Background
Considerable progress continues to be made in assisted reproductive technology (ART) fertility treatment since the birth of the first “test tube baby”, Louise Brown, in 1978 in the United Kingdom (UK), followed by other live births in Australia (1980), the United States (US) (1981), and in Sweden and France (1982) [
1,
2]. However, fertility treatment remains a complex field that involves many different dimensions over the course of patient treatment, such as hormonal treatment to produce eggs, retrieval of eggs and sperm, varied fertilization techniques, such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphologically selected sperm injection (IMSI), use of one’s own or donor eggs, fresh versus frozen embryos, number of embryos to transfer, and preimplantation genetic diagnosis (PGD) [
2]. Additionally, variations in fertility treatment exist among countries, such as illegality of donor IVF cycles in Germany; illegality of PGD and preimplantation genetic screening (PGS) in France; and illegality of embryo storage in Italy until 2009, mandating a requirement that all generated embryos be implanted.
Fertility specialists are continually examining ways to optimize the techniques and processes within the fertility treatment field to improve success in achieving live births. Recent targets of interest have included analyzing procedures for ovulation induction and triggering final oocyte maturation [
3‐
6], improving the prediction of ovarian response to stimulation [
7,
8], determining optimal duration of co-incubation of gametes [
9], assessing endometrial receptivity and implications for the use of fresh versus frozen embryos [
10,
11], examining embryo culture techniques [
12], monitoring embryo development through new techniques such as time-lapse embryo monitoring [
13], and improving embryo selection for transfer [
14]. Despite numerous improvements in fertility treatment, the number of factors that have an impact on fertility make fertility difficult to control and the desired outcome of a live birth cannot be guaranteed. Fertility specialists are continuously looking for ways to improve pregnancy rate (PR) and live birth rate (LBR) in patients.
Large ART fertility treatment registries exist through the European IVF Monitoring Consortium on behalf of the European Society of Human Reproduction and Embryology (ESHRE) in Europe [
15] and the Centers for Disease Control and Prevention (CDC) in the US [
16]. Although the registries provide comprehensive data on the current state of ART in Europe and the US, they have some important limitations. The registry reports are published with some delays, with the currently available publications reporting 2010 data in Europe, and 2012 data in the US. Additionally, the registry reports are based exclusively on quantitative data. There are no known publically available qualitative data describing the perceptions of fertility specialists regarding current unmet needs or the important developments in the field of fertility treatment. For the ESHRE report, the method of reporting data to the registry is not standardized and consequently there is variability among countries in the information reported.
ART, and more specifically IVF, continues to change and further develop with new technologies. However, many questions remain, including: What have been the true innovations in the field of fertility treatment, and how have they affected the treatment of patients? What are the differences per country in fertility treatment? Where are fertility treatments headed in the future? In the current study, an 8-country survey of fertility specialists was conducted with the aim to provide a comprehensive depiction of fertility treatments across different regions. Using a standardized survey-based approach, the goal of the research was to provide both quantitative data and qualitative perceptions from fertility specialists regarding which developments have been most important in the field of fertility treatment within the past 30 years, the current unmet needs in fertility treatment, and which anticipated improvements will be “game changers” in fertility specialty practices in the coming years.
Discussion
There are several key findings from the current survey of fertility specialists in 8 countries. There is consensus among the current survey results, the annual CDC ART registry report, and the annual ESHRE ART report that the number of infertility patients seeking fertility treatment is increasing and it is expected that the number of patients will continue to increase due to aging populations [
15,
16]. The causes of infertility appear to be universal, with the exception that in China tubal factor was reported as the most important cause of infertility, as compared to tubal factor being in the 5
th position in the other countries. As expected, ART outcomes decreased with increased patient age. There is a strong unmet need to develop techniques that will help preserve or restore fertility for older patients. The cost and/or absence of financial reimbursement for IVF fertility treatment appears to be an important barrier to patients’ access to fertility treatment.
ART outcome was reported to be the most successful in Spain, the US, and China. These countries also reported that PGD/PGS was one of the most important fertility treatment improvements in the past year, and this could potentially explain why these countries have better outcomes results. However, many other dimensions that have an effect on the outcomes of fertility treatment should be considered. Thus, the highest success rates in Spain, the US, and China cannot be driven only by the use of PGD/PGS. The number of embryos transferred, the use of fresh versus frozen embryos, as well as other environmental and psychological elements not measured in the current survey can also have an effect on clinical outcomes. The main unmet need reported by fertility specialists is better coverage for the cost of IVF. Fertility treatment is a highly technological field and is very costly, indicating it may be difficult to address this unmet need. Because ART is not fully reimbursed in the studied countries -- with the exception of France -- it is up to the leadership of the clinics to reduce the costs of the procedures.
