Medically assisted reproduction in the context of time - Chapter 7: The impact of assisted reproductive technology on the incidence of multiple gestation infants: a population perspective

Medically assisted reproduction in the context of time

Scholten, I.

Publication date

2015

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Final published version

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Citation for published version (APA):

Scholten, I. (2015). Medically assisted reproduction in the context of time.

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7

Impact of assisted reproductive

technology on the incidence of

multiple gestation infants:

a population perspective

Fertility and Sterility 2015 Jan;103(1):179-83 Irma Scholten Georgina M. Chambers Laura L. van Loendersloot Fulco van der Veen Sjoerd Repping Judith Gianotten Peter G.A. Hompes William Ledger Ben W.J. Mol

ABSTRACT

Objective

To study the value of a population view in assessing assisted reproductive technology (ART) multiple gestation infants.

Design

Descriptive comparison of ART treatment and population statistics in seven developed countries (United States, South Korea, United Kingdom, the Netherlands, Australia, Belgium, Denmark) with varying ART utilisation and single embryo transfer (SET) rates.

Setting

We used ART treatment and population statistics from national treatment registries and vital statistics collections in seven countries for the year 2006.

Patients Not applicable Interventions None

Main outcome measures

The contribution of ART multiple gestation infants to the total number of multiple gestation infants in a population was calculated in relation to utilization of ART and SET rates.

Results

The number of ART treatments leading to embryo transfer varied between 304 per million inhabitants in the USA to 1518 in Denmark. The percentage of ART cycles that utilized SET varied between 8.8% in South Korea to 53.3% in Australia. Reflecting both utilisation rates and SET rates, the percentage of multiple gestation infants in the population attributed to ART ranged from 14.7% in South Korea to 29.0% in Denmark.

Conclusion

In seven countries, the contribution of ART multiple gestation infants to all multiple gestation infants varies between 14.7% and 29.0%, a percentage that was influenced by both the SET rate per cycle and ART utilization rates. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient.

7

INTRODUCTION

The ultimate goal of fertility treatment is to achieve the birth of a healthy child in couples needing medical assistance to bear children. Particularly up until the last decade, one commonly used approach to increase the chance of success of Assisted Reproductive Technologies (ARTs) was to transfer multiple embryos (1). This approach resulted in improved pregnancy rates but also increased the risk of multiple pregnancies. The large number of multiple pregnancies occurring following ART treatment became a cause for concern, since multiple pregnancies are associated with an increase in maternal and perinatal morbidity and mortality as well as high healthcare costs (2–6).

Gerris was the first to report that single embryo transfer (SET) could prevent multiple pregnancy (7), and SET is now widely accepted as best practice for minimizing the risk associated with multiple pregnancies (8,9). Furthermore, in association with an effective cryopreservation program, SET has been shown to achieve comparable cumulative live birth rates as double embryo transfer (DET) (10–14). In view of these developments, it has been suggested that the percentage of SET cycles should be used as a quality indicator for ART, along with expressions of success based on pregnancy or live birth rates (15). The shift to SET, however, has occurred at a time of increasing utilisation of ART worldwide, with annual increases of 5-10% in most countries over the last decade (16–19). While it is clear that SET in the majority of patient groups is the best way to reduce the multiple birth rate from a patient perspective, it is also observed that after a number of failed ART cycles, couples switch to the use of Double Embryo Transfer (DET). This phenomenon could then, together with the increase of ART utilization, partly undo the reduction of multiple pregnancies that is obtained from SET. As there are considerable differences existing in both SET and utilisation rates between countries, the purpose of this study was to investigate the association between ART utilisation, SET rates and the contribution of ART multiple gestation infants to population multiple gestation infant rates.

