Institute for Endocrinology, Reproduction and Metabolism, IVF Center, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
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Abstract |
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Key words: HCG/IVF/natural cycle/pregnancy rates
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Introduction |
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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.
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Materials and methods |
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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., 1994). Patients with FSH value >10 U/l were excluded from the study (Claman et al., 1993
) because of a reduced chance to obtain an oocyte in a natural cycle in this group (Lenton et al., 1992
). 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., 1994
), 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., 1994
; Daya et al., 1995
). 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., 1992
) 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 1115). 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 69% for FSH, 510% for LH and 911% for oestradiol.
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Results |
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Discussion |
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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 et al., 1995
). 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 III
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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Secondly, the procedure is `cheap'. We did not perform an economic cost-benefit analysis, but this has been done by others (Daya et al., 1995) 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 12503100). 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; 1522% Scarduelli et al., 1994; 25% Ranoux et al., 1988; 30% Svalander et al., 1991). The three latter studies involved only (Svalander et al., 1991; Scarduelli et al., 1994
) or mostly (Paulson et al., 1992
; MacDougall et al., 1994
) 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., 1992) and, as the total cost for one live birth is five times lower in NIVF versus stimulated IVF (Daya et al., 1995
), 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.
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Notes |
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* *Long protocol including one strip of Microgynon 30, 34 weeks GnRH agonist Decapeptyl 100 µg/day (Ferring, Hoofddorp, The Netherlands), gonadotrophins Gonal F 150450 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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References |
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Submitted on April 8, 1999; accepted on October 13, 1999.