全文

Design
Cross-sectional survey on access, effectiveness, and safety of ART procedures performed in 53 countries during 2005.

Setting
A total of 2,973 clinics from national and regional ART registries.

Patient(s)
Infertile women and men undergoing ART globally.

Intervention(s)
Collection and analysis of international ART data.

Main Outcome Measure(s)
Number of cycles performed by country and region, including pregnancies, single and multiple birth rates, and perinatal mortality.

Result(s)
Overall, 1,052,363 ART procedures resulted in an estimated 237,315 babies born. The availability of ART varied by country from 15 to 3,982 cycles per million of population. Of all initiated fresh cycles, 62.9% were intracytoplasmic sperm injection. The overall delivery rate per fresh aspiration was 19.6% and for frozen embryo transfer 17.4%, with a cumulative delivery rate of 23.9%. With wide regional variations, single embryo transfer represented 17.5% of cycles, and the proportion of deliveries with twins and triplets from fresh transfers was 23.6% and 1.5%, respectively.

Conclusion(s)
Systematic collection and dissemination of international ART data allows patients, health professionals, and policy makers to examine and compare the impact of reproductive strategies or lack of them as markers of reproductive health.

Key Words
ART; assisted reproductive technology; registry; outcomes; multiple births; public health; IVF


 

This is the 11th world report on assisted reproductive technology (ART), produced by The International Committee for Monitoring Assisted Reproductive Technology (ICMART). Similar reports have been generated and published since 1989 by the International Working Group on Assisted Reproduction, later renamed ICMART. The last communication on world data included ART cycles performed during 2004 (1). The aim of this report is to provide international information on availability, effectiveness, and perinatal outcomes of ART treatment cycles performed during 2005 and babies born during 2006. It is also our aim to describe how these biomedical markers are influenced by regional characteristics. As we have shown in previous world reports, there are marked national and regional differences in access to ART by infertile couples, which ultimately influence the way in which ART is practiced 1 and 2.

Materials and methods
The data corresponding to ART treatment cycles performed during 2005 were collected from five regional ART registries compiled from national registry data in Europe and North America and from individual ART clinics gathered together in a regional registry in Latin America, Australia/New Zealand, and the Middle East, and from national registries directly reporting to ICMART in Asia and Israel. Institutional review board approval was not obtained by ICMART because such approvals were obtained as appropriate in individual countries, no individual data were submitted, and only aggregated national data were reported to ICMART.

The ICMART data collection uses forms describing the organization of each country's register, the practice of ART, and the results of IVF, intracytoplasmic sperm injection (ICSI), and frozen embryo transfer (FET), and includes initiated cycles, follicular aspirations, ETs, clinical pregnancies, deliveries, and newborns. Whenever available, these variables are further classified according to the fertilization technique, woman's age, number of embryos transferred, and gestational age at delivery. Other forms describe preimplantation genetic diagnosis (PGD), oocyte donation (OD), immediate complications for women, and congenital anomalies detected during the perinatal period. The ICMART forms for data collection can be found at www.icmartivf.org.

During the reported period (2005–2006), the 2002 ICMART–World health Organization ART glossary was used as the reference for terminology (3). The present report covers ART cycles performed during the year 2005 and is based on aggregated country data, which, after collection, were transferred to the Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden, where data were checked for consistency and a statistical report was generated. The delay in reporting data is partially due to delay in countries collecting their own data, logistical difficulties in international data collection, ICMART's development of new formats and procedures, and the transition of ICMART data collection to involve the University of Uppsala, Sweden.

