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The Promise of Single-Embryo Transfer
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     Worldwide, the use of assisted reproductive technology is increasing.1,2,3 The technology, which includes such treatments for infertility as in vitro fertilization, accounts for 2 to 3 percent of births in many European countries1 and approximately 1 percent of U.S. births overall, with higher proportions for states, such as Massachusetts, that mandate insurance coverage for the procedures.2

    Enthusiasm for assisted reproductive technology, however, is tempered by concern about adverse sequelae among the children conceived with the use of these techniques, in particular those associated with multiple births. In the United States, because two or more embryos have been routinely transferred in such procedures, 35 percent of live-birth deliveries resulting from assisted reproductive technology in 2002 included twin or higher-order multiple gestations2; in comparison, the incidence of multiple births after natural conception is less than 2 percent.4,5 In European countries, fewer embryos are transferred, on average, than in the United States. Still, in 2001, the average rate of multiple births in Europe for deliveries after conception by assisted reproductive technology was 25.5 percent.1 Because multiple gestations, even of twins, are associated with a substantial risk of low birth weight, preterm delivery, perinatal and infant mortality, and disability among survivors,4,5 there is a call for a reconsideration of the definition of "success" in assisted reproductive technology to focus on singleton live-birth delivery.5,6

    Clearly, the most effective strategy for a reduction in the number of multiple births is to transfer a single embryo during a procedure. However, this choice may be unacceptable for many couples. Although the number of embryos transferred during such a procedure declined markedly in the United States between 1996 and 2002, most of the shift was from three or more to two embryos.7 The rate of single-embryo transfer remained low among all age and treatment groups. Although single-embryo transfer is more common in Europe than it is in the United States, it nonetheless represents a minority of procedures — 12 percent overall in 2001.1

    One reason for the apparent low level of acceptance of single-embryo transfer is the concern that the procedure is associated with a lower chance of live-birth delivery than is the transfer of two or more embryos. Whereas embryos that are rated as high in quality by standardized morphologic assessment criteria are associated with increased rates of implantation and pregnancy,8 it is still not possible to predict with certainty which embryos will implant. Thus, transferring two or more embryos may offer some advantage.

    Several studies have provided information regarding the pregnancy and live-birth rates associated with single-embryo transfer. Among four randomized trials comparing the transfer of a single embryo with that of two embryos, the average pregnancy rate after single-embryo transfer was 30.7 percent, with a 2 percent risk of monozygotic twinning.9 The higher pregnancy rate after double-embryo transfer — 47.6 percent — was offset by a 33.8 percent risk of multiple-gestation pregnancy; thus, the average singleton pregnancy rates were similar (30.0 percent for single-embryo transfer and 31.5 percent for double-embryo transfer). One of these trials reported similar rates of live births among women who underwent double-embryo transfer (42.9 percent) and women who underwent single fresh-embryo transfer, which was followed, in unsuccessful cases, by the transfer of a single frozen-and-thawed embryo (38.8 percent).10

    Culturing embryos for five days, to the blastocyst stage, may allow for more accurate assessment of embryo quality and thus for enhanced selection of a high-quality embryo. Before the introduction of commercially available blastocyst culture media in 1998, very few treatment centers had the capacity to culture embryos for more than three days. A study of the transfer of blastocyst-stage embryos found pregnancy rates of 61 percent for single-blastocyst transfers and 76 percent for double-blastocyst transfers.11 In this trial, as in the other three trials of single-embryo transfer,9 patients were selected on the basis of criteria associated with better treatment prognosis, so results can be generalized only to select subgroups of patients seeking treatment with assisted reproductive technology.

    In this issue of the Journal, Papanikolaou and colleagues12 report results of a randomized trial comparing the outcome of the transfer of a single embryo cultured for three days (cleavage-stage embryo) with that of the transfer of a single embryo cultured for five days (blastocyst-stage embryo). The authors report significantly higher rates of clinical pregnancy (33.1 percent) and delivery (32.0 percent) in the blastocyst-stage group than in the cleavage-stage group (23.3 percent and 21.6 percent, respectively).12

    Although the results are encouraging, they are again generalizable only to a segment of the population being treated with assisted reproductive technology. This study was limited to women under 36 years of age with a low level of follicle-stimulating hormone on day 3 of the menstrual cycle who were undergoing their first or second trial of in vitro fertilization or intracytoplasmic sperm injection. Less than half of women undergoing treatment with assisted reproductive technology in the United States would meet the age criterion alone.2 The age distribution tends to be shifted toward younger women in many European countries, but even in these countries, a sizable proportion of women undergoing these procedures are older than 35.1

    The authors designed their study with an eye toward a Belgian policy stipulating reimbursement by health insurance agencies for six trials of in vitro fertilization under the condition that elective single-embryo transfer be performed in the first two trials in women under the age of 36 years. Yet these results have a much broader implication for practice. According to guidelines issued by the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine in 2004, in patients younger than age 35,

    no more than two embryos should be transferred in the absence of extraordinary circumstances. For patients with the most favorable prognosis consideration should be given to transferring only a single embryo.13

    The findings of Papanikolaou and colleagues suggest that using blastocysts in this setting may improve pregnancy rates while maintaining a low rate of multiple gestation.

