doi:10.1093/humrep/dem372
Human Reproduction Vol.23, No.2 pp. 316–323, 2008
Advance Access publication on November 22, 2007
Cost-effectiveness of a mild compared with a standard
strategy for IVF: a randomized comparison using cumulative
term live birth as the primary endpoint
S. Polinder1,3, E.M.E.W. Heijnen2, N.S. Macklon2, J.D.F. Habbema1,
B.J.C.M. Fauser1 and M.J.C. Eijkemans1,2
1
3
Correspondence address. E-mail: [email protected]
BACKGROUND: Conventional ovarian stimulation and the transfer of two embryos in IVF exhibits an inherent high
probability of multiple pregnancies, resulting in high costs. We evaluated the cost-effectiveness of a mild compared
with a conventional strategy for IVF. METHODS: Four hundred and four patients were randomly assigned to
undergo either mild ovarian stimulation/GnRH antagonist co-treatment combined with single embryo transfer, or
standard stimulation/GnRH agonist long protocol and the transfer of two embryos. The main outcome measures
are total costs of treatment within a 12 months period after randomization, and the relationship between total
costs and proportion of cumulative pregnancies resulting in term live birth within 1 year of randomization.
RESULTS: Despite a significantly increased average number of IVF cycles (2.3 versus 1.7; P < 0.001), lower
average total costs over a 12-month period (8333 versus E10 745; P 5 0.006) were observed using the mild strategy.
This was mainly due to higher costs of the obstetric and post-natal period for the standard strategy, related to multiple
pregnancies. The costs per pregnancy leading to term live birth were E19 156 in the mild strategy and E24 038 in the
standard. The incremental cost-effectiveness ratio of the standard strategy compared with the mild strategy was
E185 000 per extra pregnancy leading to term live birth. CONCLUSIONS: Despite an increased mean number of
IVF cycles within 1 year, from an economic perspective, the mild treatment strategy is more advantageous per
term live birth. It is unlikely, over a wide range of society’s willingness-to-pay, that the standard treatment strategy
is cost-effective, compared with the mild strategy.
Keywords: GnRH antagonist; mild ovarian stimulation; single embryo transfer; IVF
Introduction
The increasing success of IVF in the 1990s did not just result
in an increased pregnancy rate, but especially in an increase
in the incidence of multiple births (Fauser et al., 1999, 2005).
Several cost studies have demonstrated the impact of multiple births on health care resources (Callahan et al., 1994;
Gerris et al., 2004; Kjellberg et al., 2006). Conventional
ovarian stimulation along with the transfer of two embryos
in IVF exhibits an inherent high probability of multiple pregnancies, resulting in high costs due to intensive antenatal surveillance, increased chances for complications of both
mother and child with associated hospital admissions, a
higher chance for caesarian section and perinatal and postpartum care (Wolner-Hanssen and Rydhstroem, 1998;
Gerris et al., 2004; Lukassen et al., 2004). The financial
burden of multiple births on health care resources has been
316
calculated to be greater than the costs of IVF treatment
itself (Collins et al., 2000). There is a growing awareness
that the high rate of multiple pregnancies can be greatly
reduced by a single embryo transfer (SET) policy (Thurin
et al., 2004; Fauser et al., 1999, 2005; Papanikolaou et al.,
2006). However, SET results in a reduced live birth rate
per IVF treatment cycle, which can to some extent be overcome by cryopreservation of supranumerary embryos (Thurin
et al., 2004; Pandian et al., 2005). There is a clear need for
the further evaluation of efficacy and economic consequences
of different approaches in IVF, including SET.
The introduction of GnRH antagonists into clinical practice
has enabled the development of novel milder ovarian stimulation protocols (Fauser et al., 1999, 2005; Macklon et al.,
2006). Mild stimulation might be advantageous when evaluated over an entire (multiple cycle) treatment period, since
# The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
All rights reserved. For Permissions, please email: [email protected]
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Department of Public Health, Erasmus Medical Center, Dr Molewaterplein 50, PO Box 2040, 3000 CA Rotterdam,
The Netherlands; 2Department of Reproductive Medicine and Gynaecology, University Medical Center,
Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Cost-effectiveness of a mild versus standard IVF strategy
Materials and Methods
Study design
The study protocol was approved by the ethics review board of both
participating University Medical Centers (Utrecht and Rotterdam).
