An Overview of Trends in Multiple Births After ART
An Overview of Trends in Multiple Births After ART
When the national ART data collection system was developed under the 1992 Fertility Clinic Success Rate Act, it was developed to collect information on a per cycle basis. This reporting system worked well to demonstrate that clinics could successfully perform ART procedures but it has not been optimal as a means of reporting overall patient live birth rate in response to treatment. Per cycle reporting does not provide patients with a picture of their potential for delivery with a continued course of treatment. The methodology also magnifies the per cycle failures because the data used to calculate rates include more cycles of treatment for women who have not successfully achieved live birth than for women who have been successful: successful patients by definition do not continue treatment. This makes the chance of live birth appear lower and increases the pressure to transfer more embryos. Because of these limitations, there has been recent interest in changing the way we report and evaluate ART effectiveness. New paradigms look at either cumulative delivery rates or total reproductive potential.
Cumulative rates are calculated as the delivery rate following repeated cycles of treatment. Cumulative rates usually include a defined number of attempts or a specific time period in which live birth delivery is attempted. In 2009, Malizia et al. published on more than 6000 patients from one clinic and found live birth rates between 51 and 72% from a patient's first cycle up to six cycles of treatment depending on whether conservative or optimal assumptions on cycle continuation were used. Conservative calculations assume that patients who drop out would not have a live birth and optimal calculations assume that these patients would have live birth rates equal to those who actually continued treatment. Both fresh and frozen cycles were included, and live birth rate was age dependent. In 2010, using the SART CORS data, Stern et al. calculated cumulative rates for 14,265 women in Massachusetts over a 3-year period. Patients underwent an average of 1.9 cycles with some having up to 11 cycles for a cumulative delivery rate in all ages and with all treatments of 53%. Luke et al. extended these studies in 2011 using a national cohort of 246,740 women from their first cycle of treatment. Fresh and frozen cycles were evaluated separately as were donor egg cycles, age at first cycle and diagnosis. The study demonstrated that with repeated cycles of treatment, infertile women undergoing ART have live birth rates that approach natural fecundity. Conservative and optimal rates for fresh cycles using autologous oocytes at the third cycle of treatment for women under 31 years of age were 63.3 and 74.6%, respectively: they were 18.6 and 27.8% at 41–42 years of age. Gnoth et al. also demonstrated that cumulative rates approach those of natural fecundity.
The limitation of cumulative delivery rate calculations, at least as calculated from national databases, is that multiple assumptions must be made about reasons for patient discontinuation of treatment. Discontinuation can result from financial problems, generalized stress, relationship stress, decisions to adopt or opt for child-free living, and because perceived chance of achieving a birth is too low. Nevertheless, cumulative delivery rate gives more information than per cycle rates. What it does not do is provide an incentive for patients to transfer fewer embryos since overall rate might still be higher with transfer of more.
Total reproductive potential is another method for evaluating ART effectiveness in repeated cycles. First proposed by Jones in 2003, total reproductive potential is the overall chance of live birth from a single oocyte retrieval plus any frozen embryo transfer cycles that also arise from it. During a fresh ART procedure, oocytes are retrieved, inseminated and grown in culture. One or more embryos are transferred and high quality supernumerary embryos can be frozen. The total reproductive potential of a fresh cycle is the live birth rate per retrieval obtained when both the fresh cycle and the frozen cycles from those original embryos are included. This method of calculating effectiveness has the particular advantage of encouraging a reduction in number of embryos transferred. Because the rate of live birth is measured per retrieval, it can be improved by use of the frozen embryo transfer. Transfer of one embryo in each of two cycles can result in rates as high as transfer of two embryos in one cycle. The difference is a reduction in multiple birth rate.
Several recent studies have made use of total reproductive potential for encouraging the use of single embryo transfer (SET). In a landmark study, Thurin et al. performed a randomized controlled trial of single and double embryo transfer in 661 patients. The SET patients also received a frozen embryo transfer of a single embryo in a subsequent cycle and live birth rate in this frozen transfer cycle was added to the overall rate in this group. The double embryo transfer group achieved a live birth rate of 42.9%, while the SET group had a rate of 27.6% in the fresh cycle alone but reached 38.8% when fresh plus frozen cycles were added. Importantly, multiple birth rate was 33.1% versus 0.8%, respectively, in the double embryo transfer versus the SET groups. For this paradigm to work well, a clinic's embryo freezing program has to be robust and produce high rates of embryo survival and pregnancy. In addition, the study took place in Sweden where national insurance covers both fresh and frozen cycles. Nevertheless, a recent meta-analysis of studies with similar methodologies has substantiated comparable rates for the total reproductive potential of a fresh plus a frozen SET cycle versus a single cycle of double embryo transfer showing that this can be repeated in other studies.
One way to encourage patients to think in terms of total reproductive potential rather than per cycle rates is to report national data in this manner, and this is now possible using linked cycles of data from SART CORS. SART is presently considering providing total reproductive potential or a similar calculation as part of online reporting of clinic live birthrates. If patients respond to this, it could advance promotion of SET. There may be additional value to such a change in reporting. Techniques for oocyte cryopreservation (particularly rapid freezing using vitrification) have recently improved, and oocyte cryopreservation is no longer considered experimental. With development of these techniques, there may be many patients who opt for long-term storage of eggs in 'egg banks', and thus there will be extended time between retrieval and transfer. Using reporting methods such as total reproductive potential that connect retrieval and subsequent transfers from that retrieval may become even more important for assessing ART outcome in the future.
