Economic analysis

This chapter reports the economic evaluation of freezing all embryos, followed by frozen-embryo transfer, compared with fresh-embryo transfer, including a within-trial analysis of post-randomisation costs and outcomes up to and including delivery, and a model-based extrapolation of costs and outcomes over a complete cycle (including the subsequent transfer of the remaining frozen embryos in both arms). In addition, a within-trial cost–consequences summary is reported.

Objectives

The primary objective of the economic evaluation was to assess the incremental cost per additional healthy baby born of freezing all embryos, followed by frozen-embryo transfer, compared with fresh-embryo transfer in IVF. Two secondary economic objectives were to compare the cost and consequences between these embryo transfer strategies and to model the longer-term cost-effectiveness of frozen-embryo transfer compared with fresh-embryo transfer.

Methods

Study design and participants

Details of the trial design are provided in the published protocol1 and in Chapter 2. The economic analysis was based on all women randomised, except for three post-randomisation exclusions, and follows the same ITT principle as the statistical analysis in Chapter 3.

Cost and outcome assessment

Costs and outcomes were assessed from post randomisation up to and including delivery, using the trial eCRFs completed by the research staff post embryo transfer, during early pregnancy (i.e. 6–8 weeks’ gestation), at the 12- and 28-week follow-ups and 6 weeks post delivery, and the paper-based economic questionnaire completed by couples at embryo transfer. Health-care utilisation data collected post embryo transfer, during early pregnancy, at 28 weeks’ gestation and at 6 weeks post delivery were used in the economic analysis. Questions related to participant time and travel costs incurred during treatment were included in the embryo transfer economic questionnaire (see Report Supplementary Material 2). All costs are reported in 2018/19 Great British pounds. Adjustments for inflation were applied to unit costs, where necessary, using the NHS Cost Inflation Index (NHSCII).25

Assessment of health service costs

Given that the economic evaluation seeks to inform the efficient allocation of scarce health-care resources, the base-case analysis adopted the NHS and Personal Social Services perspective. The effect on patient time and travel costs was considered separately as a secondary analysis.

Cost of the primary intervention

The cost of the embryo transfer procedure was estimated based on the health service resource use observed for each arm. The additional cost of freezing all embryos, followed by frozen-embryo transfer, was estimated from resource use data recorded in the eCRF post embryo transfer for each participant who received frozen-embryo transfer. The eCRF captured the number of monitoring visits, blood tests and ultrasound scans prior to embryo transfer, and the method of endometrial preparation. The cost of preparing frozen embryos was also included for the participants who received frozen-embryo transfer. The cost of embryo freezing was applied to all participants who received frozen-embryo transfer, as well as to the participants who had their remaining embryos frozen following a fresh-embryo transfer. The unit costs that were used to value the resource use associated with the intervention are reported in Appendix 5.

The costing approach assigned costs to each component of resource use to capture patient-level variation in costs. Each resource use item was mapped to an appropriate Healthcare Resource Group (HRG), where available, and costed using the relevant NHS reference cost.26 The monitoring visit prior to transfer was assumed to be a 30-minute session led by a nurse.25 The reported methods of endometrial preparation were valued based on routine regimens obtained from clinical advice and unit costs from the British National Formulary (BNF).27 For embryo freezing and the preparation of frozen embryos, the time spent by an embryologist for each procedure was assumed to be 1 hour based on clinical advice.25

Costs of ovarian hyperstimulation syndrome

The clinical management costs associated with OHSS and pregnancy were valued using the NHS Reference Costs 2018/19.26 The resource use for managing OHSS was obtained from the eCRFs post embryo transfer and during early pregnancy. The non-elective inpatient stay cost for a 1-day stay was valued using the inpatient short stay cost, whereas inpatient stays of > 1 day were valued using the inpatient long stay cost, adjusted for length of stay using the excess bed-day cost if the stay was longer than the average length of stay. As some of the relevant data needed for the adjustment of inpatient long-stay costs were not available in the NHS Reference Costs 2018/19, the average length of stay for non-elective long stays and the non-elective excess bed-day cost were obtained from the NHS Reference Costs 2017/1828 and inflated. This approach was undertaken for all costs associated with inpatient stays in the analysis.

