The effects of prior gravidity on the outcomes of ovum donor and own oocyte cycles

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1 FERTILITY AND STERILITY Vol. 65, No.3, March 1996 Copyright t';, 1996 American Society for Reproductive Medicine Printed on acid-free paper in U. s. A. The effects of prior gravidity on the outcomes of ovum donor and own oocyte cycles Michael C. Darder, M.D. *t Yakov M. Epstein, Ph.D.:!: Susan L. Treiser, M.D., Ph.D.t Cynthia E. Comito, M.L.T.t Helane S. Rosenberg, Ph.D. Larisa Dzingala, B.A.II IVF New Jersey, Somerset, and Rutgers The State University, New Brunswick, New Jersey Objective: To determine the effects of prior gravidity on hormonal parameters, medication regimen, oocyte parameters, fertilization, and clinical pregnancy rates (PRs) in donor and own oocyte cycles. Design: A retrospective study of 64 first-attempt ovum donor cycles and 102 first-attempt IVF and ZIFT cycles using own oocytes conducted during a 2.5-year time period. Analyses of covariance and t-tests using gravidity of oocyte source (gravida versus nulligravida) and controlling for sperm parameters were used to assess differences in hormonal, endometrial, medication, and demographic parameters and were performed separately for donor cycles and for own oocyte cycles. Setting: Private fertility center. Patients: In ovum donation cycles, oocyte parameters, medication administered, and hormonal parameters of 64 oocyte donors between the ages of 21 and 35, 34 of whom were never pregnant, i.e., nulligravida and 30 who had ever been pregnant, regardless of the outcome of that pregnancy, i.e., gravida, were studied. In own oocyte cycles, oocyte parameters, medication administered, and hormonal parameters of 102 women, 54 nulligravida and 48 gravida, between the ages of 23 and 44 were studied. Main Outcome Measure: Medication requirements, hormonal response, seminal parameters, oocyte quality, fertilization, and clinical PRs. Results: For patients using their own oocytes, there were no significant differences in any of the parameters studied. In contrast, compared with their nulligravida counterparts, gravida oocyte donors had fewer poor quality oocytes, had more high quality oocytes that fertilized, had a higher proportion of their oocytes fertilize, and had a higher PR per transfer. Conclusion: A prior history of gravidity is an important predictor of clinical pregnancy in donor oocyte cycles but not in cycles in which patients use their own oocytes. Oocyte recipients may wish to consider donor gravidity in selecting their donor. Fertil Steril 1996;65: Key Words: Oocyte donor, gravidity, clinical pregnancy Received January 12, 1995; revised and accepted October 6, * IVF New Jersey. t Reprint requests: Michael C. Darder, M.D., IVF New Jersey, 1527 Highway 27, Somerset, New Jersey (FAX: ). :j: Center for Mathematics, Science, and Computer Education, Rutgers-The State University. Department of Learning and Teaching, Graduate School of Education, Rutgers-The State University. IICenter for Advanced Biotechnology and Medicine, Rutgers-The State University. Oocyte donation, a relatively new procedure for treating human infertility among agonadal women (1, 2) and women with age-related ovarian dysfunction, has increased dramatically in recent years (3, 4). Prospective recipients select either a known donor who may be a relative, friend, or a paid volunteer, or an anonymous donor. Programs establish criteria for screening potential donors (4) and exclude those who are psychologically unsuitable on the basis of evidence provided by personality tests or clinical interviews or have adverse medical conditions such as active smoking, obesity, human immunodeficiency virus, sexually transmitted diseases, irregular Papanicolaou smears, drug or alcohol problems, genetically transmittable disorders, and elevated early follicular (day 3) FSH levels. Studies investigating correlates of successful cycle outcomes have focused on recipient's endometrial characteris- 578 Darder et al. Gravidity affects oocyte donor cycle outcomes Fertility and Sterility

