In-vitro fertilization in a spontaneous cycle: easy, cheap and realistic

Transcription

1 Human Reproduction vol.15 no.2 pp , 2000 In-vitro fertilization in a spontaneous cycle: easy, cheap and realistic R.M.J.Janssens 1, C.B.Lambalk, J.P.W.Vermeiden, a decrease in endometrial receptivity (Paulson et al., 1990), R.Schats and J.Schoemaker possibly an increased risk of developing ovarian cancer (Tarlatzis et al., 1995), legal and ethical problems about surplus Institute for Endocrinology, Reproduction and Metabolism, IVF Center, Vrije Universiteit Medical Center, Amsterdam, The embryos and an increase in costs (Daya et al., 1995). These Netherlands problems are not encountered when IVF is performed in a 1 natural cycle. On the other hand, NIVF meets other problems To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, IVF Center, PO Box 7057, such as an increased risk of cancellation of the attempt due to 1007 MB Amsterdam, The Netherlands a luteinizing hormone (LH) surge (Claman et al., 1993), poor follicle development (Svalander et al., 1991), no oocyte during The results of in-vitro fertilization in natural cycles (NIVF) oocyte retrieval, no fertilization or polyspermic fertilization in women with tubal infertility at our department are with no embryo transfer as a consequence (Lenton et al., 1993) presented. The study had a prospective design. We needed and a considerably lower pregnancy rate per started cycle 75 cycles in 50 patients to obtain one oocyte from each versus SIVF (Paulson et al., 1992). Nevertheless, there is a patient. Successful oocyte recovery rate was 67% per rising interest in NIVF among patients. It feels more comfortstarted cycle and 82% per oocyte retrieval. Thirty-five able to the patient and the physical burden of NIVF is perceived embryos were transferred and resulted in four ongoing to be much lower than that of SIVF. pregnancies (5.3% per cycle, 6.5% per oocyte retrieval, In this report we present our experience with NIVF and the 11.4% per embryo transfer and 11.4% per embryo). Six results from a selected group of 50 patients who underwent, patients who participated in the study made a second in total, 75 monitored natural IVF cycles. attempt at NIVF. Five of them conceived of which four were ongoing. Cumulative ongoing pregnancy rates are 9.8% per cycle, 11.9% per oocyte retrieval, 19.5% per Materials and methods embryo transfer and 19.5% per embryo. We conclude that Patients NIVF is an easy, cheap and realistic method to obtain a Fifty patients, aged between 22 and 38 years and with a history of pregnancy for patients with tubal infertility. secondary tubal infertility, underwent in total 75 cycles of NIVF at Key words: HCG/IVF/natural cycle/pregnancy rates our department. The patients were offered a free treatment, as at that time we had no experience with NIVF. All patients had a regular ovulatory cycle between 24 and 35 days. This was confirmed by at least three biphasic basal body temperature charts prior to the Introduction treatment cycle and an endometrial biopsy, taken in a previous cycle which was in-phase with the cycle day according to the criteria During the last two decades, in-vitro fertilization (IVF) described by Noyes et al. (1950) (Claman et al., 1993). Hysterohas become a standard treatment and is offered to most salpingography, laparoscopy and/or laparotomy defined the tubal patients who fail to conceive with other assisted reproduction status as the cause of infertility. Patients with a history of tubal techniques. The first successful IVF treatment was performed ligation were also eligible for the study. Couples with a second factor in an infertile woman with tubal factor infertility and occurred besides the tubal factor were excluded from the study. The protocol in a natural cycle (Steptoe and Edwards, 1980). During the was approved by the Ethical Committee on Research with Human years following this success could not be repeated by other Subjects of the Vrije Universiteit Medical Center and all couples groups (Johnston et al., 1981; Jones et al., 1982) and IVF in participating in the study signed an informed consent. a natural cycle (NIVF) was soon replaced by IVF cycles in which ovarian stimulation was applied (SIVF). Initially Treatment protocol relatively cheap and simple stimulation therapy such as All patients underwent a baseline ultrasound scan on day 2 of their clomiphene citrate was used. This has progressively been cycle