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

R.M.J. Janssens1, C.B. Lambalk, J.P.W. Vermeiden, R. Schats and J. Schoemaker

Institute for Endocrinology, Reproduction and Metabolism, IVF Center, Vrije Universiteit Medical Center, Amsterdam, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The results of in-vitro fertilization in natural cycles (NIVF) in women with tubal infertility at our department are presented. The study had a prospective design. We needed 75 cycles in 50 patients to obtain one oocyte from each patient. Successful oocyte recovery rate was 67% per started cycle and 82% per oocyte retrieval. Thirty-five embryos were transferred and resulted in four ongoing pregnancies (5.3% per cycle, 6.5% per oocyte retrieval, 11.4% per embryo transfer and 11.4% per embryo). Six patients who participated in the study made a second 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 embryo transfer and 19.5% per embryo. We conclude that NIVF is an easy, cheap and realistic method to obtain a pregnancy for patients with tubal infertility.

Key words: HCG/IVF/natural cycle/pregnancy rates


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
During the last two decades, in-vitro fertilization (IVF) has become a standard treatment and is offered to most patients who fail to conceive with other assisted reproduction techniques. The first successful IVF treatment was performed in an infertile woman with tubal factor infertility and occurred in a natural cycle (Steptoe and Edwards, 1980). During the years following this success could not be repeated by other groups (Johnston et al., 1981Go; Jones et al., 1982Go) and IVF in a natural cycle (NIVF) was soon replaced by IVF cycles in which ovarian stimulation was applied (SIVF). Initially relatively cheap and simple stimulation therapy such as clomiphene citrate was used. This has progressively been replaced by more sophisticated and expensive protocols involving gonadotrophin-releasing hormone (GnRH) agonist or antagonist in combination with gonadotrophins and luteal support. The consequences of ovarian stimulation in IVF are well known. They include the occurrence of multiple pregnancies (Rizk et al., 1991Go; American Fertility Society, 1994Go), ovarian hyperstimulation syndrome (Rizk et al., 1992), a decrease in endometrial receptivity (Paulson et al., 1990Go), possibly an increased risk of developing ovarian cancer (Tarlatzis et al., 1995Go), legal and ethical problems about surplus embryos and an increase in costs (Daya et al., 1995Go). These problems are not encountered when IVF is performed in a natural cycle. On the other hand, NIVF meets other problems such as an increased risk of cancellation of the attempt due to a luteinizing hormone (LH) surge (Claman et al., 1993Go), poor follicle development (Svalander et al., 1991Go), no oocyte during oocyte retrieval, no fertilization or polyspermic fertilization with no embryo transfer as a consequence (Lenton et al., 1993) and a considerably lower pregnancy rate per started cycle versus SIVF (Paulson et al., 1992Go). Nevertheless, there is a rising interest in NIVF among patients. It feels more comfortable to the patient and the physical burden of NIVF is perceived to be much lower than that of SIVF.

In this report we present our experience with NIVF and the results from a selected group of 50 patients who underwent, in total, 75 monitored natural IVF cycles.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Fifty patients, aged between 22 and 38 years and with a history of secondary tubal infertility, underwent in total 75 cycles of NIVF at 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 treatment cycle and an endometrial biopsy, taken in a previous cycle which was in-phase with the cycle day according to the criteria described by Noyes et al. (1950) (Claman et al., 1993Go). Hysterosalpingography, laparoscopy and/or laparotomy defined the tubal status as the cause of infertility. Patients with a history of tubal ligation were also eligible for the study. Couples with a second factor besides the tubal factor were excluded from the study. The protocol was approved by the Ethical Committee on Research with Human Subjects of the Vrije Universiteit Medical Center and all couples participating in the study signed an informed consent.