Patients were recruited from February 2002 until March 2004
(Eijkemans et al., 2006). Patients with a regular indication for IVF
or IVF/ICSI (tubal, male and unexplained), female age ,38 years,
normal menstrual cycle (cycle length between periods 25 –35 days)
and without severe obesity or underweight (body mass index 18–
28 kg/m2) were eligible for the study. Patients were randomly
assigned to undergo either mild ovarian stimulation with GnRH antagonist co-treatment combined with SET (mild strategy, n ¼ 205),
with reimbursement of a maximum of four treatment cycles, or a
‘standard’ ovarian stimulation protocol (n ¼ 199) where pituitary
down-regulation was achieved using a GnRH agonist long-protocol
combined with the transfer of a maximum of two embryos (standard
strategy), with reimbursement of up to three treatment cycles. Full
details of the trial design, interventions and clinical outcomes have
been reported elsewhere (Eijkemans et al., 2006; Heijnen et al.,
2004, 2007).
The endpoint for this study was defined as mean total costs of IVF
treatment per couple within 12 months after randomization, including costs of resulting pregnancy and post-natal costs of the mother
and the infant(s) up to 6 weeks after the expected date of delivery.
A summary of the mean total costs has been published earlier
(Heijnen et al., 2007). In the current paper, the extended cost analysis will be addressed, including costs per completed IVF treatment
and cost per term child born. To make a full economic comparison
of the two treatment strategies, the difference between the two
groups in mean total costs will be related both to the difference in
the proportion of pregnancies leading to term live birth within 1
year of randomization and to the difference in the number of term
born children.
Cost calculations
The economic analysis was performed from a societal perspective.
The costs of the two IVF strategies were assessed in two stages.
First, the cost of IVF treatment itself, starting with the first IVF
cycle and ending with the outcome of the last IVF-cycle within 1
year (pregnant, no pregnancy or dropout). Second, the costs of
antenatal, peripartum and post-partum care were analysed in
women who became pregnant after IVF treatment.
Medical costs were calculated by multiplying the volumes of health
care use with the corresponding unit prices. The costs apply to the
financial year 2004. The costs of IVF treatment were distinguished
into medical costs in the hospital (intramural), extramural medical
costs and non-medical costs. Medical costs in the hospital consist of
scheduled and unscheduled outpatient visits, number of IVF cycles,
personnel time per cycle, use of GnRH analogues and recombinant
FSH, costs of ultrasound and hormonal monitoring, the embryo transfer procedure and costs associated with complications. Extramural
medical costs consist of general practitioner consultations, and
social worker. Non-medical costs are associated with travel and
absence from work/sick leave due to the treatment or associated complications. Cost volumes in the treatment stage were recorded with
case record forms, hospital-based management and budgetary information systems, patient questionnaires and literature (Fig. 1).
The costs of pregnancy and obstetric care were distinguished into
medical costs in the hospital (secondary obstetric care) and medical
costs outside the hospital (e.g. primary obstetric care, general practitioner care, etc.). Pregnant patients received several questionnaires
regarding health care use each covering a 3 month period of their
pregnancy. The final questionnaire covered the period around the
calculated term date, until 6 weeks thereafter. This means that the neonatal costs are covered for a 6-week period post-term. For preterm
births, the post-natal period is therefore longer and costs higher than
for term births (Bollen et al., 2003). In order to receive medical
Figure 1: Timing of the economic evaluation assessments, during
IVF treatment itself, and at three time points during pregnancy and
the perinatal period
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the amount of time needed to complete a single IVF cycle is
reduced, the costs of stimulation are lower (Hohmann et al.,
2003; Tarlatzis et al., 2006), patient discomfort and chances
for complications may be reduced and the patient dropout
rate may decrease. Milder treatment strategies including SET
may allow for more IVF cycles in the same period of time
and therefore result in a similar term live birth rate per treatment period compared with standard stimulation protocols
with the transfer of two embryos (Heijnen et al., 2004; Eijkemans et al., 2006). Such a mild treatment strategy may also
reduce costs by eliminating multiple pregnancies. As reported
recently, a mild approach in IVF results in a similar 1-year
cumulative proportion of pregnancies leading to term live
birth compared with a standard treatment strategy (standard
ovarian stimulation protocol, including GnRH agonist long
protocol co-treatment and the transfer of two embryos) in
women less than 38 years of age, while greatly reducing multiple pregnancy rates (Heijnen et al., 2007). Consequently, the
total costs of treatment (including the obstetric and post-natal
period) were significantly reduced (Heijnen et al., 2007). The
aim of the current paper is to provide additional information
concerning the economic consequences of two different treatment strategies in IVF involving ovarian stimulation protocols
and embryo transfer policies during consecutive treatment
cycles.
