Human Reproduction Update Advance Access originally published online on June 10, 2004
Human Reproduction Update 2004 10(4):309-316; doi:10.1093/humupd/dmh029
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Overall prognosis with current treatment of infertility
1 McMaster University, Hamilton, Ontario and Dalhousie University, Halifax, Nova Scotia, Canada and 2 Brussels Free University, Laarbeeklaan 101, Brussels, Belgium
3 To whom correspondence should be addressed at: 400 Mader's Cove Road, RR 1, Mahone Bay NS B0J 2E0 Canada. Email: collinsj{at}auracom.com
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Abstract |
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Few reports provide pregnancy or birth rates for large groups of infertile couples having a comprehensive range of treatments. This model utilizes published evidence about diagnosis, treatment, the duration of treatment and the proportion of couples receiving treatment. Assisted reproduction technology treatment (ART) utilization was set arbitrarily at three levels: 3, 10 or 50% of the couples that had no live birth after conventional treatment. For each diagnosis and treatment the model estimated total live births, singleton live births and multiple live births per 10 000 couples. The overall live birth rate with non-ART treatment would be 37%, involving 3725 live births, of which 3478 (93%) would be singleton and 247 (7%) would be multiple. With ART utilization at 3, 10 and 50% of couples with persistent infertility in each diagnostic category, live birth rates were 39, 43 and 47% respectively, with 8, 10 and 12% multiple births. The corresponding utilization of ART would be 244, 813 and 1481 ART cycles per 106 population per annum. Typical management of infertility would fall short of 50% live births even with extensive utilization of ART. Underlying unknown untreatable factors remain barriers to greater overall success in the treatment of infertility.
Key words: effectiveness / evidence-based medicine / protocols / randomized controlled trials / treatment
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Introduction |
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The overall impact of current management on the outcome of infertility can be measured only by studying the results for all infertility patients. In recent years, however, most studies have concentrated on the effectiveness of a single type of treatment or on the outcome within a single diagnostic category. A few studies have reported on treatment-independent live birth among all couples attending a given centre, but by design these studies excluded the impact of treatment (Eimers et al., 1994
; Collins et al., 1995; Snick et al., 1997). Thus, few reports in the last decade provide birth rates among large groups of typical infertile couples who have a characteristic range of diagnoses and undergo a comprehensive range of treatments. Knowledge of the overall effectiveness of infertility management would allow judgments to be made about the impact of new treatments on overall outcomes and would assist in health policy planning.
During the last 50 years, 20 studies have reported the overall impact of infertility management on conception during follow-up from 1 to 8 years (Frank, 1950; Turner et al., 1955; Horne, 1957; Southam and Buxton, 1957; Sloan, 1964; Raymont et al., 1969; Lamb and Cruz, 1972; Newton et al., 1974; Dor et al., 1977; Harrison, 1980; Sorensen, 1980; Thomas and Forrest, 1980; West et al., 1982; Verkauf, 1983; Kliger, 1984; Hull et al., 1985; Collins et al., 1986, 1993; Sundstrom et al., 1997; Che and Cleland, 2002). In the earliest report in 1950 from Chicago, the pregnancy rate was 26% in 134 couples followed for 18 months (Frank, 1950). In the most recent, from Shanghai in 2002, the live birth rate was 35% among 394 couples followed for 
2 years (Che and Cleland, 2002). In all these reports from 1950 to 2002, the lowest overall pregnancy rate from a reporting clinic was 19% and the highest 52%. To estimate the average live birth rate in these studies, pregnancy rates were multiplied by 0.85. The average live birth rate, weighted by inverse variance, was 31% (95% CI 30–32). Although some of the clinic reports have no more than historic interest today, the change in success over time was neither significant 
or important (adjusted 
) (Figure 1). If reports dated before 1980 were excluded, the overall average live birth rate in the remaining 11 studies was 30% (95% CI 29–31). Even these recent reports do not include the results of IVF or ICSI treatments.