Treatment protocol
All patients underwent a baseline ultrasound scan on day 2 of their cycle to exclude ovarian cysts, and a blood sample was drawn to determine baseline follicle stimulating hormone (FSH) value (MacDougall et al., 1994Go). Patients with FSH value >10 U/l were excluded from the study (Claman et al., 1993Go) because of a reduced chance to obtain an oocyte in a natural cycle in this group (Lenton et al., 1992Go). Serial transvaginal ultrasound and serum 17ß-oestradiol plus LH concentration determinations were started on day 8 or 10, depending on the length of the cycle. Patients came to the hospital between 08.00 and 10.00. Follicular diameter was established by calculating the mean value of the two largest measurements perpendicular to each other. Subsequently, patients were seen every other day until the leading follicle reached a diameter >=13 mm. From then on patients came in daily for an ultrasound, oestradiol and LH. When the follicular diameter was >=18 mm and the morning serum LH value was <=15 U/l (Scarduelli et al., 1994Go), ovulation was triggered between 23.30 and 24.00 h on that day with 10 000 IU human chorionic gonadotrophin (HCG) (Profasi; Serono, Den Haag, The Netherlands) (Paulson et al., 1994Go; Daya et al., 1995Go). The cycle was cancelled when the morning serum LH value was >15 U/l. Vaginal oocyte retrieval was scheduled 35 h after HCG administration. Oocyte retrieval could be performed on any day of the week as our centre offers a 7 days per week service. Every oocyte retrieval was performed by one of the authors (R.J.). Most patients refused pre-medication, but if preferred they received 7.5mg Dormicum per os and/or 50 mg Pethidine i.m. A single lumen aspiration needle was used. The aspiration pressure was –100 to 300 mm Hg according to standard 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 the embryo was derived from the dominant oocyte (Paulson et al., 1992Go) and no NIVF studies report multiple pregnancies after combined embryo transfer of embryos derived from dominant and secondary oocytes.

The oocyte was inseminated 3 h after oocyte retrieval with 400 000 motile spermatozoa prepared by Percoll technique with a 40/90 gradient. Fertilization was judged the next morning and where cleavage had been achieved the transfer of a single embryo was performed 48 h after oocyte retrieval using an MDT catheter (International Medical, Zutplein, The Netherlands). The embryo was deposited ~1 cm below the uterine fundus in 20 µl of culture medium. No treatment was given to support the luteal phase as all patients had an endometrial biopsy in-phase. If the cycle was cancelled before oocyte retrieval or if no oocyte was obtained during oocyte retrieval, the patient was able to start a new attempt in the next cycle. We continued the protocol until we had retrieved at least one oocyte from each of 50 different patients. All patients who had an embryo transfer came for a pregnancy test on the 15th day after oocyte retrieval according to our standard protocol. The mean period of the luteal phase was 13 days (range 11–15). Pregnancy was confirmed on the basis of early testing for HCG on day 15 after oocyte retrieval and by ultrasonic evidence of a gestational sac.

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). Ultrasound guidance was used in all cases for oocyte retrieval.

Serum assays
FSH and LH were measured by using immunometric assays in commercially available kits (Amerlite; Amersham, UK). For measuring concentrations of oestradiol we used a commercially available competitive immunoassay (Amerlite). Intra- and interassay coefficients of variation were 6–9% for FSH, 5–10% for LH and 9–11% for oestradiol.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
To obtain one oocyte from each of 50 different patients we needed a total of 75 NIVF cycles. In 33 patients the oocyte was obtained in the first cycle, 11 patients needed two, four patients three and two patients needed four consecutive attempts before the oocyte was obtained. In seven cases the treatment was cancelled because LH >15 U/l on the morning of the last check. Six patients ovulated between the HCG trigger and the planned oocyte retrieval despite the fact that no raised LH value had been detected. One patient did not come in for oocyte retrieval because of personal problems and 11 times oocyte retrieval was performed but no oocyte was obtained. Therefore, we had a successful oocyte recovery per 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 (441 ± 173 pmol/l) or was not obtained (499 ± 134 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 IGo.


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Table I. Results of 75 natural in-vitro fertilization cycles
 
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 IIGo shows the cumulative results of the 75 cycles described above together with these six additional attempts.


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Table II. Cumulative results of 81 natural in-vitro fertilization cycles
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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., 1992Go).

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., 1991Go; Fahy et al., 1995Go). We administered exogenous HCG to substitute for the mid-cycle LH surge to facilitate the timing of oocyte retrieval and planning of work schedules during day-time. It is inevitable that in NIVF there is an increased risk of failing to recover the oocyte. In those cases, a new attempt can be started in another cycle. When the protocol is not changed, the chances of obtaining the oocyte will be the same for each attempt and the patient needs to be motivated to continue. There is no consensus about the best protocol to be used in NIVF. In Table IIIGo we give an overview of 15 NIVF studies, quoting the numbers of patients and treatment cycles involved, indications for IVF, age, use of clomiphene citrate, timing of oocyte retrieval with LH surge and/or HCG and use of luteal support.


