Practice patterns and outcomes with the use of single embryo transfer in the United States

Transcription

1 Practice patterns and outcomes with the use of single embryo transfer in the United States Barbara Luke, Sc.D., M.P.H., a Morton B. Brown, Ph.D., b David A. Grainger, M.D., M.P.H., c Marcelle Cedars, M.D., d Nancy Klein, M.D., e and Judy E. Stern, Ph.D., f a Society for Assisted Reproductive Technology Writing Group a Department of Obstetrics, Gynecology, and Reproductive Biology and Department of Epidemiology, Michigan State University, East Lansing, Michigan; b Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan; c Center for Reproductive Medicine and Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Wichita, Kansas; d Division of Reproductive Endocrinology and Infertility, University of California, San Francisco, California; e Seattle Reproductive Medicine, Seattle, Washington; and f Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Objective: To evaluate factors associated with the use of elective single embryo transfer (eset) and its effect on assisted reproductive technology (ART) outcome. Design: Historical cohort. Setting: Clinic-based data. Patient(s): A total of 69,028 ART cycles of autologous fresh embryo transfers with additional embryos cryopreserved during the same cycle performed during and reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database. Intervention(s): None. Main Outcome Measure(s): Factors associated with the number of embryos transferred, and the odds of pregnancy, live birth, and multiple-infant live birth by number of embryos transferred as adjusted odds ratios (AORs). Result(s): Single embryo transfer was used more with uterine factor (AOR 1.76) and less with male factor, endometriosis, or tubal factor (AOR 0.81, 0.72, 0.83, respectively). Compared with women aged <30 years, eset was used less among women aged years and R40 years (AOR 0.74 and 0.39, respectively). Compared with White women, eset was used more with Asian (AOR 1.52) and less with Black or Hispanic women (AOR 0.73 and 0.67, respectively). Compared with eset, the likelihood of pregnancy, live birth, or multiple-infant live birth was more likely with two embryos (AOR 1.33, 1.34, and 27.4, respectively). Conclusion(s): Elective SET, used more for younger women with specific diagnoses, is associated with slightly reduced likelihood of a live birth but much reduced likelihood of multiples. (Fertil Steril Ò 2010;93: Ó2010 by American Society for Reproductive Medicine.) Key Words: Single embryo transfers, assisted conceptions, singleton pregnancies, twin pregnancies Multiple-fetus pregnancy or multiple-infant live birth remains the major adverse outcome associated with assisted reproductive technology (ART) treatment (1, 2). Despite the decline in higher-order multiple gestations since 2003, the incidence of twins resulting from ART cycles in the U.S. remains high. In 2005, 30% and 2% of live births from ART were twins and triplets or more, respectively, compared with 3% and 0.2% of all U.S. live births (1, 3). Multiple-fetus pregnancy is associated with significantly higher Received November 23, 2008; revised February 13, 2009; accepted February 25, 2009; published online April 18, B.L. has nothing to disclose. M.B. has nothing to disclose. D.G. has nothing to disclose. M.C. has nothing to disclose. N.K. has nothing to disclose. J.S. has nothing to disclose. Presented at the 64th annual meeting of the American Society for Reproductive Medicine, San Francisco, California, November 8 12, Supported by the Society for Assisted Reproductive Technology. Reprint requests: Barbara Luke, Sc.D., M.P.H., Dept. OB/GYN & Reproductive Biology, Michigan State University, B227 West Fee Hall, East Lansing, Michigan (FAX: ; lukeb@ msu.edu). maternal, neonatal, and infant morbidity and mortality. Women pregnant with multiples are nearly six times more likely to be hospitalized during pregnancy and more than twice as likely to be admitted to the intensive care unit or to die compared to women with singleton pregnancies (4 7). Although infants of multiple births comprise only 3% of all live births, they are disproportionately represented among preterm (13%), early preterm (15%), low-birthweight (21%), and very-low-birthweight (25%) infant populations (8 12). The average birthweight and gestational age is 3,316 g at 38.7 weeks for singletons, compared with 2,333 g at 35.2 weeks for twins, 1,700 g at 32.1 weeks for triplets, and 1,276 g at 29.7 weeks for quadruplets (13). Most instances of multiple-fetus pregnancy from ART result from the transfer of more than one embryo. In many European countries the maximum number of embryos transferred is mandated