Riproduzione Assistita Casa di Cura Paideia. b Center for Endocrinology. and Reproductive Medicine. c Unità di Sterilità II Clinica

Transcription

1 FERTILITY AND STERILITY VOL. 81, NO. 6, JUNE 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. A controlled trial of natural cycle versus microdose gonadotropin-releasing hormone analog flare cycles in poor responders undergoing in vitro fertilization Francesco Morgia, B.S., a Marco Sbracia, M.D., b Mauro Schimberni, M.D., a,c Annalise Giallonardo, M.D., a Claudio Piscitelli, M.D., a Pierluigi Giannini, M.D., a and Cesare Aragona, M.D. a,c Bioroma Centro di Riproduzione Assistita Casa di Cura Paideia; Center for Endocrinology and Reproductive Medicine; and Unità di Sterilità II Clinica Ostetrica e Ginecologica Università La Sapienza, Rome, Italy Received December 6, 2002; revised and accepted November 11, Reprint requests: Marco Sbracia, M.D., Center for Endocrinology and Reproductive Medicine, Via Carlo Porta 10, Rome 00153, Italy (FAX ; marcandrea@hotmail.com). a Bioroma Centro di Riproduzione Assistita Casa di Cura Paideia. b Center for Endocrinology and Reproductive Medicine. c Unità di Sterilità II Clinica Ostetrica e Ginecologica Università La Sapienza /04/$30.00 doi: /j.fertnstert Objective: To determine the efficacy of natural-cycle IVF compared with controlled ovarian hyperstimulation in poor responders. Design: Randomized, controlled study. Setting: Private center for assisted reproduction. Patient(s): One hundred twenty-nine women who were poor responders in a previous IVF cycle. Intervention(s): Fifty-nine women underwent 114 attempts of natural-cycle IVF, and 70 women underwent 101 attempts of IVF with controlled ovarian hyperstimulation with microdose GnRH analog flare. Main Outcome Measure(s): Number of oocytes retrieved, pregnancy rate (PR) per cycle, PR per transfer, and implantation rate. Result(s): The poor responders treated with natural-cycle IVF and those treated with micro-gnrh analog flare showed similar PRs per cycle and per transfer. The women treated with natural-cycle IVF showed a statistically significant higher implantation rate (14.9%) compared with controls (5.5%). When subdivided into three groups according to age ( 35 years, years, 40 years), younger patients had a better PR than the other two groups. Conclusion(s): In poor responders, natural-cycle IVF is at least as effective as controlled ovarian hyperstimulation, especially in younger patients, with a better implantation rate. (Fertil Steril 2004;81: by American Society for Reproductive Medicine.) Key Words: Natural cycle, IVF, ICSI, poor responder, minidose GnRH analog flare-up Although the first pregnancy resulting from IVF was obtained in a natural (unstimulated) cycle (1), the use of unstimulated cycles in IVF has been neglected for some time, because it has been judged to be an inefficient therapy (2). The use of a GnRH analog plus gonadotropins for controlled ovarian hyperstimulation (COH) has gained widespread popularity, and better results have been achieved with this treatment, in terms of number of oocytes collected, number of embryos obtained, and pregnancy rate (PR) (3). Despite the advantages of COH in IVF, several complications have been highlighted. Ovarian hyperstimulation syndrome, which affects up to 5% 10% of IVF cycles, can be a life-threatening condition (4). Multiple gestations occur in approximately 30% of pregnancies with COH, and these can result in premature births, high perinatal morbidity, neonatal mortality, and long-term handicaps (5, 6). Furthermore, there is increased concern regarding the association between ovarian cancer and the chronic use of gonadotropins (7). For these reasons, IVF in natural cycles has gained attention recently, even for poor-responding patients (8 14), because these problems are not encountered with unstimulated cycles. Poor-responding patients are those women who in COH for IVF show poor follicle recruitment in terms of number (generally three or four follicles) or size, despite the high dose of 1542

