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Assessment of the contribution of assisted reproduction methods for the future development of the number of live births in Czechia

Background: The key demographic trend concerns the postponement of parenthood to later ages. Moreover, the number of Czech women of reproductive age is decreasing, which will lead to a decrease in the number of live births even with higher fertility. The aims are to assess recent trends concerning using ART in Czechia and to estimate the impact of using ART on the future development of the number of live births.

two decades, Czechia has evinced one of the most rapid increases in Europe in this respect [8]. Assisted reproduction has been available in Czechia since 1997, at which time legislation was introduced allowing women under the age of 39 to undergo 3 ART cycles financed from the public health insurance system. Thus, it can be assumed that ART methods have become an important factor in terms of fertility trends in Czechia [9, 10,11].
While assisted reproduction has often been assessed in terms of the inherent health risks and the various consequences for the health of both the mother and the child [12], demographic approaches are rare since it is difficult to access reliable data. The aim of the article is to assess recent trends concerning the use of ART in Czechia and, subsequently, to estimate the impact of ART on the future development of the number of live births, especially in connection with delayed fertility, the expected growth in infertility and the changing age structure of women of reproductive age. Unique data was accessed for the period 2008-2012, the definition of which was related to two significant legislative changes. In 2006, the obligation was introduced for all reproduction centres to submit data on ART treatment cycles to the Czech Institute of Health Information and Statistics (IHIS), which led to the creation of a national register in which complete data has been recorded since 2007. In Czechia the field of reproductive medicine is currently regulated by Act No 373/2011 of the Code relating to specific health services and Law No 48/1997 of the Code of public health insurance [13,14].
The Act No. 373/2011 on specific health services, introduced the funding of a fourth ART cycle for women up to the age of 39 provided that only one embryo was transferred in each of the first two cycles. Our findings will contribute both to the refinement of the future estimation of the needs associated with newly-created population development forecasts and the estimation of future requirements concerning the capacity of reproduction centres in Czechia. At the application level, the results can be employed in the drafting of legislation on ART treatment, since the legislative availability of ART comprises a significant factor in terms of the demand for this type of treatment.

Data
Data on ART in Czechia was obtained from the National Register of Assisted Reproduction (NRAR) which is administered by the Institute of Health Information and Statistics of the Czech Republic (IHIS). The register records information on all women who have undergone ovarial stimulation or monitoring for the treatment of sterility by means of IVF [15].
The analysis is based on data on the number of ART cycles involving the transfer of embryos 1 according to the number of transferred embryos and the completed age of women in the period 2007-2012 and the number of deliveries that resulted from these cycles (which took place from approximately 1 October 2007 to 30 September 2013). In order to determine the importance of ART methods in terms of births and to calculate the demographic fertility indicators of ART treatment, it was necessary to convert the number of deliveries following ART to the number of live births and to convert the ages of women and the date of embryo transfer to the maternal age and year of birth.
The transition from the age and year of embryo transfer to the age and year of childbirth is shown below in the form of a Lexis diagram (Fig. 1). The numbers of children born dated according to the time of embryo transfer (the grey shaded square) were shifted by 9 months in terms both of the mother's completed age and the year (red square).

Fig. 1: Conversion of births from the year/age at ART to the year/age at birth
This conversion method includes several assumptions: 1) births following ART exhibit the same rate of stillbirths as births conceived without the use of ART methods according to the age of the woman and to parity.
2) ART cycles, their rate of success and resulting births are distributed evenly throughout the calendar year.
3) all the pregnancies lasted for the standard period of 9 months (40 weeks).
The application of this input data transformation method resulted in the estimation of the number of children born in a given calendar year following the use of ART methods according to the age of the mother for the period 2018-2012.
It was important for the research that only data concerning women with Czech citizenship was used in the analytical and model calculations. Due to the fact that ART is relatively easily accessible and cheap in Czechia, the country's assisted reproduction centres attract intensive reproductive tourism. In 2012, approximately 16.5% of all IVF cycles and 35.8% of FET cycles concerned foreign women, and 85.2% of the women registered for the acceptance of donated oocytes were of non-Czech citizenship [16]. According to a survey conducted by the European Society of Human Reproduction and Embryology [17], over 67% of women from Germany and over 50% of women from the United Kingdom of those who received ART treatment abroad in 2008 -2009 chose services provided in Czechia.
A certain limiting factor of the data employed concerns the fact that the numbers of births entered in the assisted reproduction register are based solely on the data provided by assisted reproduction centres and are, therefore, likely to be underestimated. Since, following an amendment to legislation, the obligation to enter the woman's identification number was abolished and data was collected in an anonymised form during the period 2010 -April 2012, it is, unfortunately, not possible to validate such data and thus to quantify the extent of underestimation.
Information on the age structure of women and live births according to the age of the mother was obtained from data provided by the Czech Statistical Office [18].

