Fertility and assisted reproduction

DOI: 10.1111/j.1471-0528.2011.02966.x
www.bjog.org

Minimising twins in in vitro fertilisation: a

modelling study assessing the costs,
consequences and costutility of elective single
versus double embryo transfer over a 20-year
time horizon
GS Scotland,a D McLernon,b JJ Kurinczuk,c P McNamee,a K Harrild,b H Lyall,d M Rajkhowa,e
M Hamilton,f S Bhattacharyag
a

Health Economics Research Unit, University of Aberdeen, Aberdeen, UK b Section of Population Health, University of Aberdeen, Aberdeen,
UK c National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK d Assisted Conception Services Unit, NHS Glasgow, Glasgow,
UK e Birmingham Womens Fertility Centre, Birmingham Womens Hospital, Birmingham, UK f Department of Obstetrics and Gynaecology,
Aberdeen Maternity Hospital, Aberdeen, UK g Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen, UK
Correspondence: Dr GS Scotland, Health Economics Research Unit, Polwarth Building, University of Aberdeen, Aberdeen AB25 2ZD, UK.
Email g.scotland@abdn.ac.uk
Accepted 25 February 2011. Published Online 8 April 2011.

Objectives To assess the cumulative costs and consequences of

double embryo transfer (DET) or elective single embryo transfer

(eSET) in women commencing in vitro fertilisation (IVF)
treatment aged 32, 36 and 39 years.
Design Microsimulation model.
Setting Three assisted reproduction centres in Scotland.
Sample A total of 6153 women undergoing treatment at one

of three Scottish IVF clinics, between January 1997 and June

2007.
Methods A microsimulation model, populated using data inputs

derived from a large clinical data set and published literature, was
developed to compare the costs and consequences of using eSET
or DET over multiple treatment cycles.
Main outcome measures Disability-free live births; twin

pregnancy rate; womens quality-adjusted life-years (QALYs);

health service costs.

Results Not only did DET produce a higher cumulative live birth
rate compared with eSET for women of all three ages, but also a
higher twin pregnancy rate. Compared with eSET, DET ranged
from costing an additional 27 356 per extra live birth in women
commencing treatment aged 32 years, to costing 15 539 per extra
live birth in 39-year-old women. DET cost 28 300 and
20 300 per additional QALY in women commencing treatment
aged 32 and 39 years, respectively.
Conclusions Considering the high twin pregnancy rate associated

with DET, coupled with uncertainty surrounding QALY gains,

eSET is likely to be the preferred option for most women aged
36 years. The cost-effectiveness of DET improves with age, and
may be considered cost-effective in some groups of older women.
The decision may best be considered on a case-by-case basis for
women aged 3739 years.
Keywords Cost-effectiveness, in vitro fertilisation, single embryo

transfer.

Please cite this paper as: Scotland G, McLernon D, Kurinczuk J, McNamee P, Harrild K, Lyall H, Rajkhowa M, Hamilton M, Bhattacharya S. Minimising
twins in in vitro fertilisation: a modelling study assessing the costs, consequences and costutility of elective single versus double embryo transfer over a
20-year time horizon. BJOG 2011;118:10731083.

Introduction
Multiple pregnancy is the commonest major complication
associated with in vitro fertilisation (IVF) treatment1 and is
caused by the replacement of more than one embryo in an
attempt to enhance pregnancy rates. The increased clinical

risks associated with multiple pregnancies has prompted

changes in practice, leading to a reduction in the number
of embryos transferred from three to two in many countries, but in 2005/06 twins still accounted for 19.9% of
all IVF live births in Europe2 compared with a natural
incidence of 11.5% in spontaneously conceived births.3

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1073

Scotland et al.

This is of significant concern not just to fertility specialists

but also to obstetricians, neonatologists and primary-care
providers as twin pregnancies are associated with increased
maternal and neonatal morbidity and mortality,4 and
increased costs to the health service.5
Considerations of safety have been a driver in many
European countries for implementation of elective single
embryo transfer (eSET) as an effective means of minimising
the twin pregnancy rate associated with IVF. This decision
has been based largely on data from randomised controlled
trials, which have shown that eSET, followed by replacement of a single frozen/thawed embryo in those who fail to
become pregnant, can virtually eliminate twins and yet
maintain live birth rates comparable with those achieved
through a double embryo transfer (DET) cycle in women
aged under 36 years.6
The Human Embryology and Fertilisation Authority
(HFEA), which regulates IVF in the UK, now advocates the
use of eSET as an effective way of reducing twins associated
with IVF7 and recommends a national target of a twin
birth rate below 10% (www.hfea.gov.uk/530.html). However, the existing randomised and observational studies
have not considered the effectiveness and cost-effectiveness
of using eSET and DET over multiple complete treatment
cycles, where all women have the opportunity to move to a
frozen cycle (if spare embryos are available) or subsequent
fresh treatment cycle, if the previous treatment fails. There
is also limited evidence regarding the cost-effectiveness of
using eSET in women who did not meet the inclusion criteria of existing randomised controlled trials.
A major source of concern among clinicians and women
is current evidence that the use of eSET will reduce overall
live birth rates.8 Women in particular are deterred from
taking up eSET, fearing that it will reduce their chances of
live birth or result in a need for additional treatment
cycles.9,10 Healthcare commissioners lack information on
how alternative embryo transfer strategies will affect health
service costs, pregnancy rates and twin pregnancy rates over
time in different subgroups of women.7
To address these concerns, this study models the effectiveness and cost-effectiveness of using eSET versus DET in
up to three full treatment cycles (i.e. three fresh cycles with
associated frozen/thawed embryo transfers when needed)
for women of different ages.