Polinder et al.
productivity due to absence from work were also taken into account,
using charges (Oostenbrink et al.). Discounting was not applied
because of the limited time horizon. Table I provides an overview
of the cost categories and data used in the cost calculations.
Statistical analysis
Analysis was carried out according to the intention-to-treat principle.
For a pragmatic (or effectiveness) trial, the focus should not be the cost
per cycle but rather the overall cost that a patient may expect over a
given treatment period (including cycles in which cryopreserved
embryos were transferred) (Vail and Gardener, 2003). Therefore, we
elected to base the analysis on a 1-year treatment period allowing sufficient time for most patients to complete all IVF treatment cycles.
Differences in mean costs between the two strategies were tested by
a two-sample t-test. Effectiveness, measured by the proportion of
cumulative pregnancies resulting in term live birth within 1 year
after randomization, was estimated by the Kaplan–Meier method.
The time period of analysis started from the moment of randomization,
to avoid post-randomization selective dropout (Eijkemans et al.,
2006).
Cost-effectiveness was assessed by calculating the incremental
cost-effectiveness ratio, defined here as the difference in average
costs between the two strategies divided by the difference in
average effects. The sampling distribution (i.e. uncertainty) of costs
and effects was investigated by bootstrapping. From this distribution,
a cost-effectiveness acceptability curve was constructed (Glick et al.,
2001), which shows the probability that the standard treatment is costeffective for a range values of the maximum monetary expenditures
Table I. Cost categories and data used in cost calculations.
Cost category
Parameter
Data collection volume of care
CRF (physician)
Medication
GnRH analoguesa
Recombinant FSH
hHCG/Progesteron
Technical procedures
Oocyte retrieval
Laboratory procedures
Embryo transfer
Intramural care
Hospital (academic)
Hospital (general)
NICU/MCUd
Physician
Ultrasound
Prenatal screening
Other therapy
Delivery
Extramural care
Obstetrician
General practitioner (inpatient)
General practitioner (home visit)
Social worker
Maternity nurse
Non-medical costs
Travel costs
Absence from work
Questionnaires patient
Cost estimate
Questionnaire obst/gyn
Unit price (E)
Calculation method
Strategy
Days
Days
*
*
*
155/235b
585/816b
15b
Cost price
Cost price
Cost price
Strategy
Strategy
Strategy
*
*
*
296
variable
233–283c
Real costs
Real costs
Real costs
Days
Days
Days
Visits
Number
*
*
*
*
*
*
*
*
*
*
*
*
*
448
356
1170
50 (28)e
42
287
Variable
Variablef
Real costs
Real costs
Real costs
Charges
Charges
Charges
Charges
Literature
*
23
20
50
54
35/h
Charges
Fees
Fees
Charges
Charges
0.11/km
29– 40/h
Guideline
Guideline
*
*
*
*
Number
Category
*
Visits
Visits
Visits
Visits
Days
*
*
*
*
*
Distance
Days
*
*
obst/gyn: obstetrics/gynaecology.
GnRH antagonist for mild treatment and GnRH agonist for standard treatment.
b
For the costs of medication, mean costs were used per couple.
c
Embryo transfer for SET E233 and for double embryo transfer E283.
d
Neonatal intensive care unit/medium care unit.
e
Physician visits: costs for an inpatient visit at the IVF department are E50 and telephonically consults are E28.
f
Delivery costs depend on delivery at home/in hospital, with or without complications, delivery with caesarean section (with or without complications).