to exclude ovarian cysts, and a blood sample was drawn to determine baseline follicle stimulating hormone (FSH) value replaced by more sophisticated and expensive protocols (MacDougall et al., 1994). Patients with FSH value 10 U/l were involving gonadotrophin-releasing hormone (GnRH) agonist excluded from the study (Claman et al., 1993) because of a reduced or antagonist in combination with gonadotrophins and luteal chance to obtain an oocyte in a natural cycle in this group (Lenton support. The consequences of ovarian stimulation in IVF et al., 1992). Serial transvaginal ultrasound and serum 17β-oestradiol are well known. They include the occurrence of multiple plus LH concentration determinations were started on day 8 or 10, pregnancies (Rizk et al., 1991; American Fertility Society, depending on the length of the cycle. Patients came to the hospital 1994), ovarian hyperstimulation syndrome (Rizk et al., 1992), between and Follicular diameter was established by 314 European Society of Human Reproduction and Embryology

2 IVF for spontaneous cycles calculating the mean value of the two largest measurements perpendic- cancelled when the morning serum LH value was 15 U/l. Vaginal ular to each other. Subsequently, patients were seen every other day oocyte retrieval was scheduled 35 h after HCG administration. Oocyte until the leading follicle reached a diameter 13 mm. From then on retrieval could be performed on any day of the week as our centre patients came in daily for an ultrasound, oestradiol and LH. When offers a 7 days per week service. Every oocyte retrieval was performed the follicular diameter was 18 mm and the morning serum LH by one of the authors (R.J.). Most patients refused pre-medication, value was 15 U/l (Scarduelli et al., 1994), ovulation was triggered but if preferred they received 7.5 mg Dormicum per os and/or 50 mg between and h on that day with IU human Pethidine i.m. A single lumen aspiration needle was used. The chorionic gonadotrophin (HCG) (Profasi; Serono, Den Haag, The aspiration pressure was 100 to 300 mm Hg according to standard Netherlands) (Paulson et al., 1994; Daya et al., 1995). The cycle was procedure. Only the dominant follicle was aspirated as it was necessary to keep the procedure as short and painless as possible. Furthermore, it has been shown that all pregnancies occurred in the cycles in which Table I. Results of 75 natural in-vitro fertilization cycles the embryo was derived from the dominant oocyte (Paulson et al., n % 1992) and no NIVF studies report multiple pregnancies after combined embryo transfer of embryos derived from dominant and secondary oocytes. Cancelled/ovulated 14 The oocyte was inseminated 3 h after oocyte retrieval with % per cycle 18.6 motile spermatozoa prepared by Percoll technique with a 40/90 gradi- Attempted oocyte retrieval 61 ent. Fertilization was judged the next morning and where cleavage had % per cycle 81.3 been achieved the transfer of a single embryo was performed 48 h Successful oocyte retrieval 50 % per cycle 66.6 after oocyte retrieval using an MDT catheter (International Medical, % per oocyte retrieval 82.0 Zutplein, The Netherlands). The embryo was deposited ~1 cm below Fertilization 44 the uterine fundus in 20 µl of culture medium. No treatment was given % per cycle 58.6 to support the luteal phase as all patients had an endometrial biopsy % per oocyte retrieval 72.1 Transferable embryos 35 in-phase. If the cycle was cancelled before oocyte retrieval or if no % per cycle 46.6 oocyte was obtained during oocyte retrieval, the patient was able to % per oocyte retrieval 57.3 start a new attempt in the next cycle. We continued the protocol until % per oocyte 70.0 we had retrieved at least one oocyte from each of 50 different patients. Pregnancies 7 % per cycle 9.3 All patients who had an embryo transfer came for a pregnancy test % per oocyte retrieval 11.5 on the 15th day after oocyte retrieval according to our standard % per oocyte 14.0 protocol. The mean period of the luteal phase was 13 days (range % per embryo transfer ). Pregnancy was confirmed on the basis of early testing for Ongoing pregnancies 4 HCG on day 15 after oocyte retrieval and by ultrasonic evidence of % per cycle 5.3 % per oocyte retrieval 6.5 a gestational sac. % per oocyte 8.0 % per embryo transfer 11.4 Ultrasound All ultrasounds were performed vaginally by one of the authors (R.J.) using Toshiba ultrasound equipment (Tosbee, Woerden, The