not possible to calculate an age-adjusted estimates for the age stratified analyses as there is too little age variation within the age strata. For any analyses that include women using donor oocytes it is not possible to calculate rates adjusted for oocyte yield in the previous cycle as women using donor oocytes will not have an oocyte yield. The age and previous oocyte yield adjusted results suggested that 3% of those who discontinued IVF did so because of poor prognosis. However, to calculate a prognostic-adjusted cumulative live-birth rate we assumed 30% of those who discontinued did so because of poor prognosis. We chose a value of ten-times that suggested by our data to obtain a conservative prognostic-adjusted estimate. Full details of how these estimates were calculated are provided in online supplementary material . As the average population live-birth success rate for a single embryo transfer is between 20-30% in high income countries, 10 – 13 we considered 20% to be a benchmark for a good live-birth rate within a cycle. All analyses were undertaken in Stata version 13 MP2. Two-sided p-values < 0.05 were considered to provide evidence against the null hypothesis. We used data on pregnancy and pregnancy loss rates from published literature to estimate live-birth rates in women who conceive naturally. 23 -254 Two prospective cohort studies of couples actively trying to conceive provided age specific pregnancy rates attained within twelve menstrual cycles. 23 , 24 Live birth rates were calculated assuming 20% of natural conceptions result in a pregnancy loss. 25

Following planned exclusions the eligible cohort included 257,665 cycles in 157,475 women. For all analyses we excluded women with missing linkage information or implausible linkage (i.e. first IVF transfer being a frozen embryo transfer without preceding ovarian stimulation). This resulted in an analysis cohort of 257,398 cycles by 156,947 women (more than 99% of the eligible cohort; Figure 1 ). Table 1 shows the characteristics of the cohort. eTable 1 shows characteristics by year of treatment. Because of the large sample size there was statistical evidence of differences in all characteristics, but for most these were small and unlikely to be clinically important. For example, median age of the women differed by one-year and median oocyte retrieval differed by one across the study period. Use of ICSI increased by 11%, and transfer of single embryos by 17%, though the live-birth rate increased by just two-percent across the study period. Table 2 shows the live-birth rate within each cycle for the whole cohort. In all women the live-birth rate for the first cycle was 29.5% (95%CI: 29.3, 29.7). The live-birth rate within cycles remained above 20% for each cycle up to and including the fourth. After their first cycle there were 110,614 women (70.5% of the analysis cohort) who did not have a live-birth. Of these, 37,704 (34.1%) discontinued treatment and 72,910 (65.9%) had at least one more cycle. eTable 2 compares characteristics between these two groups. Although there was statistical evidence of differences for all characteristics the actual differences were small. The cumulative live-birth rate continued to increase up to the ninth cycle, with a cumulative prognosis-adjusted live-birth rate of 65.3% (64.8, 65.8) by the sixth cycle ( Table 2 ). The equivalent optimal (78.0% (77.3, 78.8)) and age-adjusted (76.7% (76.0, 77.5)) estimates for six cycles were similar, while the conservative estimate was 46.8% (46.5, 47.0) ( Table 2 and eFigure 1 ). Results varied by age and oocyte source ( Figure 2 , Table 3 , eTables 3 and 4 ). In women who were younger than 40 years and using their own oocytes (133,379 women, 85% of the cohort), the live-birth rate for the first cycle was 32.3% (32.0, 32.5). This remained above 20% up to and including the fourth cycle. The previous cycle oocyte-yield adjusted and optimal estimates were similar. Six cycles achieved cumulative live-birth rates of 68.4%, (67.8, 68.9), 80.3% (79.5 to 81.0) and 50.7% (50.5, 51.0), for the prognostic-adjusted, optimal and conservative estimates, respectively. For women aged 40-42, the live-birth rate for the first cycle was 12.3% (11.8, 12.8), with six cycles achieving a cumulative live-birth rates of 31.5% (29.7, 33.3), 41.5% (38.0, 44.9), and 19.2% (18.5, 19.8) for prognostic-adjusted, optimal and conservative estimates, respectively. For women older than 42 years all rates within each cycle were less than 4% or based on too few live-births to calculate confidence intervals. Use of donor oocytes removed this age differential, as the log-rank test showed no evidence for different cumulative live-birth