Data are presented by country and region. In countries missing some data, estimations were made according to the following premises. [1] When the number of initiated cycles was unavailable, an estimation of this number was made by adding the average cycle cancellation rate (6.5%) to the number of aspiration cycles. For national registries with incomplete coverage, the number of initiated cycles per country was estimated by dividing the reported number by the percentage of participating clinics as reported or estimated by each country. [2] The number of babies born, when not reported by a registry, was estimated by using the reported clinical pregnancy rate (PR), average miscarriage rate, and multiple live birth rates in those countries that reported all of those variables. Finally, the total number of babies born worldwide from 2005 ART procedures was estimated by using the hypothesis that the missing countries, mostly in Asia, Africa, Oceania, and West Indies, performed between 10% and 20% of the world activity in ART. [3] Availability is expressed as the number of cycles (estimated) per million inhabitants in 2005. [4] The cumulative delivery rate (DR) per aspiration was calculated by adding the FET deliveries to those obtained from fresh transfers and dividing the sum by the number of aspirations.

Results
The results are presented in Table 1, Table 2, Table 3 and Table 4. Additional results are provided in Supplemental Tables 1–6 and Supplemental Figures 1–6, which are available online.























 

Availability
Data were received from 2,973 clinics in 53 countries in 2005, comprising more clinics and one more country than in 2004 (1). These clinics represented 78.8% of all registered clinics in those countries. Europe had the largest number of reporting clinics at 923 (39%), followed by Asia with 875 (37%) and North America with 370 (15.6%). The size of the reporting clinics also had geographic variations. Clinics reporting <100 cycles were mainly located in Asia (59.9%) and Latin America (43.8%). Nearly 20% of clinics performed >500 cycles per year, but large-sized clinics (>1,000 cycles) were mainly located in Australia/New Zealand (37.9%) and Israel (29.2%). Twenty-seven countries distributed in every continent could provide data on >90% of cycles that were performed in their country (Supplemental Table 1).

Table 1 reports an estimated 1,052,363 treatment cycles from participating clinics, which represented a 10.2% increase in cycles since 2004. The availability of ART varied from 15 and 19 treatment cycles per million inhabitants in the Dominican Republic and Ecuador to 3,982 per million inhabitants in Israel. Japan reported the largest number of aspirations, with 85,859 procedures, followed by the United States and France with 75,859 and 51,413, respectively. On a regional basis, Europe made the largest contribution of aspirations (56%), followed by Asia (23.3%) and North America (15.4%). Frozen embryo transfers represented 28.2% of the initiated cycles (30% in 2004). Globally, ICSI represented 63% of fertilization procedures, an increase from 60.6% in 2004, and varied according to regions. The proportion of ICSI procedures was 64% in Europe, 66.3% in North America, and 81.1% in Latin America.

Effectiveness
Table 2 reports on the outcomes of ART procedures. Pregnancy rates and DRs per aspiration were similar in IVF and ICSI: PR 29.8% vs. 28.9% and DR 20.3% vs. 19.2%, respectively. For FET cycles, the number of transferred embryos, effectiveness, and multiplicity are reported in Supplemental Table 2. Compared with 2004, the DR for FET cycles increased slightly, from 16.6% to 17.4%. The DR per aspiration varied among countries (Supplemental Figs. 1 and 2); and as expected, the cumulative DR per aspiration also varied among countries, with the highest in North America (38.0%). When combining IVF and ICSI fresh cycles (Table 3), DR per aspiration followed a slight but promising trend. In 2004 DR was 28.1% and a mean of 2.35 embryos transferred, whereas in 2005 DR was 28.5% but the mean number of embryos transferred decreased to 2.29. The overall cumulative DR (fresh plus frozen cycles) decreased from 24.3% in 2004 to 23.9% in 2005. The miscarriage rate per clinical pregnancy (Table 4) averaged 20.8% in fresh cycles, essentially the same as in 2004. The proportion of miscarriages in pregnancies generated by FET also remained essentially unchanged (24.6% in 2004 and 25.0% in 2005).

A total of 237,315 babies (Table 2) were reported born in 2005. For technical reasons, Table 2 does not include 19,100 babies born in Japan. This number has been officially confirmed by the Japan national registry (4). The proportion of women aged ≥40 years was 15.4% (similar to 14.9% in 2004) and varied among regions, from 12% in Asia to 21.3% in Australia/New Zealand and 19.1% in the Americas (Supplemental Table 3).

