Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience,

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1 FERTILITY AND STERILITY VOL. 78, NO. 5, NOVEMBER 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, James P. Toner, M.D., Ph.D., a David A. Grainger, M.D., M.P.H., b and Linda M. Frazier, M.D., M.P.H., c in cooperation with and on behalf of the Registry and Research Committees of SART of ASRM, Birmingham, Alabama Atlanta Center for Reproductive Medicine, Woodstock, Georgia Objective: To evaluate the role of recipient age on the outcome of donor egg cycles. Design: Retrospective cohort study of aggregated national cycles of donor egg therapy that are collected by Society for Assisted Reproductive Technology and the Centers for Disease Control and Prevention. Setting: Assisted reproductive technology centers in the United States that report their results to the Centers for Disease Control and Prevention by way of the Society for Assisted Reproductive Technology. Patient(s): Recipients of embryos (17,339 cycles) derived from donated eggs between 1996 and Intervention(s): None. Main Outcome Measure(s): Rates of implantation, clinical intrauterine pregnancy, pregnancy loss, and delivery based on the age of the recipient. Result(s): Success of donor egg therapy was remarkably constant among recipients aged 25 through those in their late forties. At higher ages, declining rates of implantation, clinical pregnancy, and delivery were seen, along with small increases of pregnancy loss. During the course of the 3 studied, fewer embryos were transferred and higher rates of implantation were observed. Conclusion(s): The success of donor egg therapy is unaffected by recipient age up to the later 40s, after which they begin to decline. Although recipient age per se is likely to be the major cause of this effect, other factors may contribute to this observation. (Fertil Steril 2002;78: by American Society for Reproductive Medicine.) Key Words: Donor egg, donor oocyte, pregnancy rates, success rates, SART-CORS, SART, CDC Received February 11, 2002; revised and accepted June 10, Reprints are not available. a Atlanta Center for Reproductive Medicine. b Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Kansas School of Medicine-Wichita, Wichita, Kansas. c Women s Research Institute, Department of Obstetrics and Gynecology, University of Kansas School of Medicine-Wichita, Wichita, Kasnsas /02/$22.00 PII S (02)03371-X The use of donor eggs to overcome infertility due to absent ovaries or diminished ovarian reserve has become more common, and its application in women of more advanced ages has raised the question of whether the success of this therapy declines as recipient age increases. Existing studies on this issue (1 6) have suggested contrary conclusions, but all such studies have been limited by the small number of cycles any one clinic has had the chance to examine; consequently, their power to detect such differences is low. Even in aggregate, only 627 cycles of donor egg therapy have been reported, of which only a small proportion were among women older than 45. Therefore, we sought to assess the relationship between recipient age and pregnancy outcomes in the large Society for Assisted Reproductive Technology/Center for Disease Control dataset of donor egg cycles performed in the United States between 1996 and MATERIALS AND METHODS Assisted reproductive technology (ART) cycles in the United States from 1996 to 1998 were analyzed. These data, which have been described elsewhere (7), were collected by the Society for Assisted Reproductive Technologies in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Pub. L , October 24, 1992) and are thought to represent at least 95% of all ART cycles performed in the United States during the time period. 1038

2 The dataset contained 19,757 cycles. Personal identifiers were not available in the dataset, precluding analysis by individual recipient. The following cycles were excluded from analysis: cycles in which no embryos were transferred (n 1,928; 9.8% of all cycles) or more than six embryos were transferred (n 403; 2.0% of all cycles); cycles in which age was missing (n 9) or the age group contained very small numbers of subjects ( 25, n 40 cycles, and age 54, n 38 cycles). The remaining dataset contained the 17,339 cycles used for analysis. Clinical pregnancy was defined as the presence of at least one gestational sac on ultrasound in the first trimester, and delivery as the birth of at least one live born. The denominator for pregnancy rates were cycles proceeding to egg retrieval. The implantation rate was calculated by dividing the maximum number of fetal heartbeats on ultrasound in the first trimester by the number of embryos transferred in the corresponding cycles. Pregnancy loss rate was the difference between the clinical pregnancy and delivery rates divided by the clinical pregnancy rate; by definition this included spontaneous and induced abortions, but not ectopic pregnancies. Data were analyzed using the Statistical Package for the Social Sciences, version 9.0 (SPSS Inc., Chicago, IL). Means were compared by independent