Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years

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1 Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years Yechezkel Lande, M.D., a Daniel S. Seidman, M.D., b Ettie Maman, M.D., b Micha Baum, M.D., b Jehoshua Dor, M.D., b and Ariel Hourvitz, M.D. b a Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petach-Tikva; and b IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Objective: To assess the long-term success rate among couples with primary infertility offered unrestricted, free in vitro fertilization (IVF) treatments. Design: Historical prospective cohort study. Setting: University-based tertiary medical center with unlimited coverage of IVF for couples first two children. Patient(s): Women aged <35 years, with primary infertility, referred for their first IVF treatment to the Sheba Medical Center IVF unit between 2001 and Intervention(s): Relevant data were obtained from patient files and supplemented by a standardized telephone questionnaire. Main Outcome Measure(s): Pregnancies, live births, adoptions, divorces, and discontinuations of further treatment. Result(s): During the 5- to 7-year follow-up period, 95.5% of couples conceived, and 89.6% of couples gave birth to a live infant. Of these couples, 81.3% achieved a live birth within the first 4 years of the follow-up period, and 85.1% within eight treatment cycles. Of the 14 couples (10.4%) who did not give birth to a live infant, five adopted, two divorced, four are still undergoing IVF treatments, and three (1.8%) decided not to become parents. Conclusion(s): Young couples beginning IVF treatment in an environment free of economic hurdles can be reassured that they have an excellent chance (90%) of achieving a live birth within 4 years. When IVF is provided free of cost, very few couples discontinue treatment before a live birth is achieved. (Fertil Steril Ò 2011;95: Ó2011 by American Society for Reproductive Medicine.) Key Words: Cost-free cycles, IVF, live birth rate, long-term follow-up Infertile couples beginning in vitro fertilization (IVF) treatment will undergo an intense process filled with psychological burdens, physical discomfort, considerable expense, and medical procedures with risks and side effects (1 2). One of the major difficulties, particularly after repeated failure, is that we cannot accurately predict which treatment will be successful, how many treatment cycles are required, or what the estimated duration of treatment will be before a live birth is achieved. Most of the studies in the literature have assessed the success rate of IVF treatments per cycle (3 4). Some have reported the success as the cumulative pregnancy or live-birth rate over a series of three to six treatment cycles (5 10). These studies often do not take into consideration the possibility of having a spontaneous pregnancy during treatments. They also usually do not account for couples dropping out of fertility treatments for various psychological and economical reasons before a live birth is achieved. There are relatively few studies that report pregnancy and livebirth rates per duration of treatment. Our study evaluated infertile couples over the course of 5 to 7 years after initiating treatment. By using this methodology, we hoped to create a more accurate picture, allowing more realistic expectations for couples who come for consultation before beginning fertility treatment, to assess their chances of having a live child after a number of years. The situation in Israel is unique because IVF treatments are fully covered by the national health insurance and thus are provided free of charge to all women until their first two children are born. Israeli patients are offered easy access to IVF clinics where they can immediately undergo, when medically indicated, an unlimited number of IVF treatment cycles. We assumed that for infertile patients the chances of becoming pregnant and having a live child should be greater in Israel than in most other countries because the financial cost does not play a role in the patient s decision to obtain treatment (11). The results of our study may aid in evaluating the outcome of numerous consecutive IVF cycles and may help in assessing whether the success rates justify the financial expenditure beyond three to six IVF cycles. Received February 16, 2010; revised May 16, 2010; accepted June 1, 2010; published online July 19, Y.L. has nothing to disclose. D.S.S. has nothing to disclose. E.M. has nothing to disclose. M.B. has nothing to disclose. J.D. has nothing to disclose. A.H. has nothing to disclose. Reprint requests: Yechezkel Lande, M.D., Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, 39 Jabotinsky Street, Petach-Tikva, Israel (FAX: ; y.lande@gmail.com). MATERIALS AND METHODS This historical prospective cohort study included