2 tics (5-7), recipient's prior gravidity (8, 9), recipient's age (7, 10), donor's age (2, 7, 11), donor's prior gravidity (2), and number of embryos transferred (2, 7, 12). Studies investigating the effects of a donor's prior gravidity (2, 13) found that prior donor gravidity made no difference in cycle pregnancy rate (PR). The present study investigates prior gravidity as well as a combination of demographic, hormonal, seminal, and embryologic variables as contributors to the outcomes of donor oocyte cycles and compares them with the outcomes of cycles for patients using their own oocytes. MATERIALS AND METHODS Between October 1991 and May 1994, IVF New Jersey conducted 85 ovum donor cycles involving 76 donors and 64 recipients. Included in the cohort of ovum donor cycles were instances in which a recipient had an unsuccessful cycle and attempted a subsequent cycle with a new donor. Additionally, there were several cycles in which a donor was used for a second time with a new recipient. For our research, we analyzed 64 ovum donor cycles involving only first-time recipients and first-time ovum donors. Indications for recipient status were classified into four categories: perimenopausal (n = 24), menopausal (n = 16), premature ovarian failure (n = 5), and poor oocyte quality (n = 19). Also during the time period between October 1991 and May 1994, 128 IVF and ZIFT cycles were performed in patients using their own oocytes. Some of these cycles involved women who had a failed initial cycle and attempted a subsequent IVF or ZIFT cycle. For our research we used only the first-time cycles of 102 patients using their own oocytes. Of the 64 donor cycles, 33 involved nulligravida college students, 10 involved gravida college students, 1 involved a nulligravida member of the general community, and 20 involved gravida members of the general community. The 64 donor cycles consisted of 52 IVF cycles involving 28 nulligravida and 24 gravida donors and 12 ZIFT cycles involving 6 nulligravida and 6 gravida donors. There were no significant differences in the proportions of nulligravida and gravida donors whose recipients participated in IVF and ZIFT cycles. The 102 cycles in which patients used their own oocytes consisted of76 IVF cycles involving 38 nulligravida and 38 gravida women and 26 ZIFT cycles involving 16 nulligravida and 10 gravida women. There were no significant differences in the proportions of nulligravida and gravida women participating in IVF and ZIFT cycles. Thus, for purposes of analysis, IVF and ZIFT cycles were used together in analyses. Patients using their own oocytes and ovum donors were treated with a down-regulation protocol. The protocol consisted of starting the patient in the midluteal phase of the cycle preceding the ovum pickup with leuprolide acetate (LA, Lupron; TAP Pharmaceutical, IL) 1 or 0.5 mg/d SC. A baseline ultrasound and serum E2 level were obtained after the ensuing menses. Ifthe pituitary was not suppressed or if there was evidence of a large ovarian cyst (i.e., >30-mm average diameter), LA was continued for approximately another week until pituitary suppression and cyst resolution were observed. At this time a combination of hmg (Pergonal; Serono, Randolph, MA) and FSH (Metrodin; Serono) was administered for approximately 7 to 10 days. The initial dose of hmg and/or FSH was determined by a day 3 FSH level and/or prior stimulation cycles. Follicular growth was monitored by E2levels and vaginal ultrasounds. Human chorionic gonadotropin (Profasi; Serono Laboratories, Inc.) was administered when at least two of the largest follicles reached a mean diameter of 16 to 18 mm. Transvaginal ovum aspiration was scheduled for 34 to 36 hours after hcg administration. In all cases, 10,000 IV of hcg was used. Transfer of the embryos was performed either 2 or 3 days after the transvaginal aspiration. Progesterone (100 mg 1M) injections were used for luteal phase support unless the patient had confirmed sensitivity to 1M progesterone. In that