2 gonadotropins administered, and low levels of serum E 2 peak on the day of hcg adminstration (500 1,000 pg/ml) (15). Poor responders are estimated to comprise approximately 10% of patients (16). A low response to gonadotropins is often associated with patient age, reflecting a decline in the ovarian reserve of follicles (17), and thus is seen more frequently in women aged 40, but it can also occur in young patients (18). These patients are refractory to any stimulation protocols, although many treatment strategies have been suggested, and outcomes remain poor despite the high quantity of gonadotropins administered (19). Poor responders also show lower-quality oocytes and poor pregnancy rates (PRs) (20). Several reports have suggested that performing natural-cycle IVF on these patients might be a valid alternative to egg donation and COH, in terms of costs and outcome (8, 21), but very few studies comparing naturalcycle IVF and COH in poor responders are reported in the literature. In the study reported here, we evaluated the IVF outcome in terms of PR per cycle started and per transfer in a large group of poor responders who underwent intracytoplasmic sperm injection (ICSI) with natural-cycle IVF or COH randomly. MATERIALS AND METHODS Patient Selection The study was conducted at the IVF program of the Bioroma Center, Rome, Italy, between January 2000 and July 2002 on poor-responding patients undergoing IVF. These patients had regular menstrual cycles (26 39 days) with primary infertility and poor ovarian reserve, as shown by their previous IVF outcomes. Patients included in the study were aged 43 years and had undergone a previous IVF cycle at our IVF clinic that resulted in a poor response, that is, three or fewer follicles recruited or cycle cancelled because of no follicle activation. This is our definition of a poor responder, and it agrees with that of other investigators (22); there is no generally accepted definition for poor response (23). The study was reviewed and approved by the institutional review board at the Bioroma Center. All patients undergoing IVF and participating in the study gave informed consent. All patients underwent a standard infertility evaluation, including hormonal evaluation on the 3rd day of the menstrual cycle (FSH, LH, E 2, thyroid hormones), hysteroscopy, hysterosalpingogram, complete blood examination, and semen analysis. The patients were randomized according to a computer-generated number sequence at the time that their cycle was scheduled. Patients were assigned either to natural-cycle IVF or to COH with a microdose GnRH analog flare protocol (24, 25). Patients selected for one type of treatment were not allowed to change treatment if the first IVF cycle failed. Patients refusing to be treated again with the same protocol were dropped from the study for the successive cycles. Seventy women were randomly allocated to each group; 11 women assigned to the natural-cycle group refused the randomization and chose another treatment. At the end of the study, the two groups comprised, respectively, 59 women undergoing 114 attempts with natural-cycle IVF in which no ovarian stimulation was performed, and 70 women undergoing 101 attempts of IVF with ovarian stimulation with the microdose GnRH analog flare protocol. In the patients who underwent natural-cycle IVF, from the 7th day of the cycle a daily monitoring of follicle size by transvaginal ultrasound scan was performed to measure follicular structures within the ovary and endometrial thickness and morphology. The criterion used for triggering ovulation with 10,000 IU of IM hcg (Profasi HP 5000, Serono, Italy) was a follicle 16 mm in diameter. The patients allocated to the microdose GnRH analog flare protocol group were treated with 0.05 mg buserelin (Suprefact; Hoechst, Berlin, Germany) SC twice daily from the 1st day of the menstrual cycle and 600 IU purified FSH (pfsh) (Metrodin HP, Serono, Italy) daily from the 3rd day of the menstrual cycle. From the 7th day of stimulation in these patients, daily monitoring of follicle size by ultrasound was performed, and plasma levels of E 2 were measured. From this stage, the dose of pfsh was adjusted, depending on the individual response of each patient. The criterion used for triggering ovulation with 10,000 IU of IM hcg (Profasi HP 5000) was at least two follicles 16 mm diameter. Oocyte retrieval was performed under ultrasound guidance by the transvaginal route 36 hours after injection of hcg. Either local or general anesthesia was used. Intracytoplasmic sperm injection was performed in all patients, according to published procedures (26), to