Assisted Conception Unit, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK
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Abstract |
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Key words: donor insemination/ovulation induction
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Introduction |
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The role of ovulation induction in DI is controversial. Assuming that the women requiring DI are fertile, the cost of the treatment and the side-effects, particularly the risk of multiple pregnancy, are potential reasons for avoiding ovulation induction until its need is obvious. The French CECOS reported on a 4 year experience with DI and proposed several strategic plans for DI treatment, according to the number of spontaneous and assisted conception cycles that would yield the highest fecundability and lowest risk of complications (Federation CECOS, 1995).
A previous report from this unit assessed 1001 spontaneous ovulatoryintracervical DI cycles (Ahmed Ebbiary et al., 1994). A cycle fecundability of 4.4% was obtained, no pregnancies occurred after nine treatment cycles, and early resort to other methods of assisted reproduction was recommended in women over 35 years of age and if the patient failed to conceive after nine cycles of DI.
In the cohort study reported here, a sequential step-up protocol of ovarian stimulation in our DI programme was assessed, from natural ovulatory cycles to clomiphene citrate (CC) induction of ovulation through to gonadotrophin ovulation induction. The principle behind proposing such a protocol was 3-fold: (i) by early resort to ovulation induction the cycle fecundability may be increased and consequently the cost per pregnancy reduced; (ii) starting with the natural ovulatory cycles followed by the CC-stimulated cycles prior to resorting to ovulation induction may help by filtering out the highly fertile women and thus reducing the risk of multiple pregnancy; (iii) in the presence of low sperm quality, increasing the number of follicles produced increases the probability of fertilization and therefore of an embryo reaching the uterus.
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Materials and methods |
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Patient assessment and counselling:
Prior to inclusion in the DI programme, a couple was counselled according to the Human Fertilisation and Embryology Authority guidelines (HFEA, 1995) and written consent was obtained. The female partner was fully assessed with regard to tubal patency and ovulatory status, using hysterosalpingography and midluteal phase serum progesterone assay respectively.
Natural ovulatory cycles (NC)
The patients were instructed on the use of a urinary ovulation prediction kit (Clear Plan; Unipath, Bedford, UK). An evening sample of urine was kept in the refrigerator but not routinely tested. Each morning the patient tested her first urine sample. If a positive result was obtained then the previous night's sample was tested prior to reporting the result to the clinic. If the patient had two positive results, two intrauterine inseminations were carried out on the same and following day. If she only had one positive result, a single intrauterine insemination was carried out on the following day.
CC-stimulated cycles
This treatment was used if the patient failed to conceive after three natural cycles, if anovulation was diagnosed prior to starting any treatment, or if the patient failed to ovulate in a natural cycle. Patients 3539 years of age at the time of this study were started on CC-stimulated cycles irrespective of whether previous natural cycles had been attempted. The patients were seen on cycle day 2 for a pelvic ultrasound scan to exclude any pelvic pathology prior to starting a daily dose of 100 mg CC for 5 days starting on cycle day 2. Monitoring of follicular growth was started on cycle day 9 with ultrasound scanning only. When the leading follicle was 18 mm in diameter 10 000 IU of human chorionic gonadotrophin (HCG) was administered and intrauterine DI was carried out 24 and 48 h later.
Ovulation induction cycles (OI)
This was carried out if the patient failed to conceive after three CC-stimulated cycles or if the patient was >39 years of age at the time of this study (irrespective of whether previous natural or CC cycles had been attempted). The patient was seen on cycle day 2 for a pelvic ultrasound scan to exclude pelvic pathology prior to starting intranasal administration of gonadotrophin-releasing hormone agonist (GnRHa, Synarel; Searle, Ltd, High Wycombe, Bucks, UK), starting on cycle day 2 until HCG administration, in a twice daily dose of 400 µg. The gonadotrophin administration was started on cycle day 3 as 150 IU recombinant follicle stimulating hormone (FSH, Gonal F; Serono Ltd, Welwyn Garden City, Herts, UK) for 3 days then reduced to 75 IU daily from day 4 onwards until day of HCG administration. When the leading follicle was 16 mm in diameter 10 000 IU HCG was administered and intrauterine DI was carried out 3640 h later. If the patient produced >5 follicles
14 mm diameter, the cycle was either cancelled or converted to in-vitro fertilization (IVF)embryo transfer after counselling the patient appropriately. Luteal phase support was carried out with daily 400 mg vaginal progesterone (Cyclogest; Shire Pharmaceuticals Ltd, Andover, Hants, UK). There were rest cycles in this group between the treatment cycles but the effect of these was not quantifiable.
All the patients carried out their own urinary pregnancy test 2 weeks post insemination. If the pregnancy test was positive an ultrasound scan was carried out 2 weeks later to confirm the pregnancy. A clinical pregnancy was defined as the visualization of fetal cardiac activity on ultrasound scan.