Costs of pregnancy outcomes

Data on pregnancy outcomes (e.g. miscarriage, biochemical pregnancy, ectopic pregnancy, pregnancy of unknown location and termination) were obtained from the eCRF during early pregnancy, at the 12- and 28-week follow-ups. Miscarriage and ectopic pregnancy were costed by applying the average reference cost per case, whereas termination cost varied by gestation. It was assumed that, on average, a minimum of one ultrasound scan and three beta-human chorionic gonadotropin (βHCG) blood tests would be required for biochemical pregnancy and pregnancy of unknown location.29

Costs of antenatal care

The antenatal care (ANC) costs were based on the NHS Reference Costs 2018/1926 and varied according to the maternal complications reported. Primary and secondary care contacts during pregnancy and any complications were captured in the 28-week follow-up CRF and post-delivery eCRF. It was assumed that participants had a community midwife visit following an early pregnancy scan (EPS). The complications were grouped using the Code to Group: HRG4+ 2019/20 Local Payment Grouper30 workbook to determine the corresponding HRG. Episodes of care were costed by applying either the day-case reference cost for an inpatient day care visit or the non-elective inpatient cost (stay of ≥ 1 day), adjusted for length of stay using the excess bed-day cost.

For antenatal ultrasound scans, the resource use was obtained from the eCRFs during early pregnancy, at the 28-week follow-up and post delivery. The costs of ultrasound were determined using the NHS reference cost26 and were varied in accordance with the standard recommendation for antenatal ultrasound scanning of one scan throughout the pregnancy. Any additional ultrasound scans were costed as non-routine.

Costs of delivery

The delivery method was obtained from the post-delivery eCRF and valued based on the NHS reference cost.26 The costs varied according to the delivery mode, onset method (with or without induction) and length of inpatient stay for delivery.

Participant travel and time costs

Participant costs associated with travelling to and from appointments and the time spent for a clinic visit during treatment were estimated from post randomisation to embryo transfer. Travel costs were estimated based on the number of visits to the clinic and travel expenses per visit or distance travelled by car, obtained from the economic questionnaire. Travel costs were estimated based on the expenses reported for participants who travelled using public transport and taxis, whereas the costs for travel by car were calculated using the mileage reported and the private car rate per mile of 45p per mile published by Her Majesty’s Revenue and Customs (HMRC).31 Time costs, which account for time lost from productive activities, were estimated from the economic questionnaire based on the time taken to visit the clinic. Time taken away from normal productive activities was estimated in hours, and appropriate unit costs were used to estimate the opportunity cost of time. Gross age- and sex-specific wage rates obtained from the Annual Survey of Hours and Earnings (ASHE),32 published by the Office for National Statistics, were used to cost the time lost from paid employment. To estimate the cost associated with time lost for the accompanying male partner, the partner’s age was assumed to be the same as that of the participant. The cost of time lost from unpaid work was estimated using the value of unpaid work published by the Office for National Statistics.33 Forgone leisure time was valued using the current value of non-working time, available from the Department for Transport.34 The unit costs that were used to value the time lost are reported in Appendix 5.

Outcome measures

Effectiveness for the economic evaluation was measured in terms of the number of healthy babies born and the secondary clinical outcomes of the trial. Secondary outcomes included live births, maternal safety outcomes (i.e. OHSS), pregnancy outcomes, complications of pregnancy and delivery and adverse birth outcomes.

Statistical analysis of trial economic data

Aggregating costs and effects

Resource use, costs and health outcome data were summarised by trial arm, based on the participants who had the event of interest and by ITT. The IVF costs were broken down into the following categories: freezing of embryo, endometrial preparation, embryo transfer, monitoring visits prior to frozen-embryo transfer, blood tests prior to frozen-embryo transfer, transvaginal ultrasound scans prior to frozen-embryo transfer and preparation of frozen embryos. All cost elements were summed over the follow-up period (up to and including the cost of delivery) to estimate a total NHS cost per patient.