obtain a higher fecundation rate, to maximize the chances of embryo transfer, given the low number of oocytes harvested in these patients, and to avoid differences in fertilization rate among patients treated with different techniques. Patients were informed of eventual risks for offspring produced by ICSI. Oocytes were examined 18 hours after ICSI for pronuclei and 44 hours after insemination for embryo development. The embryos obtained were categorized on day 2 or 3 into three categories, depending on their morphologic appearance. Grade A had equal and regular blastomeres without the presence of cytoplasm fragments; grade B had unequal blastomeres with or without cytoplasm fragments; and grade C were totally fragmented embryos, which were not transferred (27). Embryos were transferred hours after insemination with an embryo transfer catheter (H.G. Wallace, Colchester, Essex, United Kingdom). All transfer procedures were performed by the same physician to avoid interoperator variability. All pregnancies were confirmed by a rising titer of serum -hcg from 12 days after ET and ultrasound demonstration of the gestation sac 4 weeks after ET. Biochemical pregnancies alone have not been included. FERTILITY & STERILITY 1543

3 The same luteal phase support was used in both groups: 50 mg daily of P (Prontogest; AMSA, Rome, Italy) IM from the day of replacement. Statistical analysis was performed with Student s t-test or the Mann-Whitney U test for continuous variables and Fisher s exact test and 2 test for comparison of proportions when appropriate. Parameters analyzed were number of oocytes collected, number of embryos obtained, number of embryos transferred, PR (per cycle started, per embryo transfer), implantation rate (number of embryos observed by ultrasound per number of embryos transferred), and abortion rate. All statistical analyses were performed with commercial software (SPSS statistical package; SPSS, Chicago, IL). RESULTS We included in the study a total of 129 consecutive women who had a poor response in a previous IVF cycle (female age [mean SD] years, range 30 43; male age years, range years), who were randomly assigned to two groups: 59 women underwent 114 consecutive IVF cycles with a natural cycle, and 70 women underwent 101 consecutive IVF cycles with COH with a microdose GnRH flare protocol. Body mass index (kg/m 2 ) was in the natural-cycle group and in the COH group. Patients showed a similar distribution for infertility causes: tubal factor in 13 patients (22.0%) in the natural-cycle group and 16 patients (22.8%) in the COH group; male factor in 29 patients (49.1%) in the natural-cycle group and 32 patients (45.7%) in the COH group; hormonal factor in 7 patients (11.8%) in the natural-cycle group and 8 patients (11.4%) in the COH group; and sine causa in 10 patients (16.9%) in the natural-cycle group and 14 patients (20.0%) in the COH group. After a failed cycle, patients undergoing ovarian stimulation required a rest between stimulated cycles. Furthermore, they showed less compliance in following the protocols, owing to the expense of each ovarian stimulation, the amount of gonadotropins used for the stimulation, and the psychological stress related to cycle failure: only 20 patients (28.6%) in this group underwent two or more IVF cycles. Conversely, the patients in the natural-cycle group showed better compliance: 29 women (49.1%) underwent two or more IVF cycles. In the natural-cycle patients, the oocyte retrieval procedure was performed in 114 cycles, and oocytes were found in 88 of these (77.2%): in 3 cycles two oocytes were retrieved, and in 85 cycles one oocyte was recovered, for a total of 91 oocytes. In 21 cycles the oocytes were germinal vescicle or metaphase I, and ICSI was performed in 68 cycles with a total of 70 oocytes. In 11 oocytes, no fertilization or three pronuclei were observed; normal fertilization was observed in 59 oocytes (84.3%), and cleaving embryos occurred in 51 of these (86.4%). Embryo transfer was performed in 47 TABLE 1 Data of poor responders treated with natural-cycle IVF or COH. Parameters Natural cycle COH P No. of patients No. of cycles Cycles with oocytes (%) FSH administered (IU), 5,418 2,880 mean SD E 2 hcg day (pg/ml), 1, mean SD Cycles with transfer (%) NS No. of embryos NS No. of embryos/transfer, NS mean SD Pregnancy/cycle (%) NS Pregnancy/transfer (%) NS Implantation rate (%) Abortion rate (%) NS Note: NS not significant. Morgia. IVF with natural cycle in poor responders. Fertil Steril patients, and a pregnancy was observed in 7 (6.1% per cycle, 14.9% per transfer). In the COH patients, the oocyte retrieval was performed in 101 cycles, and oocytes were found in 83 cycles (82.2%). A total of 215 oocytes were recovered, with a number per retrieval of (range 0 4). In 29 cycles, the oocytes were germinal vescicle or metaphase I, and ICSI was performed on 172 oocytes in 81 cycles. In 13 oocytes, no fertilization or three pronuclei were observed. Normal fertilization was found in 159 (92.4%) oocytes, and there were 132 (83.0%) cleaving embryos in 69 cycles. Transfer of 127 embryos was performed in 69 cycles (68.3%); pregnancy was observed in 7 patients (PR per cycles 6.9%, PR per transfer 10.1%). The implantation rate was statistically significantly higher in the natural-cycle IVF group than in the COH group (14.9% vs. 5.5%; P.05). No multiple pregnancies were observed. No outcome differences were observed between patients in whom the transfer was performed on day 2 or 3. The data are reported in Table 1. Table 2 describes the data in patients, subdivided arbitrarily by patient age: patients aged 35 years showed the best performance in terms of PR per cycle, transfer, and patient, compared with women aged years and women aged 39 years in both the natural-cycle and COHtreated groups (14.6% vs. 4.2%; P.05). The other parameters were similar among the three age groups in both protocols. Table 3 describes the performance of the two protocols in the first, second, and third cycles performed in patients and in subsequent cycles. No differences were observed between the two protocols in all series of cycles. All pregnancies were 1544 Morgia et al. IVF with natural cycle in poor responders Vol. 81, No. 6, June 2004

4 TABLE 2 Data of poor responders treated with natural-cycle IVF (NC) or COH, stratified by women s age. 35 y y 40 y Parameters N C COH N C COH N C COH No. of patients No. of cycles Cycles with oocytes (%) FSH amount (IU), mean SD 5,432 2,906 5,432 2,906 5,432 2,906 E 2 /hcg day (pg/ml), mean SD 1, , , Cycles with transfer (%) No. of embryos obtained No. of embryos/transfer, mean SD Pregnancy/cycle (%) Pregnancy/transfer (%) Implantation rate (%) Abortion rate (%) Morgia. IVF with natural cycle in poor responders. Fertil Steril observed after no more than three consecutive attempts; patients who tried more than three times did not become pregnant. DISCUSSION The treatment of poor responders remains a challenge for IVF centers worldwide, despite several different protocols having been proposed for ovarian hyperstimulation in these patients to maximize the number of oocytes retrieved (23). Although there is no universally accepted definition for poor responders, a poor response to COH might occur in a significant number of women undergoing IVF, with a percentage ranging between 9% and 25% (28). Poor responders have been defined as those with a peak in E 2 concentration 500 or 1,000 pg/ml, those with less than four dominant follicles, patients aged 40 years, or with FSH levels on day 3 of the menstrual cycle 10 IU/mL (15). Poor response to COH is age-related, but it also occurs in young patients. It is generally accepted that poor responders have a reduced number of follicles remaining in the ovary, in both young and old patients (17). Their treatment is generally approached in different ways, either by different protocols using low amounts of GnRH analogs and high levels of gonadotropins, by egg donation, or by IVF in a natural cycle (23). In this study, we analyzed the outcome of 114 consecutive unstimulated IVF cycles in 59 women who were poor responders in previous IVF cycles, compared with the results TABLE 3 Data of poor responders treated with natural-cycle IVF (NC) or COH, stratified according to first, second, third or further cycle. Number of consecutive cycles Parameters N C COH N C COH N C COH N C COH No. of cycles Cycles with oocytes (%) Cycles with transfer (%) No. of embryos obtained No. of embryos/transfer, mean SD Pregnancy/cycle (%) Pregnancy/transfer (%) Implantation rate (%) Abortion rate (%) Morgia. IVF with natural cycle in poor responders. Fertil Steril FERTILITY & STERILITY 1545