rates between age categories ( eTable 3 ). Irrespective of age, women using donor oocytes achieved live-birth rates within each cycle of 29.6% or greater for all cycles up to and including the ninth and a cumulative live-birth rate after six cycles of 86.7% (85.2, 88.3), 91.7% (90.3, 93.1) and 75.5% (74.0, 77.1) for the prognostic-adjusted, optimal and conservative estimates, respectively ( eTable 4 ). Live-birth rates varied by male cause infertility and its treatment ( Figure 3 and eTables 5 to 7 ). Women whose infertility was due to a male related cause and who were not treated with either ICSI or donor sperm had lower live-birth rates than those with a non-male cause of infertility ( eTables 3 and 5 ). Those with a male cause of infertility who were treated with ICSI had cumulative live-birth rates, after six cycles, of 71.3% (70.5, 72.1), 82.2% (81.1,83.4) and 54.7% (54.3, 55.2) using the prognostic-adjusted, optimal and conservative, estimates, respectively ( eTable 6 ). Equivalent results for those with male infertility treated with donor sperm were 81.2% (78.6, 83.9), 90.2% (87.2, 93.1) and 65.9% (63.9, 67.9) respectively ( eTable 7 ). Live-birth rates in both of these groups were greater than in those with a non-male cause of infertility ( eTables 3 and 8 ). Figure 4 shows the live-birth rate within the first, second and third cycles plotted against the number of oocytes retrieved in the first cycle in women under 40 years of age using their own oocytes. For those in whom no oocytes were retrieved in the first cycle the live-birth rates in the second and third cycles were greater than 20%. The live-birth rates in the first, second and third cycles continued to increase with increasing oocytes retrieved in the first cycle up to around 15 oocytes; thereafter the curves flatten. Plotting the live-birth rate within any cycle against the number of oocytes retrieved in the previous cycle gave a similar pattern ( eFigure 2 ). Using published data 23 – 25 we estimated that the live-birth rate for women conceiving naturally, who had been trying for 12 menstrual cycles, varied between 58% and 74% depending on the woman’s age and frequency of intercourse ( eTable 9 ). These estimates are based on studies that only included women younger than 40. Similar cumulative live-birth rates were achieved by the fifth or sixth cycle of IVF treatment in women of this age ( Table 3 ), though, in these women, five cycles took a median of 2 years (1st, 3rd quartile: 2, 3).

To our knowledge this is the first study to have linked fresh and frozen embryo transfers to obtain estimates of live-birth rate within each IVF ovarian stimulation cycle and cumulative live-birth rates across repeated stimulation cycles. Despite a decline in the success rate within each cycle as the number of these increased, the cumulative rate across cycles increased up to the ninth in the whole cohort, those younger than 40 (using their own oocytes) and those using donor oocytes (irrespective of age). They also increased up to the eighth or ninth in women aged 40-42, though for women older than 42 (using their own oocytes) the likelihood of success was low and the cumulative live-birth rate did not appear to clearly increase beyond the fourth or fifth cycle. For those women able to use donor oocytes, age was unrelated to success. In those for whom the cause of infertility was related to a male partner problem, treatment with ICSI or donor sperm made a marked difference in the likelihood of success, with cumulative rates increasing up to the eighth or ninth cycle, whereas without treatment rates were lower than in those with other causes of infertility. In women under 40 years with a low oocyte yield in a previous cycle there was benefit in continuing with further cycles. We also found women under 40 years could achieve cumulative live-birth rates after five or six cycles that were similar to published live-birth rates achieved naturally within 12 menstrual cycles. 23 – 25 It should be noted, however, that, in these women, five cycles took a median of 2 years. Widespread adoption of single embryo transfer has reduced multiple pregnancies and adverse perinatal outcomes, but has meant that the chance of a live-birth from a single ovarian stimulation cycle is spread across multiple embryo transfers, which we have assessed here. Since this method of assessing IVF success combines all embryo transfer events following an ovulation stimulation into one analysis unit, we were unable to examine the effect of the number of embryos transferred per event. However, this method of assessing IVF success is increasingly recommended. 