Methods
A microsimulation economic model was developed to
assess the cumulative costs and consequences of adopting
either a DET policy or an eSET policy over multiple treatment cycles. Under the DET policy, modelled patients were
allowed up to three fresh treatment cycles11 with DET
followed by replacement of frozen/thawed embryos, two at

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a time, for those failing to achieve a live birth. Under the

eSET policy, all women with at least two good-quality
embryos available (i.e. eligible for eSET) received eSET
followed by replacement of frozen/thawed embryos, one at
a time, for those failing to achieve a live birth (Figure 1).
Women with fewer than two good embryos available were
modelled to receive DET or non-elective SET, depending
upon the total number of embryos available. Treatment
was discontinued when a simulated patient completed three
full treatment cycles, delivered a surviving live birth,
stopped treatment for other reasons, or reached the age of
45 years. We make the assumption that women would have
the opportunity to complete a three-cycle programme after
commencing treatment. An expert advisory group consisting of IVF specialists, an embryologist and a neonatologist
was convened to inform the model structure and assumptions. The analysis was conducted from the health and
social care perspective.

Clinical inputs
All clinical inputs used in the model are presented in the
Supporting Information (see Table S1). The total number
of embryos available and the number of good-quality
embryos available, for each simulated patient at each fresh
cycle, were drawn from age- and cycle-specific probability
distributions derived from a large clinical data set. The data
set included 6153 women undergoing treatment at one of
three Scottish IVF clinics, between January 1997 and June
2007 (10 511 fresh cycles; 3106 associated frozen/thawed
cycles). Logistic regression models derived from a subsample of 4643 women undergoing their first fresh treatment
cycle with DET were used to estimate the probability of
having a positive pregnancy test, and the probability of singleton and twin clinical pregnancy for each simulated
patient undergoing their first fresh DET cycle. Cycles
involving donated gametes were excluded from the analysis.
The mean age (SD) of women in the data set was 33.7
(4.1) years and mean (SD) BMI was 24.7 (4.0) kg/m2.
Median (interquartile range) duration of infertility was
36 (2453) months. Of the couples, 29.7% had tubal infertility, 6.1% had ovulatory problems, 13.3% had endometriosis, 45.2% had male factor problems, 22.8% had
unexplained infertility and 1.2% had other causes of infertility recorded. The median (interquartile range) number of
embryos available for transfer was five (three to eight), and
82.0% of couples had at least two good-quality embryos
available for transfer in their first fresh cycle. Womens age,
number of embryos available and the quality of embryos
transferred were included as the predictor variables in each
logistic regression model.
The clinical data set was also used to estimate age
band-specific (35, 3639, 4043, 43 years) probabilities
for biochemical pregnancy, clinical pregnancy and twin

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

Cost-effectiveness of eSET versus DET

Treatment (eSET x3 or DET x3)

Pregnancy outcomes

Neonatal outcomes

Long-term outcomes

No pregnancy

First fresh
treatment
cycle

Subsequent
fresh/frozen
cycles

Miscarriage/still birth
Neonatal
death

Singleton live birth

Twin live birth

Discontinued

NICU
admission

Preterm
birth

Term
delivery

Healthy singleton infant

Disabled singleton infant

Twins
(both healthy)
Twins
(1 healthy/1 disabled)
Twins
(both disabled)

Figure 1. Schematic representation of the model structure.

pregnancy in frozen/thawed embryo transfer cycles following DET, as well as miscarriage rates for singleton and twin
pregnancies. These age bands were chosen because they
represent cutoffs at which marked changes in IVF success
rates occur; this was based on the advice of the expert advisory group for the study.
The probability of biochemical pregnancy following fresh
eSET was estimated by applying a relative risk estimate,
derived from a large randomised controlled trial,12 to the
estimated probability of pregnancy following DET for each
simulated patient. A relative risk estimate was also applied
to the probability of pregnancy following frozen DET, to
estimate the expected pregnancy rate with frozen SET.13
A twinning rate of 0.9% was applied to clinical pregnancies
following SET.14
For pregnancies carried to 24 weeks, published data were
used to estimate plurality-dependent probabilities for stillbirth, preterm birth, neonatal mortality,15 neonatal morbidity,16,17 and longer-term childhood complications including
cerebral palsy, cognitive impairment and visual impairment.18 Probabilities for miscarriage, stillbirth, preterm
birth, neonatal morbidity, neonatal mortality and longterm complications were adjusted upwards for monozygotic
twins following eSET, using relative risk estimates derived
from the literature.1923 In addition, we adjusted the disability incidence upwards for twin survivors where the
co-twin was stillborn or died during the neonatal period,

by applying an odds ratio of 2.424 to the incidence rate

observed in surviving twin pairs.18
As neonatal event rates for twins are generally reported
on a per twin infant basis, some assumptions were required
regarding the concordance of adverse neonatal outcomes
among liveborn twin pairs. For admissions to neonatal
intensive care units, a 90% concordance rate was assumed
(based on expert opinion); i.e. nine pairs of twins in every
20 twin infants admitted. For neonatal deaths and disability
outcomes, concordance rates of 20.5% and 6.7% were
applied respectively.25
In extrapolating long-term costs, we assumed that the
modelled disability outcomes would have an adverse effect
on life expectancy. For this reason, mortality rates reported
for preterm infants with cerebral palsy were used to model
survival in disabled infants,26,27 while standard UK life
tables were used to model survival in infants without
disability.

Linking cycles
We assumed that all women failing to conceive after fresh
DET, but with cryopreserved embryos, would attempt a
frozen cycle. We further assumed that 100% of women failing to conceive following eSET would have at least one
frozen embryo available and would therefore attempt a frozen/thawed cycle and that 80% of embryos would survive
the freezing process. The impact of reducing embryo

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1075

Scotland et al.

survival to 70% was assessed through sensitivity analysis.