Netherlands; Model SSA-240A, probe 5 Mhz model PVE-528V). Table II. Cumulative results of 81 natural in-vitro fertilization cycles Ultrasound guidance was used in all cases for oocyte retrieval. n % Serum assays FSH and LH were measured by using immunometric assays in Cycles 81 commercially available kits (Amerlite; Amersham, UK). For Cancelled/ovulated 14 % per cycle 17.3 measuring concentrations of oestradiol we used a commercially Attempted oocyte retrieval 67 available competitive immunoassay (Amerlite). Intra- and interassay % per cycle 82.7 coefficients of variation were 6 9% for FSH, 5 10% for LH and Successful oocyte retrieval 56 % per cycle % for oestradiol. % per oocyte retrieval 83.6 Fertilization 50 % per cycle 61.7 Results % per oocyte retrieval 74.6 To obtain one oocyte from each of 50 different patients we Transferable embryos 41 % per cycle 50.6 needed a total of 75 NIVF cycles. In 33 patients the oocyte % per oocyte retrieval 61.2 was obtained in the first cycle, 11 patients needed two, % per oocyte 73.2 four patients three and two patients needed four consecutive Pregnancies 12 % per cycle 14.8 attempts before the oocyte was obtained. In seven cases the % per oocyte retrieval 17.9 treatment was cancelled because LH 15 U/l on the morning % per oocyte 21.4 of the last check. Six patients ovulated between the HCG % per embryo transfer 29.3 Ongoing pregnancies 8 trigger and the planned oocyte retrieval despite the fact that % per cycle 9.8 no raised LH value had been detected. One patient did not % per oocyte retrieval 11.9 come in for oocyte retrieval because of personal problems and % per oocyte 14.3 % per embryo transfer times oocyte retrieval was performed but no oocyte was obtained. Therefore, we had a successful oocyte recovery per 315

3 R.M.J.Janssens et al. started cycle of 66.6% and per performed oocyte retrieval of 82.0%. There was no difference in the oestradiol concentrations on the day of the HCG trigger between the cycles in which the oocyte was obtained ( pmol/l) or was not obtained ( pmol/l). Those 50 oocytes resulted in 35 embryos suitable for transfer (46.6% per cycle, 57.3% per oocyte retrieval, 70.0% per oocyte). In six cases no fertilization occurred, seven times there was polyspermic fertilization and two normally fertilized oocytes did not cleave. The 35 embryos transferred resulted in seven pregnancies (9.3% per cycle, 11.5% per oocyte retrieval, 14.0% per oocyte, 20.0% per embryo transfer) of which two were biochemical, one resulted in a spontaneous abortion and four were ongoing (5.3% per cycle, 6.5% per oocyte retrieval, 8% per oocyte, 11.4% per embryo transfer and per embryo) and resulted in the term birth of a healthy child. A summary of the results is given in Table I. Repeated cycles of NIVF A small number of patients (n 6) who participated in the study chose to have a second NIVF. This was either because they had no embryo transfer in the first attempt due to polyspermic fertilization (n 1), because they conceived in the first cycle and had a miscarriage (n 1), or because they failed to conceive in the first attempt and wanted to try again for their own account (n 4). From each of those six patients, an oocyte was obtained during the second attempt. All those six oocytes were fertilized and an embryo transfer was performed. Five patients conceived in this second attempt of which four pregnancies were ongoing. Table II shows the cumulative results of the 75 cycles described above together with these six additional attempts. Discussion In recent years, IVF treatments have become more complex and stressful for the patient due to lengthier and more complex ovarian stimulation protocols which are now routinely used. IVF in a natural cycle is a low-cost and low-risk treatment, easy to perform and can be repeated on a monthly basis, thereby increasing the overall chance of success (Paulson et al., 1992). There are reports about complete NIVF, namely oocyte retrieval timed on the basis of the LH surge and no luteal support after oocyte retrieval (Mahmood et al., 1991; Fahy Table III. Summary of 15 natural in-vitro fertilization studies Author, year No. of No. of No. of No. of Indication Mean age Oocyte Oocyte Luteal patients cycles natural medication for IVF SD retrieval retrieval support cycles cycles (years) a timed LH timed HCG surge Ranoux et al. (1988) N.M. N.M IU N.M. Foulout et al. (1989) Tubal 32 (24 40) 3000 IU 1500 IU HCG per 3 days Cervical