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IVF and ICSI are the most frequent types of assisted reproduction technology (ART) treatment in use today and it is of interest to understand the contribution of ART to the overall outcome of infertility management. Lacking original studies, a model has been developed to estimate the overall live birth rate with the use of current management protocols. Such a model should reflect typical diagnostic categories and incorporate the best evidence for treatment effectiveness. Of course, not all couples choose treatment, and even among those who have treatment, many do not complete what might appear in clinical judgment to be an optimal treatment programme. Therefore the model should estimate the live birth rate with the use of typical as well as optimal treatment protocols. The inclusion of untreated couples allows the results to be judged against the benchmark of clinical reality. Supplemental analyses allow for scenarios that reflect different concepts of what might be considered to be an optimal protocol.
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Materials and methods |
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English language publications were searched in Medline and the authors' reference databases using key words for specific diagnoses, treatments and outcomes. Bibliographies were cross-referenced, but no hand searches were conducted of journals or meeting proceedings. Relevance was determined after review of the abstracts and validity was evaluated by study design. The modelling assumptions for the distribution of diagnostic categories and procedures were based on the most relevant descriptive studies. The evidence selected for treatment outcomes was from systematic reviews, randomized controlled trials (RCT) and cohort studies, or consensus documents in the absence of higher level evidence. The model requires information that is available only after clinical consultation and therefore the relevance is restricted to the fraction of infertile couples who seek medical care.
Input assumptions
The input assumptions defined the diagnostic groupings, the proportion treated, the types of treatment and the ordering of treatment types. The diagnostic groupings shown in Table I were based on the unweighted average of reported distributions in secondary and tertiary care (Collins et al., 1995; Snick et al., 1997). The proportions in each diagnostic subgroup were from the tertiary care report because these subgroups were not reported from the secondary care report. For example, in the tertiary sample, 42% of the tubal abnormalities were tubal obstruction and 58% were other tubal abnormalities. When this ratio was applied to the 18.5% with tubal abnormalities in the average distribution, 7.7% 
were assumed to have tubal obstruction and 10.5% 
were assumed to have other tubal abnormalities. Cervical abnormalities, which were not identified in the tertiary clinic, were excluded from the secondary care clinic total (8% of couples) (Snick et al., 1997). The proportion of couples in each diagnostic category that chose not to have treatment was a similar unweighted average of the proportions in the same two descriptive studies (right-hand column of Table I) (Collins et al., 1995; Snick et al., 1997). Supplemental analyses were done to estimate the impact of having all couples undergo treatment.
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Procedural assumptions
The list of treatments for each diagnostic category and subcategory shown in Table II was developed from comprehensive reviews (ESHRE Capri Workshop Group, 1996, 1997, 2000; Philips et al., 2000). Couples undergoing treatment in each diagnostic category were assumed to initiate the least costly and complex treatment, and follow through the sequence of treatments to the most costly and complex, if no live birth occurred. One exception to the sequential treatment policy was in the treatment of ovulatory disorders. When live birth did not occur with clomiphene citrate treatment or gonadotrophins, then metformin plus clomiphene and laparoscopic ovarian diathermy were considered competing treatments. Although not typical of clinical protocols, this sequence ensures that more patients receive gonadotrophin treatment than either metformin with clomiphene or ovarian diathermy, both of which are used less commonly (ESHRE Capri Workshop Group, 2003). The sequence in other diagnostic categories was direct: all treated couples with no live birth after the first treatment proceeded to the next non-ART treatment.
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The duration of each treatment shown in Table II was drawn from published comprehensive reviews (ESHRE Capri Workshop Group, 1996
, 1997, 2000; ASRM Practice Committee, 2000; Philips et al., 2000). In the case of treatments administered for a specified number of cycles, an adjustment was necessary to account for the effect of treatment success on the average number of cycles. If a given treatment is usually prescribed for six cycles, for example, couples conceiving before the sixth cycle reduce the overall average number of cycles with that treatment. Thus, the average number of cycles is smaller with more effective treatments, as shown in Table III. Corresponding adjustments were made for three and four cycle treatment protocols.