Cost data were fully present with respect to resource use associated with embryo transfers and OHSS; however, given that no further resource use data were collected for 15 participants who did not undergo embryo transfer, these participants were conservatively assigned no further treatment costs other than embryo freezing and thawing, where applicable. This assumption favours the freeze-all approach because three patients in the freeze-all arm may have incurred further work-up costs prior to cancellation of their embryo transfer owing to the embryos failing to survive the thawing process. Therefore, we also conducted a sensitivity analysis in which multiple imputation was used to impute the pre-embryo-transfer monitoring visit, blood test and scan costs for these three participants.

Elements of resource use data were also missing for a small number (n = 13) of resultant pregnancies. Two of these participants who had uncomplicated pregnancies were missing entries for the number of antenatal midwifery, outpatient and inpatient attendances between 12 and 28 weeks’ gestation only. These two participants were included in the complete-case analysis by assigning a zero cost to these elements; based on a comparison with similar participants with no missing data, it was considered plausible that these elements were missing because the costs were zero and they were not missing at random. Thus, for the complete-case analysis, we retained 616 participants for the cost-effectiveness analysis using treatment plus OHSS costs, and 605 participants for the analysis of total NHS costs (inclusive of ANC and delivery care).

Recognising the uncertainty in the above approach, we also conducted a sensitivity analysis using multiple imputation to impute plausible values for all 13 participants with missing ANC and delivery care cost elements, and the work-up costs for the three cancelled frozen-embryo transfer cycles where missingness could not be ascertained. We did not, however, impute missing values for the primary clinical effectiveness outcome, allowing 614 participants to be included in the cost-per-healthy-live birth multiple-imputation analysis and 616 participants to be included in the cost-per-live birth multiple-imputation analysis.

Within-trial cost-effectiveness and cost-consequence analysis

The within-trial economic analysis was performed on an ITT basis using individual participant-level data from the trial. The cost differences were summarised by ITT against the primary and secondary clinical outcomes using a cost–consequence balance sheet. All analyses were performed using Stata^®, version 15 (StataCorp LLC, College Station, TX, USA).

For the within-trial cost-effectiveness analysis, two cost categories were used: treatment costs (including post-randomisation preparation and embryo transfer costs); and OHSS costs and full NHS costs, which, in addition to treatment and OHSS costs, included pregnancy and delivery costs. Cost-effectiveness was expressed in terms of the incremental cost per healthy baby and per live birth of freezing all embryos, followed by frozen-embryo transfer, compared with fresh-embryo transfer. The incremental treatment cost (inclusive of OHSS costs) per additional healthy baby born was estimated as the primary measure of cost-effectiveness, as the management and incidence rate of complications per pregnancy were similar between arms, with no statistically significant differences. Generalised linear models (GLMs), with adjustment for minimisation factors, were used to estimate MDs in costs and effects between the trial arms. For cost outcomes, a gamma family with log-link was selected using the modified Park test, Pearson’s correlation, Pregibon link and modified Hosmer–Lemeshow tests.35 For the effectiveness outcomes (i.e. healthy babies and live births), a Poisson family with log-link was used, as per the statistical analysis. Recycled predictions were used to recover adjusted mean values by trial arm, as well as the incremental differences between trial arms.35 The incremental cost-effectiveness ratio (ICER) for frozen-embryo transfer compared with fresh-embryo transfer was calculated as the difference in mean cost divided by the difference in mean effect. The variance surrounding the joint incremental costs and effects was characterised using non-parametric bootstrapping (i.e. 1000 iterations), with simulated output summarised graphically using cost-effectiveness plane and cost-effectiveness acceptability curves. For the sensitivity analysis using multiple imputation, the imputation model used chained equations with predictive mean matching (k = 5) to generate five imputed data sets (m = 5) nested within each bootstrapped resample (n = 1000). The imputation model included all of the missing cost elements, treatment allocation, women’s age and indicators for pregnancy and live birth as auxiliary variables.

