- Email: [email protected]
Number of embryos to transfer: better safe than sorry?
Comment
Number of embryos to transfer: better safe than sorry?
www.thelancet.com Vol 379 February 11, 2012
but these findings are controversial.6 That information on cumulative rates for fresh and frozen embryos is missing from the study by Lawlor and Nelson2 is, therefore, unfortunate. Additionally, that the data used for this study could not be provided for individuals and remain anonymised is odd, as it has been achieved in other large datasets. Different approaches have been taken to ensure that eSET is the preferred or main approach. In Sweden, state regulations allow for transfer of only one embryo except in exceptional circumstances. Since the regulations were adopted, one embryo has been transferred in 70% of all cycles and, accordingly, the number of multiple births has decreased from 25% to 5%.6 In Belgium, the government agreed to reimburse the costs of six treatment cycles in exchange for a reduction in the number of embryos transferred to one in the first two cycles as a general rule.7,8 The reduction in multiple births in Belgium now corresponds to that in Sweden.9 Data from the European programme that monitors in-vitro fertilisation show large differences between countries in the rates of multiple births after assisted conception. The rates largely parallel the direct cost to patients:10 couples who have to cover all costs themselves generally accept the risk of a multiple pregnancy to improve the likelihood of conception. Preterm deliveries that result from multiple pregnancies after assisted conception add a substantial
Published Online January 12, 2012 DOI:10.1016/S01406736(11)61478-5 See Articles page 521
Science Photo Library
Guidelines on the number of embryos to be transferred in couples attempting assisted conception is widely debated owing to adverse perinatal risks and costs associated with multiple pregnancies. In published work on perinatal outcomes after assisted conception, it is generally agreed that the high prevalence of twins explains most of the increased risk in pregnancies after assisted conception.1 Opinion has, therefore, shifted towards the view that transfer of only one embryo at a time is optimum. Debbie Lawlor and Scott Nelson,2 in The Lancet, address risks of assisted conception in relation to maternal age in a large prospective study in the UK. In women aged 40 years or older they showed that the livebirth rate was lower than that in women younger than 40 years, irrespective of the number of embryos transferred, but that in both age groups the livebirth rate was higher after transfer of two embryos, compared with one. In the older age group, multiple births occurred less often than in the younger age group. Adverse perinatal outcomes, including multiple and premature births and low birthweight, were seen more frequently after transfer of multiple embryos than after one. The authors firmly conclude that transfer of three embryos is not warranted. This important paper provides strong arguments in favour of restricting the transfer of embryos to a maximum of two per cycle, irrespective of maternal age. Lawlor and Nelson’s finding that the proportion of embryo transfer cycles resulting in a livebirth was greater with transfer of two embryos than one in both age groups is in line with previous studies.3 Improved freezing techniques for surplus embryos might compensate for reduced pregnancy rates with single embryo transfer—cryopreservation should keep the biological potential of each fertilised oocyte to a maximum and lower the number of stimulated cycles needed. To keep the number of stimulation cycles to a minimum is crucial from medical, psychological, ethical, and economic perspectives. The cumulative birthrate after elective single embryo transfer (eSET), including the transfer of a fresh embryo in one cycle followed by transfer of a thawed embryo in the next, has in some studies been similar to that in younger women who received two fresh embryos in one cycle,4,5
497
Comment
financial burden to health care; in the USA, the annual cost is estimated to be around US$1 billion.11 Despite the trend towards eSET, the costs seem to be remaining high, probably because of an overall increase in the use of assisted conception treatments. In Europe, twins account for 20% of all livebirths after assisted conception, but in the USA the corresponding proportion is 30%. This burden is a major concern, and guidelines on the number of embryos to transfer need to reflect the associated expenses. Whether the Belgian reimbursement model8 can be adopted elsewhere is worthy of consideration. Medical care should be guided by the best available evidence, and the decision to transfer more than one embryo should be based on an assessment of each patient’s prognostic factors, including age. A prediction model for outcomes after assisted conception12,13 has not yet been universally adopted. The final decision of whether to transfer one or two embryos should, therefore, be based on a cooperative approach between embryologists and clinicians, although patients with medical or obstetric contraindications to twin pregnancies should receive no more than one embryo, irrespective of age or other prognostic factors. Several strategies can be used to lower the risk of multiple births after assisted conception. The provision of information to patients and health-care providers is essential. Public funding to cover treatment costs can facilitate a reduction in the number of transferred embryos, and improvements in embryo freezing techniques will increase the cumulative pregnancy rate per cycle of oocyte retrieval. A combination of these factors will increase the likelihood that the outcome of interest will be achieved: one healthy baby at a time.
