Hum. Reprod. Advance Access originally published online on May 11, 2006
Human Reproduction 2006 21(8):1945-1950; doi:10.1093/humrep/del138
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NEW DEBATE |
A formal comparison of the practice of assisted reproductive technologies between Europe and the USA
1 Center For Human Reproduction, New York, NY 2 Foundation for Reproductive Medicine, Chicago, IL 3 Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT and 4 Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY, USA
5 To whom correspondence should be addressed at: Center for Human Reproduction, 21 East 69th Street, New York, NY 10021, USA. E-mail: ngleicher{at}thechr.com
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Abstract |
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In this study, we compared pregnancy and delivery outcomes after the utilization of assisted reproductive technologies (ART) in Europe and the United States (US). ART outcomes were compared between Europe and the US for the year 2001, based on formal reports published by the European Society for Human Reproduction and Embryology (ESHRE) and the Center for Disease Control and Prevention (CDC) in collaboration with the American Society for Reproductive Medicine (ASRM) and Society for ART (SART). Europe utilizes ART at approximately twice the rate of the US (P < 0.001). United States patients showed a significantly decreased likelihood of reaching oocyte retrieval (P < 0.001) and embryo transfer (P < 0.001). Despite this lower chance of reaching oocyte retrievals and embryo transfers, US patients experienced significantly higher clinical pregnancy rates (P < 0.001) and delivery rates per started cycle (P < 0.001) than European patients. Amongst patients reaching oocyte retrieval, the difference in clinical pregnancy rates and live birth rates was even more pronounced in favour of the US. However, US patients received significantly more embryos per embryo transfer (P < 0.001) and experienced a significantly higher multiple pregnancy rate (P < 0.001). Significant differences in favour of US patients in pregnancy rates and live birth rates were also observed for frozen embryo cycles and oocyte donation cycles, where the difference was most pronounced. The better pregnancy and live birth outcomes in the US are not explainable by the transfer of larger embryo numbers alone.
Key words: assisted reproductive technologies (ART)/Europe/IVF/pregnancy rates/United States
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Introduction |
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‘We have to face the fact that they are doing a pretty good job.’Dr Anders Nyboe Andersen, Coordinator of the European, IVF Monitoring Program [when asked why IVF rates in the USA remain consistently higher than in Europe (Johnson, 2005
)].
The way in which assisted reproductive technologies (ARTs) are practiced in the United States (US) and Europe differs in many ways. This is reflected in significant outcome variations between the continents (Center for Disease Control and Prevention, 2003; Andersen et al., 2005). Many of these differences are quite obvious, while others are not. For example, in Europe, ART often represents an insurance-covered benefit, whereas in the US it often is not (Gleicher et al., 1996; IFFS Surveillance, 2001, 2004). Whether insurance coverage is offered has been demonstrated to affect practice patterns (Jain et al., 2002). Indeed, in countries where ART is offered as a standard benefit (e.g. the Scandinavian countries), one would expect the approach to IVF to differ significantly from countries where, in principle, only the financially better off can afford it (i.e. the US). Probably the most significant differences between the US and Europe exist, however, in the regulatory environment under which ART is practiced. Paradoxically, Europe, which literally gave birth to the first ART pregnancy (Edwards et al., 1980), and which has innovated ART ever since, has, in comparison to the US, chosen a more regulatory route.
This means that in many European countries ART practices, routinely performed in the US, are prohibited. Examples are as follows: European prohibitions to treat single women, to cryopreserve human embryos (either at all, or beyond single cell stage), to select embryos (i.e. discard embryos of poorer quality), to conduct oocyte donation cycles, to pay oocyte donors (in some countries only oocyte sharing with infertile patients is permitted, a practice which in the US paradoxically is generally frowned upon because it is considered coercive), to donate embryos and perform preimplantation genetic diagnosis (PGD) (Human Fertilisation and Embryology Act, 1990; German Act, 1990; Bernat and Straka, 1992; Bernat and Vranes, 1993; IFFS Surveillance, 2001, 2004). Some countries even legislate maximal embryo numbers, to be transferred, and consider breaching felonies (German Act, 1990). Others prohibit the cryopreservation of embryos for more than a pre-specified number of years, after which time they have to be discarded by law (Human Fertilisation and Embryology Act, 1990; Hamberger and Wikland, 1993).
