Cost-Effectiveness of Single Embryo Transfers Relative to Higher Embryo Transfer Policies in Clinical Practice: A Population-Based Analysis



Fig. 21.1
Incremental cost-effectiveness ratios of embryo transfer policies for women <38. Notes: Whereas adjustments for inflation would move the ICER ratios upward on the y-axis, the relative difference in the ICERs between alternative embryo transfer policies would likely remain the same. As such, a standard healthcare inflation adjustment (based on published annual healthcare inflation for the UK) can be applied to the final ICER estimates, as well as the “willingness-to-pay’ thresholds



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Fig. 21.2
Incremental cost-effectiveness ratios of embryo transfer policies for women 38 years and older. Notes: Whereas adjustments for inflation would move the ICER ratios upward on the y-axis, the relative difference in the ICERs between alternative embryo transfer policies would likely remain the same. As such, a standard healthcare inflation adjustment (based on published annual healthcare inflation for the UK) can be applied to the final ICER estimates, as well as the ‘willingness-to-pay’ thresholds




Methods


Data on IVF clinics in the UK were provided by the Human Fertilisation & Embryology Authority (HFEA) to calculate the cost-effectiveness for each ET policy (1 embryo, 2 embryos, and 3 embryos) and treatment history category (1 cycle, 2 cycles, ≥3 cycles). Within-cycle cost-effectiveness was calculated for two age groups (<38 vs. ≥38 years) and compared between three embryo transfer shifts: from SET to 2ET, from 2ET to 3ET, and from SET to 3ET. The incremental cost-effectiveness between cycle groups was not compared in the same way, because patients in different cycle categories are assumed to have different levels of baseline fertility.


Study Population


A total of 68 clinics contributed comprehensive data to the HFEA under what can be described as a legislative mandate. The study population comprised all women undergoing at least one IVF treatment cycle with ET in the UK between 1 July 1991 and 31 December 1998 (n = 174,418). All IVF treatment cycles (with and without ICSI; fresh and frozen sperm/eggs/embryos; donor and partner’s gametes) and outcomes registered during this time were retrospectively reviewed in a non-identifiable, anonymous manner. Cases excluded from this research were all women who received a fertility therapy other than IVF with ET, all women older than 44 years of age at cycle start, and quadruplet deliveries (n = 4 sets). We based our calculations on IVF treatments involving only SET, 2ET, or 3ET (higher-order ETs were not tabulated). Accordingly, a total of 74,755 women undergoing 137,307 cycles (79 % of registered cases) met our inclusion criteria. Patients were next stratified by age, number of transferred embryos on their final cycle, and number of treatment cycles.

A health economic evaluation was performed in the form of an incremental cost-effectiveness analysis. Costs included all treatment costs, antenatal costs, and pregnancy and birth costs from parturition to the first 5 years of childhood life (inclusive). Costs were reported according to the period over which the treatments occurred, with subsequent adjustment to 2012–2013 levels using standard healthcare inflationary corrections.


Definitions: Live Birth Rate and Multiple Birth Rate


Our investigation used the standard HFEA definition of a live birth event: a maternity in which the child(ren) survive(s) 27 completed days post-delivery. Because the HFEA dataset does not distinguish between stillbirth and neonatal death, infants who died in utero or who did not survive through 27 competed days post-delivery per pregnancy were not included for analysis.

The live birth rate (LBR) as used in this study includes most cases familiar to clinicians, but the ‘average live birth rate per IVF patient’ is used here to normalise the live birth rates between increasing cycle categories. This form of LBR is often referred to as the ‘take-home’ baby rate.

Two forms of measuring the multiple birth rate (MBR) were used: the first is calculated as the MBR divided by the total number of IVF cycles, and the second method is the MBR divided by the total number of live birth events. The former statistic represents the per cycle incidence of multiple births. The latter estimation is more useful, since it represents the proportional incidence of multiple births as a function of all live births.


