Cumulative probability of live birth after three in vitro fertilization/intracytoplasmic sperm injection cycles

FERTILITY AND STERILITY VOL. 77, NO. 3, MARCH 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Cumulative probability of live birth after three in vitro fertilization/intracytoplasmic sperm injection cycles Katarina Olivius, B.Sc., a Barbro Friden, M.D., Ph.D., b Kersti Lundin, Ph.D., a and Christina Bergh, M.D., Ph.D. a Center for Reproductive Medicine, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden Received May 17, 2001; revised and accepted September 11, 2001. This study was supported by the Göteborg Medical Society and the Faculty of Medicine, Göteborg University. Reprint requests: Christina Bergh, M.D., Ph.D., Center for Reproductive Medicine, Sahlgrenska University Hospital, Göteborg University, SE-413 45 Göteborg, Sweden (FAX: 4631 829248; E-mail: christina.bergh@obgyn.gu.se). a Center for Reproductive Medicine, Sahlgrenska University Hospital. b Department of Obstetrics and Gynecology, Huddinge University Hospital, Huddinge, Sweden. 0015-0282/02/$22.00 PII S0015-0282(01)03217-4 Objective: To assess the probability of live birth after three available in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Design: Retrospective, observational study. Setting: University hospital. Patient(s): Nine hundred seventy-four couples who started their first conventional IVF or ICSI cycle between January 1996 and December 1997. A total of 1985 stimulated cycles were initiated. Intervention(s): Analysis of the cumulative live birth rate using the life-table approach with and without taking dropouts into account. Main Outcome Measure(s): Cumulative live birth rate. Result(s): The overall cumulative live birth rate after three completed stimulated cycles (including freezing/ thawing cycles) was 65.5% with an optimistic approach. For the realistic and pessimistic approaches the corresponding figures were 63.1% and 55.5%, respectively. Unexpectedly, 65% of couples not achieving a live birth interrupted the full treatment program of three cycles. Conclusion(s): The cumulative live birth rate gives the couple a more accurate prognosis of achieving a live birth after IVF/ICSI than the statistics usually provided. With the realistic estimation, 63% of the couples achieved childbirth after three available conventional IVF or ICSI cycles. Further studies are required to investigate the high drop-out rate. (Fertil Steril 2002;77:505 10. 2002 by American Society for Reproductive Medicine.) Key Words: IVF, ICSI, probability, cumulative live birth, age More than 500,000 children have been born after in vitro fertilization (IVF) since its introduction in 1978 (1). The efficiency of this treatment in terms of cumulative live birth rate has only been studied in a few centers (2 4); most studies deal with cumulative pregnancy rate (5 7) or outcome per started cycle or embryo transfer (ET). However, neither the cumulative pregnancy rate nor the efficiency of each cycle in terms of pregnancy or live birth rates is as important to the couple as the question what are our chances of having a baby after the treatment? The present study was undertaken to answer that question. In most parts of Sweden, a maximum of three IVF treatment cycles leading to one childbirth is state subsidized, therefore entailing no or minimal cost to the patient. Certain age limits exist for public IVF treatments and couples are not allowed to have genetically own children before treatment. We thereby have an opportunity to study the cumulative childbirth rate in a cohort receiving a similar set of treatments. The fact that three cycles are free makes our center a good setting for cumulative studies, compared to centers where the mere cost of the treatment makes it impossible for a large proportion of the patients to have more than one cycle (8). The aim of this study was to analyze the likelihood of live birth after the three publicly funded IVF treatments. In earlier studies, the life-table approach has most commonly been used (4, 5, 7). Life-table analysis is generally believed to give an overestimate in cumulative studies (9). This is due to the life-table analysis assumption that all 505