Ramsewak et al. (1990) N.M Tubal 33.9 N.M. Clomiphene Mahmood ey al. (1991) Tubal (22 35) N.M. Svalander et al. (1991) Tubal IU N.M. Paulson et al. (1992) Tubal IU 50 mg suppositories; 2 per day Claman et al ) N.M Tubal N.M IU 1500 IU HCG per 3 days Paulson et al. (1994) Tubal IU 50 mg suppositories; 2 per day DeLauretis et al. (1994) Tubal N.M IU N.M. Scarduelli et al. (1994) Tubal N.M IU N.M. MacDougall Tubal/PCO IU N.M. Clomiphene /PCO Daya (1995) N.M Tubal IU 50 mg suppositories 2 per day Fahy et al. (1995) Tubal 33 (25 39) None Seibel et al. (1995) All 32.8 (26 38) 2500 IU N.M. Zayed et al (24 44) 30 mg Duphaston per day IVF in-vitro fertilization; LH luteinizing hormone; N.M. not mentioned; HCG human chorionic gonadotrophin; PCO polycystic ovaries. a Range in parentheses. 316

4 IVF for spontaneous cycles et al., 1995). We administered exogenous HCG to substitute (ongoing) pregnancy rates per embryo transfer in NIVF varying for the mid-cycle LH surge to facilitate the timing of oocyte between 0 and 30% (0% MacDougall et al., 1994; 14% Paulson retrieval and planning of work schedules during day-time. It et al., 1994; 14.2% De Lauretis et al., 1994; 15 22% Scarduelli is inevitable that in NIVF there is an increased risk of failing et al., 1994; 25% Ranoux et al., 1988; 30% Svalander et al., to recover the oocyte. In those cases, a new attempt can be 1991). The three latter studies involved only (Svalander et al., started in another cycle. When the protocol is not changed, 1991; Scarduelli et al., 1994) or mostly (Paulson et al., 1992; the chances of obtaining the oocyte will be the same for each MacDougall et al., 1994) patients with a tubal infertility, while attempt and the patient needs to be motivated to continue. the others had a patient cohort biased towards mixed infertility There is no consensus about the best protocol to be used in causes including unexplained, endometriosis, male and tubal NIVF. In Table III we give an overview of 15 NIVF studies, factors. quoting the numbers of patients and treatment cycles In The Netherlands, most health insurance companies involved, indications for IVF, age, use of clomiphene citrate, reimburse the costs of three IVF attempts. Considering that timing of oocyte retrieval with LH surge and/or HCG and use there is no decrease in per cycle pregnancy rates for up to at of luteal support. least three unstimulated cycles (Paulson et al., 1992) and, as NIVF is a relatively easy procedure, especially for the the total cost for one live birth is five times lower in NIVF patient. To let a follicle grow under natural circumstances feels versus stimulated IVF (Daya et al., 1995), it can be considered more comfortable. We agree that during the study the patient to offer patients the option of replacing the first insurance had to come to the IVF centre frequently for ultrasound and paid SIVF attempt, by three or even five NIVF attempts. If blood sample controls, in accordance with the protocol. Patients the patient is not pregnant after the NIVF treatments, the participating in our standard IVF programme made on average remaining two insurance paid SIVF attempts can be utilized six visits, while the six patients in the study who had a second as preferred by the patient. attempt of NIVF came in for only three visits. This was In conclusion, we dare to say that despite an inevitably because we could more or less predict the day of HCG trigger, lower pregnancy outcome per cycle, NIVF is a relatively easy, on the basis of the results of their first attempt. Furthermore, cheap and realistic option to achieve a satisfactory pregnancy the oocyte retrieval is considerably shortened and less painful rate for patients with infertility caused by a tubal factor. in NIVF, and the patients do not have a risk for OHSS and multiple pregnancies. NIVF is also easy for the laboratory staff as it involves a considerably reduced laboratory time. References Secondly, the procedure is cheap. We did not perform an American Fertility Society, Society for Assisted Reproductive Technology (1994) Assisted reproductive technology in the United States and Canada: economic cost-benefit analysis, but this has been done by 1992 results generated from The American Fertility Society/Society for others (Daya et al., 1995) and the results are firm. It is easy Assisted Reproductive Technology Registry. Fertil. Steril., 62, to imagine that the procedure costs are less than in SIVF as