Safety and Quality
The proportion of single embryo transfers (SETs) increased from 16.3% in 2004 to 17.5%, with the highest levels reported by Sweden (69.4%), Finland (49.7%), and Belgium (48.0%) (Table 3). The proportion of twin deliveries decreased from 25.1% in 2004 to 23.6%, whereas the proportion of triplet deliveries continued to decrease, from 1.8% to 1.5%. However, these rates differed largely among countries: the percentage of twin births ranged from 6.1% in Sweden to 37.9% in Taiwan. Furthermore, the births of triplet and higher-order multiples ranged from 0 to less than 0.5% in several countries (including Sweden, Belgium, Australia, New Zealand, Norway, Denmark, France, and South Korea) to 2% to 6% in several countries in Latin America, the Middle East, and selected countries in Europe, such as Italy, Hungary, and Albania. The proportion of higher-order multiples was even higher in countries with few treatment cycles per year, such as Ecuador and the Dominican Republic (Supplemental Fig. 1). Similar rates of multiple deliveries were seen for FET, with twins at 16.1% and triplets at 0.9% (Supplemental Table 2).

The percentage of transfers with four or more embryos in fresh cycles decreased from 11.6% in 2004 to 9.8%, but with major differences among and within regions (Table 3). The lowest proportion of three or more embryos transferred was in Australia/New Zealand with only 2.4%, followed by Europe with 23.8%, and the highest in the Middle East and Asia with 72.8% and 73%, respectively. The mean number of ETs was lowest in Finland, Sweden, Australia, and Denmark, fluctuating between 1.3 and 1.72 embryos, whereas in Taiwan and South Korea as well as several countries in Latin American and the Middle East the mean number of ETs ranged between 2.5 and 3.4 embryos (Table 3). Supplemental Figure 3 provides the DR per aspiration, according to the mean number of ETs by country. It shows a great variability in the number of embryos required to reach a certain DR. Different countries require different numbers of embryos to reach a specific DR (Supplemental Figs. 2 and 3).

The proportion of premature delivery per IVF and ICSI was 26.6% for fresh transfers and 16.3% for FET, which is much lower than in 2004 (33.7 and 26.3%, respectively). The perinatal death rate was 23.2 per thousand births for fresh aspiration for IVF and ICSI, compared with 10.0 per thousand births for FET (Table 4). These data must be interpreted with caution because no data from European countries were available on these birth outcomes, and this may bias the results. The frequency of ovarian hyperstimulation syndrome (OHSS) was reported as 1.1%, with a regional range of 0.1%–7.2% (Supplemental Table 4). Again, these data must be interpreted with caution because the criteria to register and report OHSS can vary among countries and regions. The high level of OHSS (7.2%) reported in Asia is largely due to the 24.6% of cycles with OHSS reported by Taiwan, which could result from a different definition of the condition.

Special Techniques—OD, PGD, In Vitro Maturation, Surrogacy, and Multifetal Reduction
There were 30,861 OD transfers, an increase from 26,765 in 2004 (Supplemental Table 5). Of these transfers, 41.2% were performed in the United States, followed by Spain with 17.2%. Additionally, 71.0% were FETs. When adding fresh plus frozen transfers, DRs were 46.5%, with the United States highest at 54.7%. The multiple DR from OD transfers was 35.8%; and from the 13,947 babies reported from OD, 8,180, were born in United States, which represents 58.7%. Twenty-five countries reported 8,551 aspiration cycles with PGD, with a PR and DR per aspiration of 28.7% and 19.5%, respectively. A total of 1,837 babies were born after PGD (Supplemental Table 6). Very few data were reported on in vitro maturation, surrogacy, and multifetal reduction.

Discussion
The 2005 ICMART world report is the most comprehensive global statistical report on ART practice and includes measures of effectiveness, safety, and quality of services. In 2005 an estimated 1,052,363 ART cycles were reported by 2,973 clinics, resulting in an estimate of 237,315 babies. This number represents a drop of 494 babies born with respect to 2004. This marginal drop in the number of babies born does not mirror the 10.2% increment in the number of initiated cycles and clinics and likely reflects changes in therapeutic strategies, with an increase in the proportion of cycles with SET and a consequential drop in the number of twins and high-order multiple births.