Methods
Standard demographic indicators were employed in order to assess the importance of the use of ART with respect to births in Czechia, i.e. the total fertility rate (TFR), age-specific fertility rates and the mean age of women at birth, which were calculated only from births following ART treatment.
Age-specific fertility rate following ART ( where represents the number of live births to mothers at age x following ART and represents the mid-year population of women at age x.

Trends in the use of ART in Czechia in the period 2008-2012
During the period 2008-2012, the number of ART cycles performed in Czechia ranged from 12,300 to 13,500 per year. The number of births following these cycles ranged between two and three thousand during the observed period and increased over time (Tab. 1).
In the same period, an increasing trend towards ART single-embryo transfer is evident, which was supported in 2011 by the introduction of a reimbursed 4th cycle provided that only 1 embryo had been transferred in the first two cycles. While in 2008 two or more embryos were transferred in 80% of ART cycles, by 2012 the proportion had decreased to just half of ART cycles (Tab. 1). However, despite a significant decrease in multiple pregnancies, the number of live births conceived using ART increased from less than 3,000 from cycles performed in 2008 to 3,600 from cycles performed in 2011. In relative terms, there was an increase in live births following ART of the total number of live births from 2.4% to 3.3%. The slight decrease recorded in 2012 may have been related to an amendment to tissue and organ donation legislation, which abolished the obligation to register the woman's identification number from mid-2010 to its re-introduction in 2012, and which may have led to a disruption in data continuity and the loss of information on the results of ART treatment [21].

The use of ART in Czechia in the period 2008-2012 in the light of demographic indicators
The age-specific fertility rates following ART (Fig. 2) reveal that in Czechia the highest values concern those aged between 30 and 34 years. A clear increase in the fertility rate following ART commences after the age of 26. A significant decrease is then observed at the age of 35; after the age of 40, fertility rates following ART decrease to negligible values, which is closely linked to the end of the payment of ART treatment by the public health

Projections -reflection of the model assumptions concerning the demographic indicators of ART development
As follows from the description of the projection variants in the methodology section, the options regarding the future development of ART fertility suggest an increase in the agespecific fertility rate following ART compared to the period 2011-2012 due to both increasing levels of total fertility and the increasing importance of ART fertility in older age groups (Fig.   3). The exception in this respect concerns variant 1, which works with fixed total fertility rates and a fixed share of ART fertility of total fertility. It is clear from Fig. 3 that the difference between the initial state and the estimated state in 2030 assuming unchanged fertility intensities would be minimal; any partial differences would be the result merely of the changing structure of women according to age.
With respect to variant 2, which considers the constant distribution of the share of ART fertility rates of the total fertility by age over the whole of the studied period, the projected development is influenced by the expected increase in the total fertility level which, according to this variant option, would lead to an increase in the absolute age-specific fertility rate following ART as well as the TFR ART (increase from 0.043 in 2011-2012 to 0.055 in 2030, see Fig. 3).
According to variants 3 and 4, the share of fertility rates following ART of total fertility rates can be expected to increase by approximately 50% and 100% respectively by 2030 compared to the reference period of 2011-2012. If one considers the increasing share of ART fertility rates together with the medium total fertility forecast variant, the resulting fertility rates following ART and thus also the TFR ART will be significantly higher, reaching 0.082 and 0.11 by 2030 according to variants 3 and 4 respectively. The projected fertility rates include the expected trend of a continuous increase in the age of mothers at childbirth, which is also reflected in a visible shift in fertility rates following ART to older ages in variants 2 to 4.

Fig. 3: Fertility rates following ART: average for 2011-2012 and expected development in 2020 and 2030
The importance of a further shift in the mean age of women at childbirth is evident when one considers the share of ART fertility rates of overall fertility rates for selected age groups (Tab. 2). Not surprisingly, this proportion increases significantly with the age of the mother at childbirth. As already mentioned, not only does a woman's ability to conceive decrease with age, but it can also be expected that up to a certain age, most women try to conceive naturally and, therefore, are less interested in assisted reproductive treatment. With respect to the 35-39 age group, the share of fertility rates following ART of overall fertility exceeded 6% in the The remaining two variants that assume an increase in the proportion of ART fertility (V3 and V4) which is evenly distributed throughout the female reproductive period indicate, inter alia, that in this case the share of ART fertility rates of overall fertility rates after the age of 35 would be around 9% and 13% respectively in 2030 for variant 3 and more than 12% and 17% respectively in 2030 for variant 4. In order to analyse the overall future significance of ART for childbirth, it is also necessary to consider the numbers of women who will enter the age at which ART is most often performed, i.e. the so-called reproductive potential of women. According to the population forecasts for Czechia used in this article [19], the number of women aged 20-39 will decrease in the period 2012-2030, with no significant numerical change in the 40-49 age group (Fig.   4). Compared to the projection threshold, there will be a significant decrease in the number of women especially in the 30-34 (by 32%) and the 35-39 (by 27%) age groups, whereas the 20-29 age group is expected to see a decrease of 14%. Since, clearly, this represents a significant reduction in the number of women who could, theoretically, receive ART treatment, these developments should be taken into account when evaluating the total number and share of live births following ART.