Although controversial amongst many health care providers and patients, alike, such regulatory interventions have, however, also received surprising support. For example, an attempt to refute Europe’s most restrictive ART laws in Italy has recently failed, despite evidence that it has negatively affected ART outcomes (Cattoli et al., 2005; Feraretti et al., 2005; Levi Setti et al., 2005; Ragni et al., 2005; Rienzi et al., 2005). In Europe, organized medicine, indeed, at times, quite vocally supports government interventions (Braat et al., 2005), whereas in the US the medical profession usually opposes state interference (Adamson, 2002). The more aggressive drive towards single embryo transfer (SET) in the Europe is a recent example for this political discrepancy, with some European authorities, once again, advocating legal mandates (Braat et al., 2005).
Higher anecdotal pregnancy rates in the US have historically been attributed to the transfer of larger embryo numbers. This assumption has, however, never before been formally tested. Indeed, except for very limited comparisons (Fauser et al., 2005), US and European outcome data have never been formally compared, and reported outcome differences have never been formally explained. Because Europe and the US are now reporting annual ART outcomes, (Center for Disease Control and Prevention, 2003; Andersen et al., 2005) the latest such reports, available for both continents, and representing ART cycles performed during the year 2001, were utilized to conduct a formal comparison of ART outcomes.
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Materials and methods |
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European outcome data for ART procedures are now reported annually by the European Society for Human Reproduction and Embryology (ESHRE). The society’s last report was issued in 2005 for cycle data produced in the year 2001 (Andersen et al., 2005
). In the US, the Center for Disease Control and Prevention (CDC), in collaboration with the American Society for Reproductive Medicine (ASRM) and the Society for ART (SART), have been publishing a National Summary and Fertility Clinic Report on ART success rates for many years under a federal legislative mandate. US statistics for the year 2001 were published in 2004 (Center for Disease Control and Prevention, 2003) CDC and ESHRE publish their respective ART statistics in varying formats. Consequently, a direct comparison of data is not always possible. At times, the presented data allow for the extraction of additional data for the purpose of analysis. When this became necessary, the detailed process by which data were extracted and re-calculated is disclosed and described. ESHRE data were, at times, incomplete because some countries did not report all outcome parameters. ESHRE, in such instances, reported outcomes for compliant countries but did not summarize a complete ‘European-experience’, reflective of all 23 countries that had reported data to ESHRE. When this happened, we re-calculated a ‘European-experience’ based on countries that had reported data. Such re-calculations involved data from France and Iceland, which did not report the number of fresh, non-donor cycle starts, and of the Netherlands, which did not report live birth rates.
As some of the published percentage distributions in ESHRE data did not add up to 100%, where such an error exceeded 2% of a country’s total population—that country’s results were excluded from calculating the ‘European-experience’.
The statistical evaluation of comparisons between European and US outcomes was performed using standard statistical tests, utilizing SPSS for Windows, Standard Version 10.0.7 (SPSS Co., Chicago, IL, USA). A statistical difference was considered significant at a P-value of <0.05.
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Results |
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The here reported data are based on outcomes from 384 ART centres in the US and 579 in Europe. On both continents not all ART clinics reported their outcomes. A total of 107 587 cycles were subject to analysis in the US and 289 690 cycles in Europe.
Considering total patient populations in the evaluated geographic zones, the US conducted approximately 414 ART cycles per million citizens and Europe almost exactly twice as many at 829 per million (P < 0.001).
The European report did not contain summaries for age distribution because not all countries reported such data to ESHRE. Therefore, a comprehensive comparison of patient age distributions between the continents could not be made. A limited comparison was, however, possible after various corrections were made.