samples t tests or by one-way ANOVA. Proportions were compared by 2 tests. Several factors other than recipient age were associated in univariate analyses with clinical outcomes. To estimate the independent contribution of recipient age when controlling for these factors, multivariable regression analyses were performed. For dichotomous outcomes (clinical pregnancy, pregnancy loss, delivery), a stepwise logistic regression was performed using backward conditional elimination. For continuous outcomes (implantation rate, number of births), multivariate linear regressions were performed. All statistical tests were two-tailed and used an of The dataset did not permit controlling for the cases in which a particular recipient had more than one cycle, and the proportion of such cases is unknown. Graphic depiction of outcomes includes display of the moving average, calculated as the average of the particular age and the 2 above and below that age. RESULTS Of the 17,339 ART recipient cycles, 26.6% (n 4,617) occurred in 1996, 33.4% (n 5,796) in 1997, and 39.9% (n 6,926) in Most cycles used fresh embryos (76.2%; n 13,212) rather than cryopreserved embryos (23.8%; n 4,126). The mean age of the recipients was 40.9, the median 42, and the range Intracytoplasmic sperm injection (ICSI) was used in 4,035 (30.8%) fresh cycles; ICSI was not accurately reported in cycles using cryopreserved embryos, and therefore, was not analyzed in cycles using cryopreserved embryos. Assisted hatching was used in 25.4% (n 3,353) of fresh and 24.4% FIGURE 1 Frequency histogram showing the number of recipient women having ET at each age (includes cycles excluded from statistical analysis due to low frequencies). This figure shows that donor egg therapy is most common among recipients aged 35 to 45, although women as young as 20 and as old as 66 were reported. (n 1,005) of cryopreserved cycles. The same number of embryos was transferred in both fresh and cryopreserved cycles: for fresh, a mean of 3.5 and a median of 3; for cryopreserved, a mean of 3.4 and a median of 3. Among cycles with fresh embryos transferred, the implantation rate was 22.5%, the clinical pregnancy rate was 47.8%, the pregnancy loss rate was 15.8%, and the delivery rate was 40.0%. Of infants delivered, 56.8% were singleton, 37.5% were twin, and 5.6% were higher order multiples (triplets or more). Among cycles with cryopreserved embryos transferred, the implantation rate was 10.8%, the clinical pregnancy rate was 28.4%, the pregnancy loss rate was 21.6%, and the delivery rate was 22.0%. Of infants delivered, 70.1% were singleton, 27.4% were twin, and 2.5% were higher order multiples. The utilization of this therapy according to recipient age is depicted in Figure 1. Clinical outcomes by recipient age are shown in Table 1, and illustrated in Figure 2 for fresh ET cycles and Figure 3 for frozen ET cycles. No effect of recipient age was observed between ages 25 and 45. Older recipient age, however, was associated with statistically reduced implantation rates, clinical pregnancy and delivery rates. This effect first appeared among recipients in their late 40s, and become more pronounced at age 50. Pregnancy loss rates were 3% higher among recipients aged 45 versus younger recipients, a difference of borderline statistical significance (P.053). Be- FERTILITY & STERILITY 1039

3 TABLE 1 Clinical outcomes according to recipient age. Age Outcome P value Fresh/cryopreserved (n/n) 332/107 1,274/426 2,861/780 5,842/1704 2,604/ /140 Implantation (%) a 22.7/ / / / / / /.048 Clinical pregnancy (%) 45.2/ / / / / / /.077 Pregnancy loss (%) Pregnant cycles b 14.0/ / / / / / /.052 One fetal heart 16.4/ / / / / / /.012 Two fetal hearts 6.0/ / / / / / /.047 Delivery (%) 38.9/ / / / / / /.58 Infants delivered (%) c Singleton 48.1/ / / / / / /.88 Twins 44.2/ / / / / /26.9 Higher order multiple 7.8/ / / / / /3.8 a Fetal hearts detected by ultrasound/number of embryos transferred. b Among cycles in which a clinical pregnancy was achieved. c Among cycles in which a birth occurred. cause younger recipients had a higher implantation rate and a greater number of implanted embryos, this increases the likelihood of ultimate delivery; the apparent increased loss rate might have been an artifact of fewer multiple pregnancies among older recipients. To evaluate this possibility, cycles with the same number of fetal hearts were compared for pregnancy loss rate by recipient age. Among those cycles in which there was one fetal heartbeat detected by ultrasound, recipient age had a small effect on pregnancy loss rate (4.3% lower for recipients aged 45 ). Among cycles with two fetal hearts detected by ultrasound, recipient age was not related to delivery. However, as twins and higher order multiple births were more common among younger mothers (Table 1), age may affect uterine receptivity to both implantation, and to a lesser extent, pregnancy maintenance. Several factors other than recipient age were related to clinical outcomes (Table 2). Implantation rates increased over the 3 included in the dataset. At the same time, fewer embryos were transferred in the more recent : the mean