Department of Public Health and Primary Care, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK

Norfolk Suffolk and Cambridgeshire Strategic Health Authority, Victoria House, Capital Park, Fulbourn, Cambridge, CB1 5XB, UK

Cambridge University Teaching Hospitals Foundation Trust, Hills Road, Cambridge, CB2 2QQ, UK

Abstract

Background

In unexplained and mild male factor subfertility, both intrauterine insemination (IUI) and in-vitro fertilisation (IVF) are indicated as first line treatments. Because the success rate of IUI is low, many couples failing IUI subsequently require IVF treatment. In practice, it is therefore important to examine the comparative outcomes (live birth-producing pregnancy), costs, and cost-effectiveness of primary offer of IVF, compared with primary offer of IUI followed by IVF for couples failing IUI.

Methods

Mathematical modelling was used to estimate comparative clinical and cost effectiveness of either primary offer of one full IVF cycle (including frozen cycles when applicable) or "IUI + IVF" (defined as primary IUI followed by IVF for IUI failures) to a hypothetical cohort of subfertile couples who are eligible for both treatment strategies. Data used in calculations were derived from the published peer-reviewed literature as well as activity data of local infertility units.

Results

Cost-effectiveness ratios for IVF, "unstimulated-IUI (U-IUI) + IVF", and "stimulated IUI (S-IUI) + IVF" were £12,600, £13,100 and £15,100 per live birth-producing pregnancy respectively. For a hypothetical cohort of 100 couples with unexplained or mild male factor subfertility, compared with primary offer of IVF, 6 cycles of "U-IUI + IVF" or of "S-IUI + IVF" would cost an additional £174,200 and £438,000, representing an opportunity cost of 54 and 136 additional IVF cycles and 14 to 35 live birth-producing pregnancies respectively.

Conclusion

For couples with unexplained and mild male factor subfertility, primary offer of a full IVF cycle is less costly and more cost-effective than providing IUI (of any modality) followed by IVF.

Background

In any health care system, cost-effective commissioning of health care in order to maximise population health outcomes with the minimum possible resource use, is an important consideration. The UK National Institute for Clinical Excellence (NICE)

Even if some health care interventions may have a relatively low cost per treatment session, they could be less cost-effective compared to alternative treatments with a higher cost per treatment session, but also better clinical effectiveness. It is therefore legitimate to examine critically whether funding for IUI allows better management of current demand, or whether it increases activity and overall associated healthcare expenditure for those couples who are eligible for both treatment strategies

Methods

Model construction

The structure of the generic model is presented in Figure

**The structure of the generic model**

**The structure of the generic model.** U-IUI: Unstimulated IUI S-IUI: Gonadotrophin stimulated IUI C-IUI: Clomifene stimulated IUI ART: Assisted reproductive technique LBR: Live birth rate

The EVEREST checklist for health economic studies was used as a reference to our study design (

EVEREST Statement: Checklist for health economics paper. EVEREST checklist for health economics studies with respect to this study design, data collection, and analysis and interpretation of the results

Click here for file

Assumptions used in the model

Assumptions used in the calculations are presented in Table

Assumptions underlying the modelling and their corresponding sources

**Assumption**

**Source**

There is an 1:1 ratio between "fresh" and "frozen" cycles, assuming 25% of couples have 0 FET, 50% have 1 FET and 25% have 2 FET

Hypothetical assumption, based on informed judgement

IVF and IVF/ICSI ratio is 1:1

Hypothetical assumption, based on informed judgement

100% compliance and 0% drop out with IUI treatment

Hypothetical assumption, based on informed judgement

**Effectiveness**

LBR following a "full" IVF (IVF/ICSI) cycle is 19.26% (all ages)

HFEA 1995–1999^{1}

LBR following "frozen" IVF (IVF/ICSI) cycle is 10.40% (all ages)

HFEA 1995–1999^{1}

LBR following unstimulated IUI is 3.5% per cycle

Informed judgement, based on local data on effectiveness of stimulated IUI and by halving this, peer-reviewed literature^{11}