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The model evaluated three levels of ART utilization. Among couples who had no live birth after completing the non-ART treatment protocol, the proportion who had IVF or ICSI treatment was set at 3, 10 or 50%. For each level of ART utilization, the non-ART treatments remained unchanged. The time frame for the treatment model was set arbitrarily at 3 years, because follow-up studies include too few subjects under continuing observation after 3 years (Collins et al., 1995
; Snick et al., 1997). Supplemental analyses evaluated more hypothetical levels of ART utilization. Output assumptions
The number of total live births, singleton live births and multiple live births was estimated for each diagnostic category and treatment. The denominator was 105 couples, which is approximately the number of infertile couples per 106 population in Western countries (ESHRE Capri Workshop Group, 2001). The proportion of couples in each diagnostic category was multiplied by the proportion undergoing that treatment, and then by the proportion of success for that treatment cited in the highest level evidence in the relevant medical care literature. Finally, total live births were divided into singleton and multiple births.
The non-ART treatment protocols are listed in Table IV, together with the associated live birth and multiple birth rates and the relevant study references. Where the relevant references provided only pregnancy rates, these were multiplied by 0.85 to obtain live birth rates. For an example of the calculations, with clomiphene citrate treatment in oligomenorrhoea, the live birth rate is 8% per cycle, which is multiplied by the average number of completed cycles from Table III (4.7 in this case) to obtain a 36% live birth rate, which corresponds to the rate in the largest reported follow-up study (Imani et al., 1999). The 36% live birth rate is then multiplied by the number of couples in the diagnostic group from Table I (16.6% of 105) and the proportion undergoing treatment (100% minus 18.0%) to obtain 511 total live births, of which 10% are multiple births and 90% singleton births. As noted above, those who do not have a birth go on to gonadotrophin therapy.
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For ART treatment, live birth rate per cycle initiated was considered to be the same for IVF and ICSI cycles and to remain constant in each diagnostic group during the first three cycles (Meldrum et al., 1998
). The ART-associated multiple birth rate per delivery was considered to be constant across diagnostic groups. ART outcomes were unweighted averages of two 1999 registry reports. The live birth rate for 63 639 IVF and ICSI cycles in the 1999 Society for Assisted Reproductive Technology registry was 25% per cycle initiated and 37% were multiple births (Society for Assisted Reproductive Technology American Society for Reproductive Medicine, 2002). The estimated singleton live birth rate was 16% per cycle initiated. The estimated live birth rate for 220 591 IVF and ICSI cycles in the 1999 ESHRE registry was 18% per cycle initiated and 26% were multiple births (European IVF-monitoring program European Society of Human Reproduction and Embryology, 2002). The estimated singleton live birth rate was 14% per cycle initiated. For the model, the unweighted averages were: live birth rate per cycle initiated 22%; multiple birth rate 32%; and singleton live birth rate per cycle initiated 15%. Supplemental analyses were carried out to evaluate scenarios that involved treating all couples, utilizing longer ART protocols and hypothesizing even further utilization of ART.
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Results |
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Approximately 41% of couples have no treatment, and the remainder have a sequential selection of treatments specific to each of the 10 diagnostic categories. The non-ART treatment protocol would be associated with 3725 live births, an overall live birth rate of 37% (Tables Va and Vb). Of the 3725 births, 3478 (93%) would be singleton and 247 (7%) would be multiple. Within treatment subcategories, the greatest number of births was in the untreated group with unexplained infertility (752 births) followed by clomiphene treatment for oligomenorrhoea (511 births). Few births would occur among untreated couples with amenorrhoea (one birth), azoospermia (eight births) or tubal obstruction (nine births).
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Of the 3725 births before ART treatment, 1287 (37%) would occur in the 4140 untreated couples, a birth rate of 31% in the untreated group. In 5861 couples undergoing treatment, there would be 2438 births (42%) with non-ART treatment. The remaining 3423 couples would be eligible for ART treatment. Tables Va and Vb shows that when 3% of these couples have ART, a further 162 births are added of which 32% are multiple births. With ART utilization at 3%, 279 couples have 732 cycles of ART and the total live birth rate per couple is 58.2%. The 732 IVF and ICSI cycles among 105 couples over 3 years is equivalent to 244 cycles per million population per annum (cpmpa).
The impact of ART utilization is shown in Table VI. With 3, 10 and 50% ART utilization by eligible couples, there would be 244, 813 and 1481 cpmpa respectively. The number of couples having ART would be respectively 4, 14 and 29% of the 5860 treated couples. The overall live birth rate rises from 37% with non-ART treatment to 39, 43 and 47% respectively with 3, 10 and 50% ART utilization among eligible couples. Multiple births also increase from 7% with non-ART treatment to 8, 10 and 12% respectively of total births with 3, 10 and 50% ART utilization.