situation, vaginal suppositories were substituted. A pregnancy test was performed 12 days after transfer. A clinical pregnancy was defined as sonographic visualization of an intrauterine gestational sac. For ovum donor cycles, recipients were synchronized to the donor cycle by beginning oral micronized estradiol (Estrace; Mead Johnson, Princeton, NJ) or estradiol valerate (Delestrogen; Squibb, Princeton, NJ) approximately 5 to 7 days before the donor initiating hmg therapy. For women who were not menopausal, LA was started either on day 21 or on day 2 of the cycle until pituitary suppression was observed. They were then kept on the LA until they were ready to start on the E2 valerate, which was administered 1M twice weekly for an average of 2.5 to 3 weeks. The recipient began P 100 mg 1M starting on the day of the donor's retrieval (designated as day 15 of the recipient's cycle). Zygote transfer was performed laparoscopically on day 16. Embryo transfer was performed on day 17 or 18. Estradiol valerate was continued throughout the luteal phase on a twice weekly basis, and P was continued on a daily basis. A pregnancy test was performed approximately 12 days after ET. A clinical pregnancy was indicated by so no graphic visualization of an intrauterine gestational sac 4 weeks after ovum retrieval. Grading of oocytes was based on the maturity of the oocyte cumulus complex. Oocytes were graded Vol. 65, No.3, March 1996 Darder et al. Gravidity affects oocyte donor cycle outcomes 579

3 Table 1 Comparison of Endometrial, Seminal, Medication, Hormonal, Embryologic, and Fertilization Parameters, and Outcomes for Gravida and Nulligravida Oocyte Donors* Nulligravida Gravida (n = 34) (n = 30) P Endometrial thickness (mm) Medication variables No. of ampules hmg No. ampules FSH No. of days taking medication Hormonal variables Peak E2 (pg/ml):j: P on day of hcg (ng/ml) Day 3 FSH (miu/ml) Seminal variables Concentration pre-percoll (x 10 6 /ml) Motility pre-percoll (% motile) Oocyte quality variables No. of grade 3 oocytes No. of grade 4 oocytes No. of grade 5 oocytes Fertilization variables No. of grade 4 oocytes fertilized No. of grade 5 oocytes fertilized Proportion of oocytes that fertilized No. of embryos No. of embryos cryopreserved Unadjusted PR per transfer (%) PR per transfer adjusted for day 3 FSH and sperm parameters (%) Implantation rate per transfer * Values are means:!: SD. t NS, not significant :!: :!: 2.44 NSt :!: :!: 5.86 NS 9.23 :!: :!: 8.33 NS 8.35 :!: :!: 1.61 NS 1, :!: , :!: NS 1.04 :!: :!:.35 NS :!: :!: 3.72 NS :!: :!: NS :!: :!: NS 2.35 :!: :!: :!: :!: 4.92 NS 8.50 :!: :!: 5.42 NS 2.08 :!: :!: 2.47 NS 3.98 :!: :!: :!: :!: :!: :!: :!: :!: 4.09 NS 33 :!: 48 57:!: :!: 45 56:!: :!: :!:.19 NS :j: Conversion factors to SI units are as follows: E2, 3.671; hcg and FSH, Adjusted for day 3 FSH and sperm motility and concentration. on a five-point scale that used a slight modification of the classification system specified by Osborne (14). Oocyte grading was performed by either of two embryologists. Agreement between embryologists on a sample of oocytes graded was 90%. Data analyses were conducted using the SPSS for Windows data analysis system version 6.1 (SPSS Inc., Chicago, IL). Analyses of variance and covariance and t-tests were used to calculate various parameters as appropriate. Separate analyses were performed for donor oocyte cycles and for cycles in which patients used their own oocytes. RESULTS Nulligravida donors were significantly younger than gravida donors (22.3 versus 25.8 years, P < 0.001). Nulligravida women using their own 00- cytes did not differ in age from gravida women using their own oocytes (34.1 versus 34.8 years, respectively). Women using their own oocytes were significantly older than oocyte donors. Nulligravida women using their own oocytes were 34.1 years of age compared with donors who were 22.3 (P < 0.001). Similarly, gravida women using their own oocytes were 34.8 years of age compared with gravida donors who were 25.8 (P < 0.001). Table 1 contains the means and SDs for