patients complete treatment. In a life-table analysis, the patients who decline treatment after one or two cycles are given the same chances of success as the patients who actually continue the full treatment. Because the decision to drop out is, in many cases, preceded by the doctor s dissuasion from further treatment because of a poor prognosis, there is reason to believe that this group has a lower chance of achieving a live birth. This bias is the reason why the life-table approach tends to give a falsely high cumulative live birth rate. To get closer to the truth, we used two modifications of life-table analysis, in which we considered the reason for canceling treatment without achieving live birth. This yielded three estimates: an overestimate, a realistic estimate, and an underestimate (see the statistics discussion). MATERIALS AND METHODS Patients The study included all 974 couples starting their first IVF cycle between January 1996 and December 1997 at Sahlgrenska University Hospital, Gothenburg, Sweden. The data were collected from our database and from patient records. The reasons for infertility were male factor, 326 (33.5%); tubal pathology, 223 (22.9%); unexplained infertility, 189 (19.3%); other female factors, 132 (13.6%); and multifactorial, 104 (10.7%). The end point of the study was live birth. The mean age of the women was 32.5 years (range: 21 to 40 years) at the beginning of treatment. Eleven patients were 40 years old when starting their treatment; 27 patients were below 25 years. The couples were followed from the time of entering the IVF program until their treatment was completed. Most patients were offered three completed IVF cycles without charge. A cycle was considered started if ovarian stimulation had begun. A completed cycle was defined as a stimulated IVF cycle reaching ET. In this particular study, any additional freezing/thawing cycles were not counted as separate cycles but were included as parts of the stimulated cycle from which the embryos originated. Cycles where all embryos were cryopreserved due to impending ovarian hyperstimulation syndrome (OHSS) and were used later in thawing cycles were treated as completed cycles. In this study, the couples were evaluated until they had achieved a live birth, or had completed three stimulated cycles without delivery of a child, or had interrupted the treatment for various reasons before completing three cycles. In this group, 290 patients interrupted treatment before they had completed three cycles and without achieving live birth. IVF Treatment All women were treated using a stimulation protocol including downregulation with a GnRH agonist in a long protocol starting in either the follicular or the luteal phase (1.2 mg per day as a nasal spray or 1.0 mg per day as an s.c. injection; Suprecur or Suprefact, Hoechst, Frankfurt, Germany). Downregulation was followed by stimulation with recombinant follicle-stimulating hormone, FSH (Gonal-F, Serono, Geneva, Switzerland or Puregon, Organon, Oss, Netherlands) or urinary gonadotrophins (Pergonal, Fertinorm, or Fertinorm-HP, Serono). Monitoring was performed by vaginal ultrasound scans and serum estradiol measurements. When adequate stimulation was achieved ( 3 follicles of 18 mm), 10,000 IU hcg (Profasi, Serono) was administered. Fertilization was performed by conventional IVF or by ICSI, following standard techniques. In general, two embryos were transferred 2 or 3 days after oocyte retrieval using a Wallace or a Frydman TDT catheter. Luteal support was given either with s.c. hcg or with progesterone (i.m. or vaginal route). Additional embryos of good quality were cryopreserved and replaced later in spontaneous or stimulated cycles. Conventional IVF was used as the fertilization technique in the first completed IVF cycle in 446 (47%) cases, whereas ICSI was used in 482 (51%) cycles. In 16 cycles (2%), both techniques were used ( split cycles ). In ICSI cycles, ejaculated as well as epididymal and testicular spermatozoa were used for fertilization. ICSI was performed in 49.6% of the total cohort of cycles. Statistics The study represents a summary of clinical results. The cumulative probability of achieving a live birth after x number of cycles was calculated using Kaplan-Meier productlimit estimate [1 (1 p 1 )(1 p 2 ) (1 p x )]*100%, where p x is the probability of achieving live birth in cycle x. Three different assumptions were made for estimation of live birth rate. [1] All women who canceled treatment before three cycles had no probability of achieving a live birth ( pessimistic ). [2] Women who canceled treatment because of a poor prognosis had no probability of achieving a live birth whereas all other women who canceled treatment had the same probability of a live birth as the women who continued treatment ( realistic ). [3] All women who canceled treatment had the same probability of achieving a live birth as those who continued ( optimistic ). The results were calculated both per started and per completed cycle. Differences between groups were tested by the log-rank test, 2 test, or Fisher s exact test when appropriate; P.05 was considered statistically significant. RESULTS Pregnancy Rate The pregnancy rate for fresh, stimulated cycles was 31% per started cycle and 37% per ET. For thawing cycles, the pregnancy rate was 27% per ET. The cumulative pregnancy rate after three completed cycles was 65.2% in the pessimistic, 66.2% in the realistic, and 73.2% in the optimistic estimate. After three started cycles, the cumulative preg- 506 Olivius et al. Cumulative childbirth after IVF/ICSI Vol. 77, No. 3, March 2002