    Nonetheless, challenges remain. Further study is needed of methods to reduce multiple births among the many couples seeking help from assisted reproductive technology who are not considered to have the most favorable prognosis. Although achieving a pregnancy is more difficult in such cases, multiple gestation still remains a substantial risk. In the United States in 2002, for example, the risk of multiple births when conception occurred with assisted reproductive technology was 35.4 percent for women from 35 to 37 years of age, 26.9 percent for women 38 to 40 years of age, 18.6 percent for women 41 to 42 years of age, and 6.5 percent for women over 42 years of age.2 This is a particular cause for concern given the already increased risk of complications in pregnancies associated with advanced maternal age.

    In addition, the study of Papanikolaou et al. was designed to assess pregnancy and delivery rates and was not adequately powered to assess possible adverse outcomes associated with extending the culture of embryos. Past studies have suggested an association between extended embryo culture and monozygotic twinning.14 Furthermore, there is concern that in vitro culture conditions may be associated with epigenetic defects (i.e., defects not involving the DNA sequence per se but modifying gene expression), with possible effects on fetal growth and development.15

    The findings reported by Papanikolaou et al. support the efficacy of single-embryo transfer in achieving singleton live births among patients with a good prognosis and suggest that single-blastocyst transfer may be an optimal treatment. Further study is needed of the broader range of women seeking treatment with assisted reproductive technology and of the later outcomes of children conceived by blastocyst transfer.

    No potential conflict of interest relevant to this article was reported.

    The findings and conclusions in this report are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention.

    Source Information

    From the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta.

    References

    Andersen AN, Gianaroli L, Felberbaum R, de Mouzon J, Nygren KG. Assisted reproductive technology in Europe, 2001: results generated from European registers by ESHRE. Hum Reprod 2005;20:1158-1176.

    Wright VC, Schieve LA, Reynolds, MA, Jeng G. Assisted reproductive technology surveillance -- United States, 2002. MMWR Surveill Summ 2005;54:1-24.

    Bryant J, Sullivan EA, Dean JH. Assisted reproductive technology in Australia and New Zealand 2002. Assisted reproductive technology series. No. 8. Sydney: Australian Institute of Health and Welfare National Perinatal Statistics Unit, 2004. (AIHW cat. no. PER 26.)

    Martin JA, Park MM. Trends in twin and triplet births: 1980–97. National vital statistics reports. Vol. 47. No. 24. Hyattsville, Md.: National Center for Health Statistics, September 1999. (DHHS publication no. (PHS) 99-1120 9-0701.)

    The ESHRE Capri Workshop Group. Multiple gestation pregnancy. Hum Reprod 2000;15:1856-1864.

    WHO recommendations. In: Vayena E, Rowe PJ, Griffin PD, eds. Current practices and controversies in assisted reproduction: report of a meeting on "medical, ethical, and social aspects of assisted reproduction." Geneva: World Health Organization, 2002:381-96.

    Reynolds MA, Schieve LA. Trends in embryo transfer practices and multiple gestation for IVF procedures in the USA, 1996-2002. Hum Reprod (in press). (Abstract available at http://humrep.oxfordjournals.org/cgi/content/abstract/dei363v1.)

    Volpes A, Sammartano F, Coffaro F, Mistretta V, Scaglione P, Allegra A. Number of good quality embryos on day 3 is predictive for both pregnancy and implantation rates in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril 2004;82:1330-1336.

    Gerris JMR. Single embryo transfer and IVF/ICSI outcome: a balanced appraisal. Hum Reprod Update 2005;11:105-121.

    Thurin A, Hausken J, Hillensj? T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392-2402.

    Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolscraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril 2004;81:551-555.

    Papanikolaou EG, Camus D, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med 2006;354:1139-1146.

    Practice Committee, Society for Assisted Reproductive Technology, American Society for Reproductive Medicine. Guidelines on the number of embryos transferred. Fertil Steril 2004;82:773-774.

    Milki AA, Jun SH, Hinckley MD, Behr B, Giudice LC, Westphal LM. Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage transfer. Fertil Steril 2003;79:503-506.

    Jacob S, Moley KH. Gametes and embryo epigenetic reprogramming affect developmental outcome: implication for assisted reproductive technologies. Pediatr Res 2005;58:437-446.(Laura A. Schieve, Ph.D.)