by law, and the proposals that elective single embryo transfer (eset) become standard of care stem from research published by western European investigators. In the U.S., there has been a reduction in the number of 490 Fertility and Sterility â Vol. 93, No. 2, January 15, /10/$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 embryos transferred in response to national guidelines, with a concomitant drop in the rate of higher-order multiples but not of twins (14 18). Currently, both the average number of embryos transferred and subsequent multiple birth rates remain significantly higher in the U.S. than in Europe, but lower than in many Latin American and Middle Eastern countries (19, 20). Factors in the U.S. influencing contemporary ART practice and impeding a further reduction in the multiple birth rate include limited insurance coverage and the perception that transfering more embryos improves success rates (21 23). From a patient s perspective, a multiple pregnancy is often the preferred outcome of ART therapy (24 26), but few families fully comprehend the physical and social implications (27 30). In recent years, it has been proposed that eset be the standard of care in cycles when the transfer of one embryo has a high chance of resulting in a live birth (31 35). These good-prognosis patients are also at the highest risk for multiple gestations. Despite substantial discussion promoting eset, national progress toward its adoption has been slow owing to concerns that it may result in lower pregnancy and delivery rates (24, 36). It is therefore important to understand the characteristics of eset cycles that result in live birth delivery and to use this information to prospectively choose patients for whom there is a high likelihood of success with eset. The objective of this study is to review national trends in number of embryos transferred, evaluate factors associated with the use of eset, and determine the effect of eset on ART treatment outcome. To distinguish eset from transfers where only one embryo was available, this analysis was limited to cycles in which additional embryos were cryopreserved. MATERIALS AND METHODS The data source for this study was the Society for Assisted Reproductive Technology (SART) Clinic Outcomes Reporting System (CORS) database, which contains comprehensive data from >90% of all reporting clinics performing ART in the U.S. This study used data reported between January 2004 and December This included 391 clinics in 2004, 394 clinics in 2005, and 392 clinics in Data were collected and verified by SART and reported to the Centers for Disease Control in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law , October 24, 1992). This analysis included 69,028 ART cycles performed during and reported to the SART CORS online database (which included a total of 368,483 cycles during this period). The study population was limited to cycles of fresh embryo transfers using autologous oocytes among women who had additional embryos cryopreserved during the same cycle. The data were categorized by number of embryos transferred as one, two, three, or four or more, with one embryo as the reference group. Dependent variables included the number of embryos transferred and the odds of treatment outcomes of pregnancy, live birth, and singleton, twin, and multiple pregnancy. Maternal demographic factors, reproductive history, ART cycle specific parameters, and pregnancy outcomes were compared across the embryo transfer groups using c 2 and analysis of variance; logistic regression was used for dichotomized outcomes. Models were shown as unadjusted and adjusted for maternal age (<30 [reference group], 30 34, 35 39, and R40 years), race/ethnicity (White [reference group], Asian, Black, Hispanic, other, mixed, unknown), infertility diagnoses (male factor, ovulation disorders, diminished ovarian reserve, tubal factors, uterine factors, other factors, and unexplained factors), and number of fresh embryos transferred with eset as the reference group. Data were analyzed using the Statistical Package for the Social Sciences, version 16.0 (SPSS, Chicago, IL). The study was approved by the Committee for the Protection of Human Subjects at Dartmouth College and written in conjunction with the SART Research Committee. RESULTS The study population included 69,028 ART cycles. The distribution by the number of embryos transferred was: one embryo 3,037 (4.4%); two embryos 42,396 (61.4%); three embryos 17,480 (25.3%); and four or more embryos 6,115 (8.9%). The embryo transfer groups differed significantly by maternal age, race/ethnicity, infertility diagnoses, and use of intracytoplasmic sperm injection or assisted hatching. Women with