all couples referred to the Sheba Medical Center IVF unit who met the following inclusion criteria: [1] women aged %35 years at the time of referral, [2] women with primary infertility, [3] women with no IVF treatments before referral, [4] first IVF cycle performed between 2001 and 2002, and [5] a minimum of 12 months infertility before initiation of IVF treatment. Data were collected from the patients files, including basic clinical characteristics, infertility workup 568 Fertility and Sterility â Vol. 95, No. 2, February /$36.00 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 and diagnosis, and treatment results. In addition, we contacted all women who met the inclusion criteria to obtain additional information regarding treatments performed in other institutions, spontaneous pregnancies and births, and discontinuations of IVF treatments due to divorce, adoption, or other reasons. All data received from the patients files and telephone interviews were collected in a database. The results of all treatment cycles were included in the analysis, regardless of the number of IVF units that provided the treatments. The primary outcome was a live birth, confirmed by medical file or telephone interview, and live births that occurred up to April 2008 were recorded. This study was approved by the institutional review board at Sheba Medical Center, which allowed retrospective review of patients files and administration of telephone questionnaires after informed consent. All statistical analyses were conducted with SPSS software, version 15 (SPSS, Inc., Chicago, IL). The cumulative probability of the first live birth during the study period was estimated using the Kaplan-Meier method, according to the IVF cycle number and according to years of treatment. To evaluate differences between clinical characteristics of the study group and couples who were lost to follow up or refused to participate, we used a t-test. A two-sided P<.05 was considered statistically significant. RESULTS Between January 2001 and December 2002, 171 couples with primary infertility began their first IVF cycle at the Sheba Medical Center fertility unit and met the study inclusion criteria. Of these 171 couples, 6 refused to participate in the telephone questionnaire (3.5%), and 31 couples were lost to follow-up evaluation and could not be reached by telephone (18.3%). The study cohort therefore included 134 couples who agreed to participate in this study (78.4%) (Fig. 1). We evaluated the group of couples who refused to participate or were lost to follow up and found no statistically significant differences in their basic clinical characteristics compared with the study group (Table 1). During the follow-up period of 5 to 7 years, 128 (95.5%) couples conceived and 120 (89.6%) gave birth to a live child. Of the live births, 19.2% were twins. There were no triplet births in this cohort. Over 60% of the patients achieved a live birth within the first year of the follow up period; 85.1% and 88.8% achieved a live birth within 4 and 6 years of follow-up, respectively (Fig. 2A). Seventy-three patients achieved a live birth after only three treatment cycles (54.5%) and 109 (81.3%) after eight treatment cycles. The remaining 11 live births were achieved by cycle 19 (Table 2; Fig. 2B). The majority of live births were attained by IVF or intracytoplasmic sperm injection (ICSI) cycles (76.7%) and with frozen-thawed embryos (9.2%). Eleven (9.2%) live births resulted from spontaneous pregnancies, three (2.5%) from IVF with donor sperm, two (1.7%) from intrauterine insemination with donor sperm, and one (0.8%) from egg donation. During the long-term follow-up period, 14 couples (10.4%) did not give birth to a live child. Ten couples discontinued treatments without achieving a live birth, and four are still continuing fertility treatments. Of the couples who ceased treatments, five chose to adopt, two stopped infertility treatments due to divorce, and three made the choice to give up on parenthood and therefore discontinued treatments. Only two couples are still pursuing IVF treatments seriously. Of the other two couples who claimed to be continuing IVF treatments, in reality they did not complete more than three cycles over the span of the long-term follow-up period. DISCUSSION Our study provides unprecedented cumulative live-birth rates (CLBR) for young infertile couples evaluated over 5 to 7 years. The results show impressive success rates of 89.6%, with most of the live births achieved within the first eight treatment cycles. Although the majority of live births occurred within the first year of initiating treatment, it appears that a minimum period of 4 years, and possibly even 6 years, may be necessary to truly take advantage of the chance of attaining a live birth with repeated IVF cycles (see Fig. 2A). A previous study, performed