Finally, we applied observed age-specific probabilities of
going on to subsequent frozen cycles following failed frozen
cycles, and assumed that these probabilities would be the
same following eSET and DET.28,29 Age-specific discontinuation rates following completed treatment cycles (i.e. fresh
cycles with associated frozen/thawed cycles) were also estimated from the clinical data set and the same rates were
applied for eSET and DET.
Age-dependent probabilities of failing to reach embryo
transfer were applied (Scottish clinical data set) in subsequent fresh cycles, with a proportion of these failures
assumed to occur before egg recovery.30 Women experiencing cancellation before egg recovery could proceed with
another fresh cycle, without the cancelled cycle counting as
one of their three fresh attempts. Cancellations following
egg recovery were counted as one of the three fresh
attempts and these women were only eligible to proceed
with associated frozen cycles or a final fresh cycle.
For women with at least two embryos available in subsequent fresh cycles, the same approach as that in the first
cycle was used to estimate singleton and twin clinical pregnancy rates following DET and eSET. However, pregnancy
rates were adjusted downward (compared with the first
cycle) to reflect the diminishing probability of success with
increasing number of fresh cycles undertaken.31 Those
women with only one embryo available in subsequent fresh
cycles were modelled to receive non-elective SET and were
assigned age-specific probabilities of pregnancy as estimated
from the clinical data set.

Cost inputs
All cost parameters used in the model are presented in the
Supporting Information (see Table S2). Costs associated
with IVF treatment, early follow up, ovarian hyperstimulation and antenatal and obstetric care were estimated using
a detailed resource use data set for women undergoing
their first fresh treatment cycle in Aberdeen.31 Costs associated with miscarriage, ectopic pregnancy and stillbirth were
obtained from the National Tariff for the Department of
Health, Health Care Resource Groups (version 3.5) (www.dh.
gov.uk/en/Publicationsandstatistics/Publications/Publications
PolicyAndGuidance/DH_082571). Costs associated with
frozen/thawed cycles were taken from Dixon et al.32
For costs associated with neonatal admissions, we used
the average length of stay reported for singletons and twins
admitted to neonatal units in Scotland16 and applied an
average per diem cost for admissions to neonatal units
(including neonatal intensive care units and special care
baby units) in Scotland (www.isdscotland.org/isd/3601.
html). Additional autopsy and counselling costs associated
with neonatal deaths were taken from a study by Petrou
et al.33

1076

For health service costs in the first 2 years of life, we

applied annual costs for singletons and twins reported by
Henderson et al.34 but removed 80% of year one admission
costs to avoid double counting; i.e. 80% of year one admissions would be expected to occur during the neonatal period,35 which had already been captured as described above.
Following this, we applied annual health and social care
costs appropriate to the long-term modelled health outcome of each infant, using data reported by Mangham
et al.36 All costs were adjusted to a common base year
(2007/08) using the Hospital and community health
services inflation index (www.pssru.ac.uk/uc/uc2009contents.
htm).

Utility weights
Time spent by women in different states of the model was
adjusted using quality (utility) weights reflecting the relative desirability of those states on a scale where zero represents death and one represents full health (see Table S3).
This approach enabled the estimation of womens qualityadjusted life-years (QALYs).
A utility decrement associated with being infertile with
the desire for a child was derived from a US study37 in
which this state was mapped to the preference weighted
Health State Utilities Index Mark 2 (HUI2) classification
system.38 By subtracting the resultant utility weight from
the HUI2 US population norm,39 we obtained a utility decrement of 0.07 and subtracted it from Euroqol EQ-5D
(EQ-5D) UK population norms in our model.40
We assumed that a successful healthy birth outcome
would return women to the age-specific UK population
norm, whereas giving birth to a child with a disability
would be associated with an EQ-5D utility decrement of
0.07.41 For women suffering a stillbirth or neonatal/infant
death followed by no subsequent pregnancy, we applied a
utility weight of 0.543 elicited directly from infertile women
in Grampian,42 because no general population preference
weights were available for this outcome.
A secondary analysis was conducted where womens lifeyears were further adjusted using utility weights for IVF
outcomes previously obtained from a group of women
waiting to receive IVF treatment in Aberdeen.42 In this previous study, standard gamble utility weights were elicited
for: premature delivery/neonatal admission; giving birth
to a child with disability; experiencing a neonatal death
followed by no subsequent pregnancy; and treatment
failure followed by life-long childlessness.

Analysis
The analysis was conducted separately for three cohorts of
women commencing treatment at different ages: 32, 36 and
39 years. The first age group (32 years) is representative of
the mean age of women included in existing randomised

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

Cost-effectiveness of eSET versus DET

controlled trials of eSET, whereas 36 years is the age at

which an observed marked decline in the IVF success rate
begins.43 At 39 years, women face a more rapidly decreasing success rate and a limited time period in which to
achieve a live-birth (www.hfea.gov.uk/fertility-treatmenttrends.html). It is also the oldest age at which women in
the UK currently have access to NHS-funded treatment.
Womens QALYs were used to assess the costutility of the
alternative strategies over a 20-year time horizon from
the health and social care perspective. Future costs and
QALYs were discounted at a rate of 3.5% per year (www.
hm-treasury.gov.uk/green_book_guidance_discounting.htm).
Monte Carlo simulation was used to simulate the movement of women through the model and, at the same time,
characterise uncertainty in projected costs and consequences arising from input parameter uncertainty. The
uncertainty surrounding each model input was characterised by assigning an appropriate probability distribution
(Tables S1S3). The model was then analysed by simulating
the passage of 10 000 women through the model 1000
times, with a value for each parameter being drawn at
random from its assigned distribution for each of the 1000
runs. This probabilistic approach gives an estimated distribution for each modelled output. These output distributions were used to generate 95% credible intervals (CI) for
the differences in costs and outcomes between eSET and
DET. Cost-effectiveness acceptability curves were used to
present the probability of DET being cost-effective in
comparison with eSET given different values of societys
willingness to pay for a QALY.

