Institute for the Study of Fertility, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
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Abstract |
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Introduction |
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Although widely used, the success rate of AID treatments is inconsistent. Frequent problems in evaluating success rates of these treatments in many studies are: small number of treatments performed; differences in treatment protocols; heterogeneity of the population evaluated, and inclusion of patients from different clinics.
Our study was conducted to summarize the results of 1001 women treated by AID in the Institute for the Study of Infertility, Tel Aviv, Israel, during the last 18 years.
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Materials and methods |
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AID was performed according to regulations of the Israeli Ministry of Health, last revised in 1994 (Israeli Ministry of Health, 1994). Donor selection, sperm preparation and cryopreservation techniques were performed as previously described (Paz et al., 1991
; Yavetz et al., 1991
). Only young university students donated semen. Donors were accepted if sperm concentration was above 40x106/ml; sperm motility (at first hour) >50% motile (most in progressive motility); normal morphology >45% (World Health Organization, 1980
); and post-thaw motility >35% motile. Sperm quality was assessed before each insemination to assure it corresponded with the expected quality. Frozenthawed donor spermatozoa were used in 5588 (88%) cycles. Basically, a post-thaw quantity of
4x106 progressively motile spermatozoa were used per insemination (8x106/ml). Until November 1987, 550 treatment cycles of fresh donor spermatozoa were performed. Usually, a minimum of 40x106/ml spermatozoa were used. In each cycle, age was calculated according to the differences between the year of birth and year of treatment.
Healthy women with no known gynaecological abnormalities and with regular cycles, normal hormonal profile and normal bi-manual and ultrasound findings were enrolled in the programme. Tubal patency was determined by hysterosalpingography (HSG) or laparoscopy, if there was a past history of pelvic inflammatory disease or any other event that may caused mechanical disruption. In the absence of clinical suspicion of pelvic pathology, evaluation was performed when the patient failed to conceive after 36 cycles of super-ovulation.
Ovulation time was usually assessed by either baseline body temperature charts, urine LH, which was tested at home, or monitored by oestradiol and progesterone serum concentration, combined with follicular diameter assessed by ultrasound. Ovulating women were usually scheduled to begin treatment during natural cycles. Ovulation augmentation was offered to women who failed to conceive after a few cycles (14). Clomiphene citrate (CC), either alone or with human chorionic gonadotrophin (HCG), was the first choice of treatment, later continued by human menopausal gonadotrophin (HMG) combined with HCG. Inseminations were usually performed twice in each cycle (14 in each). Donor spermatozoa were introduced to the cervix by a cervical cap, or by intrauterine insemination (IUI) catheter.
Information concerning the end results was usually given by a letter or by phone call at the end of the pregnancy. This was written in the patient file only with reference to: abortions, termination of pregnancies or deliveries. We are lacking information concerning the number of gestational sacs that were present at the beginning of the pregnancy and the number of babies born. The effect of the age of women on the number of insemination cycles performed until conception was calculated. Return for treatment after pregnancy mandated the beginning of new calculations. This explained why several women underwent 3040 treatment cycles, usually in order to achieve more than one pregnancy.
The average number of cycles performed until the first pregnancy was achieved was defined as first course. The mean number of cycles performed by the same previously pregnant women until their next pregnancy was defined as second course.
Statistical analysis
Results are given as mean ± SD. 2-test was used for two categorical variables for comparison between achieving pregnancy and woman's age, or year of treatment. Correlation between treatment year and woman's age was performed by Pearson's correlation. Multivariate logistic regression analysis (WALD) was used, with pregnancy rate (PR) as the dependent variable and year of treatment, woman's age and sperm origin (fresh or frozenthawed) as the independent variables. Cumulative PR was calculated according to a published model (Cramer et al., 1979
). These tests were calculated using PC-based SPSS (Statistical Package for Social Science) software.
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Results |
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The cumulative PR calculated for 3, 6 and 12 months were 36, 53 and 75% respectively. The cumulative PR according to age groups were: (i) women <37 years: 44, 61 and 82%; (ii) women 3740: 24, 44 and 61%; and (iii) women >40 years: 13, 22 and 50% respectively.