in the Netherlands (12), included 1,456 couples who initiated IVF treatments between 1996 and 2000, whose live-birth rates were evaluated and recorded through September The CLBR found for women aged <35 years was 64.6%. It is interesting that 90% of the pregnancies were achieved within the first three cycles, and only 5.2% of the couples continued up to a sixth cycle. The lower CLBR can therefore be explained by the high dropout rate in the Netherlands after three to six cycles due to lack of insurance coverage. Another limitation was that the clinic conducting the study performed a maximum of six cycles per couple. A recent study performed in our institution (13) assessed the yield of high-order consecutive IVF treatments. The cumulative delivery rates after 14 consecutive cycles reached 87%, and each additional cycle increased the delivery rates. This emphasizes the improved success rates for couples who continue IVF treatments for a long period of time. We therefore found it necessary to assess in a cohort analysis how many couples actually continued treatment until a live birth was achieved and how many dropped out from treatment. It is interesting that, in our study, only six couples from a cohort of 134 dropped out and did not complete six treatment cycles (4.5% dropout rate). The low dropout rate may explain the high CLBR after six cycles of 73.1%. The remaining eight couples who did not achieve a live birth performed between 10 to 20 cycles, and two of them are still continuing IVF treatment despite their long lack of success. Of the 134 couples who were included in this study, 11 (8.2%) achieved a spontaneous live birth, and 20 achieved a live birth from IVF treatments completed in other institutions (14.9%). We must emphasize that the inclusion of spontaneous live births and live births achieved by IVF in other institutions is unique to our study. Other studies have considered such couples to be dropouts, but we are reporting them as succeeding in achieving a live birth. This difference may partially account for our higher live-birth rate in comparison with previous studies (12, 14). The CLBR, regardless of how or where the births were achieved, is the information that most couples seek when contemplating whether to continue with IVF treatment. One of the limitations of our study is that, of the 171 couples who met the inclusion criteria, 37 refused to answer the telephone questionnaire or were lost to follow-up evaluation and could not be reached by telephone; they were therefore not included in this study. When the clinical characteristics of the nonresponders were compared to the respondents, no significant differences were found (Table 1). Therefore, we concluded that the respondents are representative of all the patients who met the inclusion criteria. When the files of the nonresponders were reviewed, we found that 19 of the 37 couples had achieved a live birth during IVF treatments at Sheba Medical Center. If we estimate that the remaining 18 couples who discontinued treatments and were lost to follow-up evaluation had a similar outcome as the couples in our study group, 5.5 couples would have achieved a live birth from treatments in other institutions and 3.0 from spontaneous pregnancies. The total CLBR from the entire cohort of 171 would then be 86.3%, similar to the rate in our study group. Even if we assume that there were no live births in the group who discontinued treatments at Sheba without achieving a live birth and were lost to follow up, the total CLBR Fertility and Sterility â 569

3 FIGURE 1 Long-term follow-up of young women with primary infertility beginning IVF treatments at Sheba Medical Center from 2001 to Women <35 years with primary infertility beginning IVF treatments at Sheba medical center during Lost to follow up 140 Contacted by phone 6 Declined to participate 134 Women were included in the study. 108 Live births achieved Figure through 2 IVF 10 Spontaneous live births 14 Did not achieve a live birth 10 Discontinued IVF treatments 4 Continuing IVF treatments 5 Adopted 2 Divorced 3 Gave up on parenthood still remains 81.3% a much higher rate than reported in other previous studies. In a recent study, Malizia et al. (14) reported a CLBR of 65% after six consecutive cycles in patients under 35. There was no significant increase in this rate when more than six cycles were conducted. This was explained by the fact that very few couples continued past six cycles due to lack of insurance coverage. Out of over 3,000 couples who did not achieve a live birth, only 276 remained for all six cycles. This emphasizes the high dropout rate (over 90%) from continuing IVF treatments in countries where insurance coverage is limited. The low dropout rate in our study can be explained by two main factors. First, Israel s national health system offers unlimited