Claman, P., Domingo, M., Garner, P. et al. (1993) Natural cycle in vitro no medication is used (except the HCG trigger). The total fertilization embryo transfer at the University of Ottawa: an inefficient therapy for tubal infertility. Fertil. Steril., 60, price of the medication for one standard IVF programme at Daya, S., Gunby, J., Hughes, E.G. et al. (1995) Natural cycles for in-vitro our department* varies from 2800 to 6800 guilders (~Euro fertilization: cost-effectiveness analysis and factors influencing outcome ). The reduced medication costs in NIVF in com- Hum. Reprod., 10, bination with fewer visits to the centre and no risk for OHSS Fahy, U.M., Cahill, D.J. Wardle, P.G. et al. (1995) In-vitro fertilization in completely natural cycles. Hum. Reprod., 10, and multiple pregnancy with fewer days of hospitalization as Foulot, H., Ranoux, C., Dubuisson, J.-B. et al. (1989) In vitro fertilization a consequence, make NIVF a cheap treatment. without ovarian stimulation: a simplified protocol applied in 80 cycles. Thirdly, the results of NIVF are realistic. In our overall Fertil. Steril., 52, Johnston, I., Lopata, A., Speirs, A. et al. (1981) In vitro fertilization: the group, oocyte retrieval was attempted in 67 out of 81 cycles challenge of the eighties. Fertil. 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(eds), Baillière s be repeated on a monthly basis the overall success rate is Clinical Obstetrics and Gynaecology, 6, encouraging. We obtained an ongoing cumulative pregnancy MacDougall, M.J., Tan, S-L., Hal, V. et al. (1994) Comparison of natural with rate of 19.5% per embryo transfer. Other studies report clomiphene citrate-stimulated cycles in in vitro fertilization: a prospective, randomized trial. Fertil. Steril., 61, Mahmood, T.A., Kulenthram Arumugam and Templeton, A.A. (1991) Oocyte and follicular fluid characteristics in women with mild endometriosis. Br. *Long protocol including one strip of Microgynon 30, 3 4 weeks J. Obstet. Gynaecol., 98, GnRH agonist Decapeptyl 100 µg/day (Ferring, Hoofddorp, The Noyes, R.W., Hertig, A.T. and Rock, J. (1950) Dating the endometrial biopsy. Netherlands), gonadotrophins Gonal F IU/day for about 11 Fertil. Steril., 1, 3. days (Serono), Profasi IU (Serono, Den Haag, The Netherlands) Paulson, R.J., Sauer, M.V. and Lobo, R.A. (1990) Embryo implantation after and Progestan tablets mg/day for 15 days (Organon, Oss, The human in vitro fertilization: importance of endometrial receptivity. Fertil. Netherlands). Steril., 53,

5 R.M.J.Janssens et al. Paulson, R.J., Sauer, M.V., Francis, M.M. et al. (1992) In vitro fertilization in unstimulated cycles: the University of Southern California experience. Fertil. Steril., 57, Paulson, R.J., Sauer, M.V., Francis, M.M. et al. (1994) Factors affecting success of human in-vitro fertilization in unstimulated cycles. Hum. Reprod., 9, Ramsewak, S.S., Cooke, I.D., Li, T.-C. et al. (1990) Are factors that influence oocyte fertilization also predictive? An assessment of 148 cycles of in vitro fertilization without gonadotropin stimulation. Fertil. Steril., 54, Ranoux, C., Foulot, H., Dubuisson, J.B. et al. (1988) Returning to spontaneous cycles in in vitro fertilization. J. In Vitro Fertil. Embryo Transfer, 5, 304. Rizk, B. and Smitz, J. (1992) Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures. Hum. Reprod., 7, Rizk, B., Doyle, P., Tan, S.L. et al. (1991) Perinatal outcome and congenital malformations in in-vitro fertilization babies from the Bourn Hallam group. Hum. Reprod., 6, Scarduelli, C., Caccamo, A., Bailo, U. et al. (1994) Does HCG improves pregnancy rate in IVF in natural cycles? Hum. Reprod., 9 (Suppl. 4), 131. Seibel, M., Kearnan, M. and Kiessling, A. (1995) Parameters that predict success for natural cycle in vitro fertilization embryo transfer. Fertil. Steril., 63, Steptoe, P.C. and Edwards, R.G. (1978) Birth after the reimplantation of a human embryo. Lancet, ii, 336 Svalander, P., Green, K., Haglund, B. et al. (1991) Natural versus stimulated cycles in IVF ET treatment for tubal infertility. Hum. Reprod., 9 (Suppl. 4), 101. Tarlatzis, B.C., Grimbizis, G., Bontis, J. et al. (1995) Ovarian stimulation and ovarian tumours: a critical reappraisal. Hum. Reprod. Update, 1, Zayed, F., Lenton, E.A. and Cooke, I.D. (1997) Natural cycle in-vitro fertilization in couples with unexplained infertility: impact of various factors on outcome. Hum. Reprod., 12, Received on April 8, 1999; accepted on October 13,