Monitoring of ART practice, effectiveness, and outcomes at an international level is central to improving fertility services and outcomes worldwide and to monitoring the impact of policy initiatives, such as SET, over time. It is important to monitor ART to determine availability and access to fertility services, the benefits and risks of new technology, and the changes in practice, as well as to benchmark treatment and perinatal outcomes. The latter is critical to developing comprehensive statistics to inform policy and planning of ART-related health care and to provide an evidence base on ART for populations seeking fertility treatment. In this as well as in previous publications, we have endeavored to standardize reporting to allow the reader to follow trends over time.

Availability
One way of measuring access to ART is the number of countries that provide ART services. In 2005, 53 countries reported different ART procedures. There is indeed underreporting from Asia, Africa, and the Middle East. However, there is very accurate reporting from North and Latin America, Australia and New Zealand, Israel, and most European countries. Some countries have not supplied data to this report even when there are ART services available. The policy of ICMART is to include countries and not independent centers. In this context, efforts are made to help countries to start national and regional registries. Such is the case of the Middle East registry and the South African ART registry. The major difficulty, however, stems from the fact that in many countries infertility is not considered a disease, and there is little governmental interest to register a medical intervention that is socially controversial and not covered by their women's health programs.

Another way of measuring access to ART is by calculating the number of procedures performed per million inhabitants. This measure is inherently unstable, affected by a country's government policy, regulation, funding, and the number of service providers, and has continued to fluctuate with each ICMART report. Interpretation of this measure needs to be contextualized to the local legislative frameworks that countries operate under for the practice of ART. Notably, there is enormous variability internationally, with some countries having either mandatory governmental regulations or voluntary guidelines promulgated by professional societies, the latter often having significant involvement in the regulation and licensing of ART clinics. In contrast, in 2005 Canada, Finland, and until today most countries from Latin America have no guidelines or regulations in place (5). In 2005, availability ranged from 15 to 246 cycles per million population in several Latin American countries to a pro-birth high of 3,982 cycles per million population in Israel; the latter reflects both the policy framework and the availability of public or third-party payment for ART cycles. For many years Israel has had a policy of full financial coverage for ART (for two children), whereas Australia, with 2,054 cycles per million population, has had a mixed model of partial public sector, private health insurance coverage with a varying amount of patient out-of-pocket payments. In contrast, the United States and Canada had partial coverage from private health insurance; there were 341 cycles per million population in Canada, and in the United States, where only one state provided state support to treatment, the number of cycles was only 518 cycles per million. Even within Europe, there are major differences in access. Whereas in Nordic countries with sustained reimbursement and/or state support the number of cycles per million fluctuates between 1,400 and 1,600, in other countries such as Ukraine, Russia, and Serbia, coverage falls between 80 and 400 cycles per million. It is not the wealth of the country alone that determines access; it is how the wealth is distributed and the place that infertility and reproductive rights occupy in health priorities (6). These proxy measures do not replace the need for better information on the proportion of women/couples with infertility accessing ART treatment, as well as an internationally accepted measure of cost and affordability of ART treatment.

How Is ART Practiced Worldwide?
The trend of performing a high proportion of ICSI continued in 2005, with 62.9% of all cycles being ICSI. This trend was seen across all regions. Notably, the proportion of ICSI in Europe is 64.1%, quite similar to 66.4% in North America, but the proportion of ICSI in Latin America and the Middle East represent 81% and 97.9% of procedures, respectively. The proportion of ICSI in specific countries can be seen in Table 1. This confirms the adoption of ICSI as the preferred fertilization practice for ART internationally. There is still much less utilization in most European countries when compared with countries in Latin America or the Middle East. The reasons behind the high use of ICSI are difficult to understand and go beyond this report. However, it is interesting to note that the proportion of ICSI in countries such as Sweden, Norway, and Finland fluctuates between 40.7% and 47%, whereas in Germany and Belgium the proportion reaches 71% and 75%. A completely different situation is seen in Egypt with 98.3%, Brazil with 90.5%, and Argentina with 82.1%. A treatment with ICSI is evidence-based for male factor and for combined male/female factor infertility but may require further justification for other causes of infertility 7 and 8. It is worth attempting to assess the underlying explanation of why the utilization of ICSI is increasing worldwide and why it is preferred as the only fertilization technique used in a variety of countries from the developing world.