coverage for IVF treatments. When the financial burden of IVF treatments is neutralized, the dropout rate appears to decline drastically. Second, our study included all IVF cycles that were performed by the participant couples, not just the cycles performed in a single institution. It is possible that if other studies had also accounted for cycles performed in other institutions their dropout rates would have been much lower as well. A recent study performed at Boston IVF (15) to determine why insured patients drop out of IVF in the United States suggested that the dropout rate before a live birth is achieved reaches over 50% even in situations where there is full financial coverage for IVF treatments. They concluded that the psychological burden and stress were the most common reasons for terminating treatment, not necessarily the lack of financial coverage. In contrast, 570 Lande et al. Live-birth rates for free IVF Vol. 95, No. 2, February 2011

4 i l i t i i t ) TABLE 1 Clinical characteristics of the study group compared to characteristics of couples who were lost to follow-up or refused to participate. Characteristic Study group (mean ± SD) Lost to follow-up (mean ± SD) P value Patient age (y) (NS) Duration of infertility (y) (NS) FSH day 3 (miu/l) (NS) LH day 3 (miu/l) (NS) Sperm volume (ml) (NS) Sperm count ( 10 6 /ml) (NS) Sperm motility (%) (NS) Note: FSH ¼ follicle-stimulating hormone; LH ¼ luteinizing hormone; SD ¼ standard deviation. our study found the lack of financial burden to be associated with a much lower dropout rate. Of course, it is likely that full financial coverage in our study was not the only reason for the high CLBR after persistent IVF treatment. For historical, religious, and cultural reasons, giving birth to children is of supreme importance in Israeli society, and childlessness is viewed as a serious disability (16). This in turn may explain the generosity of the Israeli national health insurance in providing comprehensive financial coverage for IVF treatment for the first two children, and may also explain why our dropout rates were so low compared with other studies. A study from the mid-1980s found that cumulative pregnancy rates after six IVF cycles reached 60%, with a relatively constant 15% pregnancy rate per cycle. They predicted that the pregnancy rate remains constant even for high-order consecutive IVF cycles (17). This is contrary to the finding in our study that live-birth rates indeed remained relatively constant until the eighth cycle, but from the ninth cycle they seemed to decline drastically (see FIGURE 2 (A) Kaplan-Meier curve for cumulative live-birth rates per years of follow-up. (B) Kaplan-Meier curve for cumulative live-birth rates per embryo transfer. h ( % r v e B y o f L P r o b a b Years of Follow Up Live Birth (%) Probability of Cycle Number Fertility and Sterility â 571

5 TABLE 2 Cumulative live birth rates (CLBR) per embryo transfer cycle. ET Patients who entered cycle, n Patients who achieved a live birth, n Live birth rate per cycle, % CLBR per cycle, % Table 2, Fig. 2B). Similarly, a study from our institution from 1996 (10) reported that the CLBR of IVF reached a plateau after six cycles, and therefore insurance companies should cover treatments until the sixth cycle. In our present study, it appears that the plateau begins after the completion of eight to nine cycles (see Table 2, Fig. 2B). It should be noted that the patients included in this study began IVF treatments nearly a decade ago. Over the past decade, IVF success rates have improved significantly, with higher live-birth rates per cycle. Patients initiating IVF today, in a cost-free environment, can probably be expected to have an even higher live-birth rate within a shorter period of time and with fewer treatment cycles required. The CLBR found in our study is very high, and almost 90% of the patients achieved their desired live birth within the follow-up period. This high rate can be explained by two main factors. First, the low dropout rate from continuing IVF treatments in Israel is likely due in a large part to the full financial coverage offered for practically unlimited IVF treatments. Second, this study accounts for spontaneous births as well as births achieved from treatments performed in other institutions. According to our new findings, we can conclude that in a cost-free environment young women beginning IVF treatments can be reassured that they have a very high chance (near 90%) of becoming pregnant and achieving a live birth within 4 to 6 years. REFERENCES 1. Peddie VL, van Teijlingen E, Bhattacharya S. A qualitative study of women s decision-making at the end of IVF treatment. Hum Reprod 2005;20: Bryson CA, Sykes DH, Traub AI. In vitro fertilization: a long-term follow-up after treatment failure. 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