LBR following gonadotrophin-stimulated IUI is 7% per cycle

Based on local activity data

LBR following clomifene- stimulated IUI is 3%

Informed judgement, local activity data, and peer reviewed literature ^{12}

**Cost**

-Cost of "fresh" IVF (IVF/ICSI) is £3,214 assuming 50% of "fresh" cycles will be ICSI cycles -Cost of "frozen" IVF (IVF/ICSI) is £450 -Cost of unstimulated IUI is £449 -Cost of stimulated IUI is £1005 -Cost of Clomiphene stimulated IUI is £752

NICE estimates^{1}

90% of couples who fail IUI proceed to IVF

Hypothetical, based on informed judgement

A cycle of IVF included a fresh cycle, and when applicable, (i.e. in couples who had additional viable embryos preserved at the time of the fresh embryo transfer, and subsequently did not achieve pregnancy through the fresh cycle) frozen embryo transfer (FET) cycles. All estimates assume a "steady state" between incident need and supply of services, and a "steady state" in progression (e.g. waiting or natural lag times) for transition to a subsequent treatment stage or strategy.

Average LBR values for fresh as well as FET IVF cycles were derived from the UK's Human Fertilisation and Embryology Authority (HFEA) population-based register 1995 to 1999 as used by NICE

Unlike IVF, there is no population-based data on the effectiveness (LBR) of S-IUI. Therefore, two sets of values for LBR were considered either based on, or informed by, data derived from the experience of a local unit, which during the period of 1993 to 2003 provided 676 cycles of S-IUI to 334 different women aged < 40 years of age, and with a range of uptake of 1 to 5 cycles (^{st }to the 6^{th }cycle respectively were used. The first scenario (mean effectiveness independent of cycle order) is reasonable, as small numbers did not allow for confident calculation of LBR for subsequent to the first cycle. The second scenario reflects both the actual experience of the local unit

Unlike S-IUI, U-IUI has, at least up until the publication of the NICE guidelines

Local data on outcome of 676 cycles of S-IUI in 334 couples with unexplained infertility women aged <40 years. Results of local data on S-IUI uptake and outcome, live birth-producing pregnancy, by treatment cycle order.

Click here for file

It was assumed that on average 10% of couples who fail IUI treatment (irrespective of the number of IUI cycles received) would drop out of subfertility treatment. This was based on informed judgement, to reflect potential changes in childbearing intentions or partnership status.

Cost calculations

Costs relate to resources directly associated with fertility treatment, and exclude costs from potential complications and/or multiple pregnancy. The average costs per cycle of IVF, FET, U-IUI, and S-IUI used were the ones used in NICE's economic model

Cost-effectiveness

The perspective used in the cost-effectiveness analysis was that of the health service. The total cost to the health service was taken as the sum of the costs of the IUI and the IVF activity generated by each scenario.

Incremental cost-effectiveness ratio (ICER) was calculated as the ratio of the difference in the combined cost of "IUI + IVF" strategies minus the cost of IVF, divided by the difference in number of live birth-producing pregnancies for each treatment strategy. In this instance ICER values therefore indicate the additional cost associated with a given treatment strategy in order to produce a single additional live birth-producing pregnancy.

Sensitivity analysis

Sensitivity analysis was undertaken to examine the robustness of the modelling and to study the impact of plausible variation in the variables for which uncertainty was judged to be higher (e.g. those least well supported by population-based data or peer-reviewed publications). Therefore, the estimates of U-IUI, S-IUI and C-IUI were varied sequentially, using different value estimates from the literature, or in the absence of alternative literature estimates, based on local experience, expert opinion, or reasonable assumptions about the plausible range of uncertainty around "best estimate" values. More specifically:

• for S-IUI

An alternative LBR estimate of 8.7% per cycle (independently of cycle order) was used based on Goverde et al

• for U-IUI

An alternative LBR estimate of 4.4% per cycle (independently of cycle order) was used, assuming the LBR of U-IUI to be half of that of S-IUI ^{st }to the 6^{th }cycle respectively were also used for U-IUI, again assuming the effectiveness of U-IUI to be half of that of S-IUI

• for C-IUI

An alternative LBR estimate of 6.6% per cycle (independently of cycle order) was used based on reasonable assumption of having LBR of C-IUI in between LBR values of S-IUI and U-IUI. Additionally, an average LBR value of 2.5% per cycle was used, based on local experience and expert opinion.