The effect of previous pregnancies on success rates
The PR for those who had never been pregnant previously was 380/2959 (12.8%), for those who had aborted spontaneously or intentionally 111/999 (11.1%), and for those who had delivered in the past it was 278/2173 (12.8%) (not significant).
We calculated the average number of cycles performed until the first pregnancy (first course), and the average number of cycles performed by the same group of women when they returned for further treatments (second course). On average these women performed 4.4 ± 3.7 versus 5.9 ± 5.3 insemination cycles until pregnancy, for first versus second course respectively (P = 0.023).
Treatment modalities and success rate
Cap insemination cycles resulted in 657 pregnancies in 5095 cycles (12.9%), versus 115 pregnancies in 1041 IUI cycles (11.1%) (not significant).
The effect of different regimes on success rates
Ovulation either followed spontaneously (in 2331 cycles), or was induced by medication. CC was the most popular form of treatment, either alone (1660 cycles) or combined with HCG (1011 cycles), followed by HMG stimulation (912 cycles) or HCG alone (220 cycles). PR per cycle were 13.8, 11.6, 13.6, 11.8 and 11.8% for natural cycles, and cycles stimulated by CC, HCG, CC plus HCG and HMG respectively (not significant).
Age and success rates
Women aged 1847 years were inseminated by donor spermatozoa. The oldest pregnant woman was 44 years. A statistically significant, age-related decline in PR was found (P < 0.0001) (Table I). These results were more pronounced when dividing the female population into three groups: aged <37, 3740 and >40 years. In the <37 year age group, 620 pregnancies out of 4056 cycles (15.3%) occurred, declining to 103 pregnancies out of 1190 cycles (8.7%) between ages 37 and 40 years, and to 5.5% only (49/892) in older women (P < 0.0001). This trend was more pronounced for the delivery rate per cycle. Up to 37 years, there were 513 deliveries (12.6%), at 3740 years only 75 women delivered (6.3% per cycle) and after 40 years of age only 2.2% of the cycles ended in delivery (20/892). An opposite effect was demonstrated for abortion rate, which was found to be 14.5, 22.3 and 42.9% for women aged <37, 3740 and >40 years respectively (P < 0.0001).
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By logistic regression analysis, age was found to be the major determinant affecting the occurrence of pregnancy (P < 0.00001), while the advantage of using fresh versus frozenthawed spermatozoa entered as the second most important variable (P = 0.0008), and the year of treatment as the least important (P = 0.0026). Stepwise regression showed that the effect of age countered the effect of the treatment year (P =0.0001), as was found for the effect of fresh spermatozoa over the year of treatment (P =0.0001).
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Discussion |
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The success rate of AID depends on a wide variety of factors. Some are unchangeable, such as the age of the female, while others may be under control of good medical care, such as the quality of the spermatozoa used for insemination, insemination timing, ovulation-induction protocols used, or choice between cervical insemination and IUI. Evaluation of the importance of some of these variables is within the scope of our work. However, this is not a retrospective work aiming to evaluate the different effect of each variable on success rate, but rather a retrospective analysis of continuous work performed during 18 years period, at the same clinic, with almost unchanged protocols throughout this long period.
During the 18 year period, we had information concerning 6139 treatment cycles, which resulted in 773 pregnancies, yielding PR per cycle of 12.6%. Similar success rates are published in the literature, and was not changed much during the last few decades, remaining at ~10% per treated cycle (Table IV). The cumulative PR was found to be high (36, 53 and 75% for 3, 6 and 12 months respectively). This higher cumulative rate is superior to the 3137% cumulative probability achieved by different ovulation detection methods and ICI performed by Brook et al. (Brook et al., 1994
). This is even higher than the 21, 40 and 62% probability for 3, 6 and 12 months in women <30 years of age who participated in the AID programme of the Middlesex Hospital, London (Shenfield et al., 1993
).