Sensitivity analysis

The sensitivity analysis focused on the costing methodology for the initial interventions and missing data. A sensitivity analysis using multiple imputation chained equation was performed to assess the impact of missing data (including participants with partial missing data) on the robustness of the cost-effectiveness findings of the incremental NHS cost per baby born. The trial-based cost-effectiveness analysis was also conducted using pre-defined subgroups for women’s age at ovarian stimulation (< 35 years vs. ≥ 35 years).

Modelling of subsequent frozen-embryo transfers

Although the within-trial analysis is useful for informing cost-effectiveness in the short term, a longer time horizon is required to determine the relative cost-effectiveness of the alternative embryo transfer strategies in the context of routine IVF practice, whereby the subsequent transfer of the remaining frozen embryos can take place if the initial fresh-embryo transfer or frozen-embryo transfer fails to achieve a live birth. Therefore, a Markov model was developed to simulate progression through the subsequent transfer of the remaining frozen embryos for those failing to achieve live birth in both trial arms. This compares the policy of offering a full cycle of IVF using the freeze-all approach and a full cycle of IVF using the routine approach, in which a fresh embryo is used for the index transfer and the remaining frozen embryos are replaced in subsequent associated transfers. Although NICE3,36 recommends up to three full cycles of IVF treatment, with remaining good-quality embryos frozen and, subsequently, transferred as part of the same cycle, implementation of this guidance is low in England.37 Furthermore, the most efficient approach to the first full IVF cycle is also likely to offer the best value for money if repeated full IVF cycles are permitted. Therefore, the economic model considered one full IVF cycle. The index transfer in the model was parametrised using event rates and costs derived from the ITT analysis of the E-Freeze trial data, including post-randomisation costs for the initial embryo transfer, OHSS costs and ongoing costs associated with pregnancies. The costs and outcomes associated with subsequent frozen-embryo transfers were extrapolated using several assumptions (see Figure 11 for details). The state transition diagram for the model is provided in Figure 11. The details of the derived model parameter inputs are provided in Results.

FIGURE 11 State transition diagram for the Markov model. a, Tunnel states consisting of nine 4-week temporary states to capture progression through pregnancy. b, States were multiplied by 6 to allow for up to six subsequent frozen-embryo transfers. (Figure not reproduced here; see the original article.)

The model structure is replicated for the fresh-embryo transfer and freeze-all arms of the E-Freeze trial and runs on a fixed 4-week Markov cycle. Couples start the model in the ‘index fresh embryo transfer’ or the ‘index frozen-embryo transfer’ state based on the observed distribution in the respective arms of the E-Freeze trial. Following this, couples proceed to embryo transfer and either achieve a positive pregnancy test result or fail to become pregnant. A small proportion also receive no transfer, as observed in both arms of the trial. Those who fail to become pregnant move to either the ‘not pregnant – frozen embryos remaining’ or the ‘cycle complete – no child’ state, depending on the availability of remaining frozen embryos. Those who become pregnant move to the ‘pregnant’ state, which is a tunnel state consisting of nine temporary states that can be occupied for one 4-week cycle only. This captures progression and outcomes through the stages of pregnancy. During pregnancy, women incur ANC costs relevant to their stage of pregnancy, as observed by trial arm in the E-Freeze trial. Women can also lose their pregnancy; in these situations, they incur the cost of this event and transition to the ‘not pregnant – frozen embryos remaining’ or ‘cycle complete – no child’ state.

For those who carry their pregnancy to ≥ 24 weeks’ gestation, birth outcomes are modelled as observed by trial arm in the E-Freeze trial, and the relevant costs of delivery care are applied. To fit with the model structure and cycle length, preterm deliveries were categorised into three mutually exclusive categories as follows: < 28 weeks’, 28–32 weeks’ and 33–36 weeks’ gestation. For those transitioning to the ‘not pregnant – frozen embryos remaining’ state, the observed numbers of remaining embryos by treatment allocation arm in E-Freeze were used, in conjunction with several assumptions informed by external data,38 to inform transitions through subsequent frozen transfers of remaining embryos (see Figure 11). The model states representing subsequent embryo transfers, pregnancy following subsequent transfer, and failure to achieve pregnancy following subsequent transfer (see Figure 11), are multiplied by six to allow for up to six frozen transfers for those failing to achieve a live birth. Once a live birth has been achieved, no further transfers are modelled.