METHODS

Data collection

We studied ART data from the United States (U.S.), South Korea, United Kingdom (U.K), the Netherlands, Australia, Belgium and Denmark. These countries have different policies regarding the indications, reimbursement and the clinical practice of ART treatment, resulting in differences in SET and utilisation rates (20). For example, in the UK, treatment is primarily offered through private clinics and funded directly by patients, while in the Netherlands, treatment is primarily offered through general and university hospitals and funded by insurance companies. Previously, type of funding proved to influence the implementation of SET in the UK compared to Australia, where there is a more supportive approach towards funding ART and SET was better implemented. (7) For

each of the seven countries, we collected information on the number of ART cycles resulting in fresh embryo transfer, the number of SET cycles and the outcome of ART (number of live births, numbers of live born singletons, live born children in twin pregnancy and live born children in high order multiple pregnancies). For each country we collected information on the number of inhabitants, the number of all live born children from singleton, twin and high order multiple pregnancies and the mean female age at the birth of the first child.

In this manuscript, ART cycles refer to IVF cycles and ICSI cycles.

We sourced the number of autologous ART cycles undertaken in 2006 from national registries as were the outcomes of these cycles (21–23). Population statistics were obtained from national statistics bureaus in each country (24–30).

We used cross-sectional data for ART treatments performed in 2006 and population denominators of all infants born in 2006. This year was chosen because the potential impact of SET was already known and wide discrepancies existed in utilisation and SET rates. Therefore, treatment data from 2006 provided an opportunity to investigate the impact that differences in utilisation and SET rates had on ART’s contribution to population multiple birth rates.

ART outcome and general population

Outcome measures were (i) the number of fresh cycles leading to embryo transfer per million inhabitants, (ii) the SET rate for fresh embryo transfer cycles, (iii) the ART multiple gestation infant rate resulting from all ART cycles, (iv) the percentage of infants conceived following ART to all infants born a population, and (v) the percentage of ART multiple gestation infants to all multiple gestation infants born in a population. A multiple gestation infant was defined as a live born child out of a twin or high-order multiple pregnancy.

Institutional review board approval was not obtained since this manuscript only used free accessible, anonymous data.

RESULTS

Demographics

Table 1 shows the characteristics of the populations that were studied. The mean age at which women delivered their first child was 28 years, with the United States (mean 25 years) and the United Kingdom (mean 30 years) at the extremes. The percentage live born children as compared to the absolute number of women of reproductive age (15-49 years) in 2006 varied between 3.4% in South Korea and 5.8% in the United States.

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Utilisation and SET

The utilisation of ART differed widely among the selected developed countries. Three countries exhibited relatively high utilisation (Denmark, Belgium and Australia) and three countries exhibited relatively low utilisation (US, UK, and South Korea). The countries with the highest utilisation were Denmark and Belgium with 1518 and 1349 fresh embryo transfers per million inhabitants, respectively, while the USA and the UK recorded rates of 304 and 486 fresh embryo transfers per million inhabitants. (Table 1)

The use of Single Embryo Transfer

The use of SET also varied widely among the countries. The three countries with high utilisation exhibited high SET rates, while the reverse was true for the three countries with low utilisation rates. Belgium, Denmark and Australia recorded SET rates of 49.2%, 36.4% and 53.3% of fresh embryo transfer respectively, while UK, US and South Korea recorded SET rates of 11.6%, 10.7% and 8.8%. We were not able to obtain SET statistics for the Netherlands because it was not incorporated in the Dutch national registry in 2006.

ART births

The contribution of ART infants to the general population among the selected countries reflected utilisation of ART. Denmark and Belgium had the highest percentage ART infants, with 4.9% and 4.1% of all live born infants in 2006, respectively. Conversely, ART births accounted for respectively 1.2% and 2.0% of all live born infants in the USA and the UK respectively, and only 0.7% of all children were conceived through ART in South Korea. (Table 1)

Multiple gestation infants after ART

At a cycle level, the percentage of multiple gestation infants following ART treatment was, not surprisingly, related to the percentage of SET cycles performed in a country. Countries with a high percentage of SET cycles had a relatively low proportion of multiple gestation infants after ART, and vice versa.

The countries with the highest percentages of SET, Belgium and Australia, had the lowest percentage of ART multiple gestation infants to all ART infants, 18.6% and 20.6% respectively. In contrast, 57.4 % of live born ART infants in the US were from multiple gestation pregnancies.

From a population perspective, ART treatment in Denmark contributed 29% of total multiple gestation infants in the country, despite a relatively high SET rate of 44.3% in that country. In the US ART treatment - which was one fifth of the utilisation of Denmark but a SET rate of only 10.7% – accounted for 20% of the multiple birth infants in a population. (Table 1) (Figure 1)

T ab le 1. Popula tion and AR T da ta of se ven de veloped countries   United States South Kor ea United _Kingdom T he Nether lands Australia Belgium Denmar k Demog ra phics Inhabitants (1000’ s) 299.398 48.297 60.587 16.346 20.701 10.542 5.435 W omen in r epr oductiv e age (15-49yr) (1000’ s) 73.412 13.234 14.562 3.959 5.064 2.422 1.245 Mean ma ter nal age a t birth of fir st c hild (yr s) 25,0 29,1 30,0 28,9 28,2 27,7 28,4   Liv e bor n c hildr en 4.265.555 448.200 690.012 184.396 280.078 121.382 64.933 Liv e bor n c hildr en out of m ultiple pr egnancy 143.625 10.767 20.842 6.493 9.179 4.217 2.889   Per centage liv e bor n c hildr en in w omen of r epr odutiv e age 5,8% 3,4% 4,7% 4,7% 5,5% 5,0% 5,2% Per centage of m

ultiple infants to all infants bor

n 3,4% 2,4% 3,0% 3,5% 3,3% 3,5% 4,4%

  Utilisation and SET Number of

perf or med fr esh non-donor ET cy cles 91.059 21.790 29.416 12.169 20.821 14.226 8.253 Number of perf or med fr

esh non-donor SET cy

cles 9.743 1.920 3.412 n.a 11.098 6.999 3.004 Number of perf or med fr

esh non-donor DET cy

cles 41.887 2.971 24.592 n.a 9.485 5.861 4.894 Number of perf or med fr

esh non-donor ≥ TET cy

cles 39.429 16.899 1.412 n.a 238 1.366 355   Utilisa tion (no fr

esh ET/million inhabitants)

304 451 486 744 1.006 1.349 1.518 Utilisa tion in r epr oductiv e age (no fr esh ET/w omen in r epr oductiv e age) 1.240 1.647 2.020 3.074 4.112 5.874 6.629 Per centage fr

esh SET to all fr

esh ET 10,7% 8,8% 11,6% n.a 53,3% 49,2% 36,4%  

7

T infant to all infants bor

n 1,2% 0,7% 2,0% 2,5% 3,0% 4,1% 4,9%

  Multiple gestation inf

ants after AR T Number liv ebor n twin c hildr en after AR T (F resh&F ro zen) 26311 1546 4404 1146 1707 902 832 Number liv ebor n HOM c hildr en after AR T (F resh&F ro zen) 2799 39 87 39 50 15 6   Per centage of AR T m ultiple gesta

tion infants to all AR

T infants bor n 57,4% 50,7% 32,5% 25,7% 20,6% 18,6% 26,6% Per centage of AR T m ultiple gesta

tions infants to all infants bor

n 0,7% 0,4% 0,7% 0,6% 0,6% 0,8% 1,3% Per centage of AR T m ultiple gesta

tion infants to all m

ultiple gesta tion infants bor n 20,3% 14,7% 21,5% 18,3% 19,1% 21,7% 29,0% NB Number of SET cy cles perf or

med was not a

vailab

le f

or the Nether

DISCUSSION

The contribution of ART multiple gestation infants to all multiple gestation infants from a population perspective has not been assessed before. In our study, we found that the contribution of ART multiple gestation infants to all multiple gestation infants varied between 14.7% and 29.0%. This percentage was not only influenced by the SET rate per cycle, but also by ART utilization rates. Our study provides further evidence of the importance of SET in clinical practice, but also demonstrates the need to consider the implications of ART on a population level. There is a need for a standardized population based measure that reflects both ART utilisation and SET rates to reflect the population impact of ART iatrogenic multiple births.