Specifically, Finland, Ireland and the UK experiences had to be omitted because their respective age distributions did not add up to 100% and the error exceeded 2% of the population. The subsequent comparison of age distributions between the continents suggested that the US population was slightly older. This conclusion could be reached because the age group between 30 and 39 years represented an identical 69% of total populations in the US and in Europe, whereas the age group under 35 years represented 56% of the European but only 45% of the US population (P < 0.001). Above age 39, the US and Europe report outcomes in different age groupings which do not allow for comparisons.
Europe also did not report the underlying indications for entry into ART, prohibiting an aetiological comparison of patient populations. Neither Europe, nor the US, reported duration of infertility. Although unlikely, differences in population characteristics can, therefore, not be ruled out.
Although Europe did not report the total number of fresh non-donor cycle starts (80 864 in the US), it was possible to calculate a total cycle number, excluding the two non-reporting countries, France, Iceland and the Netherlands, which did not report live birth rates. When this was done, Europe reported 176 152 cycles, over twice the US number.
Both reports included detailed numbers for ART cycles reaching oocyte retrieval/oocyte aspiration (Table I). Although Europe conducted a much larger number of retrievals (162 952) in comparison with the US experience (69 515), the percentages of cycles utilizing ICSI were remarkably similar at 49.9% and 49.4%, respectively. Similarly, as a percentage of retrievals, the number of patients reaching embryo transfer was remarkably similar at 94.1 and 94.0%, respectively (Table I). Table II presents the pregnancy cycle outcomes of fresh, non-donor cycles as a percentage of cycle starts. US patients demonstrated a significantly lower likelihood of reaching oocyte retrieval (US 86.0% versus Europe 92.5%; R = 2.02; 95% CI 1.96–2,07; P < 0.001) and embryo transfers (US 80.8% versus Europe 87.0%; R = 1.59; 95% CI 1.55–1.62; P < 0.001). This European advantage was, however, lost once pregnancy rates were compared. Indeed, the US results demonstrated a significantly higher clinical pregnancy rate per cycle start (32.8%) in comparison with Europe (24.3%; R = 0.66; 95% CI 0.64–0.67; P < 0.001). Similarly, the US live birth rate (27.0%) significantly exceeded the European rate (17.4%; R = 0.57; 95% CI 0.56–0.58; P < 0.001).
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Table III summarizes pregnancy and live birth rates as a percentage of oocyte retrievals and embryo transfers. Even though all European countries reported this statistic, in order to maintain consistency of the European data, the European experience was compared to the US data, once again, excluding the data from France, Iceland and the Netherlands. Clinical pregnancy rates were 38.2% in the US and 26.2% in Europe (R = 1.74; 95% CI 1.70–1.77; P < 0.001). As a percentage of embryo transfers, the respective percentages were 40.6 and 27.9% in favour of US results (R = 1.77; 95% CI 1.73–1.80; P < 0.001). A significantly higher percentage of pregnancies (82.2%) reached delivery in the US than in Europe (71.6%; R = 1.83; 95% CI 1.76–1.90; P < 0.001).
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A comparison of embryo numbers transferred is summarized in Table IV. The US experience reflected statistically fewer single embryo transfer cycles (P < 0.001), two-embryo transfer cycles (P < 0.001) and more three- (P < 0.001) and four/plus-embryo transfers (31.9% US versus 5.5% Europe; P < 0.001). The US experience demonstrated also a statistically higher multiple pregnancy rate (38.6%) than the European data (25.5%; P < 0.001).