Deterministic sensitivity analysis

Given the uncertainty surrounding the probability of
women moving to cycles involving transfer of frozen/
thawed embryos, and the relative chances of success in
these cycles following failed eSET and DET, deterministic
sensitivity analysis was conducted to ascertain the influence
of three key parameters: (i) the background probabilities of
moving to a first frozen/thawed transfer following failed
DET and eSET; (ii) the relative probability of moving to
subsequent frozen/thawed cycles following failed frozen
SET; and (iii) the relative probability of pregnancy following frozen SET compared with frozen DET. Further, we
assessed the impact of changes to the twin pregnancy rate
following eSET, to represent the possibility of less stringent
implementation.
The impact on findings of varying the size of the utility
decrement associated with infertility was assessed, as was
the impact of applying a temporary decrement for neonatal
admissions that resulted in a good long-term outcome.
Finally, we conducted an analysis to assess how cost-effectiveness would change if women were to be allowed access
to publicly funded treatment aged 40 years and above.

Results
The modelled clinical outcomes associated with the alternative strategies are presented in Table 1. The cumulative live
birth rate is higher with DET than with eSET across all
three cohorts.
Elective SET is associated with a higher singleton live
birth rate than DET in the 32- and 36-year-old cohorts,
whereas the two strategies are almost equivalent with
respect to this outcome in the 39-year-old cohort. There
is a significantly lower twinning rate with eSET across all
ages, and consequently fewer stillbirths, neonatal deaths
and infants affected by long-term disability. The twinning rate associated with DET also appears to decrease
with age.
The health service cost associated with both eSET and
DET declines with age because of the decreasing probability
of pregnancy and live birth. Elective SET is less costly than
DET in all three cohorts, although the additional cost associated with DET also tends to decrease as womens age
increases. This is because DET is associated with a lower
twin pregnancy rate in older women, which results in a
lower relative increase in the cost per additional live birth
with DET.
From the data presented in Table 1, the incremental cost
per live birth for DET versus eSET comes to 27 356,
18 580 and 15 539 in the 32-, 36- and 39-year-old
cohorts, respectively.
Considering the QALYs accruing to women (Table 2)
DET is associated with a greater number of QALYs in all
three cohorts and the incremental cost per additional
QALY associated with DET also decreases with womens age.
Figure 2 indicates the probability of DET being considered
cost-effective for women of different ages, given different
values of societys willingness to pay for a QALY.

Deterministic sensitivity analysis

The findings were most sensitive to the changes in the
probabilities of moving to subsequent frozen/thawed treatment cycles following failed eSET and DET, and the size of
the utility decrement associated with infertility.
Doubling the probability of moving on to subsequent
frozen/thawed cycles in the eSET arm, relative to the
observed probability of moving to subsequent frozen/
thawed cycles following DET, slightly reduced the costeffectiveness of DET in 32-year-old women [incremental
cost-effectiveness ratio (ICER): 29 500 per additional
QALY], but had limited impact on the overall findings in
older women.
Changing the relative probability of pregnancy with frozen/thawed SET compared with frozen/thawed DET (from
0.615 to 0.70), slightly reduced the cost-effectiveness of
DET in women of all ages (ICERs 32 300, 25 100, and

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1077

1078

2.9 (0.8 to 5.0)

8.0

4.0 (1.5 to 6.7)

2.9

5.8

3.4 (1.1 to 5.8)

7.7
4.3
4.6 (1.7 to 7.7)

4.0

10.5
6.0

Stillbirths and neonatal deaths

per 1000 women treated

5.0

10.6

5.6 (2.6 to 8.8)

6.5 (3.0 to 10.3)

7.5
No. of infants with long-term
disability per 1000 women treated

14.0

17.2 (14.5 to 20.0)

19.1
1.9
21.1 (18.7 to 23.3)
23.4
2.3
25.1 (23.5 to 26.8)
2.5
Twin live birth rate (as %
age of all live births)

27.6

0.0 ()3.3 to 3.3)

28.7
28.7
)5.0 ()8.5 to )1.7)
39.3
48.9
Singleton live birth rate (%)

40.2

)8.7 ()12.7 to )4.9)

34.3

4.3 (1.2 to 7.3)

30.9
26.5
2.2 ()1.2 to 5.4)
38.6
36.4
1.4 ()2.3 to 4.8)
45.4
Term live birth rate (%)

46.8

7.6 (4.1 to 11.0)

37.1
29.4
6.9 (3.2 to 10.4)
47.4
40.5
8.1 (4.2 to 11.7)
58.5
50.4
Live birth rate (%)

1181 (802 to 1599)

10 390
9209
1282 (878 to 1679)
11 732
10 451
2215 (1760 to 2624)
13 405
11 190
Health service costs (mean)

Diff. (95% CI)

DET
Diff. (95% CI)
DET
eSET

DET

Diff. (95% CI)

eSET

36-year-old women
32-year-old women

Table 1. Cumulative costs and outcomes following up to three fresh treatment cycles with eSET or DET (with associated frozen cycles)

eSET

39-year-old women

Scotland et al.