number of embryos transferred was 3.7 in 1996, 3.6 in 1997, and 3.3 in 1998 (P.001). Consequently, the rates of clinical pregnancy, pregnancy loss, delivery, and multiple births were not associated with treatment year. Use of fresh rather than cryopreserved embryos was associated with higher rates of implantation, clinical pregnancy, delivery, and multiple births, but lower rates of pregnancy loss (Table 2 and Fig. 4). The number of embryos transferred increased success rates up to three embryos; transferring additional embryos was not associated with higher success. A recent publication based on the same dataset has detected a significant benefit of having extra embryos cryopreserved (8). Older recipients were more likely to have been treated in recent (P.001). For example, 42.7% of the recipients aged were treated in 1998 (3.57% of all donor egg cycles in that year), whereas 33.4% of the total were treated in 1997 (3.18% of cycles) and only 21.6% received treatment in 1996 (2.52% of cycles). Use of ICSI was associated with slightly higher clinical pregnancy rates in fresh cycles, although the implantation rates with and without the procedure were clinically similar (Table 2). Assisted hatching did not appear to enhance clinical outcomes among either fresh or cryopreserved cycles. Because several factors were related to clinical outcomes, multivariable regressions were used to control simultaneously for each of these factors. The regressions were used to characterize the independent effect of recipient age on clinical outcomes and to rank them in order of strongest to weakest predictors. Recipient age was independently associated with all four clinical outcomes (implantation, clinical pregnancy, pregnancy loss, and delivery). Implantation was independently predicted by embryo type (fresh vs. cryopreserved), treatment year, and ICSI. Clinical pregnancy was independently associated with embryo type, treatment year, number of embryos transferred, and ICSI. Delivery was independently associated only with the number of fetal hearts seen on initial ultrasound. Increased numbers of births 1040 Toner et al. Recipient age effects in the U.S. Vol. 78, No. 5, November 2002

4 FIGURE 2 Clinical outcomes in fresh donor egg cycles. Each panel shows mean SEM as the line with markers and error bars, and a moving average as the line without markers to show the general trend. Panels include the implantation rate (top left), clinical pregnancy rate (top right), pregnancy loss rate (defined as the proportion of clinical pregnancies lost before delivery; bottom left), and the delivery rate (bottom right). This figure demonstrates essentially constant success rates for all four outcomes until recipients are in their late 40s, at which point success steadily declines in all areas. were independently associated with embryo type, ICSI, and younger recipient age. DISCUSSION Among women who receive donor eggs, this study clearly demonstrates that overall success rates (as judged by implantation, clinical pregnancy, pregnancy loss, delivery, and multiple pregnancy rates) remain unchanged from the mid-20s until the late 40s, at which point they begin to decline. On the basis of the large number of cycles included in this analysis, it is clear that these reductions begin at about age 48, and become striking beyond age 50. Whether declines continue past age 55 is difficult to judge given the few such cycles included, even in this large dataset. These results support the probability that age-related uterine factors play a role in the decline in fertility with increasing age. Some earlier investigators have also seen lower pregnancy rates among older women using donor eggs. In the Borini et al. study (5), the pregnancy rate per transfer was higher (47.3%) among 57 recipient women aged 21 to 39 than in 57 recipient women who were 40 to 49 old (24.5%; P.01). Similarly, the implantation rate per embryo transferred was 24.8% among the younger and 14.9% among those older (P.05). No difference in miscarriage rates was observed. In the Moomjy et al. investigation (6), a significant decline in the implantation rate was associated with increasing recipient age (P.002), although recipient age did not affect the clinical pregnancy, delivery, or miscarriage rate among 381 consecutive fresh ET cycle using donor eggs. The lack of an effect of recipient age that has been reported in other studies can be explained by the lower power of those prior studies. In one investigation, 162 FERTILITY & STERILITY 1041