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Table V summarizes the experiences with frozen embryo cycles. The European data did not list the number of cycle starts, but both data sets listed the respective number of embryo transfers (US 12 700 and Europe 41 583, respectively). These numbers reflected in the US experience 16.3% of all fresh and frozen non-donor embryo transfers and in the European experience 18.0% (R = 1.13; 95% CI 1.11–1.16; P < 0.001). The European data reflect only clinical pregnancy rates, whereas the US reports only live birth rates. The two data sets are, therefore, statistically not comparable. However, because live birth rates are uniformly lower than pregnancy rates, it seems obvious that clinical pregnancy rates after frozen embryo transfer are higher in the US than in Europe. Indeed, if the same discrepancy between pregnancy rate and delivery rate of 28.4% is hypothetically calculated for these frozen cycles, as was observed in the European experience for fresh cycles, the live birth rate per embryo transfer in the European experience would be only 11.7% in comparison with a 17.2% rate in the US data. Such a difference, if statistically comparable, would be highly significant.
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Table VI presents a comparison in oocyte donation cycles. Such cycles represented 9.7% of the complete US fresh cycle experience, but only 3.4% of the European experience (R = 0.32; 95% CI 0.31–0.33; P < 0.001). Once again, the European experience reports only pregnancy rates, whereas the US data show only live births. The data sets can, therefore, not be statistically compared. The numbers, however, also once again, clearly demonstrate higher pregnancy rates in the US experience, as live birth rates in the US exceed pregnancy rates in Europe quite dramatically. If, once again, a hypothetical calculation is made, assuming a 28.4% reduction in deliveries from pregnancy rates, as the fresh IVF cycle experience in Europe demonstrated, then the presumptive live birth rate after oocyte donation in Europe would be 23.9%, approximately half the US rate of 47.0%. If statistically comparable, such a difference would be highly significant.
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Discussion |
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The here presented comparison between European and US ART outcome data presents strong evidence that ART outcomes, if judged based on pregnancy and delivery rates, are significantly higher in the US than in the European experience. Indeed, these outcome differences are apparent in all ART cycle formats, that is, fresh-, cryopreserved (frozen-thawed) and oocyte donation cycles.
The data also suggest that outcome differences involve pre-retrieval cycle management as well as post-retrieval activities. For example, although European patients had a significantly higher chance of reaching oocyte retrieval (i.e. a significantly lower risk of cycle cancellation before retrieval), once retrieval was reached all further outcome parameters deteriorated to the disadvantage of European patients.
These findings suggest that Europe is more hesitant to cancel ART cycles than the US. Why that might be the case is open to speculation but may, to at least some degree, explain the poorer pregnancy outcomes in Europe because ART cycles with poor response parameters often not only produce low oocyte numbers but, frequently, also result in poor oocyte and embryo qualities (Pellicer et al., 1987).
Differences in insurance coverage and pregnancy as well as delivery rates, probably explain why Europe shows twice the utilization of ART procedures of the US. This, of course, raises questions about the cost-effectiveness of the European approach towards ART. Because of many legal and regulatory restrictions, European data on frozen embryo transfers and oocyte donations are difficult to interpret. For example, if oocyte donations in Europe, in some countries, have to come from infertile women, the US, where oocyte donors are usually young, healthy and fertile, can be expected to demonstrate an outcome edge. Indeed, the most dramatic differences in pregnancy rates between the two continents, considering all forms of ART, are seen in oocyte donation cycles where patient variability should be the smallest and differences should, therefore, be only minimal. After all, given an ideal choice, oocyte donors, in principle, should be young, healthy and fertile (Cohen et al., 1999).
It is difficult to ascertain one explanation for these rather vast differences in pregnancy outcomes between the continents. The difference in regulatory environments can, however, be assumed to play a role. That legislative interventions can adversely affect ART outcomes has been well demonstrated in the Italian model (Ragni et al., 2005). Legislative restrictions can also lead to outcome distortions due to medical tourism. An increasing number of European patients, indeed, appear to have become medical tourists in response to lack of service offerings in their own countries (Storrow, 2005). Medical tourism can serve as a ‘safety valve’ for patient demand (Pennings, 2004) but usually leads to patient migration from higher towards lower quality services. The overall outcome shift will be, therefore, negative. Such a trend has, indeed, been observed (Storrow, 2005).