For the key outcomes that drive differences in the live birth rate and healthy baby rate between the trial arms, the model utilises relative risks (and 95% CIs) for frozen-embryo transfer and fresh-embryo transfer (ITT) applied to the baseline probabilities of events observed in the fresh-embryo transfer arm of E-Freeze [positive pregnancy following embryo transfer, RR 0.91 (95% CI 0.77 to 1.08); any pregnancy loss following a positive pregnancy test, RR 1.18 (95% CI 0.76 to 1.84); delivery prior to 33 weeks’ gestation for ongoing pregnancies at 24 weeks’ gestation, RR 0.60 (95% CI 0.15 to 2.34); and delivery between 33 and < 37 weeks’ gestation for ongoing pregnancies at end of week 32 of gestation, RR 1.17 (95% CI 0.39 to 3.52)]. The relative risk for OHSS is also applied (0.44 95% CI, 0.15 to 1.3). For other parameters, trial arm-specific event counts and costs are derived from the observed E-Freeze outcome and cost data. The details of these derived model parameter inputs are provided in Results.

Following internal validation of the model output for the index embryo transfer against the trial-based cost-effectiveness findings, the model was used to extrapolate the costs and consequences of transferring the remaining frozen embryos. For this, the distribution of remaining embryos by trial arm in the E-Freeze trial for those not achieving live birth was used to estimate the proportion of women expected to have remaining embryos available for a second, third, fourth, fifth, sixth and seventh embryo transfer attempt. This required two key assumptions:

1. The remaining frozen embryos are thawed and replaced one at a time.
2. The transfer of each remaining frozen embryo has an equal chance of resulting in pregnancy and live birth, regardless of the approach to the first transfer and the total number of embryos remaining frozen.

For all subsequent frozen-embryo transfers, the event rates and costs were based on those observed for the index transfer in the frozen arm of the E-Freeze trial. The following adjustments were also made:

1. It was assumed that not all couples with remaining frozen embryos available after each failed transfer would return to use them (i.e. a discontinuation rate was applied after each failed transfer).
2. The survival rate for thawed embryos was set to 88%, in line with data from the E-Freeze trial.
3. The chance of pregnancy with subsequent frozen-embryo transfers was assumed to be lower, relative to the chance of pregnancy in the index transfer in the freeze-all arm of the E-Freeze trial.
4. A duration of three model cycles (i.e. 12 weeks) was assumed between each embryo transfer attempt.

The adjustments described in 1 and 3 above were based on an Australian population-based study reporting on the cumulative live birth rate (CLBR) following a freeze-all strategy compared with a fresh-embryo transfer strategy,38 including a good-prognosis group with a similar number of embryos available and a similar live birth rate as those of the E-Freeze cohort. Following each failed embryo transfer and using the reported data, a discontinuation rate was calculated as the proportion of women with remaining frozen embryos who did not return for a further transfer. This was taken as the average across the fresh-embryo transfer and freeze-all groups in the best prognosis subgroup of the Australian study. The relative adjustment to the pregnancy rate in subsequent frozen-embryo transfers compared with index frozen-embryo transfer cycles was derived using data reported for the freeze-all group of the best-prognosis subgroup of the Australian study. No more than six subsequent frozen-embryo transfers were incorporated in the model, as < 5% of the E-Freeze cohort had more than six embryos remaining frozen following failure of the index transfer, and the increase in the expected live birth rate from allowing a sixth transfer was < 0.1% compared with that from allowing up to five subsequent frozen-embryo transfers.

The model also included final birth outcome states, as it was originally intended to extrapolate longer-term costs and health outcomes per child born following treatment. This was in anticipation of a potential trade-off between maximising the live birth rate and maximising the health baby rate. However, the E-Freeze trial data indicated that, as a proportion of live births, the healthy baby rate was the same (71%) in both arms. Therefore, a decision was made not to include these in the current model. Although there were differences in the percentages of live births falling into the categories of preterm delivery and abnormal birthweight, these differences were based on very small numbers and, therefore, are highly uncertain. This would consequently translate into a high degree of uncertainty around any modelled difference in expected child health service costs or health outcomes.