Results

For a hypothetical cohort of 100 couples with unexplained or mild male factor subfertility, the cost of primary offer of one full cycle of IVF would be £321,700, with a cost-effectiveness ratio of £12,600/live birth-producing pregnancy (Table

Cost, outcome, cost-effectiveness ratio and incremental cost-effectiveness ratio (ICER) of providing unstimulated IUI (U-IUI), gonadotrophin stimulated IUI (S-IUI) and clomifene stimulated IUI (C-IUI) to a hypothetical cohort of couples with unexplained or male factor subfertility.

**U-IUI (LBR = 3.5%)**

**Full cycle of IVF**

**Overall**

**Order of cycle**

**No. of cycles**

**Live- birth Deli-very from IUI**

**Cost £**

**Cost/outcome (£/delivery)**

**No. of couples having one full cycle of IVF**

**Live birth delivery from one full cycle of IVF**

**Cost £**

**Total live birth delivery (IUI+ IVF)**

**Total cost £**

**Total cost/total outcome (£/Delivery)**

**ICER**

**U-IUI (LBR-3.5%)**

**0**

0

0

0

100

26

321,700

26

321,700

12,600

Ref

**1**

100

4

44,900

12,800

87

22

279,400

26

324,300

12,700

18,600

**2**

196

7

88,200

12,800

84

21

269,600

28

357,900

12,600

13,200

**3**

293

10

131,600

13,000

81

21

260,200

31

391,800

12,700

13,400

**4**

390

13

175,000

13,200

78

20

251,100

33

426,100

12,800

13,600

**5**

487

16

218,500

13,400

75

20

242,300

36

460,800

13,000

13,900

**6**

584

19

262,000

13,600

73

19

233,800

38

495,900

13,100

14,200

**S-IUI (LBR = 7%)**

**0**

0

0

0

100

26

321,700

26

321,700

12,600

Ref

**1**

100

7

100,500

14,400

84

21

269,300

28

369,800

13,000

24,000

**2**

193

14

194,000

14,400

78

20

250,400

33

444,400

13,300

17,500

**3**

286

20

287,900

14,700

72

19

232,900

38

520,800

13,700

16,600

**4**

380

25

382,300

15,200

67

17

598,900

42

598,900

14,100

17,300

**5**

475

30

477,200

15,700

63

16

678,600

46

678,600

14,600

17,800

**6**

570

35

572,400

16,200

58

15

759,800

50

759,800

15,100

18,300

**C-IUI (LBR = 3%)**

**0**

0

0

0

100

26

321,700

26

321,700

12,600

Ref

**1**

100

3

75,200

25,100

87

22

280,900

25

356,000

14,000

*

**2**

197

6

148,100

24,700

85

21

272,400

28

420,600

15,300

49,400

**3**

294

9

221,200

24,600

82

21

264,000

30

485,200

16,300

40,900

**4**

391

12

294,200

24,500

79

20

255,600

32

549,700

17,200

38,000

**5**

488

15

367,200

24,500

77

20

247,100

34

614,300

17,900

36,600

**6**

585

18

440,200

24,500

74

19

238,700

37

678,900

18,600

32,500

* It was not possible to estimate a meaningful ICER (ICER = (£356073-£321733)/(25.3–25.6) = -£114,467/Live birth-producing pregnancy as compared to full cycle of IVF).