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Spontaneous abortion rates were 17.3% per pregnancy (134 women aborted), four extrauterine pregnancies (0.5%), and 13 pregnancies were selectively terminated due to severe fetal malformations (1.7%). These spontaneous abortion and extrauterine PR do not differ from those of the normal population. Similar findings have been obtained from the results of 21 597 AID pregnancies gathered from a collaborative study of the French Centre for Cryopreservation of Eggs and Spermatozoa (CECOS Federation) (Lansac et al., 1997). They found 18% fetal loss, 0.9% tubal pregnancy, and 1.9% fetal malformation rate. Recently, considering only pregnancies of
20 weeks duration, Hoy et al. showed that the overall prevalence of birth defects did not differ much between AID and control births (Hoy et al., 1999
). However, they found a higher chromosomal abnormality rate in the AID group, compared with controls [seven of 1552 pregnancies (0.4%) compared with 13 of 7717 pregnancies (0.2%) respectively].
The effect of previous pregnancies on success rates
In the present study, past fertility and delivery history were not found to be important for present fertility potential. Intuitively, it was assumed that those women with secondary infertility would perform better than women with primary infertility. The classification we used (never been pregnant, those who had abortion and those who delivered in the past), is not comparable with primary and secondary infertility, since most women who had never been pregnant did not try to do so, and thus their fertility potential had never been tested. Moreover, those who had been pregnant previously may have conceived in their youth, and despite the indication of past fertility and probable tubal patency, this could not serve as a predictor for present fertility potential. Similar findings were reported for nulligravidae versus multigravidae (Shenfield et al., 1993).
In contrast to our expectations, women performed better on first versus second course, indicating that success is not a positive predictor for the next trial. This contradicts previous findings in the literature (Shenfield et al., 1993). However, two factors may contribute to these findings: first, those who had previously been treated by fresh spermatozoa returned later for treatment using frozenthawed spermatozoa. A second possible explanation might have been the older age of those who returned for treatment several years after their last pregnancy.
Treatment modalities and success rate
Different treatment modalities, i.e. cap insemination versus IUI, had no effect on PR. Nevertheless, we routinely started treatment with cap insemination due to its physiological nature. Only after several failures was treatment modified to IUI. Thus, a lower fertility potential, indicated by failure to conceive with cap insemination, may contribute to lower success rate with IUI treatments. Most authors have found that IUI is more advantageous than intracervical insemination (ICI) (Hurd et al., 1993; Williams et al., 1995
; Matorras et al., 1996
). Ford et al. published an analysis of 11 studies involving frozenthawed semen, comparing the use of IUI with ICI (Ford et al., 1997
). They revealed that in comparison with timed ICI, IUI significantly increased the PR, both with and without gonadotropin stimulation of the female partner [odds ratio (95% confidence interval) 1.92 (1.023.61) and 2.63 (1.524.54) respectively]. Tur et al. published interesting findings of a higher incidence of multiple pregnancy after IUI (32%) than that of ICI (21%) with donor spermatozoa (Tur et al., 1997
). Although IUI is probably superior to ICI, its disadvantages should also be considered, i.e. more invasive procedure, its use obligates sperm processing, it requires on average more donor semen, and for all these reasons the procedure is far more expensive.
The effect of different regimes on success rates
We showed that neither treating women on natural cycles, nor using different ovulation induction protocols, had any net effect on success rate (P = 0.314). Caution should be used in interpretation of these results, since the working chart of each patient demanded no or minimal intervention (no medical treatment). Failure to conceive usually prompted initiation of CC alone, or in combination with HCG, and only if pregnancy was not yet achieved were patients then treated with gonadotrophins. Therefore, this was not a controlled study comparing different regimes, but only evaluation of results achieved during this time frame.
Studies comparing the efficacy of different ovulation induction protocols usually involved IUI with fresh husband spermatozoa, and usually favour the use of HMG plus IUI over any other alternative (Ombelet et al., 1995). In contrast, studies involving the use of donor semen usually suffered from the same limitations as in our work (Matilsky et al., 1998
). However, Depypere et al., who used frozen donor semen, found HMG plus IUI to be more advantageous than natural or CC-stimulated cycles (PR of 23.9, 12.5 and 13.1% respectively, P < 0.03) (Depypere et al., 1994
).