21 600 per QALY in the 32-, 36- and 39-year-old cohorts

respectively). Applying the assumption that 70% (as
opposed to 80%) of frozen embryos survive the freezing
process, slightly improved the cost-effectiveness of DET in
all age groups.
Varying the twin pregnancy rate following eSET, to
reflect potential variation in implementation, had a substantial impact on cost-effectiveness of the alternative strategies. For example, increasing the twin pregnancy rate to
5% following planned eSET reduced the ICER for DET versus eSET to 23 900 per QALY in 32-year-old women,
18 500 per QALY in 36-year-old women, and 17 300
per QALY in 39-year-old women. Raising the twin pregnancy rate following planned eSET to 10% increased costeffectiveness of DET even further (e.g. to 20 100 per
extra QALY in 32-year-old women). However, caution is
required when interpreting these results as we could not
ascertain how imperfect implementation of eSET would
affect the live birth rate.
Reducing the size of the utility decrement associated
with infertility by 25% substantially reduced the costeffectiveness of DET (ICERs  41 300, 35 100 and
32 900 per QALY in the 32-, 36- and 39-year-old
cohorts, respectively). Applying a large but temporary utility decrement of 0.5 over the duration of the neonatal
period when neonates were admitted, to reflect the potential stress associated with this event, had little impact on
the results. We also assessed the impact of assuming that
womens quality of life would return to baseline levels
over the 2 years following a stillbirth or neonatal death.
Given the low absolute probability of this event, this
change also had little impact on findings. When womens
life-years were quality adjusted using standard gamble
utility weights previously elicited from women waiting to
undergo IVF treatment in Aberdeen,42 the apparent costeffectiveness of DET improved substantially in women of
all ages; the ICERs for DET versus eSET being 9400,
7300 and 5700 per additional QALY in the 32-, 36and 39-year-old cohorts respectively.
Finally, raising the starting age of women to 40 resulted
in the health service costs being marginally lower with
DET, whereas the live birth rate remained marginally
higher; the mean difference (95% CI) in cost and live birth
rate coming to 126 ()620 to 487) and +2.4% ()0.8 to
5.6), respectively. These differences were not significant in
the 40-year-old cohort because of the diminishing pregnancy rates and higher discontinuation rates limiting the
potential for DET to exert its per cycle superiority. In
terms of QALYs, there was very little to choose between
the strategies; the mean difference (95% CI) for DET versus
eSET equating to )0.01 QALYs ()0.057 to 0.037). The twin
pregnancy rate associated with DET in 40-year-old women
was 12.1%.

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

Cost-effectiveness of eSET versus DET

Table 2. Incremental costutility of DET versus eSET by age of women when they start treatment
Strategy
(age group)

32 years
eSET
DET
36 years
eSET
DET
39 years
eSET
DET

Mean health
service costs

Difference in health
service costs

Womens
QALYs

Difference in
womens QALYs

Additional cost per

additional QALY (Health
service perspective)

11 190
13 405

*
2215 (17602624)

13.226
13.304

*
0.078 (0.0270.133)

*
28 263

10 451
11 732

*
1282 (8781679)

13.077
13.136

*
0.059 (0.0120.110)

*
21 722

9209
10 390

*
1181 (8021599)

12.933
12.991

*
0.058 (0.0120.108)

*
20 278

*Comparison group.

Strengths and weaknesses

Probability cost-effective

0.9
0.8
0.7
0.6
0.5

39 years

0.4

36 years

0.3

32 years

0.2
0.1
0
0

10,000
20,000
30,000
40,000
Willingness to pay per QALY

50,000

Figure 2. Cost-effectiveness acceptability curves for DET versus eSET

by age at which women commence treatment.

Discussion
A strategy of elective DET was associated with not only a
higher cumulative live birth rate compared with eSET
across women of all ages, but also a higher rate of twin
pregnancy and associated complications (stillbirths, neonatal deaths and adverse child health outcomes), particularly
in younger women. From the health service perspective, the
DET strategy varied from costing an additional 27 356 per
extra live birth in 32-year-old women to an extra 15 539
per extra live birth in 39-year-old women.
Compared with eSET, DET cost 28 300 per additional
QALY for women commencing treatment aged 32 years,
21 700 per extra QALY for women commencing treatment aged 36 years, and 20 300 per extra QALY in
women starting treatment aged 39 years.

The greatest challenge in assisted reproduction is to formulate effective and cost-effective strategies of embryo transfer
such that the risk of multiples is minimised without sacrificing success rates. This is the first study to assess the
cumulative costs and consequences of using alternative
embryo transfer strategies over multiple treatment cycles
for women of different ages. The model structure was
developed through consultation with a panel of experts,
and we used a large observational data set of contemporaneous data from three of four teaching-hospital-based IVF
centres in Scotland, combined with data from randomised
controlled trials, to estimate singleton and twin pregnancy
rates following eSET and DET. To our knowledge this is
also the first study to estimate QALYs associated with alternative approaches to assisted reproduction.
It has been argued that QALYs are unsuitable for comparison of assisted reproductive technologies, on the
grounds that they are not geared towards capturing the
benefit of creating life, but rather the benefit of improving
health.44 However, if we view infertility as a disruption
to normal function that limits an individuals opportunity
to live a good life,45 and assisted reproductive technologies
(ART) as interventions that couples access to overcome
their infertility and improve their quality of life, then the
benefits of ART to prospective patients can in theory be
measured using QALYs. We chose to concentrate on
womens QALYs rather than the expected QALYs for both
partners, as women are the main recipient of IVF treatment. This approach can be seen as a way of putting ART
on an equal footing with chronic diseases; economic evaluations of other medical interventions for chronic, noninfectious diseases generally assess the health benefits accruing
to the one main recipient of treatment, rather than the

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Scotland et al.

health improvements accruing to all individuals affected by

the decision to treat.
As relatively few eSET procedures have been performed
in the UK until recently,43 we were unable to estimate the
probability of pregnancy following eSET directly. To overcome this problem we estimated pregnancy rates following
eSET by applying a constant relative reduction to the pregnancy rate that would be expected with DET. To ensure
the applicability of this relative reduction to our modelled
cohorts, we applied the same selection criteria for eSET as
was used in the randomised controlled trials from which
the multiplier was derived.46 This approach yielded live
birth rates following eSET that were congruent with those
observed in other randomised trials.6
A further weakness was that we were unable to assess
relative cost-effectiveness of transferring blastocyst-stage
embryos as opposed to cleavage-stage embryos. This is a
question that we will be able to address in the future, as
this practice gains wider clinical acceptance.
Finally, the process of modelling multiple fresh and frozen cycles over a prolonged time horizon, introduced an
additional degree of uncertainty into the analysis. This was
the result of assumptions being required regarding the
probability of women moving to frozen/thawed cycles, and
subsequent fresh treatment cycles, following failed eSET
and DET.