single embryo transfers were more likely to be younger and White or Asian (Table 1). The percentage of live births by number of embryos transferred and characteristics of women treated are given in Table 2. The highest percentage of live births overall and within age, race, and diagnosis categories occurred with two embryos transferred; this group also had the highest percentage of multiple births. The highest percentage of singleton live births occurred with one embryo transferred. The outcome of therapy according to number of embryos transferred is shown in Table 3. The embryo transfer groups differed significantly by treatment outcome, complications of therapy, number of fetal heartbeats on early ultrasound, and pregnancy outcomes. Women with eset were more likely to have one fetal heartbeat on early ultrasound and a singleton live birth. The model of factors associated with the transfer of one versus more than one embryo is shown in Table 4. Compared with women <30 years of age, eset was significantly less likely to be used for women aged R35 years. Compared with White women, eset was significantly more likely to be used with Asian women and less likely to be used with Black or Hispanic women. It also was significantly less likely to be used with the diagnoses of male factor, endometriosis, and tubal factors and more likely to be used with the diagnosis of uterine factors. Fertility and Sterility â 491

3 TABLE 1 Characteristics and therapy of women by number of fresh embryos transferred. No. of embryos transferred All R4 No. of cycles 69,028 3,037 42,396 17,480 6,115 P value across embryo transfer groups Maternal age, yrs Mean SD <.0001 % < <.0001 % % % R Race/ethnicity, % <.0001 Black/African American Hispanic/Latino Asian White Other Mixed Unknown/not stated Nulligravida, % <.0001 Infertility diagnosis, % Male factor <.0001 Endometriosis <.0001 Ovulation disorders <.0001 Diminished ovarian <.0001 reserve Tubal factors <.0001 Uterine factors <.0001 Other factors <.0001 Unexplained factors ICSI, % all or some <.0001 Assisted hatching, <.0001 % all or some Note: ICSI ¼ intracytoplasmic sperm injection. The unadjusted and adjusted treatment outcome models are shown in Table 5. Adjustment for the woman s age, race/ethnicity, and infertility diagnosis did not substantially change the coefficients. With transfering two versus one embryo, the chances of achieving a pregnancy and live birth as the treatment outcome were 33% and 34% more likely, respectively, but the likelihood of a twin outcome was also 27-fold greater. Transfering three embryos versus one did not significantly improve the chances of pregnancy, but did increase the odds of a live birth by 11%; risk that the live birth would be a twin or a multiple were increased 24-fold and 29-fold, respectively. Transfering four or more embryos versus one did not significantly improve the odds of either pregnancy or live birth, but significantly increased the odds of a multiple birth outcome. DISCUSSION The present findings, based on 3 years of national data on cycles of autologous fresh embryo transfers with additional 492 Luke et al. Use and outcomes of single embryo transfer in the U.S. Vol. 93, No. 2, January 15, 2010

4 TABLE 2 Percent of live births by number of fresh embryos transferred and characteristics of women treated. No. of embryos transferred All R4 No. of cycles 69,028 3,037 42,396 17,480 6,115 P value across embryo transfer groups Overall births, % <.0001 Singleton live births, % <.0001 Multiple live births, % <.0001 Woman s age (yrs) at start of therapy, % < < < R Woman s race/ethnicity, % White <.0001 Asian <.0001 Black <.0001 Hispanic <.0001 Other Mixed <.0001 Unknown <.0001 Infertility diagnosis, % Male factor <.0001 Endometriosis <.0001 Ovulation disorders <.0001 Diminished ovarian reserve <.0001 Tubal factors <.0001 Uterine factors <.0001 Other factors <.0001 Unexplained factors <.0001 embryos cryopreserved, indicate that eset is significantly more likely to be used for women <35 years old, who are White or Asian and with the diagnosis of uterine factor. The use of eset is associated with lower odds of achieving a pregnancy or live birth, but also a greatly reduced risk that the live birth will be a twin or other multiple. Among women <40 years old, increasing the number of embryos transferred from one to two increases the success rate of pregnancy and live birth by about 7% in absolute terms and 10% 20% in relative terms. However, it increases the chance of a multiple birth from 2% to 37%, an increase of 35% in absolute terms, but 1,750% in relative terms. The risk of multiple gestation and the subsequent adverse sequelae make it imperative that we move toward an