Model-based analysis

The model was run probabilistically over a time horizon of 5 years, using 1000 random draws from distributions assigned to each clinical and cost input parameter. The results of the model were assessed in terms of the incremental cost per healthy baby and the incremental cost per live birth. Costs incurred beyond year 1 in the model were discounted using a rate of 3.5%, in line with the NICE reference case,39 but birth outcomes were not discounted because there is no guidance on the discount rate to apply to these outcomes in the context of fertility treatment. The probabilistic model output was summarised using cost-effectiveness scatterplots and cost-effectiveness acceptability curves, indicating the probability of each strategy being preferred on grounds of cost-effectiveness by increasing levels of societal willingness to pay per additional healthy baby or additional live birth. A further deterministic sensitivity analysis was undertaken to assess the robustness of the model findings to key structural uncertainties and costing assumptions.

Results

Health service resource use and costs

Table 19 summarises NHS resource use by trial arm and Table 20 summarises costs by trial arm. A total of 601 participants received an embryo transfer, with 117 participants not receiving their allocated treatment. As a result, 223 participants received frozen-embryo transfer, including 21 who were allocated to fresh-embryo transfer. Prior to frozen-embryo transfer, participants had additional monitoring visits, blood tests and transvaginal ultrasound scans. The crossover participants had slightly fewer monitoring visits and transvaginal scans, but more blood tests. The resource use associated with IVF translated to an average post-randomisation treatment cost of £1538 and £1216 in the freeze-all and fresh-embryo transfer arms, respectively, giving an unadjusted cost difference of £322. Compared with frozen-embryo transfer, a larger number of participants developed OHSS in the fresh-embryo transfer arm (8% vs. 4%, respectively), and participants in the fresh-embryo transfer arm had more outpatient visits and inpatient day case visits and a longer inpatient length of stay than participants in the freeze-all arm. The mean OHSS costs by treatment allocation were £17 for frozen-embryo transfer and £201 for fresh-embryo transfer.

Of the 293 participants with a positive pregnancy test result at 2 weeks post embryo transfer, 100 suffered pregnancy loss. The number with pregnancy loss was slightly larger in the freeze-all arm, at 52 (37%), than in the fresh-embryo transfer arm, at 48 (31%). The mean cost of pregnancy loss was £89 and £75 for frozen-embryo transfer and fresh-embryo transfer, respectively. As a result, 193 participants had a live birth delivery, with more babies delivered in the fresh-embryo transfer arm than in the freeze-all arm. No obvious, notable differences were observed in the resource use associated with ANC in participants with ongoing pregnancy or in the delivery costs for those achieving live birth. The mean cost of ANC and delivery was higher in the fresh-embryo transfer arm (see Table 22) owing to the higher pregnancy rate and the smaller proportion of participants experiencing pregnancy loss.

The resource use from randomisation to delivery translated to a total, average, unadjusted NHS cost of £3431 in the freeze-all arm and £3574 in the fresh-embryo transfer arm, resulting in an unadjusted difference of £143. A breakdown of direct medical costs per participant experiencing each type of resource use event is presented in Appendix 6.

Participant travel and time costs

Table 21 presents the travel and time costs for attending clinic appointments between the time of treatment allocation and embryo transfer. A larger number of participants in the freeze-all arm reported at least one clinic visit (135 vs. 41 in the fresh-embryo transfer arm), and participants in the freeze-all arm also reported a larger average number of clinic visits (1.6 vs. 0.6 in the fresh-embryo transfer arm). This translated to an average travel cost of £30 for the thawed freeze-all arm and £25 for the fresh-embryo transfer arm.