Measuring Effectiveness: Cumulative Live Birth Rates & Total Reproductive Potential
When the national ART data collection system was developed under the 1992 Fertility Clinic Success Rate Act, it was developed to collect information on a per cycle basis. This reporting system worked well to demonstrate that clinics could successfully perform ART procedures but it has not been optimal as a means of reporting overall patient live birth rate in response to treatment. Per cycle reporting does not provide patients with a picture of their potential for delivery with a continued course of treatment. The methodology also magnifies the per cycle failures because the data used to calculate rates include more cycles of treatment for women who have not successfully achieved live birth than for women who have been successful: successful patients by definition do not continue treatment. This makes the chance of live birth appear lower and increases the pressure to transfer more embryos. Because of these limitations, there has been recent interest in changing the way we report and evaluate ART effectiveness. New paradigms look at either cumulative delivery rates or total reproductive potential.
Cumulative rates are calculated as the delivery rate following repeated cycles of treatment. Cumulative rates usually include a defined number of attempts or a specific time period in which live birth delivery is attempted. In 2009, Malizia et al. published on more than 6000 patients from one clinic and found live birth rates between 51 and 72% from a patient's first cycle up to six cycles of treatment depending on whether conservative or optimal assumptions on cycle continuation were used. Conservative calculations assume that patients who drop out would not have a live birth and optimal calculations assume that these patients would have live birth rates equal to those who actually continued treatment. Both fresh and frozen cycles were included, and live birth rate was age dependent. In 2010, using the SART CORS data, Stern et al. calculated cumulative rates for 14,265 women in Massachusetts over a 3-year period. Patients underwent an average of 1.9 cycles with some having up to 11 cycles for a cumulative delivery rate in all ages and with all treatments of 53%. Luke et al. extended these studies in 2011 using a national cohort of 246,740 women from their first cycle of treatment. Fresh and frozen cycles were evaluated separately as were donor egg cycles, age at first cycle and diagnosis. The study demonstrated that with repeated cycles of treatment, infertile women undergoing ART have live birth rates that approach natural fecundity. Conservative and optimal rates for fresh cycles using autologous oocytes at the third cycle of treatment for women under 31 years of age were 63.3 and 74.6%, respectively: they were 18.6 and 27.8% at 41–42 years of age. Gnoth et al. also demonstrated that cumulative rates approach those of natural fecundity.
The limitation of cumulative delivery rate calculations, at least as calculated from national databases, is that multiple assumptions must be made about reasons for patient discontinuation of treatment. Discontinuation can result from financial problems, generalized stress, relationship stress, decisions to adopt or opt for child-free living, and because perceived chance of achieving a birth is too low. Nevertheless, cumulative delivery rate gives more information than per cycle rates. What it does not do is provide an incentive for patients to transfer fewer embryos since overall rate might still be higher with transfer of more.
Total reproductive potential is another method for evaluating ART effectiveness in repeated cycles. First proposed by Jones in 2003, total reproductive potential is the overall chance of live birth from a single oocyte retrieval plus any frozen embryo transfer cycles that also arise from it. During a fresh ART procedure, oocytes are retrieved, inseminated and grown in culture. One or more embryos are transferred and high quality supernumerary embryos can be frozen. The total reproductive potential of a fresh cycle is the live birth rate per retrieval obtained when both the fresh cycle and the frozen cycles from those original embryos are included. This method of calculating effectiveness has the particular advantage of encouraging a reduction in number of embryos transferred. Because the rate of live birth is measured per retrieval, it can be improved by use of the frozen embryo transfer. Transfer of one embryo in each of two cycles can result in rates as high as transfer of two embryos in one cycle. The difference is a reduction in multiple birth rate.
Several recent studies have made use of total reproductive potential for encouraging the use of single embryo transfer (SET). In a landmark study, Thurin et al. performed a randomized controlled trial of single and double embryo transfer in 661 patients. The SET patients also received a frozen embryo transfer of a single embryo in a subsequent cycle and live birth rate in this frozen transfer cycle was added to the overall rate in this group. The double embryo transfer group achieved a live birth rate of 42.9%, while the SET group had a rate of 27.6% in the fresh cycle alone but reached 38.8% when fresh plus frozen cycles were added. Importantly, multiple birth rate was 33.1% versus 0.8%, respectively, in the double embryo transfer versus the SET groups. For this paradigm to work well, a clinic's embryo freezing program has to be robust and produce high rates of embryo survival and pregnancy. In addition, the study took place in Sweden where national insurance covers both fresh and frozen cycles. Nevertheless, a recent meta-analysis of studies with similar methodologies has substantiated comparable rates for the total reproductive potential of a fresh plus a frozen SET cycle versus a single cycle of double embryo transfer showing that this can be repeated in other studies.
One way to encourage patients to think in terms of total reproductive potential rather than per cycle rates is to report national data in this manner, and this is now possible using linked cycles of data from SART CORS. SART is presently considering providing total reproductive potential or a similar calculation as part of online reporting of clinic live birthrates. If patients respond to this, it could advance promotion of SET. There may be additional value to such a change in reporting. Techniques for oocyte cryopreservation (particularly rapid freezing using vitrification) have recently improved, and oocyte cryopreservation is no longer considered experimental. With development of these techniques, there may be many patients who opt for long-term storage of eggs in 'egg banks', and thus there will be extended time between retrieval and transfer. Using reporting methods such as total reproductive potential that connect retrieval and subsequent transfers from that retrieval may become even more important for assessing ART outcome in the future.
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