Comparison with other studies

A recent study47 simulated cumulative outcomes from a
single complete cycle with eSET (with frozen embryos
thawed one at a time) and a single complete cycle with
DET (with frozen embryos thawed two at time), using
statistical models developed from a large observational data
set. Roberts et al.47 found that DET produced a higher
expected live birth rate than eSET (30.8% versus 27.8%)
when success rates for frozen embryos matched those
observed in their clinical data set, but their analysis
suggested that eSET might outperform DET if outcomes
following frozen embryo transfer were to improve.
Although differences in the structure and assumptions of
our model prevent a direct comparison of predicted success
rates, we found that DET retained a higher probability of
live birth compared with eSET even when we increased the
relative probability of success in frozen single embryo
transfers. This apparent difference in findings is probably
because we applied observed cryopreservation rates and
discontinuation rates following failed frozen cycles, rather
than the assumption that women freeze and use all goodquality embryos associated with a single egg recovery before
proceeding to a new cycle.
Our findings are broadly consistent with those of previous economic evaluations that found a single fresh DET
to be more costly and marginally more effective than a

1080

single cycle with eSET followed by replacement of a single

frozen/thawed embryo in those who failed to becme pregnant.48 In the only other economic evaluation of eSET
that took womens age into consideration, Dixon et al.32
compared the costs and consequences of one fresh DET
and one fresh eSET (followed by one frozen/thawed SET)
and also found that the cost-effectiveness of DET increases
with age.
Previous attempts to model multiple treatment cycles
over time29,49 came to the conclusion that DET would generate a higher live birth rate at higher cost to the health
service and society. However, our study suggests that the
additional health service costs associated with DET decrease
as women get older. Further comparisons between this and
previous studies are hampered by the fact that previous
studies did not assess cost-effectiveness by womens age
or only considered costs incurred up to 6 weeks after
delivery.29,49

Interpretation
This study suggests that a DET strategy would produce
not only a higher live birth rate than eSET for women of
all ages but also a higher twin pregnancy rate. The difference in the twin pregancy rates between the strategies
decreases as womens age increases, and as a consequence
the additional health service costs associated with DET
also decrease as women age. It is the higher twinning
rate that drives the higher cost increases associated with
DET in younger women. The preferred strategy for
women commencing treatment at different ages depends
upon how much society is willing to pay for an additional live birth, coupled with concerns about the acceptability of the observed twin pregnancy and complication
rates.
No guidance exists on how much society should be willing to pay for a live birth so we estimated womens QALYs
associated with the alternative strategies. The additional
cost per extra QALY was found to decrease with womens
age because of the lower probability of twin pregnancy and
associated complications with DET in older women. In the
UK, interventions that cost below 20 000 to 30 000 per
additional QALY are often considered cost-effective.50
Applying this threshold range, and applying the primary
utility assumptions, DET would be more likely to be considered cost-effective for women commencing treatment
aged 36 years or over, and less likely to be considered costeffective in younger women (Figure 2).
However, limited availability of population preference
weights for the different IVF treatment/outcome scenarios
makes it difficult to draw firm conclusions from the QALY
analysis. The incremental cost per QALY was found to be
highly sensitive to the size of the quality of life decrement
associated with infertility. Reducing this decrement from

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Cost-effectiveness of eSET versus DET

0.07 to 0.05 resulted in DET costing over 30 000 per additional QALY in women of all ages.
Costutility was also sensitive to the source of the preference values. Application of preference weights previously
elicited from women waiting to undergo IVF treatment in
Aberdeen,42 resulted in a more favourable incremental cost
per QALY ratio for DET across women of all ages. The driver behind this change was the low utility weight that infertile women assigned to the outcome of being infertile
following treatment failure (childlessness for life). This is
consistent with the findings of previous studies suggesting
that many women have a clear preference for DET despite
being aware of the risks associated with twin pregnancy.9,10

members of the Advisory Group on Multiple Births to the

HFEA.

Contribution to authorship
SB, GS and KH were responsible for the original idea and
developed the study protocol and funding application with
JJK, MR and HL. DM advised on statistical aspects of the
study design and undertook the statistical analyses underpinning the cost-effectiveness model. PM and MH advised
on the design and analysis of the cost-effectiveness models.
All the authors were involved in the discussion and interpretation of results. GS conducted the economic modelling
and drafted the paper. All authors contributed to the
writing of further drafts. GS is the guarantor for the study.

Policy implications
The HFEA in the UK has recently introduced a twin pregnancy target of no more than 10% of all IVF births, with
which clinics are obliged to comply. Given the very high
twin pregancy rates expected with DET in 32- and 36-yearold women, coupled with higher health service costs and
uncertainty relating to the expected QALY gains, eSET is
likely to be the favoured strategy in these women. However, with the twinning rate associated with DET decreasing
and the difference in health service costs between the strategies becoming smaller as women age, DET may be considered cost-effective in some groups of older women. For
women aged 3739 years, the decision over embryo transfer
may best be considered on a case-by-case basis, though our
model suggests that DET will have a higher likelihood of
being considered cost-effective for older women within in
this age range. If women were allowed to commence publicly funded treatment aged 40 years, our model suggests
that while eSET and DET may be more or less equivalent
in terms of costs to the health service, DET may produce a
marginally higher live birth rate (though not significant at
the 5% level). This suggests DET may offer the most efficient approach to IVF in women aged 40 years and over,
should NHS-funded treatment be made available to these
women.