increased use of eset in ART cycles. Achieving this shift in clinical practice would be facilitated by a better understanding of factors influencing the use of eset and the effect of embryo number on cycle outcome. Unfortunately, the evidence is conflicting concerning the effect of SET on pregnancy and live birth rates, with some studies reporting a - reduction in these rates (37, 38), others not (39 48). Selection of appropriate patients for eset may be the key in this regard (41, 47, 48), as well as the ability to choose the best embryos after extended embryo culture (49, 50) or better methods to assess embryo quality and viability (51 53). Nevertheless, there is still considerable disagreement about whether SET is appropriate for the majority of ART cycles (54). Advantages to the use of eset over multiple embryo transfer are clear. A reduction in the multiple-infant live birth rate with SET directly affects maternal medical risk (55) and the Fertility and Sterility â 493

5 TABLE 3 Outcome of therapy by number of fresh embryos transferred. No. of embryos transferred All R4 No. of cycles 69,028 3,037 42,396 17,480 6,115 P value across embryo transfer groups Treatment outcome (%) Not pregnant <.0001 Clinical intrauterine gestation Other a Complication of therapy (%) Hyperstimulation <.0001 Fetal hearts on ultrasound, % < R Pregnancy outcome (%) Live birth <.0001 Stillbirth Fetal losses b Plurality of live births No. of pregnancies c 32,819 1,313 21,546 7,644 2,316 % Singleton <.0001 % Twins % RTriplets a Includes biochemical, ectopic, and heterotopic pregnancies. b Includes spontaneous and iatrogenic losses. c Gestations R154 days and birthweights R300 g. commensurate costs of medical care (56 58). In addition, research suggests that even in singleton live births, embryonic or early fetal loss is associated with significantly increased risks for lowered birthweight, shortened gestation, and reduced birthweight-for-gestation (59 63). These birthweight reductions may be heralded by increased rates of first-trimester bleeding (64). Despite the risks of transfering multiple embryos, there continues to be low use and acceptance of eset, although this analysis was based on transfers which occurred primarily before the most recent SART guidelines recommending SET in appropriate good-prognosis patients. In the present study, we found that, on a national basis, among cycles with additional cryopreserved embryos, <5% transferred a single embryo and >60% transferred two embryos. There are many reasons for the low use of SET. One major factor is a perceived reduction in pregnancy rates. In a study of patient preferences, Twisk et al. (36) found that even with a predicted equivalent pregnancy rate for SET and double embryo transfer (DET) only 46% of couples chose the former. In addition, if pregnancy rates were predicted to be lower for SET by as little as 1% to 5%, the proportion of women electing this method dropped to 34% and 15%, respectively. In another study of twin-prone patients, 61% indicated a preference for DET (65). Other factors moderating a woman s choice for SET include advancing age and repeated treatments, both of which affect a perceived urgency for treatment success (66). Improved patient education (46) and strong encouragement by clinic doctors (66) are important factors to reverse this trend. Adding to this encouragement are the results of the present study, suggesting that the actual difference in the live birth rate between SET and DET is minimal in an age-adjusted model. One way of encouraging patients to choose SET is to define the parameters under which there is a high likelihood of 494 Luke et al. Use and outcomes of single embryo transfer in the U.S. Vol. 93, No. 2, January 15, 2010

6 TABLE 4 Factors associated with single embryo transfers. Independent variable AOR 95% CI P value Woman s age, yrs <30 yrs 1.00 Reference yrs yrs <.0001 R40 yrs <.0001 Woman s race/ethnicity White 1.00 Reference Asian <.0001 Black Hispanic Other Mixed Unknown <.0001 Infertility diagnosis Male factor <.0001 Endometriosis <.0001 Ovulation disorders Diminished ovarian reserve Tubal factors Uterine factors <.0001 Other factors <.0001 Unexplained factors Note: AOR ¼ adjusted odds ratio; CI ¼ confidence interval. success. In the present study, we found that SET is used more frequently for women under age 35 years, with no difference between women aged <30 and years, and less frequently in women over age 35 years. This was not surprising, because it is well known that younger patients using their own eggs have higher pregnancy rates and a greater chance of live birth, and of a multiple birth, than older patients. In addition, owing to the increased