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Table III. Summary of 15 natural in-vitro fertilization studies
 
NIVF is a relatively easy procedure, especially for the patient. To let a follicle grow under natural circumstances feels more comfortable. We agree that during the study the patient had to come to the IVF centre frequently for ultrasound and blood sample controls, in accordance with the protocol. Patients participating in our standard IVF programme made on average six visits, while the six patients in the study who had a second attempt of NIVF came in for only three visits. This was because we could more or less predict the day of HCG trigger, on the basis of the results of their first attempt. Furthermore, the oocyte retrieval is considerably shortened and less painful 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.

Secondly, the procedure is `cheap'. We did not perform an economic cost-benefit analysis, but this has been done by others (Daya et al., 1995Go) and the results are firm. It is easy to imagine that the procedure costs are less than in SIVF as no medication is used (except the HCG trigger). The total price of the medication for one standard IVF programme at our department varies from 2800 to 6800 guilders (~Euro 1250–3100). The reduced medication costs in NIVF in combination with fewer visits to the centre and no risk for OHSS and multiple pregnancy with fewer days of hospitalization as a consequence, make NIVF a `cheap' treatment.

Thirdly, the results of NIVF are realistic. In our overall group, oocyte retrieval was attempted in 67 out of 81 cycles with a cancellation percentage of 17% which is comparable with those reported by others (10% Zayed et al., 1997; 17% Fahy et al., 1995; 20% Ranoux et al., 1988). Oocytes were successfully collected in 56 out of 67 attempts (69.1% per started cycle), resulting in 41 transferable embryos (50.6% per started cycle). The high failure rate at each step is a disadvantage of NIVF versus SIVF cycles, but as NIVF can be repeated on a monthly basis the overall success rate is encouraging. We obtained an ongoing cumulative pregnancy rate of 19.5% per embryo transfer. Other studies report (ongoing) pregnancy rates per embryo transfer in NIVF varying between 0 and 30% (0% MacDougall et al., 1994; 14% Paulson et al., 1994; 14.2% De Lauretis et al., 1994; 15–22% Scarduelli et al., 1994; 25% Ranoux et al., 1988; 30% Svalander et al., 1991). The three latter studies involved only (Svalander et al., 1991Go; Scarduelli et al., 1994Go) or mostly (Paulson et al., 1992Go; MacDougall et al., 1994Go) patients with a tubal infertility, while the others had a patient cohort biased towards mixed infertility causes including unexplained, endometriosis, male and tubal factors.

In The Netherlands, most health insurance companies reimburse the costs of three IVF attempts. Considering that there is no decrease in per cycle pregnancy rates for up to at least three unstimulated cycles (Paulson et al., 1992Go) and, as the total cost for one live birth is five times lower in NIVF versus stimulated IVF (Daya et al., 1995Go), it can be considered to offer patients the option of replacing the first `insurance paid' SIVF attempt, by three or even five NIVF attempts. If the patient is not pregnant after the NIVF treatments, the remaining two `insurance paid' SIVF attempts can be utilized as preferred by the patient.

In conclusion, we dare to say that despite an inevitably lower pregnancy outcome per cycle, NIVF is a relatively easy, cheap and realistic option to achieve a satisfactory pregnancy rate for patients with infertility caused by a tubal factor.


    Notes
 
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, IVF Center, PO Box 7057,1007 MB Amsterdam, The Netherlands

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* *Long protocol including one strip of Microgynon 30, 3–4 weeks GnRH agonist Decapeptyl 100 µg/day (Ferring, Hoofddorp, The Netherlands), gonadotrophins Gonal F 150–450 IU/day for about 11 days (Serono), Profasi 10 000 IU (Serono, Den Haag, The Netherlands) and Progestan tablets 3x200 mg/day for 15 days (Organon, Oss, The Netherlands).


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 Introduction
 Materials and methods
 Results
 Discussion
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Submitted on April 8, 1999; accepted on October 13, 1999.