FIGURE 1 Cumulative probability of live birth after IVF or ICSI in the total population. P.0063, optimistic vs. pessimistic estimate. P.0274 realistic vs. pessimistic estimate. FIGURE 2 Cumulative probability of live birth after IVF and ICSI for different age groups. P.0178, 20 to 29 years vs. 35 to 40 years, log-rank test. P.0021, 30 to 34 years vs. 35 to 40 years, log-rank test. nancy rate was 61.4%, 61.8%, and 67.1% (pessimistic, realistic, and optimistic estimate, respectively). Live Birth Rate Nine hundred seventy four women underwent 1,985 started stimulated cycles; 97% (n 1,927) of the started cycles reached oocyte retrieval and 83% (n 1,652) reached ET. That is, 333 stimulated cycles did not reach ET. Cancellation occurred before oocyte aspiration in 58 cycles and after oocyte aspiration in 275 cycles. In 28 cycles all embryos were cryopreserved due to impending hyperstimulation and were used in subsequent thawing cycles. Thus, 944 patients completed at least one IVF cycle. The remaining 30 patients started one (n 16), two (n 11), or three (n 3) cycles but did not reach transfer due to poor fertilization or poor stimulation. The cumulative live birth rate for all patients after three completed cycles was 63.1% in the realistic estimation. The pessimistic and optimistic outcome was 55.5% and 65.5%, respectively (Fig. 1). The corresponding frequencies per three started cycles were 50.9% ( pessimistic ), 56.3% ( realistic ), and 57.1% ( optimistic ) (Table 1). When the women were divided into three age groups, 20 to 29 years, 30 to 34 years, and 35 to 40 years at the beginning of treatment, the cumulative live birth rate in the realistic estimation was similar for the two younger age groups but decreased in the oldest group (Fig. 2, Table 2). However, TABLE 1 Estimated pessimistic, realistic, and optimistic live births rates per started cycle and per completed cycle. Cycle number a No. of cycles Live births b Cumulative live birth rate, % (95% CI) Pessimistic Realistic Optimistic Per started cycle 1 974 296 (30.4%) 30.4 (27.5 33.3) 30.4 (27.5 33.3) 30.4 (27.5 33.3) 2 588 140 (23.8%) 44.8 (41.6 47.9) 46.7 (43.5 50.0) 47.0 (43.7 50.2) 3 314 60 (19.1%) 50.9 (47.8 54.1) 56.3 (52.9 59.8) 57.1 (53.6 60.6) 4 103 29 (28.2%) 54.7 (51.5 57.9) 65.2 (61.2 69.2) 69.2 (64.7 73.7) Per completed cycle 1 944 331 (35.1%) 35.1 (32.0 38.1) 35.1 (32.0 38.1) 35.1 (32.0 38.1) 2 491 135 (27.5%) 49.4 (46.2 52.6) 52.1 (48.8 55.5) 52.9 (49.5 56.3) 3 217 58 (26.7%) 55.5 (52.4 58.7) 63.1 (59.6 66.7) 65.5 (61.8 69.2) a Started cycles number 5 and 6 (n 22) with three births were not included in this table. b Completed cycles number 4 (n 16) with four births were not included in this table. FERTILITY & STERILITY 507

TABLE 2 Live births (freeze transfers included) per completed cycle according to cycle number and age. Female age (y) Cycle number No. of cycles No. of live births (%) 20 29 1 266 96 (36%) 2 139 36 (26%) 3 65 22 (34%) 4 4 0 30 34 1 421 155 (37%) 2 216 70 (32%) 3 89 25 (28%) 4 7 1 (14%) 35 42 1 257 80 (31%) 2 136 29 (21%) 3 63 11 (17%) 4 5 3 (60%) when the patients were divided into groups according to infertility diagnosis, no statistically significant difference was noted between the groups (Fig. 3). Frozen/Thawing Cycles Of 328 thawing cycles initiated, 262 of these went to transfer. In 66 cases no embryos survived after thawing. The thawing cycles resulted in 52 live births or 10% of the overall live birth rate. The probability of a live birth per completed thawing cycle was 20%. Seventy-two patients still had embryos cryopreserved at the time of this study; 67 of these women had not yet delivered a child. FIGURE 3 Cumulative probability of live birth after IVF and ICSI for different diagnoses. Obstetric Outcome In this cohort of 974 women, altogether 524 children were born alive. Five children were dead at birth, 4 of them from four separate twin pregnancies and 1 from a singleton pregnancy. One patient was pregnant in the second trimester at the time of data collection and was treated as a live birth. Two patients underwent legal terminations due to fetal polycystic kidney disease and trisomy 3. Twin birth occurred in 23% of all live births in this study. No deliveries of higher order occurred. Women younger than 30 years delivered twins more often than did women aged 30 to 34 years and 35 to 40 years (34%, 19% and 18%, respectively; P.0008 and.0025, respectively), reflecting a higher implantation rate. DISCUSSION To our knowledge, this study is the largest cumulative live birth rate study including ICSI procedures with surgically retrieved spermatozoa. A striking finding in this study was that there was no statistically significant difference in the cumulative childbirth between the optimistic (65.5%) and the realistic (63.1%) estimates and no apparent clinically significant difference either. In contrast, the pessimistic estimate was significantly lower compared to both the optimistic and the realistic estimates. This