*
Data used in the cost calculations.
a
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information regarding birth, questionnaires were sent to the responsible obstetrician.
For the most important cost items, unit prices were determined by
following the micro-costing method (Gold et al., 1996), which is
based on a detailed inventory and measurement of all resources
used. During the determination of unit prices, two embryos were transferred in the majority of cycles. Therefore, all unit prices are determined for the transfer of two embryos. The calculation of the unit
price of the IVF treatment consisted of detailed measurement of
investments in manpower, equipment, materials, housing and overhead. The salary schemes of hospitals and other health care suppliers
were used to estimate costs per hour for each caregiver. Taxes, social
securities and vacations were included, as well as the costs of the time
that could not be assigned to other patients. The costs of equipment
included those of depreciation, interest and maintenance. Costs for
inpatient days in hospital were calculated from real, basic costs per
day using detailed information from the financial department of the
hospital. For the unit price per inpatient day in hospital, a distinction
was made between general and university hospitals. These estimates
included overhead and indirect costs. Other charges associated with
inpatient and outpatient care were derived from previous publications
(Oostenbrink et al.), in order to render our results more comparable
with other research and to make these unit costs independent from
the specific hospital prices. For these items, we used charges as a
proxy of real costs. In the Netherlands, a ‘fee for service’ system is
used for the reimbursement of medical interventions and diagnostic
procedures. In order to calculate the costs for medication, we used
pharmacotherapeutic charges. Costs caused by loss of economic
Cost-effectiveness of a mild versus standard IVF strategy
that society would be willing to pay for an extra pregnancy that leads
to a term live birth. By way of sensitivity analysis, we determined
costs, term live birth rate and cost-effectiveness, based on all treatment
cycles that patients went through instead of the limited 12 months time
frame. In addition, the outcome of term live birth was relaxed to all
live births, to make a comparison possible with other studies that
did not take into account the toll involved in multiple pregnancies
as a result of the transfer of two embryos.
Missing cost items arising due to non-response to the questionnaires
were imputed, and stratified by randomization arms to avoid the loss
of data. For this purpose, the AregImpute method in S-plus (MathSoft.
Inc., Seattle, WA, USA, version 2000) was used. A comparison of
the costs between both treatment strategies was performed with the
independent group t-test.
Costs per cycle
The response rate of the economic evaluation questionnaires
during treatment was 81% for all IVF cycles and did not
differ significantly between the two treatment strategies.
Almost 75% of the pregnant women responded to at least
two of the three economic evaluation questionnaires during
pregnancy and the neonatal period. The mean direct medical
costs per IVF cycle were lower for the mild strategy (1559
versus E1977; P ¼ 0.001), mainly due to lower costs for medication and technical procedures (Table II). Per cycle, women in
the mild treatment strategy had on average fewer days of sick
leave during pregnancy when compared with the standard
treatment strategy (23 versus 30; P ¼ 0.029).
Clinical outcomes and costs per 12-months
An extensive description of the clinical outcomes and total
costs per patient within 1 year was presented in our earlier
publication (Heijnen et al., 2004, 2007). In Table III, the
most relevant outcomes are summarized.
For the mild strategy, the duration between cycles was
shorter (88 + 49 versus 109 + 38 days; P , 0.001), yet more
Table II. Intramural medical costs (E) per cycle for the standard and mild
IVF treatment.
Medication
GnRH analoguea
FSH
Technical procedures
Oocyte retrieval/
laboratory
Embryo transfer
Embryo cryo transfer
Intramural care
Ultrasound
Hospital admission
Visits
Laboratory
Total costs per cycle
Mild
(mean + SD)
Standard
(mean + SD)
P-value*
155 + 71
585 + 236
235 + 70
816 + 337
,0.001
,0.001
323 + 210
352 + 184
0.038
151 + 112
17 + 68
222 + 110
14 + 60
,0.001
NS
151 + 69
26 + 167
42 + 51
108 + 123
1559 + 608
157 + 94
72 + 471
43 + 59
65 + 82
1977 + 803
NS
0.059
NS
,0.001
0.001
CRF: case record form, cryo: cryopreservation.
a
GnRH antagonist for mild treatment and GnRH agonist for standard
treatment.