Details of ethics approval

Conclusions

The following supplementary materials are available for this

article:
Table S1. Model parameters, (clinical inputs).
Table S2. Model parameters, (costs).
Table S3. Model parameters, (utility values and decrements).
Additional Supporting Information may be found in the
online version of this article.
Please note: Wiley-Blackwell are not responsible for the
content or functionality of any supporting information
supplied by the authors. Any queries (other than missing
material) should be directed to the corresponding
author. j

Given the high twin pregnancy rates associated with DET

in women aged 36 years and under, coupled with increased
costs to the health service for uncertain QALY gains, a
selective eSET policy is likely to be the preferred option for
women in this age group. As women get older, the likelihood of DET being considered cost-effective from the
health service perspective increases.

Disclosure of interests
One of the authors (MH) is Chair of the British Fertility
Association. Two of the authors (MH and SB) are

The North of Scotland Research Ethics Committee confirmed that a formal ethics application was not required
for this study based on anonymised routine data and published literature.

Funding
This study was funded by the Chief Scientist Office of the
Scottish Governments Health Directorates (SGHD). The
views expressed here are those of the authors and not necessarily those of the SGHD.

Acknowledgements
The authors wish to thank the members of the advisory
group for the project: Dr Anthony Harrold (Consultant
Gynaecologist, NHS Tayside), Dr Maybeth Jamieson (Consultant Embryologist, Assisted Conception Unit Glasgow),
Dr Mark Hamilton (Consultant and Subspecialist in Reproductive Medicine, Aberdeen Fertility Centre), Dr Clem Tay
(Consultant and Subspecialist in Reproductive Medicine,
Simpson Fertility Centre) and Dr Sumesh Thomas
(Consultant Neonatologist, Aberdeen Maternity Hospital).

Supporting information

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References
1 ESHRE Campus Course Report. Prevention of twin pregnancy
after IVF/ICSI by single embryo transfer. Hum Reprod 2001;16:
790800.
2 De Mouzon J, Goossens V, Bhattacharya S, Castilla JA, Ferraretti AP,
Jorsak V, et al. Assisted reproductive technology and intrauterine
inseminations in Europe, 2006: results generated from European
registers by ESHRE. Hum Reprod 2010;25:185162.
3 Bortolus R, Parazzini F, Chatenoud L, Benzi G, Bianchi MM, Marini A.
The epidemiology of multiple births. Hum Reprod Update 1999;5:
17987.
4 Blondel B, Kaminski M. Trends in the occurrence, determinants, and
consequences of multiple births. Semin Perinatol 2002;26:23949.
5 Ledger WL, Anumba D, Marlow N, Thomas CM, Wilson EC. Cost of
Multiple Births Study Group (COMBS Group). The costs to the NHS
of multiple births after IVF treatment in the UK. BJOG 2006;113:
215.
6 Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of
embryos for transfer after IVF and ICSI: a Cochrane review. Hum
Reprod 2005;20:26817.
7 El-Toukhy T, Khalaf Y, Braude P. IVF results: optimize not maximize.
Am J Obstet Gynecol 2006;194:32231.
8 Roberts SA, Fitzgerald CT, Brison DR. Modelling the impact of single
embryo transfer in a national health service IVF programme. Hum
Reprod 2009;24:12231.
9 Newton CR, McBride J, Feyles V, Tekpetey F, Power S. Factors
affecting patients attitudes toward single and multiple embryo
transfer. Fertil Steril 2007;87:26978.
10 Blennborn M, Nilsson S, Hillervik C, Hellberg D. The couples decision making in IVF: one or two embryos at transfer? Hum Reprod
2005;20:12927.
11 National Collaborating Centre for Womens and Childrens Health
on behalf of the National Institute for Clinical Excellence. Fertility:
assessment and treatment for people with fertility problems. Clinical
Guideline. Royal College of Obstetricians and Gynaecologists,
London: RCOG Press, 2004.
12 Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell
A, et al. Elective single embryo transfer versus double embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392402.
13 Le Lannou D, Griveau J-F, Laurent M-C, Gueho A, Veron E, Morcel
K. Contribution of cryopreservation to elective single embryo transfer in IVF-ICSI. Reprod BioMed Online 2006;13:36875.
14 Vitthala S, Gelbaya TA, Brison DR, Fitzgerald CT, Nardo LG. The risk
of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis. Hum Rep Update 2009;15:4555.
15 Pinborg A, Lidegaard , La Cour Freiesleben N, Anderson AN. Consequences of vanishing twins in IVF/ICSI pregnancies. Hum Reprod
2005;20:28219.
16 Penny G. Scottish Perinatal and Infant Mortality and Morbidity
Report 2001. Edinburgh: Information & Statistics Division, NHS Scotland, 2002.
17 Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal
outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261.
18 Stromberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M,
Stjernqvist K. Neurological sequelae in children born after in-vitro
fertilisation: a population-based study. Lancet 2002;359:4615.
19 Sperling L, Kiil C, Larsen LU, Qvist I, Schwartz M, Jrgensen C, et al.
Naturally conceived twins with monochorionic placentation have the
highest risk of fetal loss. Ultrasound Obst Gyn 2006;28:64452.
20 Pharaoh POD. Neurological outcome in twins. Semin Perinatol
2002;7:22330.