This study assessed the problem of multiple gestation infant after ART from a population as well as from an individual perspective and therewith, it provides a new insight into an acknowledged problem. This study shows that unless SET is adopted in the vast majority of cycles, absolute numbers of ART multiple births and their contribution to multiple births in a population can be substantial. For this study we collected data from seven developed countries with different policies regarding the indications and reimbursements of treatment with ART. We chose 2006 as our index

7

year because there was wide variation in both SET and utilization which allowed us to test the usefulness of ART population based statistics. Since then, SET and utilization rates have increased in many countries. However, the importance of population based measures continue to hold. For example, in 2010, the ART multiple gestation infant to all multiple gestation infants rate remained highest in Denmark, being 31.2% (29.0% in 2006) despite a SET rate that rose to 45.2% (36.4% in 2006). The utilization rate also rose to 2357 fresh ET’s per million inhabitants (1518 in 2006). The 2010 ART multiple gestation infant rate to all multiple gestation infants rate was lowest in the United States, being 13.0% (20.3% in 2006), as a result of a low utilization of 277 fresh ET’s per million inhabitants (304 in 2006), despite the SET rate being low as well; 15.4% (10.7%)(31–33). Our study thus clearly shows the importance of assessing the burden of iatrogenic multiple births from a clinical as well as population perspective, and demonstrates the feasibility and possible nuances in deriving a population measure of fertility treatment safety and efficacy. ART treatment should maximize the chance to have a healthy singleton baby through equitable accessible for patients who benefit from it. Any population measures of ART treatment should reflect both of these aims.

ART is not the only cause of iatrogenic multiple births. Non-ART treatments such as intrauterine insemination (IUI) with hyperstimulation and ovulation induction (OI) also account for a substantial number of multiple pregnancies (34). Due to the lack of registration of non-ART treatment strategies and the variability of their use among countries, their impact can only be measured indirectly (35) and therefore, we could not take it into account in our study. Furthermore, we did not account for a potential difference in ART success rates between countries, which may influence the number of ART cycles performed.

Global utilisation of ART procedures continues to rise (19,36) and SET is widely seen as the solution for the problem of multiple gestations after ART (37). However, few trials exist to inform the most clinically and cost-effective treatment pathways for different patient groups. Furthermore, it is the overall burden of iatrogenic multiple birth that needs to be considered, and therefore registers to collect data on IUI and OI are needed to provide a complete picture of the impact of fertility treatment on multiple birth rates.

The wide variation among countries surveyed in both utilisation and SET rates may partly reflect the wide variation in clinical pathways leading to ART treatment, funding arrangement and socio-demographic factors. Population measures of ART treatment would highlight such differences and add to the discourse around appropriate measure of safety and effectiveness as well as the discussion on indications for ART treatment.

Based on our analysis, we advocate that in the comparison of the ART policy and outcomes in different countries, besides an individual treatment perspective, a population perspective should be developed.

We propose the use of the rate of the ART multiple gestation infants to all multiple gestations infants and the percentage of SET cycles of all treatment cycles. This would give a population perspective on the contribution of ART to multiple pregnancies rather than using the treatment perspective alone. The proposed measures give insight on both multiple pregnancies after ART and whether they are guided by embryo transfer policy or utilization. Given the possible differences in utilisation of non-ART treatment we also advocate that the outcomes of these treatments should be included in population measures Registration of the indication for treatment and the ratio of ART multiple gestations to all multiple gestations might give more insight to the differences between countries. In conclusion, both utilization of ART and embryo transfer policies influence the impact of multiple gestation infants after ART on the overall population. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient.

7

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