Age and success rates
Advanced age was found to have a negative effect on PR (P < 0.0001) and on the delivery rate, and a positive effect on abortion rate. These findings are not surprising, since the importance of age in every aspect of natural and artificial reproduction is common knowledge. This includes almost every study involving AID (Shenfield et al., 1993; Kang and Wu, 1996
). The decline in fertility rate with age probably results from a combination of progressive follicular depletion, decline in granulosa function and poor oocyte quality (Hughes et al., 1990
; Navot et al., 1991
) and reduced endometrial receptivity (Yaron et al., 1993
).
Surprisingly, however, in those who conceived, increased age was not found to affect the number of insemination cycles needed to achieve the pregnancy (Figure 1, r = 0.177). This can be explained by assuming that those women who are fertile will remain so at every age, and that their fertility potential will remain less affected with advancing age.
The connection between the year of treatment and success rate
Donor sperm banking and AID treatment started more than two decades ago. It was expected that PR would increase with time, because of the advanced new technologies in ovulation induction and in timing of insemination. Nevertheless, In our hands, this did not occur, and in fact PR significantly decreased during the years of the study period (P = 0.005). This could theoretically be explained by the fact that our patients' population has grown older (Figure 2), and therefore PR declined. The same decline in PR was found for women <40 years of age (P = 0.024), and not for women >40 years of age (P = 0.369).
The fact that PR declined in women aged <40 years may hint at another explanation. Until November 1987, fresh donor spermatozoa were used for treatment, yielding better results (PR = 17.8%). Thereafter, frozenthawed spermatozoa were used, with a lower PR (12.1%). If only cycles performed with frozenthawed spermatozoa are considered, i.e. 5589 insemination cycles resulted in 675 pregnancies, an unchanged PR with advancing years is found (P < 0.05).
Consecutive cycle effect on PR
PR deteriorates with consecutive cycles (Table III). This again is a common phenomenon in the literature. However, pregnancies are recorded even after the 18th cycle, thus for a woman who desired to conceive by as simple an intervention as possible, or could not afford a more sophisticated medical procedure, such as IVF, treatment continuation is a relevant option.
The effect of freezing and thawing on success rates
PR were higher when using fresh versus frozenthawed semen (P < 0.0001). Most authors agree that there is a reduction in PR with the use of frozenthawed versus fresh semen (Richter et al., 1984; Subak et al., 1992
). PR after freezing and thawing was found to be in positive correlation with post-thaw motility (Johnston et al., 1994
; Clarke et al., 1997
). However, reduced post-thaw motility is a common phenomenon after freezing, probably connected with loss of membrane integrity or the generation of reactive oxygen species (Aitken et al., 1989
). In this regard, we previously reported that the freezingthawing process does not impair the capability of recovered spermatozoa to bind to the zona pellucida (Gamzu et al., 1992
). Moreover, fertilization in vitro and implantation rates seem to be similar for fresh and frozenthawed spermatozoa (Mahadevan et al., 1982
). These findings may hint at the major contribution of the use of higher total motile spermatozoa in fresh donor samples (>40x106/ml), probably responsible for a parallel increased in the number of cells with normal cell function.
In summary, the major merit of this paper is a description of the success rates of artificial insemination with donor spermatozoa over an extended period of time. Information regarding results of 6139 insemination cycles with donor spermatozoa performed in our institution during an 18 year period was analysed. Overall PR per cycle was 12.6%. Cumulative PR for 3, 6 and 12 months of treatment were 36, 53 and 75%, respectively. No effect was found for the woman's past fertility history. No superiority was found for different modes of treatment, or medication used for induction of ovulation. As was expected, age was found to be a major determinant for success rates. Due to the increased age of the female population attending our clinics over the years, no improvements in PR were demonstrated in our results, although progress in medical surveillance and knowledge would have been expected to have had certain positive effects. The mandatory change from the use of fresh donor spermatozoa to the use of frozenthawed spermatozoa at the end of the 1980s had a seriously detrimental effect on PR.
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Notes |
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References |
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Submitted on January 1, 2001; accepted on July 10, 2001.