Safety
The number of embryos transferred per ART cycle varies among countries. The average number decreased from 2.47 in 2002 to 2.35 in 2004 and 2.29 in 2005. This slight but consistent reduction coincides with a marginal increase in SET from 16.0% to 17.5% and DET from 46.9% to 48.3%. Conversely, the proportion of three or more embryos transferred decreased from 37.4% in 2003 to 36.7% in 2004 and 34.2% in 2005. This progressive decline in the transfer of multiple embryos has decreased the rate of multiple deliveries after ART. In fact, between 2004 and 2005 the proportion of twin births dropped from 25.1% to 23.6%, whereas the proportion of triplets decreased from 1.8% to 1.5%.

One of the main differences between countries has to do with the way safety and effectiveness are balanced; and the number of embryos transferred is a reflection of such balance. In countries where access to ART is facilitated by national health policies, such as Nordic countries and Australia and New Zealand, the proportion of three and four embryos transferred fluctuate between 0 and 2.2%. Conversely, in the United States, where access to ART is dealt with individually, 47.5% of transfers include three and four embryos. An extreme situation is seen in developing countries in Latin America and the Middle East. Three and four embryos are transferred in 70.9% of cases in Brazil, 64.8% in Mexico, 75% in Egypt, and 79.7% in Lebanon. As a result of ET policies, or the lack of them, the proportion of twins varied between 6% and 15.8% in the Nordic countries and Australia and New Zealand. In Latin America twin births represented 22.1%, whereas in the United States twins represented 29.8% of births after fresh transfers. Overall, the proportion of triplets and more is almost nonexistent in the first group of countries; it is 2.4% in United States and fluctuates between 2.2% and 9.1% in Latin American countries.

The variability in the way ART is practiced continues to provide stark evidence that the most modifiable and preventable risk factor to avoid multiple pregnancy and its known sequel is the number of embryos transferred per procedure.

Effectiveness
Effectiveness remains difficult to measure using cycle rather than women-based data because cumulative PRs cannot be calculated directly but can only be indirectly estimated. Furthermore, there is no global concept of how to measure success rate. Whereas in some communities success is restricted to one healthy newborn, in others, healthy twins constitute a marker of success. There is indeed sufficient global data to show that perinatal morbidity and mortality are increased with multiple births (9), so the outcome of a single healthy baby should be considered the ultimate measure of effectiveness. However, the move toward SET varies enormously in different countries and in different psychosocial realities. In Europe, countries such as Sweden, Finland, Denmark, and Belgium are all directing their efforts to prefer SET over two or three embryos; in fact, 70% of transfers in Sweden are SET, followed by Finland and Belgium on the order of 48%. Similarly and in a different psychosocial environment, Australia has moved in the same direction, with 43.5% of SET. In contrast to this reality, in the United Kingdom, United States, and most of Latin America no more than 10% of transfers are SET. The major difference between the United Kingdom and countries in the Americas is the proportion of three and four embryos transferred, which in the United States is 47.5% but in the United Kingdom is as low as 4.8%. One could reasonably argue that the United Kingdom occupies the middle ground in terms of the number of ETs; Sweden and Australia have adopted SET under different policy environments, whereas in contrast the United States and other American countries are trying to avoid higher-order multiples by lowering the transfer of three and four embryos to a maximum of two.