Cost/unit; IVF = £3,214, U-IUI = £449, S-IUI = £1,005, C-IUI = £752Live birth delivery refers to live birth- producing pregnancyFigures are rounded to the nearest hundred

Cost-effectiveness of 'head-to-head' comparison of primary IUI vs. primary IVF

Primary offer of one to six cycles of U-IUI or C-IUI, or up to three cycles of S-IUI is less costly than one cycle of fresh IVF. However, when comparing the cost-effectiveness of U-IUI, S-IUI and C-IUI to one full cycle of IVF, IVF is more cost-effective (Table

Cost-effectiveness of "IUI + IVF" vs. primary IVF

Assuming a mean U-IUI LBR of 3.5% per cycle

For six cycles of U-IUI the cost of IUI followed by IVF would be £495,900 with a cost-effectiveness ratio of £13,100/live birth-producing pregnancy (Table

Assuming a mean S-IUI LBR of 7% per cycle

For one to six cycles of S-IUI per couple, the total cost of "IUI+IVF" would range from £369,000 to £759,800, equivalent to £13,000 to £15,100 per live birth-producing pregnancy. The ICER would increase with increase in cycle order (Table

For one to six cycles of IUI, the "IUI + IVF" treatment strategy would be more costly and less cost-effective than one full cycle of IVF.

Figure

Cost and cost-effectiveness (per live birth-producing pregnancy) of different uptake of IUI and S-IUI among a hypothetical cohort of 100 couples eligible for both IUI and IVF

Cost and cost-effectiveness (per live birth-producing pregnancy) of different uptake of IUI and S-IUI among a hypothetical cohort of 100 couples eligible for both IUI and IVF. Assumes constant LBR of 7% and 3.5% for S-IUI and IUI.

Assuming a mean C-IUI LBR of 3% per cycle

Among the three IUI modalities, C-IUI (with the lowest LBR) had the worst cost-effectiveness ratio and the worst ICER.

When assuming that LBR of IUI (any modality) was decreasing with cycle order, all above scenarios showed consistently similar results, with higher cost and worst cost-effectiveness and ICER values for "IUI+IVF" compared to IVF only.

Opportunity costs

Table

Cost difference, number of additional full cycles of IVF that could be purchased and corresponding additional number of live birth-producing pregnancies by the estimated cost difference of providing "IUI+IVF" compared to primary offer of IVF

**"IUI + IVF" for those failing IUI**

**IUI modality**

**One cycle of IUI**

**Two cycles of IUI**

**Three cycles of IUI**

**Four cycles of IUI**

**Five cycles of IUI**

**Six cycles of IUI**

**U-IUI (LBR = 3.5%)**

Cost difference "IUI+IVF" vs. primary IVF

£2,600

£36,100

£70,100

£104,400

£139,100

£174,200

N^{o }of IVF cycles that would be purchased by the cost difference

1

11

22

32

43

54

N^{o }of live birth-producing pregnancies expected from IVF cycles that would have been purchased by the cost difference

0

4

6

8

11

14

**S-IUI (LBR = 7%)**

Cost difference "IUI+IVF" vs. primary IVF

£48,100

£122,600

£199,100

£277,200

£356,900

£438,000

N^{o }of IVF cycles that would be purchased by the cost difference

15

38

62

86

111

136

N^{o }of live birth-producing pregnancies expected from IVF cycles that would have been purchased by the cost difference

4

10

16

22

28

35

**C-IUI (LBR = 3%)**

Cost difference "IUI+IVF" vs. primary IVF

£34,300

£98,900

£163,400

£228,000

£292,600

£357,200

N^{o }of IVF cycles that would be purchased by the cost difference

11

31

51

71

91

111

N^{o }of live birth-producing pregnancies expected from IVF cycles that would have been purchased by the cost difference

3

8

13

18

23

28

Figures are rounded to the nearest hundred.

Sensitivity analysis

After considering different plausible LBR values for S-IUI, U-IUI and C-IUI, the primary offer of IVF remained more cost-effective than providing "IUI+IVF" (Table

Sensitivity analysis estimates of incremental cost-effectiveness ratios (ICER) of providing "IUI+IVF" compared to primary offer of IVF, varied sequentially.