Among the 164 participants who reported at least one clinic visit, women in the freeze-all arm reported spending less time in the clinic per visit than women in the fresh-embryo transfer arm. In total, 145 participants reported taking time off from paid work (see Appendix 7). The mean productivity cost associated with time away from usual activities was £50 for the freeze-all arm and £27 for the fresh-embryo transfer arm. When travel and time costs were summed, the average patient’s time and travel cost came to £80.09 and £52.05 for the freeze-all arm and the fresh-embryo transfer arm, respectively.

Cost-effectiveness analysis results

The cost-effectiveness analysis was conducted using the complete-cases data set, and the incremental cost per baby born is presented in Table 22. The adjusted mean treatment cost (including OHSS) per participant was £1402 for the fresh-embryo transfer arm and £1573 for the freeze-all arm, resulting in an adjusted MD of £171. The mean treatment cost was significantly higher in the freeze-all arm than in the fresh-embryo transfer arm. The mean adjusted healthy baby rate was 0.242 in the fresh-embryo transfer arm and 0.204 in the freeze-all arm, producing an adjusted MD of –0.039 (95% CI –0.104 to 0.023) in favour of the fresh-embryo transfer arm. The cost-effectiveness scatterplot, using 1000 bootstrapped iterations, in Figure 12 shows that frozen-embryo transfer was more costly than fresh-embryo transfer in the majority of iterations (≈ 99%). In addition, the healthy baby rate was lower for frozen-embryo transfer than fresh-embryo transfer in 89% of iterations, in line with the MD, in effect favouring fresh-embryo transfer over frozen-embryo transfer. Thus, frozen-embryo transfer was dominated by fresh-embryo transfer. Based on the cost-effectiveness acceptability curves in Figure 13, frozen-embryo transfer had a low chance of being cost-effective at all willingness-to-pay thresholds. Similar findings were noted for the cost-effectiveness analysis using live birth as the measure of effect. (see Table 24, and Figures 12 and 13).

FIGURE 12 Trial-based incremental cost-effectiveness scatterplots for frozen-embryo transfer vs. fresh-embryo transfer. (a) Treatment costs: healthy baby; (b) treatment costs: live birth; (c) NHS costs: healthy baby; and (d) NHS costs: live birth. (Figure not reproduced here; see the original article.)

FIGURE 13 Trial-based cost-effectiveness acceptability curves for frozen-embryo transfer vs. fresh-embryo transfer. (a) Treatment costs: healthy baby; (b) treatment costs: live birth; (c) NHS costs: healthy baby; and (d) NHS costs: live birth. (Figure not reproduced here; see the original article.)

When the total NHS costs were used in the analysis, the adjusted mean NHS cost per participant was £3551 for the fresh-embryo transfer arm and £3454 for the freeze-all arm, resulting in an adjusted MD of £97 (fresh-embryo transfer vs. freeze all). The mean treatment costs for fresh-embryo transfer were slightly higher than those for frozen-embryo transfer because of higher ANC and delivery costs, driven by the higher pregnancy and delivery rates. The ICER for frozen-embryo transfer compared with fresh-embryo transfer, representing cost savings per unit reduction in effect, came to £2425 and £1742 for one less healthy baby and one less live birth, respectively.

Sensitivity and subgroup analyses results

As the cost of transvaginal scans was the main driver of the increased treatment costs for the freeze-all arm compared with the fresh-embryo transfer arm, several sensitivity analyses were conducted using alternative costing methodologies for the scan (Table 23). In addition, multiple imputation was conducted to assess the impact of the base-case assumptions around missing cost data (Table 24). Prespecified subgroup analyses based on age and the number of previous embryo transfers were also conducted (Table 25). The cost-effectiveness scatterplots and cost-effectiveness acceptability curves are shown in Appendix 8.

Alternative costing methodology

Table 23 shows the results of the sensitivity analyses. Using alternative, more conservative, assumptions for costing transvaginal ultrasound scans and pre-embryo transfer monitoring, the incremental treatment cost of frozen-embryo transfer was reduced and was no longer significant under the lowest scan-cost scenario. However, both alternative analyses led to similarly low probabilities of frozen-embryo transfer being cost-effective compared with fresh-embryo transfer (see Appendix 8).