5 FIGURE 3 Clinical outcomes in donor egg cycles using cryopreserved embryos. Each panel shows mean SEM as the line with markers and error bars, and a moving average as the line without markers to show the general trend. Panels include the implantation rate (top left), clinical pregnancy rate (top right), pregnancy loss rate (defined as the proportion of clinical pregnancies lost before delivery; bottom left), and the delivery rate (bottom right). This figure illustrates no consistent age-related trends among recipients of cryopreserved embryos derived from donor eggs; insufficient power exists at the higher ages to make reliable estimates of age effects. cycles among recipients 42 of age resulted in the same clinical pregnancy, miscarriage, and delivery rates as 145 cycles among recipients 42 of age (1). Another group (2) studied 627 donor ET cycles and saw no influence of recipient age on clinical pregnancy rates. Two other studies also found no effect of recipient age on pregnancy rates in donor ET cycles, and these studies involved 418 and 300 consecutive donor ET cycles, respectively (3, 4). In the current study, delivery rate was reduced among older recipients primarily due to the lower clinical pregnancy rates and implantation rates seen in these women. There was also a 3% excess risk of fetal loss past age 44, but this was not statistically significant (P.053). In this study, once a woman became pregnant through ART with donor eggs, her chances were 80% that she would deliver an infant. Pregnancy loss rates did not vary significantly by recipient age when women with the same number of implantations were compared. Multiple births were more common among younger recipients in this study. This finding is similar to the inverse relationship with age seen among women whose own eggs are transferred (7). The data in the present study suggest that the reason younger recipients are at greater risk for multiple births is probably due to their higher uterine receptivity as manifested by higher implantation rates. The lower receptivity of older recipients could be due to concomitant factors, which accrue with increased age, such as leiomyomata and synechiae. The age-related effects in donor egg therapy were obvious in cycles using fresh embryos, but not in cycles using cryopreserved embryos. Because the preparation of the recipient 1042 Toner et al. Recipient age effects in the U.S. Vol. 78, No. 5, November 2002

6 TABLE 2 Clinical outcomes according to factors other than recipient age. Factor Implantation % a Clinical pregnancy % Pregnancy loss % b Singletons No. births % c Twins Higher order multiples Embryo type Fresh/Cryo. Fresh/Cryo. Fresh/Cryo. Fresh/Cryo. Fresh/Cryo. Fresh/Cryo. 22.2/ / / / / /2.5 P value Treatment year / / / / / / / / / / / / / / / / / /3.0 P value.001/ /.23.46/.42.36/.089 Embryos transferred / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /3.6 P value.001/ / / ICSI (fresh cycles only) d No Yes P value Assisted hatching No 22.3/ / / / / /2.8 Yes 21.9/ / / / / /1.7 P value.59/.34.33/.25.23/.26.55/.54 Note: One-way ANOVA was performed for treatment year, and independent samples t tests were performed for ICSI and assisted hatching for the outcomes of implantation, clinical pregnancy, and pregnancy loss. 3 3or2 3 2 tests were performed for the outcome of multiple births. a Fetal hearts detected by ultrasound/number of embryos transferred. b Among cycles in which a clinical pregnancy was achieved. c Among cycles in which a birth occurred. d The use of ICSI is reported only for fresh cycles because in cryopreserved cycles the use of ICSI in the original cycle is underreported. is essentially identical in both cycle types, it is difficult to attribute this difference to anything besides either an effect of freezing on embryos or the process of embryo selection. The data clearly confirm the lower quality of cryopreserved embryos after thawing. Lower implantation, pregnancy, and delivery rates, as well as higher rates of pregnancy loss were observed. These effects could be due to a direct effect of cryopreservation, to the cryopreserved embryos being those not selected for fresh transfer (and hence of lower initial quality), or to both factors. Coupled with the lower power to detect differences in the women using cryopreserved embryos (due to fewer cases), this lower embryo quality may mask any effect of recipient age on outcome in these cases. This study has several significant strengths. The sample size permitted analysis of 3,573 donor cycles among recipients aged and 440 donor cycles among recipients aged 50 54, a substantially larger number of cycles than has previously been analyzed. Although the dataset did not collect all the potentially relevant clinical features that affect outcome, regression models were applied to generate hypotheses about other important features. These analyses confirmed that other characteristics were related to clinical outcomes among fresh ET cycles: specifically, treatment year, embryo type (fresh vs. cryopreserved), and the number of embryos transferred. The overall reduction in the number of embryos transferred during the 3 examined demonstrates the admirable restraint clinics are showing to reign in the problem of multiple pregnancies. It is also good to note an increased implantation rate across, as it suggests practitioners are better able to establish the conditions for success. Nonetheless, these trends have had opposing effects on the multiple pregnancy rate, therefore the higher implantation rate has negated the benefit of fewer transferred embryos. Consequently, in the under study there were no significant reductions in the rate of twins or high order multiples. The FERTILITY & STERILITY 1043