1082

21 Hack KEA, Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK, et al.
Increased perinatal mortality and morbidity in monochorionic versus
dichorionic twin pregnancies: clinical implications of a large Dutch
cohort study. BJOG 2008;115:5867.
22 Petterson B, Stanley F, Henderson D. Cerebral palsy in multiple births
in Western Australia: genetic aspects. Am J Med Genet 1990;37:
34651.
23 Glinianaia SV, Pharoah POD, Wright C, Rankin JM. Fetal and infant
death in twin pregnancy: neurodevelopmental consequences for the
survivor. Arch Dis Child Fetal Neonatal Ed 2002;86:F915.
24 Scher AI, Petterson B, Blair E, Ellenberg JA, Grether JK, Haan E, et al.
The risk of mortality or cerebral palsy in twins: a collaborative population based study. Pediatr Res 2002;52:67181.
25 Pinborg A, Loft A, Schmidt L, Greisen G, Rasmussen S, Anderson
AN. Neurological sequelae in twins born after assisted conception:
controlled national cohort study. BMJ 2004;329:311.
26 Hutton JL, Phaoah POD, Rosenbloom L. Effects of cognitive, motor
and sensory disabilities on survival in cerebral palsy. Arch Dis Child
2002;86:849.
27 Strauss D, Brooks J, Rosenbloom L, Shavelle R. Life expectancy in
cerebral palsy: an update. Dev Med Child Neurol 2008;50:48793.
28 van Montfoort P, Fiddelers AA, Janssen JM, Derhaag JG, Dirksen
CD, Dunselman GAJ, et al. In unselected patients, elective single
embryo transfer prevents all multiples, but results in significantly
lower pregnancy rates compared with double embryo transfer: a
randomized controlled trial. Hum Reprod 2006;21:33843.
29 Fiddelers AAA, Dirksen CD, Dumoulin JCM, van Montfoort APA,
Land JA, Janssen JM, et al. Cost-effectiveness of seven IVF strategies: results of a Markov decision-analytic model. Hum Reprod
2009;24:164855.
30 Maheshwari A, Scotland G, McTavish A, Bell J, Hamilton M, Bhattacharya S. Direct health services costs of providing assisted reproduction services in older women-Retrospective cross-sectional
analysis. Fertil Steril 2010;93:52736.
31 Templeton A, Morris JK, Parslow W. Factors that affect outcome of
in-vitro fertilisation treatment. Lancet 1996;348:14026.
32 Dixon S, Nasiri FF, Ledger WL, Lenton EA, Duenas A, Sutcliff P, et al.
Cost-effectiveness analysis of different embryo transfer strategies in
England. BJOG 2008;115:75866.
33 Petrou S, Bischof M, Bennet C, Elbourne D, Field D. Cost-effectiveness of neonatal extracorporeal membrane oxygenation based on 7year results from the United Kingdom Collaborative EMCO trial.
Pediatrics 2006;117:16409.
34 Henderson J, Hockley C, Petrou S, Goldacre M, Davidson L. Economic
implications of multiple births: inpatient hospital costs in the first 5
years of life. Arch Dis Child Fetal Neonatal Ed 2004;89:F5425.
35 Pinborg A, Loft A, Rasmussn S, Anderson AN. Hospital care utilisation of IVF/ICSI twins until 27 years of age: a controlled Danish
national cohort study. Hum Reprod 2004;19:252936.
36 Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N. The cost of
preterm birth throughout England and Wales. Pediatrics 2009;123:
e31227.
37 Institute of Medicine. Neisseria Gonorrhea. In: Stratton KR, Durch JS,
Lawrence RS, editors. Vaccines for the 21st Century: A Tool for
Decision Making. Washington, DC: National Academy Press; 2000.
pp. 25765.
38 Torrance GW, Feeny DH, Furlong WJ, Barr RD, Zhang Y, Wang Q.
Multi-attribute preference functions for a comprehensive health
status classification system: Health Utilities Index Mark 2. Med Care
1996;34:70222.
39 Luo N, Johnson JA, Shaw JW, Feeny D, Coons SJ. Self-reported
health status of the general adult US population as assessed by
EQ-5D and Health Utilities Index. Med Care 2005;43:107886.

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

Cost-effectiveness of eSET versus DET

40 Kind P, Hardman G, Macran S. UK Population Norms for EQ-5D.

Discussion Paper 172. York: Centre for Health Economics, University
of York; 1999.
41 Kuhlthau K, Kahn R, Hill KS, Gnanasekaran S, Ettner SL. The wellbeing of parental caregivers of children with activity limitations.
Matern Child Health J 2010;14:15563.
42 Scotland GS, McNamee P, Peddie VL, Bhattacharya S. Safety versus
success in elective single embryo transfer: womens preferences for
outcomes of in vitro fertilisation. BJOG 2007;114:97783.
43 Human Fertilisation and Embryology Authority.A long term analysis
of the HFEA Register data (19912006). Human Fertilisation and
Embryology Authority 2008; [www.hfea.gov.uk]. Last accessed
17 March 2011.
44 Devlin N, Parkin D. Funding fertility: issues in the allocation and
distribution of resources to assisted reproduction technologies. Hum
Fertil 2003;6:S26.
45 McMillan J. Allocating fertility services by medical need. Hum Fertil
2001;4:113.

46 Kjellberg AT, Carlsson P, Bergh C. Randomised single versus double

embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis. Hum Reprod 2006;21:2106.
47 Roberts SA, McGowan L, Hirst WM, Brison DR, Vail A, Lieberman
BA. Towards single embryo transfer? Modelling clinical outcomes of
potential treatment choices using multiple data sources: predictive
models and patient perspectives. Health Technol Assess 2010;14:
1237.
48 Fiddelers AAA, Severens JL, Dirksen CD, Dumoulin JCM, Land JA,
Evers JLH. Economic evaluations of double- versus single- embryo
transfer in IVF. Hum Reprod Update 2007;13:513.
49 De Sutter P, Gerris J, Dhont M. A health-economic decision-analytic
model comparing double with single embryo transfer in IVF/ICSI.
Hum Reprod 2002;17:28916.
50 Appleby J, Devlin N, Parkin D. NICEs cost effectiveness threshold.
How high should it be?. BMJ 2007;335:3589.

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

1083