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Supplemental analyses of hypothetical scenarios involving 105 infertile couples, all of whom receive treatment, are shown in Table VII. With a 50% ART utilization rate among couples who have not conceived with non-ART treatment, 30% of the couples receive ART, requiring 2572 cpmpa. ART accounts for 1711 (29%) of the 5941 births, and 51% of the 1080 multiple births, which are 18% of the total births. With a 100% ART utilization rate, 61% of the couples receive ART, requiring 5144 cpmpa. ART accounts for 3422 (45%) of the 7652 births, and 68% of the 1636 multiple births, which are 21% of the total births. With 100% ART utilization and a six cycle ART protocol, the same 61% of couples would require 7778 cpmpa and hypothetically the overall live birth rate would be 94%. However, 23% of the births would be multiple, and ART would account for 76% of the multiple births.
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Table VIII shows the distribution of singleton and multiple births by diagnostic group in the model that involved 10% utilization of ART treatment. The likelihood of both singleton and multiple birth is highest with amenorrhoea and oligomenorrhoea. With azoospermia, the likelihood of singleton but not multiple birth is above average, and in both endometriosis categories the likelihood of multiple birth, but not singleton birth, is above average. With tubal disease, the likelihood of any birth is less than one-half that in the average diagnostic group.
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Discussion |
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This model of the overall prognosis with current treatment of infertility was based on clinical trials and follow-up studies. Of course, models of the prevalence of disease and results of diagnosis and treatment that are not based on empirical observations necessarily entail numerous assumptions. Uncertainties about the range of prevalence and effectiveness are to be expected and the potential impact of such uncertainties can be consequential. Until empirical data are available, the model should be viewed as no more than a single estimate of the real situation. The overall likelihood of live birth without use of ART treatment is
37%, compared with 31% in the infertility clinic follow-up studies in Figure 1 (Frank, 1950; Turner et al., 1955; Horne, 1957; Southam and Buxton, 1957; Sloan, 1964; Raymont et al., 1969; Lamb and Cruz, 1972; Newton et al., 1974; Dor et al., 1977; Harrison, 1980; Sorensen, 1980; Thomas and Forrest, 1980; West et al., 1982; Verkauf, 1983; Kliger, 1984; Hull et al., 1985; Collins et al., 1986, 1993; Sundstrom et al., 1997; Che and Cleland, 2002). The 6% difference is not surprising: the model did not take attrition rates within and between non-ART treatments into account because they have not been published. In the non-ART model, couples in all diagnostic categories who initiate treatment continue treatment until ART is required. Approximately 41% of couples have no treatment, reflecting published observations (Wilcox and Mosher, 1993). The distribution of births among diagnostic groups makes clinical sense, with more births in women with ovulatory deficiency, which can be readily treated, and fewer in women with tubal disease, which is difficult to treat.
Assuming that ART utilization rates are 3, 10 and 50%, overall live birth rates would increase from 37% to 39, 43 and 47% respectively. Thus, ART births would account for two of the 39 percentage points with 3% ART utilization, for six of the 43 percentage points with 10% ART utilization and for 10 of the 47 percentage points with 50% ART utilization. As expected, the better outcomes were associated with more multiple births: from 7% with non-ART treatment to 8, 10 and 12% of all births respectively, with ART utilization rates at 3, 10 and 50%. The 3 and 10% ART utilization rates were set to approximate reality in North America and Northern Europe. Three per cent ART utilization corresponds to 244 cpmpa, compared with estimates of 196 cpmpa for Canada and 126 cpmpa for the USA in 2002 (Collins, 2002). Ten per cent ART utilization corresponds to 813 cpmpa, compared with 943 cpmpa (including cryopreservation and oocyte donation cycles) in eight Northern European countries in 1999 (European IVF-monitoring program European Society of Human Reproduction and Embryology, 2002). Fifty per cent ART utilization was considered optimal in a recent review, assuming that one-half of couples eligible for insurance-covered ART might give up the opportunity for personal reasons (ESHRE Capri Workshop Group, 2001). Even this optimal protocol of current treatment for infertility would fall short of 50% success, however, unless untreated couples were excluded.