7 FIGURE 4 Clinical outcomes compared among cycles using fresh and cryopreserved embryos. In each panel, the delivery rate (heaviest line), clinical pregnancy rate (medium line), and pregnancy loss rate (lightest line) are moving averages. The precise means for each age and for each outcome are shown as markers. This comparison of clinical outcomes among fresh and cryopreserved embryo transfers illustrates the clear age-related trends in fresh cycles of donor egg therapy that are not apparent among cryopreserved cycles. { clinical pregnancy rate; E miscarriage rate; x delivery rate. This might be due to reduced uterine blood flow with increased age (9), a decreased sensitivity to P effects (10), or even more direct interference from uterine leiomyomas, which become more common with age. Other reasons for lower success rates exist. Among them is the possibility of a sperm factor. Because the dataset does not capture the age of the sperm donor (whether it be husband or donor), it is not possible to analyze this factor directly. However, in general there is a strong correlation between the ages of wives and their husbands, therefore it is likely that the recipients in their 50s have partners of that age or greater, and it is possible that this confounds the apparent link to female recipient age. Another possibility is that the age of the egg donor was correlated with the age of the recipient. Known donors, for instance, might be close in age to their recipients, so to the extent that the dataset contains large numbers of known donor cycles, this bias might exist. Again, because this information is not captured in the dataset, the concern cannot be answered directly. In this, the largest experience with donor egg therapy yet evaluated, lower implantation and pregnancy rates among recipients of donor eggs were seen to begin in the late 40s, and become pronounced in the 50s. Although the cause of this decline cannot be confirmed in the present study, declining endometrial receptivity is a leading possibility. Couples in their 50s contemplating donor egg therapy should be aware of these age-related effects. Acknowledgments: The authors thank Martin Beaird for providing the dataset, the CDC for suggestions regarding presentation, and all clinics that submitted data to SART and thereby made this analysis possible. We also thank members of the Registry and Research Committees of SART who provided their input to this manuscript: Dale W. Stovall, M.D. (Medical College of Virginia), Michael P Steinkampf, M.D. (University of Alabama Birmingham), Lucinda L Veeck, M.L.T, hd.sc. (Cornell University), Benjamin Gocial, M.D. (Jefferson University), Eric S. Surrey, M.D. (Colorado Center for Reproduction), Maria Bustillo, M.D., Marcelle I. Cedars, M.D. (University of Colorado), David R. Meldrum, M.D., Kaylen M. Silverberg, M.D., and Judy J. Stern, Ph.D. American Society for Reproductive Medicine guidelines specifying lower numbers of embryos for transfer (issued in late 1999) were not in force when these cycles were performed, therefore the impact of these altered guidelines on lowering the multiple pregnancy rate awaits later evaluation. This study strongly suggests that women at and beyond their late 40s have a lower chance for success with donor eggs than younger recipients. It is not possible, given the nature of the available data, to assign a cause to this decline. Diminished uterine receptivity is one attractive possibility. References 1. Legro RS, Wong IL, Paulson RJ, Lobo RA, Sauer MV. Recipient s age does not adversely affect pregnancy outcome after oocyte donation. Am J Obstet Gynecol 1995;172: Remohi J, Gartner B, Gallardo E, Yalil S, Simon C, Pellicer A. Pregnancy and birth rates after oocyte donation. Fertil Steril 1997;67: Paulson RJ, Hatch IE, Lobo RA, Sauer MV. Cumulative conception and live birth rates after oocyte donation: implications regarding endometrial receptivity. Hum Reprod 1997;12: Sauer MV, Paulson RJ, Ary BA, Lobo RA. Three hundred cycles of oocyte donation at the University of Southern California: assessing the effect of age and infertility diagnosis on pregnancy and implantation rates. J Assist Reprod Genet 1994;11: Borini A, Bianchi L, Violini F, Maccolini A, Cattoli M, Flamigni C Toner et al. Recipient age effects in the U.S. Vol. 78, No. 5, November 2002

8 Oocyte donation program: pregnancy and implantation rates in women of different ages sharing oocytes from single donor. Fertil Steril 1996; 65: Moomjy M, Cholst I, Mangieri R, Rosenwaks Z. Oocyte donation: insights into implantation. Fertil Steril 1999;71: Schieve LA, Peterson HB, Meikle SF, Jeng G, Danel I, Burnett NM, Wilcox LS. Live-birth rates and multiple-birth risk using in vitro fertilization. JAMA 1999;282: Reynolds MA, Schieve LA, Jeng G, Peterson HB, Wilcox LS. Risk of multiple birth associated with in vitro fertilization using donor eggs. Am J Epidemiol 2001;154: Meldrum DR. Female reproductive aging ovarian and uterine factors. Fertil Steril 1993;59: Steer CV, Tan SL, Mason BA, Campbell S. Midluteal-phase vaginal color Doppler assessment of uterine artery impedance in a subfertile population. Fertil Steril 1994;61:53 8. FERTILITY & STERILITY 1045