**Varied variables**

**Source of assumption**

**ICER (£/live birth-producing pregnancy)**

**1 cycle of IUI**

**2 cycles of IUI**

**3 cycles of IUI**

**4 cycles of IUI**

**5 cycles of IUI**

**6 cycles of IUI**

**S-IUI**

LBR = 8.7%

Goverde et al ^{13}

£10,400

£10,900

£11,600

£12,300

£13,000

£13,800

LBR varying by cycle order*

Local unit's experience and peer-reviewed literature ^{6–10}

£7,700

£12,300

£16,800

£19,900

£24,300

£28,300

**U-IUI**

LBR = 4.4%

LBR of U-IUI as half of that of S-IUI^{11}

£0

£7,500

£8,700

£9,300

£9,800

£10,200

LBR = 2%

Local experience and expert opinion

¶

£91,700

£42,400

£35,700

£33,300

£32,100

LBR varying by cycle order±

LBR of U-IUI as half of that of S-IUI^{11}

£41,600

£40,400

£47,600

£51,900

£54,900

£57,100

**C-IUI**

LBR = 6.6%

Reasonable assumption, LBR of C-IUI between the values of LBR of U-IUI and S-IUI

£9,500

£10,500

£10,700

£10,800

£10,900

£10,900

LBR = 2.5%

Local experience and expert opinion

¶

£81,900

£53,900

£46,900

£43,700

£41,900

* LBR of S-IUI of 10%, 6%, 4%, 4%, 2%, 2% for cycles 1 to 6 respectively

± LBR of U-IUI of 5%, 3%, 2% 2%, 2%, 2% for cycles 1 to 6 respectively.

¶It was not possible to estimate a meaningful ICER because of very small denominator in case of one cycle of U-IUI (when LBR = 2%) and one cycle of C-IUI (when LBR = 2.5%) as compared to 1 full cycle of IVF.

ICER was estimated based on cost and effectiveness of "IUI+IVF" compared to full cycle of IVF.

Figures are rounded to the nearest hundred

Sensitivity analysis estimates of cost difference, and the additional number of live birth-producing pregnancies by the estimated cost difference of providing "IUI+IVF" compared to primary offer of IVF, varied sequentially.

**Variable varied**

**Cost difference £ [("IUI+IVF") - IVF]**

**S-IUI**

**1 cycle of IUI**

**2 cycles of IUI**

**3 cycles of IUI**

**4 cycles of IUI**

**5 cycles of IUI**

**6 cycles of IUI**

LBR = 8.7%

£43,100

£111,900

£183,400

£257,400

£333,800

£412,200

LBR varying by cycle order*

£39,400

£114,200

£199,500

£287,200

£379,900

£474,400

**U-IUI**

LBR = 4.4%

£0

£30,700

£62,100

£94,100

£126,600

£159,700

LBR = 2%

£6,900

£45,300

£83,700

£122,300

£161,000

£199,900

LBR varying by cycle order±

£53,800

£141,100

£233,400

£326,800

£420,300

£514,000

**C-IUI**

LBR = 6.6%

£23,900

£76,300

£128,900

£181,600

£234,200

£286,800

LBR = 2.5%

£35,800

£102,100

£168,400

£234,700

£301,000

£367,300

**No. of live births expected from full cycles of IVF that could be purchased by the estimated cost difference**

**S-IUI**

LBR = 8.7%

3

9

15

20

27

33

LBR varying by cycle order*

3

9

16

23

30

38

**U-IUI**

LBR = 4.4%

0

2

5

7

10

13

LBR = 2%

1

4

7

10

13

16

LBR varying by cycle order±

4

11

19

26

33

41

**C-IUI**

LBR = 6.6%

2

6

10

14

19

23

LBR = 2.5%

3

8

13

19

24

29

* LBR of S-IUI of 10%, 6%, 4%, 4%, 2%, 2% for cycles 1 to 6 respectively

± LBR of U-IUI of 5%, 3%, 2% 2%, 2%, 2% for cycles 1 to 6 respectively.

Figures of cost differences are rounded to the nearest hundred.