obstetric risks in older women, there is an incentive on the part of the clinician to avoid multiple gestations in this population (55). Recent research from Finland among women aged years using eset versus DET indicated similar pregnancy and live birth rates while dramatically reducing the multiple-infant live birth rate (67). This provides encouraging evidence that the age range for eset can be effectively extended. The present data also demonstrate racial/ethnic differences in the use of eset, with eset used more often among Asian women and less often among Black and Hispanic women. The reasons for these differences are unclear. They could reflect differences in embryo morphology, patient preferences, or other characteristics such as education or economic situation that may vary by race. The other possibility is that known or suspected racial and ethnic differences in pregnancy and delivery rates are influencing practitioner decisions to transfer more embryos (67 70). Diagnosis was also associated with the use of SET. Patients were more likely to have SET if they had a diagnosis of uterine factor. This is not surprising, given that uterine anomalies may make multiple gestations particularly risky and could drive the decision for SET. Couples were less likely to have SET if they had diagnoses of male factor, endometriosis, or tubal factor. Male factor may result in poorer-quality embryos or a concern that a greater number of embryos will be chromosomally abnormal (71). Endometriosis may also result in poor-quality oocytes or embryos (72) or a lower number of embryos for selection due to decreased ovarian reserve (73, 74). The presence of a hydrosalpinx is associated with lower implantation rates and higher incidence of preclinical pregnancy loss (75, 76). When adjusted for age, race, and diagnosis, women were somewhat more likely to achieve pregnancy and a live birth after DET than after SET. However, transfer of more than two embryos was not associated with further improvements in pregnancy and live birth rates. The data suggest that there is some advantage to transfering multiple embryos in younger White women with specific diagnoses. This additional advantage of DET over SET pales when balanced against the 27- fold increased risk that the live birth will be a multiple. This study and findings are subject to several limitations. The SART CORS data available did not permit us to distinguish the effect of individual clinic practice regarding the use of eset. Some clinics encourage the use of eset and council their patients accordingly; others do not. Differences among clinics between implantation rates and overall ART success rates are likely to influence the number of embryos recommended for transfer. Further limiting our ability to interpret these data are potential inconsistencies in the accuracy and definition of infertility diagnoses. This information, because it is compiled at over 350 clinics nationwide, is subject to variation in the extent of evaluation as well as diagnostic criteria used. Nevertheless, the large number of cases in this database has allowed us to observe trends in the data that would have been less evident in smaller cohorts. The database also has no information on a crucial factor in choosing number of embryos to transfer: embryo morphology. This limited our ability to analyze the effect of embryo quality on the choice to transfer more than one embryo. Finally, the prevalence of eset and associated outcomes may be different when comparing cleavage-stage versus blastocyst-stage transfers, data also not available in the current Fertility and Sterility â 495

7 TABLE 5 Treatment outcome models by number of embryos transferred. Unadjusted model Adjusted model a Treatment outcome OR 95% CI P value AOR 95% CI P value Pregnancy 2 embryos < < embryos R4 embryos Live birth 2 embryos < < embryos R4 embryos < Singleton live birth 2 embryos < < embryos < <.0001 R4 embryos < <.0001 Twin live birth 2 embryos < < embryos < <.0001 R4 embryos < <.0001 Multiple live birth 2 embryos < < embryos < <.0001 R4 embryos < <.0001 a Models adjusted for woman s age (<30, 30 34, 35 39, and R40 yrs), race/ethnicity (White, Asian, Black, Hispanic, other, mixed, and unknown/not stated), and infertility diagnosis (male factor, endometriosis, ovulation disorders, diminished ovarian reserve, tubal factors, uterine factors, other factors, and unexplained factors). OR ¼ odds ratio; other abbreviations as in Table 4. dataset. Despite these limitations, these findings add to the growing body of literature that supports the use of eset, particularly to minimize the adverse outcome of multiple-fetus pregnancy and multiple-infant live birth. The data show that eset is being used for better-prognosis patients who have a higher likelihood of pregnancy and live birth. Parameters include younger White or Asian women who have diagnoses more likely to result in pregnancy. When adjusted for these variables, the outcome data show little value, in terms of live birth, to increasing numbers of embryos transferred. Therefore, on the basis of this retrospective analysis, the known risks associated with multiple gestations and the modest difference in live birth rate would support increased use of eset in good-prognosis patients. Nevertheless, we realize, as we have argued previously (22), that there are many difficulties limiting a more generalized use of eset. These limitations include lack of universal insurance coverage, failure to differentiate eset cycles from other cycles in national ART reporting, and patient preference for twins. Against these odds, the data in this paper can support those clinicians with an interest in encouraging patients toward eset. REFERENCES 1. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Reproductive Technology assisted reproductive technology success rates: national summary and fertilityclinic reports. Atlanta: Centers for Disease Control and Prevention, Reynolds MA, Schieve LA, Martin JA, Jeng G, Macaluso M. Trends in multiple births conceived using assisted reproductive technology, United States, Pediatrics 2003;111: Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Munson ML. Births: final data for National vital statistics reports, vol. 56, no. 6. Hyattsville, MD: National Center for Health Statistics, Bouvier-Colle MH, Varnoux N, Salanave B, Ancel P-Y, Breart G. Casecontrol study of risk factors for obstetric patients admission to intensive care units. Eur J Obstet Gynecol and Reproductive Biology 1997;74: Luke et al. Use and outcomes of single embryo transfer in the U.S. Vol. 93, No. 2, January 15, 2010

8 5. Conde-Agudelo A, Belizan JM, Lindmark G. Maternal morbidity and mortality associated with multiple gestations. Obstet Gynecol 2000;95: Senat MV, Ancel PY, Bouvier-Colle MH, Breart G. How does multiple pregnancy affect maternal mortality and morbidity? Clin Obstet Gynecol 1998;41: Mackay AP, Berg CJ, King JC, Duran C, Chang J. Pregnancy-related mortality among women with multifetal pregnancies. Obstet Gynecol 2006;107: Donovan EF, Ehrenkranz RA, Shankaran S, Stevenson DK, Wright LL, Younes N, et al. Outcomes of very low birth weight twins cared for in the National Institute of Child Health and Human Development Neonatal Research Network s intensive care units. Am J Obstet Gynecol 1998;179: Stevenson DK, Wright LL, Lemons JA, Oh W, Korones SB, Papile L-A, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December Am J Obstet Gynecol 1998;179: Martin JA, MacDorman MF, Mathews TJ. Triplet births: trends and outcomes, National Center for Health Statistics vital and health statistics, vol. 21, no. 55. Hyattsville, MD: National Center for Health Statistics, Martin JA, Hamilton BE, Ventura SJ, Mencker F, Park MM, Sutton PD. Births: final data for National vital statistics reports; vol. 51, no. 2. Hyattsville, MD: National Center for Health Statistics, Russell RB, Petrini JR, Damus K, Mattison DR, Schwarz RH. The changing epidemiology of multiple births in the United States. Obstet Gynecol 2003;101: Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S. Births: final data for National vital statistics reports, vol. 55, no. 1. Hyattsville, MD: National Center for Health Statistics, American Society for Reproductive Medicine. Practice Committee opinion. Guidelines on number of embryos transferred. Birmingham, AL: American Society for Assisted Reproductive Medicine, January American Society for Reproductive Medicine. Practice Committeeopinion. Guidelines on number of embryos transferred. Birmingham, AL: American Society for Assisted Reproductive Medicine, November Society for Assisted Reproductive Technology, American Society for Reproductive Medicine. Guidelines on the number of embryos transferred. Fertil Steril 2004;82: Society for Assisted Reproductive Technology, Practice Committee of the American Society for Reproductive Medicine. Guidelines on the number of embryos transferred. Fertil Steril 2006;86:S Stern JE, Cedars MI, Jain T, Klein NA, Beaird CM, Grainger DA, Gibbons WE. Assisted reproductive technology practice patterns and the impact of embryo transfer guidelines in the United States. Fertil Steril 2007;88: Adamson GD, de Mouzon J, Lancaster P, Nygren K-G, Sullivan E, Zegers-Hochschild F. International Committee for Monitoring Assisted Reproductive Technology (ICMART). World collaborative report on in vitro fertilization, Fertil Steril 2006;85: Andersen AN, Goossens V, Ferraretti AP, Bhattacharya S, Felberbaum R, de Mouzon J, Nygren KG. European IVF-Monitoring (EIM) Consortium, for the European Society of Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE. Hum Reprod 2008;23: Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril 2003;80: Gibbons W, Grainger D, Cedars M, Jain T, Klein N, Stern J. Continuous quality improvement and assisted reproductive technology multiple gestations: Some progress, some answers, more questions. Fertil Steril 2007;88: Henne MB, Bundorf MK. Insurance mandates and trends in infertility treatments. Fertil Steril 2008;89: Pinborg A, Loft A, Schmidt L, Andersen AN. Attitudes of IVF/ICSI-twin mothers toward twins and single embryo transfer. Hum Reprod 2003;18: Ryan GL, Zhang SH, Dokras A, Syrop CH, Van Voorhis BJ. The desire of infertile patients for multiple births. Fertil Steril 2004;81: Hojgaard A, Ottosen LD, Kesmodel U, Ingerslev HJ. Patient attitudes toward twin pregnancies and single embryo transfer a questionnaire study. Hum Reprod 2008;22: Elster N, Institute for Science, Law, and Technology Working Group on Reproductive Technology. Less is more: the risks of multiple births. Fertil Steril 2000;74: Bryan E. The impact of multiple preterm births on the family. BJOG 2003;110: D Alton M. Infertility and the desire for multiple births. Fertil Steril 2004;81: Ellison MA, Hall JE. Social stigma and compounded losses: quality-oflife issues for multiple-birth families. Fertil Steril 2003;80: ESHRE Campus Report. Prevention of twin pregnancies after IVF/ICSI by single embryo transfer. Hum Reprod 2001;16: Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Update 2005;11: Nakhuda GS, Sauer MV. Addressing the growing problem of multiple gestations created by assisted reproductive therapies. Sem Perinatol 2005;29: S oderstr om-anttila V, Vilska S. Five years of single embryo transfer with anonymous and nonanonymous oocyte donation. Reprod Biomed Online 2007;15: Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Vercruyssen M, Barudy-Vasquez J, et al. Elective single day 3 embryo transfer halves the twinning rate without decrease in the ongoing pregnancy rate of an IVF/ICSI programme. Hum Reprod 2002;17: Twisk M, van der Veen F, Repping S, Heineman MJ, Korevaar JC, Bossuyt PM. Preferences of subfertile women regarding elective single embryo transfer: additional in vitro fertilization cycles are acceptable, lower pregnancy rates are not. Fertil Steril 2007;88: van Montfoort AP, Fiddelers AA, Janssen JM, Derhaag JG, Dirksen CD, Dunselman GA, et al. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared to double embryo transfer: a randomized controlled trial. Hum Reprod 2006;21: van Montfoort AP, Fiddelers AA, Land JA, Dirksen CD, Severens JL, Geraedts JP, et al. eset irrespective of the availability of a good-quality embryo in the first cycle only is not effective in reducing overall twin pregnancy rates. Hum Reprod 2007;22: Vilska S, Tiitinen A, Hyden-Granskog C, Hovatta O. Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth. Hum Reprod 1999;14: Martikainen H, Tiitinen A, Tomas C, Tapanainen J, Orava M, Tuomivaara L, et al., Finnish ET Study Group. One versus two embryo transfer after IVF and ICSI: a randomized study. Hum Reprod 2001;16: Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril 2004;81: Thurin A, Hausken J, Hillensj o T, Jablonowska B, Pinborg A, Strandell A, Bergh C. Elective single-embryo transfer in in vitro fertilization. N Engl J Med 2004;351: Criniti A, Thyer A, Chow G, Lin P, Klein N, Soules M. Elective single blastocyst transfer reduces twin rates without compromising pregnancy rates. Fertil Steril 2005;84: van Monfoort AP, Dumoulin JC, Land JA, Coonen E, Derhaag JG, Evers JL. Elective single embryo transfer (eset) in the first three IVF/ ICSI treatment cycles. Hum Reprod 2005;20: Veleva Z, Vilska S, Hyden-Granskog C, Tiitinen A, Tapanainen JS, Martikainen H. Elective single embryo transfer in women aged years. Hum Reprod 2006;21: Ryan GL, Sparks AE, Sipe CS, Syrop CH, Dokras A, Van Voorhis BJ. A mandatory single blastocyst transfer policy with educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy rates. Fertil Steril 2007;88: Fertility and Sterility â 497