Multiple imputation

Table 24 presents the results of sensitivity analyses using the multiple imputation approach. The incremental treatment costs were slightly increased (frozen-embryo transfer vs. fresh-embryo transfer) following this approach, and the total NHS cost savings (inclusive of pregnancy delivery costs) were slightly lower (frozen-embryo transfer vs. fresh-embryo transfer). The incremental NHS cost per healthy baby (£2109) and per live birth (£1399) was, consequently, slightly lower for fresh-embryo transfer than for frozen-embryo transfer.

Subgroup analyses

Table 25 reports the results of subgroup analyses by age. In women aged ≥ 35 years, the healthy baby rate was slightly higher in the freeze-all arm, although the difference was not statistically significant, leading to a positive ICER of £24,308 per additional healthy baby. Based on the results of the non-parametric bootstrap, frozen-embryo transfer was found to have a 46.5% chance of being the preferred intervention at the willingness-to-pay threshold of £20,000 per healthy baby (see Appendix 8). The cost-effectiveness findings for other subgroups remained less favourable to frozen-embryo transfer than to fresh-embryo transfer.

Costs and consequences summary

The summary of costs and consequences was consistent with the cost-effectiveness findings. Frozen-embryo transfer incurred higher treatment and patient costs than fresh-embryo transfer. There were no significant differences in all primary and secondary outcome measures between the trial arms (Table 26), although, directionally, the majority of the outcome measures favoured fresh-embryo transfer over frozen-embryo transfer. The exceptions to this were preterm delivery and low birthweight, which were proportionally higher in the fresh-embryo transfer arm than in the freeze-all arm, although this was based on small numbers of events, with no statistically significant differences found.

Modelling of subsequent frozen-embryo transfers

All of the derived parameter inputs for the cost-effectiveness model are provided in Appendix 9. The results of the modelling exercise, allowing for up to six subsequent frozen-embryo transfers, are provided in Table 27, and Figures 14 and 15. The results show that, allowing for the transfer of the remaining embryos, the incremental cost associated with frozen-embryo transfer can be expected to increase further, whereas the difference in effect can be expected to narrow slightly. This is driven by the higher initial failure rate in the freeze-all arm than that in the fresh-embryo transfer arm, resulting in a larger proportion of the cohort retuning for further frozen-embryo transfers than fresh-embryo transfers. Allowing for this, fresh-embryo transfer continues to dominate frozen-embryo transfer in terms of treatment costs per healthy baby and live birth, and in terms of NHS costs per health baby and live birth. Considering the uncertainty around the joint incremental costs and effect (see Figure 14), fresh-embryo transfer retains the higher chance of being preferred on grounds of cost-effectiveness across all values of willingness to pay per health baby or live birth, compared with frozen-embryo transfer (see Figure 15).

FIGURE 14 Model-based cost-effectiveness scatterplots for frozen-embryo transfer vs. fresh-embryo transfer. (a) Treatment costs (including OHSS): healthy baby; (b) treatment costs (including OHSS): live birth; (c) NHS costs: healthy baby; and (d) NHS costs: live birth. (Figure not reproduced here; see the original article.)

FIGURE 15 Model-based cost-effectiveness scatterplots for frozen-embryo transfer vs. fresh-embryo transfer. (a) Treatment costs (including OHSS): healthy baby; (b) treatment costs (including OHSS): live birth; (c) NHS costs: healthy baby; and (d) NHS costs: live birth. (Figure not reproduced here; see the original article.)

Model-based sensitivity analysis

Table 28 presents the results of several key sensitivity analyses around the model-based estimates of cost-effectiveness, using incremental treatment cost (including OHSS) per additional healthy baby as the measure of cost-effectiveness. Assuming no discontinuation among those eligible for subsequent frozen-embryo transfers and applying more conservative costs for transvaginal scans and monitoring prior to frozen-embryo transfer, fresh-embryo transfer remains, on average, more effective and less costly than thawed frozen-embryo transfer. Cost-effectiveness acceptability curves for the model-based sensitivity analysis are provided in Appendix 10.