hormonal and embryologic variables for gravida and nulligravida oocyte donor cycles. There were no significant differences in the amounts of hmg and FSH administered to nulligravida compared with gravida donors. Additionally, nulligravida donors did not differ from gravida donors in their day 3 FSH levels. Also, these two groups did not differ in the peak E2 or P levels they attained. Both groups produced an equal number of oocytes. Endometrial thickness was comparable in both groups. However, nulligravida donors produce significantly more poor quality oocytes (2.35 versus 1.43, P < 0.05). To investigate fertilization differences between these groups, we used analyses of covariance that controlled for donor day 3 FSH and for semen volume and concentration. Gravida donors had significantly more high quality oocytes that fertilized (5.98 versus 3.98, P = 0.05), had a significantly larger proportion oftheir oocytes fertilize (0.61 versus 0.45, P = 0.04), and produced significantly more embryos (9.1 versus 6.4, P = 0.03). Unadjusted PRs (per transfer) of gravida donors were significantly higher than those for nulligravida donors (57% versus 33%, P = 0.05.) When covariance analyses that controlled for day 3 FSH and sperm parameters were performed, gravida donors still had significantly higher PRs per transfer (56% versus 27%, P = 0.04). 580 Darder et al. Gravidity affects oocyte donor cycle outcomes Fertility and Sterility

4 Table 2 Comparison of Endometrial, Seminal, Medication, Hormonal, Embryologic, and Fertilization Parameters, and Outcomes for Gravida and Nulligravida Patients Using Own Oocytes* Nulligravida Gravida (n = 54) (n = 48) P Endometrial thickness (mm) Medication variables No. of ampules hmg No. of ampules FSH No. of days taking medication Hormonal variables Peak E2 (pg/ml):j: P on day of hcg (ng/ml):j: Day 3 FSH (miu/ml):j: Seminal variables Concentration pre-percoll (x 106/mL) Motility pre-percoll (% motile) Oocyte quality variables No. of grade 3 oocytes No. of grade 400cytes No. of grade 5 oocytes Fertilization variables No. of grade 4 oocytes fertilized No. of grade 5 oocytes fertilized Proportion of oocytes that fertilized No. of embryos No. of embryos cryopreserved Unadjusted PR per transfer (%) PR per transfer adjusted for day 3 FSH and sperm parameters (%) Implantation rate per transfer * Values are means:+: SD. t NS, not significant :+: :+: 2.39 NS :+: :+: 7.78 NS :+: :+: NS 8.98 :+: :+: 1.22 NS 1, :+: , :+: 1, NS 1.00 :+: :+:.30 NS 12.77:+: :+: 3.78 NS :+: :+: NS :+: :+: NS 2.30 :+: :+: 2.79 NS 5.06 :+: :+: 3.29 NS 5.35 :+: :+: 7.16 NS 2.58 :+: :+: 2.66 NS 3.36 :+: :+: 6.06 NS.46 :+:.30.46:+:.30 NS 5.61 :+: :+: 7.02 NS 2.41 :+: :+: 5.71 NS 24 :+: :+: 48 NS 24 :+: :+: 47 NS.08:+:.20.13:+:.24 NS :j: Conversion factors to SI units are as follows: E2, 3.071; hcg and FSH, Adjusted for day 3 FSH and sperm motility and concentration. Table 2 contains the means and SDs for hormonal and embryologic variables for gravida and nulligravida cycles of patients using their own oocytes. Examination of Table 2 reveals that there were no significant differences between nulligravida and gravida patients on any of the variables examined. DISCUSSION Previous studies that investigated prior gravidity of women using their own oocytes (2, 13) found that prior gravidity is not associated with increased PRs. One of those studies (13) involved the use of donor sperm. The results of our investigation of women using their own oocytes are consistent with the findings of these studies. In contrast, our investigation of oocyte donors revealed that gravida donors had a significantly higher PR than nulligravida oocyte donors. The only other study investigating gravidity of oocyte donors (2) found that PR did not differ as a function of gravida: donors with proven fertility had a 51% PR compared with 46% for donors with no proven fertility. Clearly, more research on this question is needed. In the present investigation, donors were significantly younger than women using their own oocytes. This difference in