Donor selection and cryopreservation of semen
Potential donors were counselled and screened according to the HFEA (1995) guidelines, and a written consent was obtained. The minimum semen requirements for donor acceptance were 40x106 motile spermatozoa/ml in the pre-freezing sample and 10x106 in the post-thaw sample. The spermatozoa were frozen using a commercial freezing protectant (Sperm Freeze; Conception Technologies, San Diego, CA, USA). The samples were quarantined in the vapour storage facility, which minimizes the risk of transmission of infection. They remained in storage for 6 months prior to the final human immunodeficiency virus (HIV) and hepatitis B and C check. A number of vials were then transferred to the mobile tank for clinical use.
Donor insemination
The semen vials were removed from the storage tank and allowed to thaw at room temperature. Sperm preparation for insemination was carried out using Pure Sperm (Nidacom, Gothenburg, Sweden) density gradient centrifugation. No fewer than 2x106 motile spermatozoa were inseminated. If required, samples were also obtained from other HFEA-licensed centres. A track record was maintained for in-house donors. Track records for the samples purchased were obtained from the relevant centres.
Statistical analysis
Statistical analysis was carried out using Minitab for Windows statistical package (Minitab Inc., State College, PA, USA). The 2-test was used to compare categorical data and the KaplanMeier survival analysis method was used to calculate the cumulative pregnancy rates. Analysis of variance was used to compare the post-thaw sperm parameters between the three different treatment protocols.
The cost of treatment
The cost of natural ovulatory, CC-stimulated and ovulation induction cycles was £250, £260 and £700 respectively. The cost per pregnancy was defined as the total cost of all the treatment cycles divided by the total number of clinical pregnancies achieved.
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Results |
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Discussion |
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Several studies aiming to improve cycle fecundability have assessed the several parameters involved in DI treatment. Recruiting sperm donors with a defined minimum sperm quality rather than the conventional criteria has been suggested (Federation CECOS, 1989). However, sperm survival following cryopreservation and sperm ability to fertilize the oocyte in vivo are the crucial factors. Due to the high cost of recruiting and screening donors and of sperm cryopreservation, not to mention the difficulty of recruitment, improved timing of a single insemination has been favoured over random peri-ovulatory insemination as being more likely to achieve success. Moreover, the superiority of two inseminations over a single insemination has been regarded as controversial (Centola et al., 1990
; Lincoln et al., 1995
). In a retrospective study, double intracervical inseminations were reported to be superior to single insemination in terms of pregnancy rate per cycle and cumulative pregnancy rate (Deary et al., 1997
). In this study we reported clinical pregnancy rates in the natural cycle similar to those reported by Deary et al. (1997) despite only selective use of double insemination. We, however, used double insemination when accurate timing of ovulation could not be ascertained primarily because the frequency of insemination and timing of ovulation are inter-related. Improved timing would alleviate the need for more than one insemination. Although ultrasound scanning is the most accurate method of predicting the time of ovulation, it was not found to be significantly better than serum luteinizing hormone (LH) (Vermesh et al., 1987
). On the other hand, urinary LH detection has been reported to be accurate (Vermesh et al., 1987
) and reliable, which added to the simplicity of its use by the patient, which reduces the cost of treatment (Robinson et al., 1992
). It was found that serum LH offers a more accurate method of timing insemination, which was reflected in a higher pregnancy rate than was obtained with urinary LH prediction (Horne et al., 1998
). However, that study was non-randomized, and the fact that patient opinion was influenced by suggesting that serum LH detection would be more accurate may affect the validity of their conclusion. Furthermore, the inconvenience to the patients caused by serum LH testing and the added cost of the treatment should be carefully considered, particularly when adopting a non-evidence-based procedure. Perhaps urinary LH detection combined with double insemination offers better results with less inconvenience.
Whole thawed semen traditionally has been inseminated intracervically; however, several studies compared the pregnancy rate with intrauterine versus intracervical insemination and despite the controversy surrounding the superiority of either method, the weight of evidence is in favour of intrauterine insemination (Byrd et al., 1990; Patton et al., 1992
; Wainer et al., 1995
; Williams et al., 1995
).
The question of the role of ovulation induction in DI programmes is still unresolved and is not expected to be answered in the near future due to the scarcity of studies on this subject. Most studies concerning ovulation induction and intrauterine insemination have been on couples with unexplained infertility and mild male factor infertility where fresh husband's semen was used. Therefore caution should be exercised when applying the findings of such studies to the resolution of the DI programme question.