Some of the here reported outcome differences may, after all, still be due to differences in patient populations. Unfortunately, CDC and ESHRE collect and report ART outcome data differently. Therefore, direct comparisons are not always possible. Moreover, neither data set, as published, allows for a detailed correction for patient ages and underlying aetiologies that have led patients into ART. CDC data report aetiologies but ESHRE does not. Moreover, neither party reports length of infertility. The published data on both sides of the Atlantic also do not allow for a comparison of ethnicity. Recent data suggest that Asian and African women may have poorer ART outcomes than Caucasian patients (Gleicher and Barad, 2006).
Available, published data suggest, however, that patient populations in Europe and the US are, indeed, surprisingly similar. For example, age, and available aetiology, data, such as the practically identical prevalence of ICSI cycles, suggest that population characteristics between the continents are very similar and that, therefore, data outcomes can, indeed, be compared. Both organizations would, nevertheless, be well advised to standardize data collection and reporting in order to facilitate better comparisons.
The study confirms that the US transfers more embryos than Europe (Table IV). Indeed, only 33.5% of US, and 63.7% of European, cycles received one or two embryos. In contrast, almost twice the number of patients had three or four embryos transferred (66.4%) in the US than in Europe (36.3%). In addition, multiple pregnancies were significantly more frequent in the US (38.6%) than in Europe (25.5%).
These observation lend credence to the argument that the higher US pregnancy rates may be the consequence of larger embryo transfer numbers (Toner, 2002). Multiple pregnancy rates, especially if of high order (triplets or more), are now considered avoidable and an indicator of poor quality of care (Templeton and Morris, 1998) because multiple births are associated with increased perinatal morbidity, mortality and cost (Gleicher et al., 2000).
This study, however, also strongly suggests that the larger number of embryos, transferred in the US, may, at most, be responsible for only a small part of the outcome difference between the continents: Templeton and Morris (1998) were the first to report that pregnancy rates practically peak with the transfer of two embryos and that the transfer of larger embryo numbers in younger women did not further increase pregnancy rates. This fact has since been confirmed in a number of studies and, indeed, is also confirmed by the CDC data for the 2001 US experience (Center for Disease Control and Prevention, 2003).
The biggest difference in embryo transfer numbers was observed in women who received four or more embryos. This group represented 31.9% of US women and only 5.5% of European patients. Voluntary embryo transfer guidelines in the US call for such an increase with advancing female age (American Society for Reproductive Medicine, 1999; Adamson, 2002) and are based on the observation that the transfer of larger embryo numbers will, for all practical purposes, only affect pregnancy rates in older women, where larger embryo numbers, indeed, may marginally improve outcomes (Barlow, 2005).
As noted before, in this comparison the US population appeared marginally older. This fact alone warrants, therefore, slightly larger embryo transfer numbers. However, US data also suggest that women above age 39 represented only approximately 15% of the total US cycle volume. Because IVF cycles in women at advanced ages result in lower pregnancy rates, whatever impact the transfer of larger embryo numbers in older women may have had on the overall US experience, it can not explain, but a small fraction, of the outcome differences noted.
If the number of embryos transferred was, indeed, decisive, one would also expect to see more cryopreservation where fewer embryos are transferred. The European data does not demonstrate such a compensatory increase in frozen embryo cycles (18.0% in comparison with the 16.3% US rate), although because of legislative restrictions cryopreservation data in Europe are difficult to interpret.
The here presented data suggest, in summary, that ART cycle management patterns in Europe and the US are distinctively different. These differences appear primarily driven by greatly diverging regulatory environments on both sides of the Atlantic and, at least based on pregnancy rates, do not appear to benefit the European population. European practice patterns, of course, result in fewer multiple births and may allow wider access to care than the US.
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Submitted on January 9, 2006; resubmitted on January 25, 2006; resubmitted on February 15, 2006; accepted on February 17, 2006.
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