5 , 10 – 13 Our results show how success rates per embryo transfer event are misleadingly lower, compared with the rate within each ovarian stimulation cycle. Furthermore, we have previously shown, using unlinked data from the same population, that the number of embryos transferred in one event has a relatively modest effect on live-birth rate, with a difference of 9% in women younger than 40 years and 16% in those aged 40 years or older, comparing double to single embryo transfer. 15 Despite the differences in the definition of cumulative success between our study and the previous largest study (from the US), in which cumulative live-birth rates were estimated on the basis of each embryo transfer, 5 and differences in health systems between the US and UK, both studies found age differences in rates and that these were removed with the use of donor oocytes. In the US study, those with a male cause of infertility had one of the highest cumulative live-birth rates per embryo transfer, but that study did not examine the effect of different treatments (ICSI or sperm donation) and it may be that all of those with male cause infertility in the US receive one of these treatments. The key limitation of all studies looking at cumulative outcomes with repeat IVF is how one treats those who discontinue treatment. As seen in our data, and in previous studies, 5 , 7 the extremes of the optimal and conservative estimates often vary markedly, for example in our data the optimal and conservative estimates were 78.0% and 46.8%, respectively, for the whole cohort. This is because of the differences between these two, in what they assume would have been the live-birth rate in those who discontinued IVF, had they continued; for the optimal estimate this is assumed to be the same as those who did continue, whereas the conservative estimate it is assumed to be zero. We examined the likelihood that such discontinuation was due to poor prognosis based on age and previous cycle oocyte retrieval. These analyses suggested approximately 3% of those who discontinued did so because of poor prognosis. This small proportion was because although these two were important predictors of live-birth, few women receiving IVF are older than 40 years (only 15% in our national population cohort) and most women have a high oocyte yield (median 9 per cycle in our cohort). However, to account for other factors, for example pre-treatment reproductive hormone levels, smoking and body mass index (BMI), which have been linked to live-birth success, 7 , 22 but that were not available in this study, we assumed a 30% discontinuation due to poor prognosis. Because of the legal requirement for all UK clinicians to provide data on all ART patients, the HFEA were able to link cycles to individual women even if they moved between clinics within the UK. However, treatment abroad would be absent from our data. A European study, conducted 6 years ago, found very few UK couples travelled for ART to 49 clinics in six (non-UK) European countries with high rates of cross-border patients. 26 We were only able to assess live-birth as an outcome: future studies should also consider potential adverse effects of continued treatment, including ovarian hyper-stimulation syndrome and possible increased risk of preterm birth, low birth weight or congenital anomalies. 16 , 27 , 28 We acknowledge that for some couples the emotional stress of repeat treatments may be undesirable and the cost of a prolonged treatment course, with several repeat oocyte stimulation cycles, may be unsustainable for health services, insurers or couples. However, we think the potential for success with further cycles should be discussed with couples. A cost-effectiveness analysis is beyond the scope of this study, and the difficulties of undertaking such analyses for IVF, in which decisions related to how one values a new life and whether ‘benefits’ and ‘costs’ for both parents and the child should be included, are well-documented. 29 The costs of IVF treatment vary between countries, whether publicly or privately funded, and the treatment type used, but are in the range of $14,000 (£9,000, €12,000) to $17,000 (£11,000, €15,000) per cycle. 1 , 29 , 30 These costs exclude assessment prior to starting IVF and are based on transfer of one fresh embryo. Assuming each addition frozen embryo transfer costs $4000 to $5000, 30 the cost per couple of continuing to six, rather than having just three cycles, could be as much as $132,000 compared to $66,000 (assuming one fresh and one frozen transfer per cycle). Among women in the UK undergoing IVF, the cumulative prognosis-adjusted live-birth rate after six cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond three or four.