In the hypothetical models which include only treated couples, success rates are 59% with 50% utilization of ART, 76% with 100% ART utilization, and 94% if there were 100% utilization of a six cycle ART protocol. The high levels of success involve extensive deployment of empirical ART treatments at levels that are >10-fold higher than North America in 1999 (Society for Assisted Reproductive Technology American Society for Reproductive Medicine, 2002) and 3–9-fold higher than the 1999 average in Northern Europe (European IVF-monitoring program European Society of Human Reproduction and Embryology, 2002). Given that the higher level of success is due mainly to ART treatment, the attendant multiple birth rates in treated couples are also high: 10, 16 and 22% respectively with 50% utilization of ART, 100% ART utilization with a three cycle protocol and 100% ART utilization with a six cycle protocol. Note that these are percentages of all births, not just ART births.
The 50% ART utilization model requires exceptional deployment of ART. To achieve a 47% live birth rate would involve 1706 couples undergoing 4443 cycles in 3 years or 1481 cpmpa. This level of ART availability in the population has been reported from very few countries: Israel, Denmark, Finland and Iceland (Collins, 2002; European IVF-monitoring program European Society of Human Reproduction and Embryology, 2002). The ART utilization required in the all-treatment models shown in Table VII would range from 2500 to 7800 cpmpa, and such levels of utilization may not be achievable with present ART technology and currently available services. Even to achieve only 1400 cpmpa would require an 8-fold higher utilization of ART in North America and a 2-fold increase in Northern Europe (Collins, 2002).
The extensive deployment of costly ART to achieve live birth rates >50% may give rise to economic and commitment issues. While the present model did not assess cost, it has been reported previously that the estimated average cost per IVF/ICSI cycle in 2002 was US$9547 in the USA and US$3518 in 25 other countries (Collins, 2002). An 8-fold increase over 65 000 cycles per annum in the USA would cost US$5 billion (Society for Assisted Reproductive Technology American Society for Reproductive Medicine, 2002). A 2-fold increase over 220 000 cycles per annum in Europe would cost nearly 
2 billion (European IVF-monitoring program European Society of Human Reproduction and Embryology, 2002). Although the high cost may be one deterrent to large increases in utilization, it is also questionable whether 50% of all couples with persistent infertility would be prepared to make such a commitment to ART.
The desirable objective of treatment for infertility is a healthy child, an outcome best indicated by the singleton live birth rate. The singleton live birth rates were 35, 36, 38 and 41% respectively with 0, 3, 10 and 50% ART utilization. The corresponding multiple birth rates were 7, 8, 10 and 12% of all births. The 12% multiple birth rate in the 50% ART utilization model is a serious increase over 7% without ART when it is considered that this rate applies to all births, not just those among couples undergoing ART. The higher morbidity and mortality of multiple births is a further economic burden of increased ART utilization, at least as ART is presently practised.
The models show that many infertile couples would not conceive within a 3 year interval and some would never conceive. Achieving <50% overall success with optimal use of current treatment is an indication that much information is missing with respect to the causation, diagnosis and management of infertility. In some diagnostic groups, specific treatment theoretically should restore normal fertility. Indeed, the induction of ovulation for amenorrhoea did achieve the highest level of success (78% of couples in the 10% ART model). More than 20% did not have a live birth, however, although only 7.5% did not have treatment. This shortfall appears to reflect the existence of associated fertility defects, only some of which are detectable with available tests. When amenorrhoea and azoospermia are present, they are likely to be true causes of the infertility, and specific treatment is associated with marked improvements. Amenorrhoea and azoospermia account, however, for <10% of a typical infertility clinic case load. With tubal disease, treatment also is imperfect: live birth rates were <25%, despite extensive treatment, reflecting deficiencies in knowledge of tubal disease. In other categories, treatment is empirical in all cases (unexplained infertility), or many cases (oligozoospermia, endometriosis). Even the models with all couples treated fall short of complete success, indicating the possibility that many apparent causes of infertility are not true causes, and that many apparently specific treatments are empiric rather than specific. Missing information about the true causes of infertility severely limits knowledge of the prognosis for successful conception and live birth and hinders the selection of specific treatment. Clearly, research is needed to discover the underlying unknown and therefore untreated factors that remain barriers to greater success in the treatment of infertility.
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