Results of the projection estimates -development of the number of live births following ART
The results of the calculations for all the considered ART fertility development variants reveal two fundamental findings. Due to the declining reproductive potential of women (cf. Fig. 4), if the use of ART methods remains unchanged there will be a decrease in the number of live births following ART in the period up to 2030 (Fig. 5). This decrease would be most pronounced if neither the use of ART nor the total fertility level changed over the observed period ( Fig. 6 -V1). Moreover, according to the medium variant of the fertility forecast, even the expected increase in the total fertility level would be insufficient to stabilise, let alone lead to an increase in the number of children born following ART at the end of the period under observation (Fig. 6 -V2). With concern to this decrease, it is necessary to bear in mind the overall decrease in the number of live births that will, undoubtedly, occur during the period under study even with increasing total fertility levels (cf. Fig. 6 -V2-V4 "total" category) since it is deeply embedded in changes in the age structure and decline in the overall number of women of reproductive age.
An increase in the number of live births following ART would occur only if there were an increase in the use of ART methods (Fig. 6). Depending on the expected level of the increase in the use of ART, this development would be relatively significant and constant; by 2030, the number of live births following ART would increase from the initial 3.5 thousand to 4.9 thousand and 6.5 thousand according to variants 3 and 4 respectively (Fig. 5). In relative terms, this would represent an increase from the initial 3.2% of the total number of live births to 5.0% (V3) and 6.8% (V4) in 2030 (Fig. 6).