It has been reported that CC does not enhance the success rate of DI but human menopausal gonadotrophins (HMG) may have a favourable effect (Depypere et al., 1994). The value of HMG in failed DI programmes was also reported (Shenfield et al., 1992
), a cumulative pregnancy rate of 22% being achieved after three treatment cycles. However, a cumulative pregnancy rate of 55% was reported using pituitary down-regulation and ovulation induction (Hercz et al., 1994
). The superiority of pituitary down-regulation and HMG over HMG alone after failed DI for ovulatory disorders has also previously been reported (Gerris et al., 1989
). On the other hand, the recourse to IVF after six failed natural DI cycles has been recommended (Robinson et al., 1993
) who reported a cumulative pregnancy rate of 83% after four treatment cycles.
Although ovarian stimulation may seem an attractive answer to increasing the pregnancy rate in DI programmes, we believe that the natural cycle treatment should be the mainstay of this form of treatment simply due to its low cost and the negligible risk of multiple pregnancy. However, it appears from various reports in the literature as well as most clinicians' personal experience that at some point introduction of assisted reproduction into DI programmes is necessary. The controversy is over the timing of its introduction and the modality used. The French report (Federation CECOS, 1995) suggested five treatment strategic plans, according to the modality and timing of introducing assisted reproduction, and they predicted a cumulative pregnancy rate of 5990%, and a multiple pregnancy rate of 734%. They also predicted that the earlier the introduction of ovulation induction, the higher the multiple pregnancy rate, and that IVF carries the highest risk of multiple pregnancy, especially triplets.
Female age is an important determinant in the success of DI treatment (Federation CECOS, 1989Federation-CECOS, 1993; Shenfield et al., 1993
). Early recourse to ovulation induction in women of >35 years to improve their fecundity in DI programmes has been suggested (Ahmed Ebbiary et al., 1994
). We have carefully considered the literature reports on all the factors that may influence the success rate in DI treatment, and have designed the strategic plan we described in this prospective cohort study.
As described earlier we felt that, despite the controversy, the weight of evidence was in favour of intrauterine over intracervical insemination, that urinary LH prediction is simpler and less costly compared to serum LH prediction, and that early resort to ovulation induction in older women improves their success rate. We also applied two inseminations instead of one in selected cases where accurate prediction of ovulation was not confirmed. The cycle fecundability and cost per pregnancy are inter-dependent: by significantly increasing the pregnancy rate per cycle the cost per pregnancy will fall.
As for minimization of the multiple pregnancy rate, we believe that two important factors contributed: (i) the filtering out of the highly fertile young women through natural and CC-stimulated cycles, and (ii) not allowing those who produced more than five mature follicles (14 mm diameter) to proceed to insemination. When we used the same ovulation induction protocol for patients with unexplained infertility, the multiple pregnancy rate was 45% (Lashen et al., 1998
) which supports the hypothesis that filtering out the highly fertile women through the natural and CC-stimulated cycles helped to reduce the multiple pregnancy rate. However, this will need to be confirmed by using various combinations of the suggested protocol. It has also been reported (Valbuena et al., 1996
) that the risk of multiple pregnancy in ovulation induction cycles during both donor and husband insemination is related to age and follicular activity.
The advantage of down-regulating the pituitary gland prior to ovarian stimulation for intrauterine insemination is a controversial issue (Dodson et al., 1990; Gagliardi et al., 1991; Sengoku et al., 1994
; Manzi et al., 1995
). Studies on DI patients suggested that pituitary down-regulation results in a higher pregnancy rate but these studies were too small to allow a valid conclusion (Gerris et al., 1989
; Hercz et al., 1994
). Nonetheless, we believe that pituitary down-regulation provides some flexibility in monitoring the cycle, in timing insemination, and in cycle cancellation without the risk of hyperstimulation, and when converting the overstimulated cycles into IVF. Furthermore, by using the short flare-up protocol, the gonadotrophin dose requirement is similar to that when using gonadotrophin alone (Sengoku et al., 1994
). Cycle cancellation, however, was significantly higher in the OI patients in this study. Nevertheless, without accurate means of predicting the over-responders, avoiding cancellation may prove difficult as reducing the gonadotrophin dose may result in an increase in poor response unless a lower gonadotrophin dose was selectively used in younger patients. Although the numbers are small, the CPR/C was similar in the women over and under 35 years of age, which supports the concept of early recourse to OI in older women.
Finally, the strategic plan of DI which we have proposed was prospectively tested in this study and proved cost-effective with a very low risk of multiple pregnancy. Out of the five strategic plans suggested by the French study group (Federation CECOS, 1995), they preferred the plan in which six intracervical insemination plus natural cycles were followed by six intrauterine insemination plus ovulation induction cycles, which were in turn followed by four IVF cycles. They estimated a cumulative pregnancy rate of 90%, an average of seven cycles per patient and a multiple pregnancy rate of 7%. In our proposed strategy we achieved a cumulative pregnancy rate of 88%, and a multiple pregnancy rate of 3% in nine cycles (2.2 cycles per patient), without resorting to IVF, which makes our plan more cost-effective.
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Acknowledgments |
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Notes |
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References |
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Submitted on January 11, 1999; accepted on April 15, 1999.