In terms of future development, the fertility specialists reported that improved embryo selection and implantation rates are expected to change the field of fertility treatment. There appears to be little room for improvement in the hormonal treatment used to produce eggs and several techniques are available to produce embryos, including IVF, ICSI, IMSI, and donor eggs. With the advent of time-lapse monitoring of embryo development and PGD/PGS procedures, embryo selection is one of the newest areas of development in fertility treatment. However, these procedures are approved in only a few countries and have raised some ethical discussions in most. The factors underlying the implantation rate of embryos are not well understood, specifically, there is a need to better understand why good embryos do not successfully implant. Finally, the survey did not attempt to find the root causes of infertility in order to move away from palliating the consequences of infertility and toward the prevention and best treatment of infertility.
The current study survey results compare favorably with and further extend the findings within the most recently reported CDC ART National Summary Report [
16]. The CDC report is based on 456 fertility clinics within the US, whereas the current study survey includes only 91 US clinics [
16]. The CDC reports ART efficacy for fresh, non-donor eggs, or embryos compared with the current study report of all procedures combined. However, fresh, non-donor embryos represent the majority of procedures in the current study, supporting the comparability between the reports. The fertility treatment outcomes data as measured by embryo transfers, PR, and LBR reported in the current survey of fertility specialists in the US are similar to the CDC registry report data. The comparison suggests that ART efficacy is stable, with no shift in fertility treatment having had an impact on efficacy of treatment, which is consistent with the lack of any major improvements in ART procedures since 2012. The comparison of the current study survey data with the CDC registry report shows that the number of ICSI procedures has increased from 68 % reported by the most recent CDC registry report in 2012 to 73 % reported in 2015 in the current survey (ranging from 68 % in patients <35 years old to 76 % in patients >42 years old). The reported main causes of infertility remained the same, with male factor, ovulatory dysfunction, diminished ovarian reserve, and both female and male factor being the most common causes of infertility, as reported by both the CDC registry report examining 2012 data and the current survey. When comparing the number of embryo transfers with the CDC 2012 registry data report, there was a trend toward more frequent use of single embryo transfer in the current survey.
The comparison of the current study survey results among European countries, China, and Japan with existing registry data is more challenging. The ESHRE registry report (2010) is based on 104 fertility clinics in France, 114 clinics in Germany, 202 clinics in Italy, 103 clinics in Spain, and 72 clinics in the UK [
15]. The current survey report includes 29 fertility clinics in France, 33 in Germany, 23 in Italy, 38 in Spain and 34 in the UK. The comparison of outcomes data is complicated because the ESHRE registry reports outcomes data using a different breakdown in the number of cycles, presenting ART outcomes results per type of procedure and per age group; whereas the current study survey split the data only per age group [
15,
17]. The number of embryos transferred is more easily compared between the studies, and as was found in comparison with the CDC 2012 report, a trend was observed toward more frequent single embryo transfer in the current survey than in the ESHRE 2010 report. To our knowledge, this is the first report on fertility treatment in China and Japan, therefore no comparison of the current survey results with registry or other data from these countries is possible.
It should be noted that this research has a number of limitations. As with any survey, our findings may be influenced by the recall and response bias of the surveyed individuals. Additionally, only a subset of fertility specialists participated in our survey, and as with all analyses, caution should be used when generalizing results to an entire population. However, the response rate obtained in our survey is in line with what would be expected for this type of survey [
18]. Regarding the recruitment of participants, two approaches were used: in the US, France, Germany, Italy, Spain, and the UK, fertility specialists were contacted directly by the Deerfield Institute, and were recruited by e-mail or postal mail. In China and Japan, survey participants were recruited using a panel provider (i.e., the M3 panel) and were invited by e-mail. This might include a bias as the M3 panel includes only physicians who accepted to be part of the panel, while the Deerfield Institute had access to the full population of fertility specialists. It is important to note that all respondents answered the same questions and there was no difference in the questionnaire outside of translation whether respondents were recruited by the Deerfield Institute or the M3 panel. Although patient demographic (e.g., age, smoking, obesity) and biochemical (e.g., hormonal status) characteristics may play a role in fertility treatment outcomes, such patient-level data was outside the scope of the current survey. Future research is needed to examine the influence of patient-level characteristics as well as the patient assessment and preparation protocols used by fertility specialists prior to treatment to ascertain the similarities and differences in global outcomes.
Competing interests
CA: Is an employee of Deerfield Institute.
DG: Is an employee of Deerfield Institute.
Authors’ contributions
Made substantial contributions to conception and design or acquisition of data: CA + DG. Made substantial contribution to analysis and interpretation of data: CA + DG. Involved in drafting the manuscript or revising it critically for important intellectual content: CA + DG. Gave final approval of the version to be published: CA. Agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: CA.