5 in 101 IVF cycles in 70 poor responders treated with a microdose GnRH analog flare protocol. Our data show that IVF in a natural cycle is an affordable and valid alternative in poor responders. Although the PR per cycle was relatively low (6.1%), the PR per transfer was 14.9%. This was similar to what was observed in the stimulated patients (PR per cycle 6.9%, PR per transfer 10.1%). These results are in agreement with those reported in a recent meta-analysis of published reports (14) and in an earlier report by Daya et al. (29). These articles reported PRs per cycle and per transfer overlapping our data. However, the patients included in these reports were not only poor responders and were younger than those in our sample. However, the group of our patients treated with a natural-cycle protocol showed a better implantation rate than controls, 14.9% vs. 5.5%. This difference might be due to a better endometrial growth in the natural cycle and avoidance of the detrimental effects on the endometrium of hyperstimulation (30, 31) or a better quality of oocytes recovered in the natural-cycle patients, owing to the more physiological method of follicular development and recruitment (20, 32). An increase of abortion rate was observed in natural-cycle patients, but the numbers were too small to permit evaluation. The distribution of pregnancies and the other parameters in our group of poor responders when they were subdivided by age produced interesting data. In younger patients (aged 35 years), the PR per cycle and transfer was significantly higher than in older women, despite there being no differences per rate of oocytes found, embryos obtained, and transfers performed among the age groups. The implantation rate also was constantly higher in all age groups of naturalcycle IVF patients than in the corresponding age groups of hyperstimulated women, which confirms that in naturalcycle IVF, independently from women age, there is a better chance for the embryo to implant. Recently, it has been reported that young poor responders showing elevated basal FSH levels have low numbers of oocytes in the ovaries but of good quality, because they had a relatively good PR (22), as in our study. Our data show that in poor responders, a natural-cycle protocol is at least as effective as a microdose flare-up protocol. When the patients were subdivided by age or compared only with the first cycle, no differences were observed between the two treatments. Although the data of age subgroups can not be considered definitive owing to the small numbers, they show an interesting trend regarding the effectiveness of the natural cycle in young women (aged 35 years) when compared with the other treatment, hyperstimulation with high dosage of gonadotropins. A trend exists toward a lower chance of pregnancy with increasing age in women. In younger patients, the natural cycle (which does not require the use of expensive drugs and costs significantly less) leads to pregnancy in 35% of patients after two to three attempts, compared with 15% in COH cycles. Our data agree with those of other investigators (15, 22), who reported that younger poor responders have a better chance of becoming pregnant. In our experience, poor responders who tried a naturalcycle protocol three times maximized their chance of pregnancy; women who tried more than three times did not achieve pregnancy. Only a few of our patients attempted three times, thus this is not a definitive observation. On the other hand, the physician should limit to three attempts of natural-cycle IVF in these patients. In our study, the use of IVF with a natural-cycle protocol was a valuable alternative to COH in poor responders. In these patients, natural-cycle IVF is at least as effective as COH, especially in younger patients, with a better implantation rate. This alternative should be proposed to poor responders, because the natural cycle is cheaper than hyperstimulation and permits a more friendly approach to IVF with results comparable to those with COH, at least in these patients. References 1. Steptoe PG, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978;2: Claman P, Domingo M, Garner P, Leader A, Spence JE. Natural cycle in vitro fertilization-embryo transfer at the University of Ottawa: an inefficient therapy for tubal infertility. Fertil Steril 1993;60: Hughes EG, Fedorkow DM, Daya S, Sagle MA, Van de Koppel P, Collins JA. The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials. Fertil Steril 1992;58: Elchalal U, Schenker JG. The pathophysiology of ovarian hyperstimulation syndrome views and ideas. Hum Reprod 1997;12: Bergh T, Ericson A, Hillensjo T, Nygren KG, Wennerholm UB. Deliveries and children born after in-vitro fertilisation in Sweden : a retrospective cohort study. Lancet 1999;354: Elster N. Less is more: the risks of multiple births. The Institute for Science, Law, and Technology Working Group on Reproductive Technology. Fertil Steril 2000;74: Duckitt K, Templeton AA. Cancer in women with infertility. Curr Opin Obstet Gynecol 1998;10: Bassil S, Godin PA, Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders. Hum Reprod 1999;14: Rongieres-Bertrand C, Olivennes F, Righini C, Fanchin R, Taieb J, Hamamah S, et al. Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation. Hum Reprod 1999;14: Janssens RM, Lambalk CB, Vermeiden JP, Schats R, Schoemaker J. In-vitro fertilization in a spontaneous cycle: easy, cheap and realistic. Hum Reprod 2000;15: Nargund G, Waterstone J, Bland J, Philips Z, Parsons J, Campbell S. Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Hum Reprod 2001;16: Ng EH, Chui DK, Tang OS, Lau EY, Yeung WS, Chung HP. In vitro fertilization and embryo transfer during natural cycles. J Reprod Med 2001;46: Omland AK, Fedorcsak P, Storeng R, Dale PO, Abyholm T, Tanbo T. Natural cycle IVF in unexplained, endometriosis-associated and tubal factor infertility. Hum Reprod 2001;16: Pelinck MJ, Hoek A, Simons AH, Heineman MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod Update 2002;8: Hanoch J, Lavy Y, Holzer H, Hurwitz A, Simon A, Revel A, et al. Young low responders protected from untoward effects of reduced ovarian response. Fertil Steril 1998;69: Pellicer A, Lightman A, Diamond MP, Russell JB, DeCherney AH. Outcome of in vitro fertilization in women with low response to ovarian stimulation. Fertil Steril 1987;47: Pellicer A, Ballester MJ, Serrano MD, Mir A, Serra-Serra V, Remohi J, et al. Aetiological factors involved in the low response to gonadotro Morgia et al. IVF with natural cycle in poor responders Vol. 81, No. 6, June 2004

6 phins in infertile women with normal basal serum follicle stimulating hormone levels. Hum Reprod 1994;9: Jacobs SL, Metzger DA, Dodson WC, Haney AF. Effect of age on response to human menopausal gonadotropin stimulation. J Clin Endocrinol Metab 1990;71: Karande V, Gleicher N. The diameter of the proximal tube large enough for a single sperm or do you need more? Fertil Steril 1999;72: Jenkins JM, Davies DW, Devonport H, Anthony FW, Gadd SC, Watson RH, et al. Comparison of poor responders with good responders using a standard buserelin/human menopausal gonadotrophin regime for in-vitro fertilization. Hum Reprod 1991;6: Janssens RM, Lambalk CB, Schats R, Schoemaker J. Successful invitro fertilization in a natural cycle after four previously failed attempts in stimulated cycles: case report. Hum Reprod 1999;14: van Rooij IAJ, Bancsi LF, Broekmans FJ, Looman CW, Habberna JD, te Velde ER. Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertlization. Fertil Steril 2003;79: Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 2000;73: Scott RT, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril 1994;61: Schoolcraft W, Schlenker T, Gee M, Stevens J, Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol. Fertil Steril 1997;67: Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992;340: Veeck LL. Fertilization and early embryonic development. Curr Opin Obstet Gynecol 1992;4: Keay SD, Liversedge NH, Mathur RS, Jenkins JM. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol 1997;104: Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA, YoungLai EV. Natural cycles for in-vitro fertilization: cost-effectiveness analysis and factors influencing outcome. Hum Reprod 1995;10: Paulson RJ, Sauer M, Lobo RA. Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil Steril 1990;53: Simon C, Cano F, Valbuena D, Remohi J, Pellicer A. Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients. Hum Reprod 1995;10: Fauser BC, Devroey P, Yen SS, Gosden R, Crowley WF Jr, Baird DT, et al. Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum Reprod 1999;14: FERTILITY & STERILITY 1547