Liv Bente Romundstad Fertility Clinic, St Olav’s University Hospital, NTNU, Faculty of Medicine, Department of Public Health and General Practice, NO-7491 Trondheim, Norway [email protected] I have received travel expenses from MSD and Ferring. 1 2
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5
6
7
8
9
10
11
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Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Update 2005; 11: 575–93. Lawlor DA, Nelson SM. Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study. Lancet 2011; published online Jan 12. DOI:10.1016/S0140-6736(11)612671. Pandian Z, Bhattacharya S, Ozturk O, Serour G, Templeton A. Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2009; 2: CD003416. Thurin A, Hausken J, Hillensjo T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004; 351: 2392–402. McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials. BMJ 2010; 341: c6945. Karlstrom PO, Bergh C. Reducing the number of embryos transferred in Sweden—impact on delivery and multiple birth rates. Hum Reprod 2007; 22: 2202–07. Ombelet W, Cadron I, Gerris J, et al. Obstetric and perinatal outcome of 1655 ICSI and 3974 IVF singleton and 1102 ICSI and 2901 IVF twin births: a comparative analysis. Reprod Biomed Online 2005; 11: 76–85. Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and infertility treatment: registration, reflection and reaction—the Belgian project. Hum Reprod Update 2005; 11: 3–14. Van Landuyt L, Verheyen G, Tournaye H, Camus M, Devroey P, Van Steirteghem A. New Belgian embryo transfer policy leads to sharp decrease in multiple pregnancy rate. Reprod Biomed Online 2006; 13: 765–71. Connolly MP, Hoorens S, Chambers GM. The costs and consequences of assisted reproductive technology: an economic perspective. Hum Reprod Update 2010; 16: 603–13. Bromer JG, Ata B, Seli M, Lockwood CJ, Seli E. Preterm deliveries that result from multiple pregnancies associated with assisted reproductive technologies in the USA: a cost analysis. Curr Opin Obstet Gynecol 2011; 23: 168–73. van Loendersloot LL, van Wely M, Repping S, van der Veen F, Bossuyt PM. Templeton prediction model underestimates IVF success in an external validation. Reprod Biomed Online 2011; 22: 597–602. Nelson SM, Lawlor DA. Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles. PLoS Med 2011; 8: e1000386.
Improving Alzheimer’s disease outcomes in Down’s syndrome Published Online January 10, 2012 DOI:10.1016/S01406736(11)61929-6 See Articles page 528
498
More than 40% of people with Down’s syndrome in the UK are aged 40 years or older,1 and one in 10 of these individuals develops Alzheimer’s disease. This rate rises to one in three of those who are older than 50 years and more than half of those older than 60 years.2 This progression is very distressing for parents and family carers because it can come at a time when—facing the physical and social challenges of ageing—they are least able to provide care, resulting in high caregiver burden.3
Thus, the MEADOWS trial4 reported by Marisa Hanney and colleagues in The Lancet is an important attempt to improve outcomes of adults with Down’s syndrome and Alzheimer’s disease. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist that improves cognitive function in older adults with moderate-to-severe Alzheimer’s disease in the general population, was a rational choice for a trial of Alzheimer’s disease treatment in adults with Down’s www.thelancet.com Vol 379 February 11, 2012
Number of embryos to transfer: better safe than sorry?