*Independent groups t-test.
Cost-effectiveness analysis
The cost per ongoing pregnancy leading to term live birth was
E19 200 (E8333/0.434) in the mild strategy and E24 000
(E10 745/0.447) in the standard strategy and the costs per
term live born child were E19 200 (E8333/0.434) in the
mild strategy and E20 197 [E10 745/(0.447þ0.085)] in the
standard strategy. The incremental cost-effectiveness ratio of
the standard strategy compared with the mild strategy was
E185 000 per extra pregnancy leading to term live birth
(Heijnen et al., 2007) and E24 600 per term live born child
(Table IV). The uncertainty in both costs and effects, as
assessed by 5000 bootstrap samples, is depicted in Fig. 4
(upper panel), and the corresponding cost-effectiveness acceptability curve Fig. 4 (lower panel). The latter curve shows that
there is only a 20% probability that the standard treatment strategy is cost-effective up to a ceiling ratio of E50 000 per extra
pregnancy leading to term live birth and at a ceiling ratio of
E100 000, this probability does not exceed 40%. The dotted
line shows the acceptability curve when effectiveness is
expressed as term live born child instead of term live birth.
The probability that the standard treatment strategy is costeffective reaches 80% from a ceiling ratio of E60 000 onwards.
Sensitivity analyses
The drop-out rate per cycle was significantly lower in the mild
treatment group compared with the standard group [odds ratio
(OR) ¼ 0.53; P ¼ 0.04, Heijnen et al., 2007]. Further, there
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Results
frozen cycles were performed (54 versus 30; P ¼ 0.016). The
cumulative treatment costs of the standard treatment strategy
were higher in the first 4 months. However, over the complete
12-months period, treatment costs of the mild treatment strategy were comparable with those of the standard strategy
(Fig. 2).
IVF treatment, pregnancy and the neonatal period revealed
lower total costs for the mild strategy (8333 versus E10 745;
P ¼ 0.006), as reported previously (Heijnen et al., 2007).
The costs of intramural care during IVF treatment was significantly higher for the mild strategy (750 versus E576; P ¼
0.006) (Heijnen et al., 2007), which is due to the higher
mean total number of cycles within 1 year. The medical costs
during pregnancy for the mild strategy were half the costs of
the standard strategy (530 versus E1061; P ¼ 0.03), due to
the requirement for more medical care (outpatient visits, hospital admissions). Furthermore, the costs of the obstetric and
post-natal period per ongoing pregnancy were significantly
higher for the standard strategy (4136 versus E1947; P ,
0.001), due to more hospital admissions and more prolonged
duration in hospital for mother and child.
Within 12 months after randomization there were 16 pregnancies leading to preterm live birth (,37 weeks) in the standard treatment group, versus 6 in the mild treatment group
(P ¼ 0.02) (Heijnen et al., 2007). Early preterm live birth
(,32 weeks gestation) resulted in relatively low costs of pregnancy and perinatal period, primarily due to a low neonatal survival rate. Late preterm live birth (32– 37 weeks gestation)
did result in relatively high costs, especially in case of twin
pregnancies (Fig. 3).
Polinder et al.
Table III. Clinical outcomes and costs (E) within 12 months after randomization of 404 patients randomized for a mild or standard strategy in IVF, as a basis
for the current health economics evaluation.
Randomized (n)
Mild (205) (mean + SD)
Standard (199) (mean + SD)
2.3
86
43.4
0
1.4
36
1.7
86
44.7
8.5
3.7
32
,0.001
NS
NS
,0.001
0.04
NS
1083 + 734
750 + 561
1626 + 1088
1948 + 2280
991 + 584
576 + 693
1737 + 1069
1740 + 1845
NS
0.006
NS
NS
530 + 984
449 + 931
1061 + 2076
504 + 854
0.001
NS
542 + 375
342 + 374
684 + 498
379 + 1177
8333 + 5418
1088 + 1164
1653 + 1337
593 + 348
802 + 2270
10 745 + 11 225
,0.001
,0.001
,0.001
NS
0.006
Source: Heijnen et al. (2007).