is good news and should encourage couples to continue treatment. An important aspect of the pessimistic estimate is that this estimate reflects the daily clinical situation. It is obvious that there are other factors than prognosis (e.g., physical, psychological, and social factors) that influence couples to continue or discontinue infertility treatment. In a previous comparison from our center (10), the cumulative live birth rates were 50%/51% after three cycles (started/completed). The statistics used in that study represent the pessimistic estimate in the present study. The present results of 51%/56% (started/completed) indicate an increase in the live birth rates by 1%/5% in 5 to 6 years. This may be considered a modest increase, but one must bear in mind that between the two studies, the number of routinely transferred embryos has been reduced from three to two. A similar mean number of started cycles per patient was performed in these two studies: 2.04 in the later study and 2.07 in the earlier study. However, a slightly less mean number of embryo transfers was performed in the later study: 1.69 vs. 1.99 (fresh cycles) and 0.27 vs. 0.58 (freezing/thawing cycles). It should also be noted that the present study includes patients where spermatozoa were surgically retrieved, which was not the case in 1995. The results are comparable to the results presented by Engmann et al. (3), who reported a cumulative optimistic pregnancy rate and live birth rate of 54% and 48%, respectively, after three started cycles. In the study by Stolwijk et al. (6), the cumulative ongoing pregnancy-rate after three started cycles was 45.5% in the realistic estimate. The 508 Olivius et al. Cumulative childbirth after IVF/ICSI Vol. 77, No. 3, March 2002

difference in our estimates may be due not only to differences in the measured variables (ongoing pregnancy vs. live birth), but also to the time period when the studies were performed. Our study reflects IVF/ICSI treatments from 1996 to 2000 whereas the Dutch study covers the years 1991 to 1997, during which time the ICSI technique was introduced but not well established. According to Swedish law, it is possible to cryopreserve embryos for 5 years. In this study, 67 of the women without delivery still had embryos cryopreserved. The real cumulative live birth rate may therefore be even higher than indicated in this study. The cumulative live birth rate was higher in women under 35 years of age than in the older women, whereas the twin birth rate was higher in women under 30 years of age. It is well known that younger women have higher implantation rates in general (11) and the findings from this study are consistent with other studies of cumulative pregnancy or birth rates (4, 6). This knowledge may be used in the clinical situation both for adequate information before treatment and when deciding on the number of embryos to transfer. The cause of infertility did not seem to influence the live birth rate in this study. This is in accordance with the results of Templeton et al. (8). However, it has been reported that tubal infertility, particularly sactosalpinx, may reduce pregnancy rates in IVF treatment (12). The same tendency, although not statistically significant, was noted in the present study. A large proportion (65%) of the couples in the present study who did not achieve birth of a child did not proceed through the full treatment program consisting of three IVF cycles. This was an unexpected finding, and the patients reasons for declining efficient, free treatments are not fully known. In the group of couples declining treatment, 12 couples separated, and 27 patients became spontaneously pregnant; in 50 cases the physician in charge recommended termination of the treatment due to a poor prognosis; 41 quit because of troublesome treatment, and 19 patients quit for other reasons. The remaining 141 patients interrupted treatment for unknown reasons. It is known that some patients have been offered only two subsidized cycles. It also may be possible that IVF treatment is such a physical and emotional burden that many couples simply cannot bear to complete three cycles. It is clear that IVF treatment is both physically and emotionally stressful. Studies agree that emotional consequences such as depression, increased anxiety, lowered selfesteem, and marital problems follow IVF treatment, at least in the short term (13, 14). Many studies concerning stress and IVF treatment agree that the most stressful time in an IVF cycle is the wait to find out the result of the treatment (15, 16); the treatment in itself is stressful, but not to the same degree. Long-term follow-up study of IVF patients reveals that couples remaining childless report a greater negative impact of infertility on their marriages than couples who succeed in getting a biological child or adopting a child after IVF treatment (17). In a recent study, the reasons for stopping treatment before conceiving were evaluated in an Australian IVF center with a questionnaire (16). Even if up to six cycles were offered free of charge, the mean number of started cycles per patient was 3.1, regardless of whether the couple achieved a live birth. The four most common reasons for quitting treatment were I d enough (66%), emotional cost (64%), could not cope with more treatment (42%), and physical cost (39%). Although the Swedish system may be somewhat different, all the above reasons are probably valid for our patients as well. There is no economic bias for choosing to discontinue treatment. A study investigating the reasons for declining treatment in the cohort of patients in our material is ongoing. Recently, an intense debate regarding reduction of the number of embryos per transfer from two to one has arisen in Sweden. There is one reflection relevant to clinical practice to be made in this context. Although it is necessary to reduce the frequency of multiple births after assisted reproductive techniques, one should probably proceed with great caution in view of these results. Reduction of the number of embryos per transfer to a single embryo will most probably lead to the need of an increased number of cycles before succeeding, at least in certain groups of patients. If a large proportion of the patients cannot cope with three free treatment cycles, it may not be advisable to reduce the number of embryos to one per transfer for all patients regardless of age, infertility reason, and prognosis. Our findings concerning cumulative live birth rate and also the dropout rate are of importance when selecting and advising patients for single embryo transfers and when designing studies on that topic. Acknowledgment: The authors thank Nils-Gunnar Pehrsson for valuable advice and for assistance in performing the analysis. References 1. Steptoe P, Edwards R. Birth after reimplantation of a human embryo. Lancet 1978;2:366. 2. Fukuda J, Kumagai J, Kodama H, Murata M, Kawamura K, Tanaka T. Upper limit of the number of IVF-ET treatment cycles in different age groups, predicted by cumulative take-home baby rate. Acta Obstet Gynecol Scand 2001;80:71 3. 3. Engmann L, Maconochie N, Bekir JS, Jacobs HS, Tan SL. Cumulative probability of clinical pregnancy and live birth after a multiple cycle IVF package: a more realistic assessment of overall and age-specific success rates? Br J Obstet Gynaecol 1999;106:165 70. 4. Tan SL, Royston P, Campbell S, Jacobs HS, Betts J, Mason B, et al. Cumulative conception and livebirth rates after in-vitro fertilization. Lancet 1992;339:1390 4. 5. Dor J, Seidman DS, Ben-Shlomo I, Levran D, Ben-Rafael Z, Mashiach S. Cumulative pregnancy rate following in-vitro fertilization: the significance of age and infertility reason. Hum Reprod 1996;11:425 8. 6. Stolwijk AM, Wetzels AMM, Braat DDM. Cumulative probability of achieving an ongoing pregnancy after in vitro fertilization and intracytoplasmatic sperm injection according to a woman s age, subfertility FERTILITY & STERILITY 509

diagnosis and primary or secondary subfertility. Hum Reprod 2000;15: 203 9. 7. Alsalili M, Yuzpe A, Tummon I, Parker J, Martin J, Daniel S, et al. Cumulative pregnancy rates and pregnancy outcome after in-vitro fertilization: 5000 cycles at one center. Hum Reprod 1995;10:470 4. 8. Templeton A, Morris JK, Parslow W. Factors that affect outcome of in-vitro fertilization treatment. Lancet 1996;348:1402 6. 9. Walters DE. A plea for a more fastidious and objective use of statistics. J. Assist Reprod Genet 1994;11:63 73. 10. Bergh C, Josefsson B, Nilsson L, Hamberger L. The success rate in a Swedish in-vitro fertilization unit: a cohort study. Acta Obstet Gynecol Scand 1995;74:446 50. 11. Strandell A, Bergh C, Lundin K. Selection of patients suitable for one-embryo transfer may reduce the rate of multiple births by half without impairment of overall birth rates. Hum Reprod 2000;15:2520 5. 12. Strandell A, Lindhard A, Waldenstrom U, Thorburn J, Janson PO, Hamberger L. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999;14:2762 9. 13. Newton CR, Hearn MT, Yuzpe AA. Psychological assessment and follow-up after in vitro fertilization: assessing the impact of failure. Fertil Steril 1990;54:879 86. 14. Boivin J, Tafekman JE. Stress levels across stages of in vitro fertilization in subsequently pregnant and non pregnant women. Fertil Steril 1995;64:802 10. 15. Connolly KJ, Edelmann RJ, Bartlett H, Cooke ID, Lenton E, Pike S. An evaluation of counseling for couples undergoing treatment for in vitro fertilization. Hum Reprod 1993;8:1332 8. 16. Hammarberg K, Astbury J, Baker HWG. Women s experience of IVF: a follow-up study. Hum Reprod 2001;16:374 83. 17. Leiblum SR, Aviv A, Hamer R. Life after infertility treatment: a long-term investigation of marital and sexual function. Hum Reprod 1998;13:3569 74. 510 Olivius et al. Cumulative childbirth after IVF/ICSI Vol. 77, No. 3, March 2002