www.thelancet.com Vol 379 February 11, 2012
but these findings are controversial.6 That information on cumulative rates for fresh and frozen embryos is missing from the study by Lawlor and Nelson2 is, therefore, unfortunate. Additionally, that the data used for this study could not be provided for individuals and remain anonymised is odd, as it has been achieved in other large datasets. Different approaches have been taken to ensure that eSET is the preferred or main approach. In Sweden, state regulations allow for transfer of only one embryo except in exceptional circumstances. Since the regulations were adopted, one embryo has been transferred in 70% of all cycles and, accordingly, the number of multiple births has decreased from 25% to 5%.6 In Belgium, the government agreed to reimburse the costs of six treatment cycles in exchange for a reduction in the number of embryos transferred to one in the first two cycles as a general rule.7,8 The reduction in multiple births in Belgium now corresponds to that in Sweden.9 Data from the European programme that monitors in-vitro fertilisation show large differences between countries in the rates of multiple births after assisted conception. The rates largely parallel the direct cost to patients:10 couples who have to cover all costs themselves generally accept the risk of a multiple pregnancy to improve the likelihood of conception. Preterm deliveries that result from multiple pregnancies after assisted conception add a substantial
Published Online January 12, 2012 DOI:10.1016/S01406736(11)61478-5 See Articles page 521
Science Photo Library
Guidelines on the number of embryos to be transferred in couples attempting assisted conception is widely debated owing to adverse perinatal risks and costs associated with multiple pregnancies. In published work on perinatal outcomes after assisted conception, it is generally agreed that the high prevalence of twins explains most of the increased risk in pregnancies after assisted conception.1 Opinion has, therefore, shifted towards the view that transfer of only one embryo at a time is optimum. Debbie Lawlor and Scott Nelson,2 in The Lancet, address risks of assisted conception in relation to maternal age in a large prospective study in the UK. In women aged 40 years or older they showed that the livebirth rate was lower than that in women younger than 40 years, irrespective of the number of embryos transferred, but that in both age groups the livebirth rate was higher after transfer of two embryos, compared with one. In the older age group, multiple births occurred less often than in the younger age group. Adverse perinatal outcomes, including multiple and premature births and low birthweight, were seen more frequently after transfer of multiple embryos than after one. The authors firmly conclude that transfer of three embryos is not warranted. This important paper provides strong arguments in favour of restricting the transfer of embryos to a maximum of two per cycle, irrespective of maternal age. Lawlor and Nelson’s finding that the proportion of embryo transfer cycles resulting in a livebirth was greater with transfer of two embryos than one in both age groups is in line with previous studies.3 Improved freezing techniques for surplus embryos might compensate for reduced pregnancy rates with single embryo transfer—cryopreservation should keep the biological potential of each fertilised oocyte to a maximum and lower the number of stimulated cycles needed. To keep the number of stimulation cycles to a minimum is crucial from medical, psychological, ethical, and economic perspectives. The cumulative birthrate after elective single embryo transfer (eSET), including the transfer of a fresh embryo in one cycle followed by transfer of a thawed embryo in the next, has in some studies been similar to that in younger women who received two fresh embryos in one cycle,4,5
497
Comment
financial burden to health care; in the USA, the annual cost is estimated to be around US$1 billion.11 Despite the trend towards eSET, the costs seem to be remaining high, probably because of an overall increase in the use of assisted conception treatments. In Europe, twins account for 20% of all livebirths after assisted conception, but in the USA the corresponding proportion is 30%. This burden is a major concern, and guidelines on the number of embryos to transfer need to reflect the associated expenses. Whether the Belgian reimbursement model8 can be adopted elsewhere is worthy of consideration. Medical care should be guided by the best available evidence, and the decision to transfer more than one embryo should be based on an assessment of each patient’s prognostic factors, including age. A prediction model for outcomes after assisted conception12,13 has not yet been universally adopted. The final decision of whether to transfer one or two embryos should, therefore, be based on a cooperative approach between embryologists and clinicians, although patients with medical or obstetric contraindications to twin pregnancies should receive no more than one embryo, irrespective of age or other prognostic factors. Several strategies can be used to lower the risk of multiple births after assisted conception. The provision of information to patients and health-care providers is essential. Public funding to cover treatment costs can facilitate a reduction in the number of transferred embryos, and improvements in embryo freezing techniques will increase the cumulative pregnancy rate per cycle of oocyte retrieval. A combination of these factors will increase the likelihood that the outcome of interest will be achieved: one healthy baby at a time.