The cumulative rates differ from the raw percentages, because the cumulative rates were calculated using the Kaplan–Meier method, accounting for censoring
due to pregnancies within 1 year that did not lead to a term live birth.
b
Indirect costs involve traffic costs and absence from work/sick leave.
a
Figure 3: Distribution of the costs of pregnancy and perinatal period
against the total duration of pregnancy, separately for singleton and
multiple pregnancies
Figure 2: (Upper panel) Total costs per IVF cycle, including costs of
resulting pregnancies and the perinatal period. Bars are positioned at
the median of the time at start of the cycle. (Lower panel) Cumulative
total costs up until 12 months, including costs of all pregnancies and
the perinatal period resulting from conceptions within 12 months
320
were 12 patients (6%) in the mild strategy group and 15
patients (8%) in the standard strategy who switched to the
other stimulation protocol or embryo-transfer strategy. Censoring these patients at the moments of switching resulted in
1-year estimates of term live birth of 43.2% in the mild and
44.6% in the standard group (Heijnen et al., 2007), very
similar to the results of the base-case analysis (Table IV).
The results of the sensitivity analysis are summarized in
Table IV. The number of patients still in treatment after 12
months was 72 and 68 in the mild and standard groups, respectively. The sensitivity analysis on all available treatment cycles
(including cycles performed after the 12 months period, and
including cycles in excess of the three or four cycles that
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Mean number of cycles within 1 year (n)
Pregnancy within 1 year leading to term live birth (n)
Cumulative term live birth rate from pregnancies within 1 year (%)a
Multiple pregnancies leading to term live birth per randomized couple (%)
Incidence of ovarian hyperstimulation syndrome (%)
Number of dropouts
Costs of IVF treatment with 1 year
Technical procedures
Intramural care
Medication
Indirect costsb
Costs of pregnancy and delivery from pregnancies within 1 year
Medical costs
Delivery
Costs of the neonatal period from pregnancies within 1 year
Hospital admission mother
Hospital admission child
Maternity care
Indirect costsb (pregnancy þ neonatal)
Total costs within 1 year
P-value
Cost-effectiveness of a mild versus standard IVF strategy
Table IV. Costs, effects and incremental cost-effectiveness ratio of patients randomized for a mild or standard strategy in IVF: results from bases-case analysis
and sensitivity analysis.
Mild
Term live birth 12 months (base-case analysis)
Live birth 12 months
Term live birth all cyclesb
Live birth all cycles2
Term live born child 12 months
Live born child 12 months
Term live born child all cyclesb
Live born child all cyclesb
Incremental C/E ratioa
Standard
Mean total costs (E)
Effectiveness (%)
Mean total costs (E)
Effectiveness (%)
8333
8333
10 033
10 033
8333
8333
10 033
10 033
43.4
45.5
55.6
59.0
43.4
46.0
56.6
60.0
10 745
10 745
12 657
12 657
10 745
10 745
12 657
12 657
44.7
50.9
51.8
61.3
53.2
63.9
62.3
73.8
185 000
44 700
Dominated
115 000
24 600
13 500
46 000
19 100
a
C/E ratio, cost-effectiveness ratio.
Analysis on all available treatment cycles, including cycles performed after the 12 months period, and including cycles in excess of the three or four cycles that
were refunded.
b
Discussion
Figure 4: (Upper panel) Distribution from 5000 bootstrap samples of
the difference in mean costs against the difference in the rate of
pregnancies within 1 year, leading to term live birth. (Lower panel)
Cost-acceptability curve of the standard treatment strategy being costeffective compared with the mild strategy, for a range of society’s
willingness to pay, per term live birth (lower curve) and per term
born child (upper curve)
were refunded) revealed that in the mild strategy, a total of 114
term live births occurred (56% of patients) versus 103 (52%) in
the standard strategy (P ¼ 0.4). The mean number of started
IVF cycles was significantly higher in the mild strategy (2.80
versus 2.05; P , 0.001), but the mean total costs per patient
We have previously published the clinical outcomes of this
trial, which showed that in women below 38 years of age, a
mild strategy in IVF results in a similar proportion of cumulative pregnancies resulting in term live birth within 1 year of randomization compared with a standard strategy, while greatly
reducing the multiple pregnancy rate (Heijnen et al., 2007).