When comparing results in different countries and regions, it is important to adjust values according to the age of the population treated and to the mean number of embryos transferred. In Australia 21.9% of the population treated is aged ≥40 years, and the proportion of three and four embryos transferred is only 2.2%. Under these circumstances, DR per aspiration is 21.0%. In Brazil the proportion of women aged ≥40 years is also 21.9%, and DR per aspiration reaches 25.3%. However, in this country the proportion of three and four embryos transferred is 70.9%; thus, the proportion of twins and triplets in Brazil is 22.3% and 5.4%, compared with 15.4% and 0.4% in Australia. When comparing countries that treat a much younger population, such as France, Germany, and the United Kingdom, the proportion of women aged ≥40 years is 12.7%, 11.1%, and 16.1%, respectively. In these countries the percentage of three and four embryos transferred is 23.4% and 22.9% in France and Germany, respectively, and only 4.8% in United Kingdom. Despite these differences in ET, DR per aspiration is 18.3% for France, 17.9% for Germany, and 24.8% for the United Kingdom. It could be reasonably concluded that treatments are more effective in the United Kingdom because with a similar population and fewer embryos transferred, DRs are higher and with fewer multiples. A special consideration is United States, also with 19.1% of women aged ≥40 years and a DR per aspiration as high as 31.7%. However, 47.5% of transfers include three and four embryos, and twins and triplets are 29.8 and 2.4%, respectively.

In parallel with the progressive reduction in the number of fresh embryos transferred, one would expect an increasing proportion of FET. Compared with 2004, the overall proportion of FET cycles (28%) is two percentage points lower when compared with 2004. In spite of this, the overall proportion of twins dropped from 25.1% to 23.6%, and high-order births decreased from 1.8% to 1.5%. The largest reduction was in Latin America, where twin births dropped from 37.4% to 22.1% and high-order multiples from 13.2% to 4.5%—still much higher than in most European countries.

Limitations
The quality and completeness of data reflect local data collection practice. This varies by individual country and region and depends on the local regulatory environment and whether data supply to the national or regional registries is voluntary or mandatory. Although many countries supplied incomplete data, the major outcomes (procedures, pregnancies, deliveries, and babies) are largely comparable across registries. The promotion of data standards and common terminology internationally has strengthened since 2002 with the development of the original and then revised ICMART glossaries 10, 11, 12 and 13; and more recently with the publication of the ICMART toolbox, which is designed to support data collection practice for countries setting up registries to monitor ART. However, there may still be discrepancies in the use of the ICMART glossary and the data available in countries, and these data need to be interpreted with caution.

In 2004, one-fifth of the clinics in participating countries did not report information on ART treatment and outcomes to their national and/or regional registries. This may reflect the local regulatory environment for ART practice, including requirements for national reporting. Critically, factors such as whether the collection is mandatory or voluntary, whether it has leadership and support from the country's leading professional fertility organization, and its funding model (e.g., government, patient, or private sector funded) underpin the sustainability of the collection and quality of monitoring at the country level. The value of the world report is its capacity to benchmark practice internationally; the limitation is that this benchmarking is only as valid as the data supplied. The most significant gaps in the data remain a number of populous countries, including China, Pakistan, Bangladesh, Indonesia, Philippines, and regional sub-Saharan Africa, which did not have registries at the time of compilation of the 2005 world report data collection.

In conclusion, this ICMART world report on ART treatments in 2005 continues to show unequal access to ART treatments worldwide. However, throughout the years this world report has shown a continued increase in the number of reporting clinics and ART treatment cycles worldwide. Large regional differences persist in the way ART is practiced, notably in the number of embryos transferred and consequently the rate of multiple births. Of note is the continuing rise in ICSI worldwide and the slow but steady adoption of SET as the first-line management for selected women/couples. These changes in practice are already differentially impacting the multiple birth rate and perinatal outcomes of countries, with Australia and New Zealand, Europe, and the Americas continuing to reduce the proportion of multiple births, particularly higher-order multiple births, in contrast to increases in the Middle East. The total number of babies born through ART worldwide in the year 2005 is underestimated because there are no data on several countries in Asia, the Middle East, and Africa. However, it is reasonable to assume that between 240,000 and 250,000 babies were born as a result of ART procedures performed during 2005.