Discussion
The main contribution of the article concerns the evaluation of trends in the use of ART aimed at estimating its impact on the future development of birth rates based on the example of Czechia. The prognostic approach to the analysis of ART has, to date, been applied only rarely in the expert literature. A major problem in this respect consists of the absence of data on age-specific fertility rates following ART, which is essential when attempting to assess the impact of the use of ART on birth rates. At present, the authors are not aware of any other study that has addressed the estimation of the expected development of ART over the longer term.
The only similar study published to date concerns the estimation of the development of the use of ART in Denmark [11]. The authors projected the complete cohort fertility following ART of Danish women born in the 1960s and 1970s. They assumed more fertility development variants and two scenarios of the development of the use of ART -a constant share of births following ART according to age and the extrapolation of the trend in ART use.
The analysis concluded that the completed fertility of women from the 1960s and 1970s generations increased by an average of 0.05 children per woman as a consequence of ART use. While our data did not allow us to determine the cohort fertility level, it was possible to conclude that ART contributed to total fertility rate in Czechia by only a slightly lower value than in Denmark, i.e. 0.034-0.045 in the period 2008-2012 (Fig. 3). Variants 3 and 4 of our analysis assume ever-increasing demand for ART treatment. One of the starting points for this approach concerns the expected further increase in the mean age of women at childbirth and the inevitable increase in infertility with the age [2]. While the degree of compensation for declining fertility (due to the postponement of attempting a first pregnancy to later ages) via reproductive treatment methods is difficult to quantify, the results of models constructed for France and the Netherlands [23,3,24] suggest that despite the considerable benefits of ART, the overall decline in fecundity cannot be fully compensated for via this approach. Not only do the ability to conceive and the success rate of ART treatment decrease with age, but the risk of miscarriage increases significantly [25,26].
Logically, therefore, the use of ART treatment has the potential to exert a greater impact on the birth rate if women are treated at younger ages [10].
In the European context, Czech women undergo ART treatment at relatively younger ages, a fact that is closely related to national legislation [27]. As can be seen from Tab. 2, the share of fertility rates following ART increases sharply with age, and Fig. 3 indicates that fertility intensity following ART is concentrated in the 30-34 age group. These trends stem not only from the unquestionable decline in ART success rates for women aged 35 and over [28], but also from the fact that ART cycles are paid by the health insurance system, according to legislation (see above), only for women up to the age of 39. This distribution is unlikely to change significantly over time, and any major shift in the maximum fertility age following ART will most likely be linked to ground-breaking advances in terms of improving the effectiveness of infertility treatment for older women.
A further aspect that serves to support the assumption of a future increase in the proportion of live births from ART concerns male infertility. According to the results of a range of recent research studies, the quality of semen is declining dramatically throughout Europe, even among younger men [29]. According to the research, this trend may also result in a decline in birth rates. Although the effects on fecundity have not yet been reliably demonstrated, the increasing age of fathers is most likely to contribute to an overall increase in infertility. It has been reported that the age of the man exerts a significant effect on the ability to conceive, although this effect is not as significant as in the case of women [30]. Although ART has the potential to alleviate the effects of male infertility, it is important to note that views on the increase in male infertility are far from uniform. Some Czech doctors have claimed that, to date, it has proved difficult to compare the results of spermiograms and that rather than a decrease in the sperm concentration of healthy men, the concentration is, in fact, slightly increasing [31].
In connection with male infertility, recent research has also addressed the potential effect of ART on the semen quality of young men conceived via such methods [32]. The initial results indicate that the sperm concentration of men conceived via the ICSI method is significantly lower than that of their spontaneously conceived peers. Moreover, attention is increasingly being focused on the possible adverse effects of ART on the physical and mental development of children born following ART treatment. While a higher risk of pre-term birth and lower birth weight in infants conceived using ART has already been reliably demonstrated, it is still too early to be able to confirm potential longer-term risks employing a sufficiently large sample of the population [33].
The use of ART has also raised a number of ethical concerns [34], of which the number of embryos transferred is the most significant issue from the demographic point of view. As has been shown via data gathered in Czechia, the increase in the number of women using ART has contributed to a significant increase in the incidence of multiple births, a development that is linked to a range of health and economic risks [34] and which has also significantly contributed to the afore-mentioned concerns about the adverse consequences of ART [35].
However, due to the progress of reproductive medicine, the transfer of just one embryo has become increasingly common in recent years in developed countries [20], including in Czechia (Tab. 1) encouraged by an amendment to national legislation. Since 2011, four cycles of ART have been funded by the health insurance system conditional on the transfer of a single embryo during the first two cycles [14].
Future changes in legislation will undoubtedly affect the use of ART. Recently, proposals have been submitted in Czechia concerning expanding the availability of ART to a wider range of women, e.g. raising the age limit to 43 and increasing the number of cycles covered by the health insurance system have been discussed as part of the compilation of a new family policy concept. It is not unreasonable to assume that such changes will be reflected in an increase in the demand for ART and, subsequently, an increase in the number of live births.
It is possible that the consequences of the extension of ART methods for birth rates in Czechia as presented herein is limited by the quality of the data provided. Although the IHIS asserts that it registers practically all ART cycles performed in the country, the data on births may be underestimated since reporting a ART cycle birth is not a mandatory requirement. In addition, the IHIS covers only those ART cycles performed in Czechia and, thus, does not include cases where Czech women undergo ART treatment abroad. Moreover, it is not possible to determine whether women were able to conceive spontaneously despite having undergone ART treatment. Some women who use ART can decide to treat their perceived infertility sooner than is necessary (9). Indeed, some authors have estimated that between 15% and 35% of women who undergo ART treatment are able to conceive naturally [11]. However, since more detailed longitudinal analysis (including with respect to the Czech data) would be needed in order to verify these claims, we have not considered this issue in our projection assumptions.

Conclusions
ART treatment is becoming an increasingly important factor in Czechia and is already influencing various birth rate characteristics; moreover, its importance can only be expected . The enhanced potential of ART is limited by the reproductive potential of women at the age at which such treatment is most frequently performed.
Future trends concerning the use of ART will be influenced not only by the development of the age of women and men at childbirth and the related prevalence of infertility in the population, but also by advances in reproductive medicine and changes in legislation. The projections presented herein should, therefore, be understood as merely an outline of potential future development trajectories in the overall context of the complicated links between the use of ART treatment and the various factors that influence birth rates.

Ethics approval and consent to participate
Not applicable

Consent for publication
Not applicable

Availability of data and materials
The datasets used and analysed during this study are available from the corresponding author on reasonable request

Competing interests
Not applicable

Funding
This research was supported by the Czech Science Foundation (Project 18-08013S: 'Transition towards the late childbearing pattern: individual prospects versus societal costs') and Charles University Research Centre programme UNCE/HUM/018.

Authors contributions
BB analyzed all data and calculated projections. TP was a major contributor in writing the manuscript. AŠ performed data conversion and contributed to data analysis and interpretation.
JK prepared the concept of the manuscript, specified research aims contributed to writing the manuscript. All authors read and approved the final manuscript.