In the current study, we assessed in detail the consequences
of both IVF treatment strategies in terms of costs in order to
provide an integrated evaluation of the health economics of
the two treatment strategies. The overall costs resulting from
treatment up until 12 months after randomization (including
costs associated with resulting pregnancies and delivery)
were lower for the mild strategy compared with the standard
strategy, despite a higher average number of IVF cycles for
the mild strategy. This is mainly due to a reduction of multiple
pregnancies and preterm births in the mild strategy. The costs
per extra term live birth of the standard compared with the mild
strategy are unacceptably high.
The real advantage of the mild strategy is the anticipated added
long-term quality of life and the avoidance of the very high longterm costs resulting from the increased morbidity of twins after
birth (De Sutter et al., 2002; Adashi et al., 2003; Wennerholm
2004). In the current study, the neonatal costs were covered
until 6 weeks after expected date of delivery. The long-term
medical prognosis for the children born in this study period
cannot be predicted but the future costs for these (in some cases
severely ill) children are likely to be very large (Petrou et al.,
2001). The incidence of disabilities is markedly increased in multiple pregnancies, and the associated long-term costs would
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were significantly lower compared with the standard strategy
(E12 657 + 12 791 versus E10 033 + 5869; P ¼ 0.009).
Therefore, the mild strategy is dominant in the cost-effectiveness analysis, i.e. it is both cheaper and more effective than
the standard strategy.
In total, there were 116 term born children in the mild strategy versus 124 in the standard strategy. The incremental costeffectiveness ratio of the standard strategy compared with the
mild strategy is therefore E46 035 per term live born child
and E19 097 for all live born children for all cycles.
Polinder et al.
322
counting a twin as two live born children will be more in
favour of the effectiveness of the standard strategy. However,
the cost-effectiveness ratio is still in favour for the mild strategy,
even after relaxing term live birth to all live born children.
A term born twin may be perceived as a positive outcome, reducing the need for subsequent IVF treatments. However, in
addition to the increased perinatal morbidity, mortality and
long term health consequences associated with twin pregnancies,
parents of multiple pregnancies have been shown to be at greater
risk of depression and anxiety (Leonard 1998; Baor et al., 2004).
Furthermore, when weighing the benefits of the transfer of one
or two embryos, account should also be taken of the live
births which may occur following the subsequent transfer of
surplus embryos (El Toukhy et al., 2003), of which more will
remain when just one fresh embryo is transferred. The
drop-out rate per cycle was significantly lower in the mild treatment group compared with the standard group (OR ¼ 0.53; P ¼
0.04, Heijnen et al., 2004, 2007). Thus, although more cycles are
needed with the mild strategy, they are better tolerated by
patients. Further, there were 12 patients (6%) in the mild strategy
group and 15 patients (8%) in the standard strategy who
switched to the other stimulation protocol or embryo-transfer
strategy. Censoring these patients at the moments of switching
resulted in 1-year estimates of term live birth of 43.2% in the
mild and 44.6% in the standard group (Heijnen et al., 2004,
2007), very similar to the results of the base-case analysis.
These data show that the results of the trial are not biased by
the fact that patients were in a randomized controlled trial
instead of in a real-life situation. We have chosen not to
perform a separate sensitivity or scenario analysis excluding
these patients, since the impact on results would be trivial.
Standard effectiveness outcomes in economic evaluation
studies such as quality adjusted life-years were not employed,
because their use in certain pregnancy situations can be difficult to interpret and sometimes misleading (Ganiats, 1996).
In general, a greater acceptance of mild treatment strategies
in IVF will increase the number of cycles needed to achieve the
same number of live births. Despite this higher average number
of cycles for the mild strategy (and therefore higher treatment
costs), we found in our study that overall costs per term live
birth were lower compared with the standard treatment strategy. This is mainly due to the health economic benefit of the
reduction of multiple pregnancies in the mild stimulation
approach. The impact of multiple gestations and their associated complications on costs is dramatic.