Discussion

The findings suggest that for couples with unexplained or mild male factor subfertility, primary offer of a full IVF cycle is less costly and more cost-effective than primary offer of any IUI modality followed by IVF (for IUI failures). Importantly, the cost of primary IUI (any modality) increases and its cost-effectiveness decreases with increasing number of IUI cycles offered. Between S-IUI and U-IUI, S-IUI followed by IVF was associated with higher cost and lower cost-effectiveness compared with U-IUI followed by IVF. The sensitivity analysis findings indicate that the main finding of inferior cost-effectiveness of the primary IUI, compared with primary IVF, is robust. A previous study on cost impact implications of the 2004 NICE guidance has failed to reach similar conclusions, as it did not accurately simulate real life patient experience and clinical management

In principle, a prospective randomised controlled trial would have been a superior study design to answer this study's research question. However, such a study would have had to entertain certain practical obstacles, including ethical clearance, and may not be forthcoming for many years to come. At the same time resource allocation and service development policy decisions have to be made currently and in the near future. In the absence of RCT-based evidence, mathematical modelling synthesising evidence from various high quality sources is the only rational way to support health care policy decision-making

Published data comparing the cost-effectiveness of IVF versus IUI are scarce. Some studies indicate that IUI may be more cost-effective than IVF in cases of unexplained and moderate male subfertility

The majority of the literature on IUI effectiveness comes from uncontrolled retrospective case series and cohort designs, could overestimate treatment effectiveness because of selection bias and consideration of clinical pregnancy as opposed to live birth as the study outcome. Also, the number of abandoned cycles is generally excluded from the denominator, leading to inflated estimates of effect

We used a mean LBR value of 7% for S-IUI based on local experience on 676 cycles of S-IUI over 10 years. In most studies the pregnancy rate per cycle of S-IUI is approximately 10%

The effectiveness (LBR) of IUI was judged to be 3.5% per treatment cycle -this represents an informed judgement, based on the literature. Many experts would support that this is actually a high estimate, but we preferred to use a "generous" estimate. If the true estimate is lower, any bias introduced from this assumption would have favoured the cost-effectiveness of U-IUI, and would have made IVF less cost effective, i.e. if a lower LBR value for U-IUI was used, the results would have been even more favourable for primary offer of IVF as the preferred treatment strategy.

We used average success rates rather than age- and indication-specific LBRs. Maternal age affects outcomes of IUI, but so does for IVF

The modelling of costs has concentrated on the nominal cost of IVF and IUI. Other essential aspects of the service (e.g. diagnostic activity, incident and follow-up appointments, counselling) have not been calculated, because they were assumed to be already occurring (i.e. requiring no 'new' money) and to be similar to both treatment strategies. The cost associated with complications, such as multiple gestation and birth, were also not included in calculations. Evidence suggests that there is no statistically significant difference in the incidence of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy rate between S-IUI and IVF

Lastly, anecdotally, undergoing IUI followed by IVF may be more psychologically distressing to the couple compared to IVF alone, as it may be more frustrating to have, on average, comparatively more failed treatment cycles -although direct evidence about this assumption is lacking. However, some patients may have a positive preference for IUI or an aversion for IVF (on philosophical, or religious grounds). We acknowledge that traditional methods of cost-effectiveness analysis like the ones used in this study, are not useful tools when dealing with philosophically-grounded patient preferences – which however are exceptional, rather than the norm.

Conclusion

Our study indicates that for couples with unexplained or mild male factor subfertility, a primary treatment offer of any modality of IUI instead of primary offer of IVF is cost-ineffective, and therefore associated with considerable opportunity costs. The additional and avoidable costs incurred put pressure on the health care system to cope with extra demand and activity for a treatment of low effectiveness, making the wider availability of the most effective treatment (IVF) more difficult, and thus disadvantaging couples who could have otherwise benefited from it.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

GL and NP constructed the mathematical model, reviewed the literature on estimates of treatment effectiveness, and inputted data into the model. RM collected and provided original data on IUI effectiveness used in the model and helped with literature search and interpretation. All authors contributed to the writing of the manuscript. GL is the guarantor.

Acknowledgements

We would like to thank our health economist colleagues Mr Ed Wilson, Dr Jon Sussex and Professor Ceri Phillips for helpful comments in earlier version of the manuscript. We also thank all members of the Norfolk, Suffolk and Cambridgeshire Subfertility Services Advisory Group, for helpful discussions of aspects of this work presented to the Group and for providing the key operational stimulus for the work.

Pre-publication history

The pre-publication history for this paper can be accessed here: