Conception rate after in vitro fertilization in patients who conceived in a previous cycle

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1 FERTILITY AND STERILITY Copyright < The American Fertility Society Printed on acid-free paper in U.S.A Conception rate after in vitro fertilization in patients who conceived in a previous cycle Alexander Simon, M.D.* Cohen Ronit, M.D. Aby Lewin, M.D. Nathan Mordel, M.D. Gershom Zajicek, M.D.t Neri Laufer, M.D. In Vitro Fertilization Unit. Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel Objective: To evaluate whether a previously successful in vitro fertilization and embryo transfer (IVF-ET) cycle is a favorable prognostic factor for a subsequent cycle. Design: A retrospective comparison between current IVF patients who have previously conceived in an IVF versus natural cycle. Setting: The IVF unit of a university hospital. Patients: consisted of 51 patients (70 cycles of IVF-ET) who previously conceived in an IVF-ET cycle, and group B included 141 patients (201 cycles ofivf-et) who previously conceived in a natural cycle. All couples with male factor infertility were excluded. Ovulation induction protocol was identical for both groups and consisted of gonadotropin-releasing hormone agonist pretreatment followed by gonadotropin stimulation. Main Outcome Measures: Pregnancy rate per ET, cumulative pregnancy rate, and livebirth rate in both groups. Results: The following parameters were comparable for both groups: age, menotropin dosage required for an adequate stimulation, ovarian response, mean number of oocytes retrieved per cycle, fertilization and cleavage rates, and the mean number of embryo transferred. attained a significantly higher pregnancy rate (PR) than group B (31.4% versus 19.4%). also achieved a significantly higher livebirth rate (22.9% versus 11.4%) than group B. Similarly, the cumulative PR curves and the cumulative livebirth rate curves for three consecutive IVF-ET cycles differed significantly between the two groups. Conclusion: A previous successful IVF cycle is a positive prognostic factor for a repeated IVF attempt. This effect could be because of either an improved endometrial response or a better embryo quality. It may be that this patient population is relatively immune to the known untoward effects of ovulation induction on endometrial development and, therefore, may represent a potential clinical model that can be used to further identify the factors influencing uterine receptivity after ovulation induction. Fertil Steril1993;59:343-7 Key Words: In vitro fertilization, secondary infertility, in vitro fertilization results, cumulative pregnancy rate The overall pregnancy rate (PR) for in vitro fertilization (lvf) cycles is approximately 15% to 25% per embryo transfer (ET) (1-3). This rate is Received June 12, 1992; revised and accepted October 9, * Reprint requests: Alexander Simon, M.D., Department of Obstetrics and Gynecology Hadassah University Hospital, Post Office Box 12000, Jerusalem, Israel t Hubert H. Humphrey Center for Experimental Medicine and Cancer Research, Hadassah University Medical School, Jerusalem, Israel. still considerably lower than that calculated for a natural cycle and reflects the relatively low efficacy of assisted reproductive techniques. In many patients, ovulation induction disrupts the delicate synchronization between all factors necessary for successful implantation. Identifying subgroups of patients able to attain higher conception rates after IVF-ET is important because these patients may serve as a model for isolation and characterization of variables conducive to implantation un- Simon et al. IVF results after a previous success 343

2 der conditions of pharmacological ovarian stimulation. Several factors have been identified that influence either the success or failure rate of the IVF process. The fecundity rate for IVF cycles drops significantly after the age of forty (4, 5). Male factor is found to negatively affect IVF -ET results because of low fertilization rates causing an overall low success rate per ovum pick-up (6). The introduction of gonadotropin-releasing hormone agonists (GnRH-a) in the protocols for ovulation induction not only enables better cycle scheduling and lower cancellation rates but also improves the result for specific cycles in terms of number of oocytes retrieved, fertilization rates, and PRs (7,8). The number of embryos transferred has a direct effect on the PR in that the probability for conception improves as the number of embryos transferred increases. However, as more embryos are transferred (>4), the multiple PR increases, whereas the overall PR does not improve (9). The ovarian response to induction to ovulation is an important factor affecting IVF success rates. Plasma estradiol (E2) levels on the day of human chorionic gonadotropin (hcg) administration that were higher and then continued to rise after the injection resulted in a greater number of retrieved 00- cytes and improved follicular and luteal phases. This may, in turn, result in improved endometrial response and higher PRs (10, 11). Two additional factors that may affect PR and outcome in IVF cycles are embryo quality and uterine receptivity. The relative contribution of each of these factors is yet unclear (12). Secondary infertility has not been associated with significantly improved IVF outcome when compared with primary infertility (2, 11), suggesting that a former successful in vivo conception may not serve as a positive predictor for subsequent in vitro attempts. On the other hand, Barlow et al. (13) reported that patients who had a chemical pregnancy during their first IVF cycle had a significantly higher rate of clinical pregnancies in a repeat attempt. This study was undertaken to evaluate whether a previ- 0usly successful IVF-ET cycle is a favorable prognostic factor for a repeat attempt. MATERIALS AND METHODS All IVF cycles performed for patients with secondary infertility between April 1988 and September 1991 were retrospectively analyzed and divided into two groups. included 51 patients who un- derwent 72 IVF cycles and had a history of conceiving during a previous IVY attempt. These patients underwent a repeat IVY attempt after either a delivery, abortion, or ectopic pregnancy (EP). Group B served as a control and consisted of 141 patients who underwent 206 IVY cycles and previously conceived in a natural cycle (delivery, abortion, or EP). The inclusion of patients with dissimilar outcomes in both groups incorporate in the most reliable way the contribution of both embryo quality and uterine receptivity to PRo The cancellation rate in groups A and B were similar (2.8% and 2.4%, respectively) and enabled comparison of 70 IVF -ET cycles of group A to 201 IVF-ET cycles in group B. Ten patients (14 IVF -ET cycles) who were initially included in group B conceived and subsequently underwent another IVF attempt at which time they were assigned to group A. All couples with male factor infertility, as defined by the World Health Organization criteria (14), were excluded. All patients in the study were treated with similar ovulation induction protocol. A dose of 0.5 mg/d of the GnRH-a (Decapeptyl; Ferring Pharmaceuticals, Malmo, Sweden) was begun during the midluteal phase of the preceding cycles, and three ampules per day of human menopausal gonadotropin (hmg, Pergonal; Teva Pharmaceuticals, Ramat Gan, Israel) were added on cycle day 3. Human chorionic gonadotropin (10,000 IU, Chorigon; Teva Pharmaceuticals) was administered according to previously published criteria (15). All accessible follicles were aspirated using the transvaginal ultrasound, and all oocytes were scored for maturity. After ET, daily injections of 50 mg of progesterone (P, Geston; Paines and Byrne Limited, Greenford, United Kingdom) were administered to all women. Several parameters known to affect the IVY success rate were compared between groups A and B: age, hmg dose required for adequate stimulation, serum E2 and P levels on the day of hcg administration (day 0) and days -1 and +1, cycle day of hcg administration, number of oocytes retrieved, fertilization rate, cleavage rate, number of embryos transferred, and the clinical PRo Only clinical gestations (i.e., ultrasonographic demonstration of a gestational sac and fetal cardiac activity or products of conception on pathological examination of material from abortus or ectopic gestations) were included. Livebirths were defined as a birth after 28 weeks of gestation. All data were analyzed using a statistical package on a Vax/Vms computer. The cumulative PR and the cumulative livebirth rate were calculated ac- 344 Simon et al. IVF results after a previous success Fertility and Sterility

3 Table 1 Ovarian Response for Induction of Ovulation and Laboratory Results After Oocytes Retrieval in Groups A and B (n = 51) P (n = 141) value Age (y) Interval from last conception to current IVF-ET (y) No. of hmg ampules for an adequate response Day ofhcg 34.9 ± 0.5* 3.2 ± ± ± ± 0.3 NSt 5.8 ± 0.3 < ± 1.1 NS 14.0 ± 0.4 NS E2 (pg/ml); P (ng/ml) Day before hcg 909 ± 73; 1.0 ± ± 43; 0.9 ± 0.1 NS Day ofhcg 1,252 ± 64; 1.2 ± 0.3 1,272 ± 50; 1.2 ± 0.1 NS Day after hcg 1,357 ± 98; 3.0 ± 0.5 1,429 ± 67; 4.1 ± 0.4 NS Oocytes/patient Fertilization rate (%) Cleavage rate (%) ET/patient 7.8 ± ± ± 0.4 NS 65.6 NS 88 NS 3.4 ± 0.1 NS * Values are means ± SE. t NS, not significant. cording to the method of Berkson and Gage (16) and Olive (17). Differences between the cumulative curves were tested with the use of Mantel's (18) statistical method. Other statistical methods used comparison by ANOV A and the X2 test. Data are presented as mean ± SE. RESULTS Seventy IVF-ET cycles of patients with infertility after a previous IVF conception (group A) were compared with 201 IVF -ET cycles of patients with infertility after conception in a natural cycle (group B). The two groups did not differ in their mean age, dosage of hmg needed for an adequate ovarian response or follicular phase duration. However, the interval from last pregnancy to the current IVF treatment was significantly higher in group B (Table 1). This, in turn, reflects the lag time passed until patients in group B were referred to an IVF treatment compared with patients in group A. The later group was already diagnosed to require an IVF treatment and therefore were referred directly to another attempt when desiring another child. The ovarian response was assessed by the serum E2 and P levels on the day of heg administration (day 0) and days -1 and + 1. Estradiol levels were similar in the two groups (Table 1). Progesterone levels were also similar for both groups. The number of oocytes retrieved per cycle (7.8 ± 0.6 and 8.4 ± 0.4), fertilization rate (68.5% versus 65.6%), and cleavage rate (94% versus 88%) were similar in groups A and B, respectively (Table 1). The calculated number ofet per cycle also did not differ between the groups (3.3 ± 0.1 and 3.4 ± 0.1, respectively). A total of 22 clinical pregnancies were achieved in group A for a PR of 31.4% per ET. This rate was significantly higher (P < 0.05) than that of the control group in which 39 pregnancies were achieved, resulting in a PR of 19.4% per ET. Similarly, the livebirth rate was significantly higher (P = 0.02) in group A than in group B (22.9% and 11.4%, respectively). The better outcome in group A compared with group B was further demonstrated when the implantation rate and the ongoing implantation rate were calculated (11.9% versus 7.1% and 9.2% versus 4.5%, respectively) (Table 2). Since the PR per ET depends on the number of cycles of IVF -ET in each group, it is more accurate to calculate and compare the cumulative PR and the cumulative livebirth rate for each group. Table 3 shows the cumulative PR for three consecutive cycles of ET in the two groups. The results for both cumulative PR and the cumulative livebirth Table 2 Clinical Results After IVF-ET in Secondary Infertility Related to IVF () and Nonrelated to IVF () No. of ET cycles No. of pregnancies No. of deliveries Pregnancy/patient (%) Delivery/patient (%) Pregnancy /ET (%) Delivery/ET (%) Implantation rate (%) Ongoing implantation rate (%) (n = 51) (n = 141) P value < Simon et al. IVF results after a previous success 345

4 r rate are plotted in Figure la and B. There is a significant difference between the cumulative pregnancy curves of groups A and B for three consecutive cycles (37.3%, 42.1%, 61.4% and 21.3%, 30.9%, 49.8%, respectively) (Mantel statistic = 3.65; P = 0.05). Similarly, a significant difference is found between the cumulative livebirth curves of these two groups (25.5%, 31.2%, 54.1% and 12.1%, 19.2%, 33.9%, respectively) (Mantel statistic = 5.08; P = 0.02). DISCUSSION This study is the first to demonstrate that a previously successful IVF cycle is a positive prognostic factor for a repeat attempt. Several factors affect IVF success rate including: age (4, 5), male factor (6), GnRH-a use (7, 8), ovarian response (10, 11), and the number of embryos transferred (9). Because it has been shown that secondary infertility after natural conception does not seem to affect IVF results (2, 11), it seems that the reproductive performance of the subgroup of patients with secondary infertility after a previously successful IVF cycle (group A) is different. This is supported by the observation of Barlow et al. (13) that when a chemical pregnancy was achieved in a previous IVF attempt, a higher rate of an ongoing pregnancy is anticipated in a repeated cycle. Groups A and B had similar mean ages, ovarian responses to ovulation induction, and numbers of transferred embryos, suggesting that these variables do not account for the differences in conception rates between the groups. The improved reproductive performance of patients after a previous IVF conception may emanate either from better embryo quality or uterine receptivity. The latter is difficult to assess and seems to be indirectly dependent on ovarian stimulation (19, 20). The former is currently evaluated by criteria of embryo morphology (21, 22) and cleavage rates (23). It was demonstrated that 30% to 70% of endometrial biopsies obtained from women undergoing 60 - ~ W 50!;( ~a: 40 ->!;(o... z ::let 30 :::E Z OW ::I" 20 a: Il A B ~ W 40 W!;( >a: ~:J: ::I!!: 30 :::E 1Il ::IW 0> ::::i NUMBER OF CYCLES NUMBER OF CYCLES Figure 1 The cumulative PR (A) and livebirth rate (B) after IVF-ET in patients with secondary infertility after a previous successful IVF cycle (group A) versus natural cycle (group B). pharmacological ovulation induction and IVF were "out of phase." The exact mechanism by which this disruption of normal endometrial development occurs is unclear. It was assumed that this untoward effect was the result of either excessive endometrial stimulation by estrogen secretion or, alternatively, that it was caused by premature P secretion during the follicular phase. It may be hypothesized that women with secondary infertility after a successful Table 3 Life Table Analysis of Cumulative PR in Secondary Infertility Related (group A) and Nonrelated (group B) to IVF After IVF -ET Completing cycle Censored Pregnant Cumulative proportion pregnant Cycle Simon et al. IVF results after a previous success Fertility and Sterility

5 IVF cycle are immune to untoward endometrial side effects of ovulation induction and may, therefore, serve as a unique model for better understanding and isolating factors affecting endometrial, receptivity. More studies are needed to clarify whether improved uterine receptivity or the production of embryos with a higher capability for implantation is responsible for the better PRs in such a unique group. In summary, a previous IVF success is a positive prognostic factor for patient undergoing an IVF cycle. Therefore, it is possible to counsel a patient who previously conceived in an IVF cycle that she has an enhanced chance to conceive again in a repeat attempt. Furthermore, this patient population provides an ideal model for future studies on variables conducive to endometrial receptivity and implantation after ovulation induction. REFERENCES 1. Seppala M. The world collaborative on in vitro fertilization and embryo replacement: current state of the art in January Ann NY Acad Sci 1985;442: Fertility Society of Australia. IVF and GIFT pregnancies Australia and New Zealand Sydney: National Perinatal Statistics Unit, Medical Research International, Society for Assisted Reproductive Technology (SART), The American Fertility Society. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1990 results from the IVF-ET registry. Fertil Steril 1992;57: Romeu A, Muasher SJ, Acosta AA, Veeck LL, Diaz J, Jones GS, et al. Results of in vitro fertilization attempts in women 40 years of age and older: the Norfolk experience. Fertil Steril 1987;47: Padilla SL, Garcia JE. Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil Steril 1989;52: Acosta AA, Chillik CF, Brugo S, Ackerman S, Swanson RJ, Pleban P, et al. In vitro fertilization and the male factor. Urology 1986;28: Frydman R, Forman RG, Belaisch-AllartJ, Hazout A, Rainhorn JD, Freis N, et al. Improvements in ovarian stimulation for in vitro fertilization. Ann NY Acad Sci 1988;541: Chetkowski RJ, Kruse LR, Nass TE. Improved pregnancy outcome with the addition of leuprolide acetate to gonadotropins for in vitro fertilization. Fertil Steril 1989;52: Medical Research International and the Society for Assisted Reproductive Technology, The American Fertility Society. In vitro fertilization/embryo transfer in the United States: 1987 results from the IVF-ET registry. Fertil Steril1989;51: Laufer N, DeCherney AH, Tarlatzis BC, Naftolin F. The association between preovulatory serum 17 fi-estradiol pattern and conception in human menopausal gonadotropin-human chorionic gonadotropin stimulation. Fertil Steril 1986;46: Wood C, McMaster R, Rennie G, Trounson A, Leeton J. Factors influencing pregnancy rates following in vitro fertilization and embryo transfer. Fertil Steril1985;43: Rogers PA, Milne BJ, Trounson AO. A model to show human uterine receptivity and embryo viability following ovarian stimulation for in vitro fertilization. J In Vitro Fert Embryo Transf 1986;3: Barlow P, Lejeune B, Puissant F, Englert Y, Van Rysselberge M, Degueldre M, et al. Early pregnancy loss and obstetrical risk after in-vitro fertilization and embryo replacement. Hum Reprod 1988;3: World Health Organization. WHO Laboratory manual for the examination of human semen and semen -cervical mucus interaction. 2nd ed. Cambridge: The Press Syndicate of the University of Cambridge, Caspi E, Ron-El R, Golan A, Nachum H, Herman A, Soffer Y, et al. Results of in vitro fertilization and embryo transfer by combined long-acting gonadotropin-releasing hormone analog D-Trp-6-luteinizing hormone-releasing hormone and gonadotropins. Fertil Steril1989;51: Berkson J, Gage RP. Calculation of survival rates for cancer. Mayo Clin Proc 1950;25: Olive DL. Analysis of clinical fertility trials: a methodologic review. Fertil Steril1986;45: Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50: Paulson RJ, Sauer MV, Lobo RA. Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil Steril 1990;53: Navot D, Scott RT, Droesch K, Veeck LL, Liu H-C, Rosenwaks Z. The window of embryo transfer and the efficiency of human conception in vitro. Fertil Steril 1991;55: Veeck LL. Oocyte assessment and biological performance. Ann NY Acad Sci 1988;541: Puissant F, Van Rysselberge M, Barlow P, Deweze J, Leroy F. Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod 1987;2: Claman P, ArmantDR, Seibel MM, WangTA, Oskowitz SP, Taymor ML. The impact of embryo quality and quantity on implantation and the establishment of viable pregnancies. J In Vitro Fert Embryo Transf 1987;4: Simon et al. IVF results after a previous success 347