This study may contribute to the more widespread introduction
of mild ovarian stimulation along with a SET policy in IVF.
Clinicians, health care providers and patients should be aware
that an extra treatment cycle might be considered a low price
for the prevention of the lifelong compromised quality of life
of offspring. If structured, written information about risks and
complications of multiple pregnancies and the consequences of
the transfer of fewer embryos is provided, patients may
become more inclined to the transfer of one embryo rather than
two (Murray et al., 2004; Bhattacharya and Templeton, 2004).
An adequate reimbursement system is a vital point to make
SETwork (Saldeen and Sundstrom, 2005). Society will carry a
large part of the costs for the complications associated with
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certainly have impact on cost analysis because indirect long
term costs will outway perinatal costs (Petrou et al., 2001;
Wennerholm 2004). This strengthens our conclusion that the
mild treatment strategy with SET is distinctly more costeffective. Recently published randomized trials comparing the
costs of IVF with the transfer of one or two embryos (Lukassen
et al., 2004; Kjellberg et al., 2006; Fiddelers et al., 2006), differed
from our study in that costs were calculated on first treatment
cycles only and only standard ovarian stimulation protocols
with GnRH agonist long protocol co-treatment were employed.
Our study combined a SET strategy with a GnRH antagonist
mild stimulation protocol. A seeming advantage of standard
over mild stimulation is that more fresh embryos will be
obtained and therefore more embryos available for cryopreservation, which is important in compensating for the reduced
chances of SET (Thurin et al., 2004; Pandian et al., 2005).
However, this advantage might be counterbalanced by having
relatively more good quality embryos after mild stimulation: a
recent study of our group shows that embryos obtained after
mild stimulation are euploid more often than after standard stimulation (Baart et al., 2007). Nevertheless, findings of these studies
were consistent with the results of the present study, showing
lower total costs with SET compared with the transfer of two
embryos (Kjellberg et al., 2006; Fiddelers et al., 2006). The
costs of paediatric health care were markedly reduced due to a
considerable reduction of multiple pregnancies (Kjellberg et al.,
2006). Another randomized trial concluded that one cycle SET
was less expensive, but also less effective compared with one
cycle with the transfer of two embryos. It depends on the society’s
willingness to pay for one extra IVF cycle, whether the transfer of
one or two embryos is preferred from a cost-effectiveness point of
view (Fiddelers et al., 2006). Other studies comparing different
embryo transfer policies were not randomized controlled trials.
Instead, theoretical extrapolations or decision-analytic calculations were used (Wolner-Hanssen and Rydhstroem, 1998;
De Sutter et al., 2002; Garceau et al., 2002).
Our study shows a robust finding about the costeffectiveness from a societal perspective, when combining
SET with a mild stimulation regime compared with double
embryo transfer with a standard stimulation regime and analysing a complete treatment course over a 12 month time frame.
Two recent reviews have identified several problems in achieving a definitive assessment of the cost-effectiveness of SET
(Fiddelers et al., 2007; Scotland et al., 2007). Inconsistencies
between studies in definitions of outcomes and time horizon,
in- or exclusion of frozen/thawn embryos and differences in
economic perspective made comparisons difficult (Fiddelers
et al., 2007). By way of sensitivity analysis, we determined
costs, effectiveness and cost-effectiveness, based on other definitions of outcomes to make comparisons possible with other
studies. The cost-advantage of the mild strategy remained
significant in a sensitivity analysis that included all cycles,
irrespective of time frame, and the cost-effectiveness results
were even more in favour of the mild strategy in that analysis.
When calculating the chance of term live birth per couple,
twin live births were counted as being equivalent to one live
birth. It may be argued that a term-born twin should count as
two live births. Defining preterm born children as success and
Cost-effectiveness of a mild versus standard IVF strategy
multiple pregnancy and birth. Governments therefore might have
regulatory interest in how IVF is performed. By funding IVF,
they will accrue costs in the short term, but might also be able
to establish guidelines for the number of embryos transferred.
The possible need for a higher number of treatment cycles to
achieve pregnancy after SET, might increase treatment costs.
However, in the long run, governments will profit by saving
the costs of complications associated with multiple pregnancies.
Funding
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