Liv Bente Romundstad Fertility Clinic, St Olav’s University Hospital, NTNU, Faculty of Medicine, Department of Public Health and General Practice, NO-7491 Trondheim, Norway [email protected] I have received travel expenses from MSD and Ferring. 1 2
3
4
5
6
7
8
9
10
11
12
13
Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Update 2005; 11: 575–93. Lawlor DA, Nelson SM. Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study. Lancet 2011; published online Jan 12. DOI:10.1016/S0140-6736(11)612671. Pandian Z, Bhattacharya S, Ozturk O, Serour G, Templeton A. Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2009; 2: CD003416. Thurin A, Hausken J, Hillensjo T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004; 351: 2392–402. McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials. BMJ 2010; 341: c6945. Karlstrom PO, Bergh C. Reducing the number of embryos transferred in Sweden—impact on delivery and multiple birth rates. Hum Reprod 2007; 22: 2202–07. Ombelet W, Cadron I, Gerris J, et al. Obstetric and perinatal outcome of 1655 ICSI and 3974 IVF singleton and 1102 ICSI and 2901 IVF twin births: a comparative analysis. Reprod Biomed Online 2005; 11: 76–85. Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and infertility treatment: registration, reflection and reaction—the Belgian project. Hum Reprod Update 2005; 11: 3–14. Van Landuyt L, Verheyen G, Tournaye H, Camus M, Devroey P, Van Steirteghem A. New Belgian embryo transfer policy leads to sharp decrease in multiple pregnancy rate. Reprod Biomed Online 2006; 13: 765–71. Connolly MP, Hoorens S, Chambers GM. The costs and consequences of assisted reproductive technology: an economic perspective. Hum Reprod Update 2010; 16: 603–13. Bromer JG, Ata B, Seli M, Lockwood CJ, Seli E. Preterm deliveries that result from multiple pregnancies associated with assisted reproductive technologies in the USA: a cost analysis. Curr Opin Obstet Gynecol 2011; 23: 168–73. van Loendersloot LL, van Wely M, Repping S, van der Veen F, Bossuyt PM. Templeton prediction model underestimates IVF success in an external validation. Reprod Biomed Online 2011; 22: 597–602. Nelson SM, Lawlor DA. Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles. PLoS Med 2011; 8: e1000386.
Improving Alzheimer’s disease outcomes in Down’s syndrome Published Online January 10, 2012 DOI:10.1016/S01406736(11)61929-6 See Articles page 528
498
More than 40% of people with Down’s syndrome in the UK are aged 40 years or older,1 and one in 10 of these individuals develops Alzheimer’s disease. This rate rises to one in three of those who are older than 50 years and more than half of those older than 60 years.2 This progression is very distressing for parents and family carers because it can come at a time when—facing the physical and social challenges of ageing—they are least able to provide care, resulting in high caregiver burden.3
Thus, the MEADOWS trial4 reported by Marisa Hanney and colleagues in The Lancet is an important attempt to improve outcomes of adults with Down’s syndrome and Alzheimer’s disease. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist that improves cognitive function in older adults with moderate-to-severe Alzheimer’s disease in the general population, was a rational choice for a trial of Alzheimer’s disease treatment in adults with Down’s www.thelancet.com Vol 379 February 11, 2012