age may explain why gravidity was associated with better fertilization and a higher PR for donors but not for women using their own oocytes. A few possibilities for the significantly higher PRs among gravida than nulligravida oocyte donors in the present investigation came to mind. First, whereas gravida donors have proven fertility, the nulligravida donors represent a group in which the fertility potential is unknown. Within this group it can be expected that some proportion will experience decreased fertility that may be related to ovum quality. Second, gravida donors may be drawn from a population of highly fertile individuals, and their gravidity is a marker for this higher fertility. Supporting this theory is the fact that a large number of gravida donors reported that the ease of which they conceived their own children was a major determinant in deciding to become an ovum donor. Finally, the pregnancy experience may induce some sort of change in the oocytes that increases the likelihood of a pregnancy. We are unaware of any investigations that would support this concept. The significantly higher PR for gravida donors has implications for recipient selection of donors. Many recipients inform the ovum donor coordinator in our practice that they would prefer the youngest possible donor and would prefer a college student as their Vol. 65, No.3, March 1996 Darder et al. Gravidity affects oocyte donor cycle outcomes 581

5 donor, and these donors are often nulligravida. When counseling these and other patients regarding the choice of an ovum donor, it may be advisable to indicate that a gravida donor may improve their probability of conceiving. Acknowledgments. The authors thank Richard Bodine, B.A., and Rebeccah Velasquez, B.A., for their technical assistance. REFERENCES 1. Bergh PA, Navot D. Oocyte donation-extending a woman's reproductive life span. Assist Reprod Rev 1992;3: Rotsztejn DA, Ord T, Balmaceda J, Asch R. Variables which influence the selection of an oocyte donor. Hum Reprod 1992; 7: Braverman AM, Ovum Donor Task Force of the Psychological Special Interests Group of The American Fertility Society. Survey results on the current practice of ovum donation. Fertil Steril 1993;59: Sauer MV, Paulson RJ. Understanding the current status of oocyte donation in the United States: what's really going on out there? Fertil Steril 1992;58: Check JH, Nowroozi K, Choe J, Lurie D, Dietterich C. The effect of endometrial thickness and echo pattern on in vitro fertilization outcome in donor oocyte-embryo transfer cycle. Fertil SteriI1993;59: Levran D, Ben-Shlomo I, Dor J, Ben-Rafael Z, Nebel L, Mashiach S. Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model. Fertil Steril 1991;56: Antinori S, Versaci C, Hossein G, Panci C, Caffa B. Oocyte donation in menopausal women. Hum Reprod 1993;8: Burton G, Abdalla HI, Kirkland A, Studd JWW. The role of oocyte donation in women who are unsuccessful with in-vitro fertilization treatment. Hum Reprod 1992; 7: Navot D, Drews MR, Bergh PA,Guzman I, KarstaedtA, Scott RT Jr, et al. Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation. Fertil Steril 1994; 61: Flamingi C, Borini A, Violini F, Bianchi L, Serrao L. Oocyte donation: comparison between recipients from different age groups. Hum Reprod 1993;8: Meldrum DR. Female reproductive aging-ovarian and uterine factors. Fertil Steril 1993;59: Pados G, Camus M, Van Waesberghe L, Liebaers I, Van Steirteghem A, Devroey P. Oocyte and embryo donation: evaluation of 412 consecutive trials. Hum Reprod 1992;7: Shenfield F, Doyle P, Valentine A, Steele SJ, Tan SL. Effects of age, gravidity and male infertility status on cumulative conception rates following artificial insemination with cryopreserved donor semen: analysis of 2998 cycles of treatment in one centre over 10 years. Hum Reprod 1993;8: Osborne J. Oocyte retrieval and maturation. In: Trounson A, Gardner DK, editors. Handbook of in vitro fertilization. Boca Raton:CRC Press, 1993: Darder et al. Gravidity affects oocyte donor cycle outcomes Fertility and Sterility