9 47. Styer AK, Wright DL, Wolkovich AM, Veiga C, Toth TL. Single-blastocyst transfer decreases twin gestation without affecting pregnancy outcome. Fertil Steril 2008;89: Khalaf Y, El-Toukhy T, Coomarasamy A, Kamal A, Bolton V, Braude P. Selective single blastocyst transfer reduces the multiple pregnancy rate and increases pregnancy rates: A pre- and postintervention study. BJOG 2008;115: Gardner DK, Sakkas D. Assessment of embryo viability: the ability to select a single embryo for transfer a review. Placenta 2003;24(Suppl B). S Gardner DK, Lane M. Toward a single embryo transfer. Reprod Biomed Online 2003;6: Katz-Jaffe MG, Gardner DK, Schoolcraft WB. Proteomic analysis of individual human embryos to identify novel biomarkers of development and viability. Fertil Steril 2006;85: Urbanski JP, Johnson MT, Craig DD, Potter DL, Gardner DK, Thorsen T. Noninvasive metabolic profiling using microfluidics for analysis of single Preimplantation embryos. Anal Chem 2008;80: van Montfoort AP, Geraedts JP, Dumoulin JC, Stassen AP, Evers JL, Ayoubi TA. Differential gene expression in cumulus cells as a prognostic indicator of embryo viability: a microarray analysis. Mol Hum Reprod 2008;14: Gleicher N, Barad D. The relative myth of elective single embryo transfer. Hum Reprod 2006;21: Luke B, Brown MB. Contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality. Fertil Steril 2007;88: Luke B, Brown MB, Alexandre PK, Kinoshi T, O Sullivan MJ, Martin D, et al. The cost of twin pregnancy: maternal and neonatal factors. Am J Obstet Gynecol 2005;192: Collins J. Cost-effectiveness of in vitro fertilization. Semin Reprod Med 2001;19: Chambers GM, Chapman MG, Grayson N, Shanahan M, Sullivan EA. Babies born after ART treatment cost more than nonart babies: a cost analysis of inpatient birth-admission costs of singleton and multiple gestation pregnancies. Hum Reprod 2007;22: Pinborg A, Lidegaard O, la Cour Freiesleben N, Andersen AN. Consequences of vanishing twins in IVF/ICSI pregnancies. Hum Reprod 2005;20: De Sutter P, Delbaere I, Gerris J, Verstraelen H, Goetgeluk S, Van der Elst J, et al. Birthweight of singletons after assisted reproduction is higher after single- than after double-embryo transfer. Hum Reprod 2006;21: Pinborg A, Lidegaard O, la Cour Freiesleben N, Andersen AN. Vanishing twins: a predictor of small-for-gestational age in IVF singletons. Hum Reprod 2007;22: Luke B, Brown MB, Grainger DA, Stern JE, Klein N, Cedars M. The effect of early fetal losses on singleton assisted-conception pregnancy outcomes. Fertil Steril. In press. 63. Luke B, Brown MB, Grainger DA, Klein N, Stern JE, Cedars MI. Impact of embryo transfer number on singleton implantation pregnancy outcome. 64th annual meeting, American Society for Reproductive Medicine, San Francisco, California, November 8 12, Fertil Steril 2008;90:S De Sutter P, Bontinck J, Schutysers V, Van der Elst J, Gerris J, Dhont M. First-trimester bleeding after assisted reproduction. Hum Reprod 2006;21: Van Peperstraten AM, Kreuwel IA, Hermens RP, Nelen WL, Van Dop PA, Grol RP, Kremer JA. Determinants of the choice for single or double embryo transfer in twin prone couples. Acta Obstet Gynecol Scand 2008;87: de Lacey S, Davies M, Homan G, Briggs N, Norman RJ. Factors and perceptions that influence women s decisions to have a single embryo transferred. Reprod Biomed Online 2007;15: Sharara FI, McClamrock HD. Differences in in vitro fertilization (IVF) outcome between white and black women in an inner-city, universitybased IVF program. Fertil Steril 2000;73: Nichols JE, Higdon HL, Crane MM, Boone WR. Comparison of implantation and pregnancy rates in African American and White women in an assisted reproductive technology practice. Fertil Steril 2001;76: Purcell K, Schembri M, Frazier LM, Rall MJ, Shen S, Croughan M, et al. Asian ethnicity is associated with reduced pregnancy outcomes after assisted reproductive technology. Fertil Steril 2007;87: Seifer DB, Frazier LM, Grainger DA. Disparity in assisted reproductive technologies outcomes in black women compared with white women. Fertil Steril 2008;90: Tesarik J. Paternal effects on cell division in the human preimplantation embryo. Reprod Biomed Online 2005;10: Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril 2008;90: Matalliotakis IM, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sakkas D. Women with advanced-stage endometriosis and previous surgery respond less well to gonadotropins stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril 2007;88: Ragni G, Somigliana E, Benedetti F, Paffoni A, Vegetti W, Restelli L, Crosignani PG. Damage to ovarian reserve associated with laparoscopic excision of endometriomas: a quantitative rather than qualitative injury. Am J Obstet Gynecol 2005;193: Barmat LI, Rauch E, Spandorfer S, Kowalik A, Sills ES, Schattman G, et al. The effect of hydrosalpinges on IVF-ET outcome. J Assist Reprod Genet 1999;16: Hammadieh N, Coomarasamy A, Ola B, Papaioannou S, Afnan M, Sharif K. Ultrasound-guided hydrosalphinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum Reprod 2008;23: Luke et al. Use and outcomes of single embryo transfer in the U.S. Vol. 93, No. 2, January 15, 2010