Sensitivity Analysis


There was uncertainty regarding values of several estimated parameters in our analysis. Sensitivity analysis allows assessment of robustness of conclusions to changes in key parameters by assigning varying ranges to uncertain parameters over realistic ranges and re-evaluating the conclusions for different combinations. This can be accomplished by using a one-way sensitivity analysis, where only one variable is changed at a time. In probabilistic sensitivity analysis, parameter ranges are used to estimate likelihood of cost-effectiveness. In multi-way sensitivity analysis, several variables are changed concurrently. Finally, in the extreme scenario analysis a nominal estimate of cost-effectiveness is determined, and uncertain parameters are varied using their extreme ‘maximum’ and ‘minimum’ values. This latter approach was utilised for the present analyses (i.e. low cost/low resource use vs. high cost/high resource use) to estimate the extent to which the conclusions in this chapter may change with maximum and minimum variations in the cost and resource assumptions.


Data organisation and Presentation of Statistical Significance


Our initial analysis was confined to records of IVF patients who completed no more than three treatment cycles because >90 % of the national study population underwent only one, two, or three treatment cycles. All results are reported as exact (or mean) values. Differences in live birth rates and multiple birth rates between subgroups of women were compared by Student’s t-test, with differences considered significant if two-tailed p-values were ≤0.05.


Sources of Cost Estimations


For purposes of this analysis, the estimated average cost per IVF cycle is £2,876.26 (±681.63) excluding medications. This estimate was derived from the author’s (CAJ) 2003 telephone survey of charges in the 70 UK clinics that provided IVF services [3]. The number of treatment cycles (and thus cycle costs) will change for different patient populations (1 cycle, 2 cycles, and ≥3 cycles).

Average antenatal bed days were estimated by Henderson et al. [4] at 1.09 days (SE = 0.01) for women expecting a singleton child, 8.35 days (SE = 0.51) for those expecting twins, and 32 days (SE = 11.22) for those expecting triplets. A cost per bed day of £277.40 (±41.53) was based on figures provided by the Oxford Radcliffe Hospitals NHS Trust (www.​orh.​nhs.​uk) multiplied by the average number of bed days reported by Henderson et al. [4]. This cost per bed day was compared to a national estimate of £318.93 in the sensitivity analysis. Resulting antenatal costs were calculated at £302.37 (SE = 2.77) per singleton delivery, £2,316.28 (SE = 141.47) per twin delivery, and £8,876.77 (SE = 3,112.41) per triplet delivery.

‘Cost of the first 5 years of child life’ was adapted from a report on long-term health service costs for hospital stays associated with singleton, twin, and triplet births up to 5 years of age [4]. That computation was derived from the Oxford Record Linkage Study (ORLS), which recorded health data on all women and infants who lived and delivered in Oxfordshire or West Berkshire between January 1, 1970, and December 31, 1993. Their study included all delivery costs for the mother, as well as hospital service utilisation costs from birth through baby’s first 5 years of life. These costs were adjusted for inflation estimated at £2,345.69 (±12.50) per singleton delivery, £11,715.88 (±80.46) per twin delivery, and £37,462.66 (±467.13) per triplet delivery.

For each IVF case, the hospital costs described above were added to IVF treatment costs to generate a total cost. To bring these historical economic figures in line with current levels, all costs were inflated by £2,004 using NHS Hospital and Community Health Services pay and price deflators provided by the UK Department of Health (www.​statistics.​gov.​uk/​statbase). This total cost included the cost of IVF treatment (without gonadotropins and other medications), hospital visits during the antenatal period, intrapartum care, and any paediatric hospitalisation from birth through the first 5 years of life. Mode of delivery was included neither in the HFEA dataset nor in the report by Henderson et al. [4]. Accordingly, delivery costs were excluded from our analysis.


Measuring Incremental Cost-Effectiveness


Here, effectiveness is defined as the average number of live birth events per woman in each category as classified by age, cycle, and number of transferred embryos. The incremental cost-effectiveness ratio (ICER) is calculated for each group of women as the cost of achieving an additional live birth event in a higher embryo category. ICERs are expressed in terms of (a) maternal age (<38 vs. ≥38 years), (b) number of treatment cycles (1, 2, or ≥3 cycles), and (c) number of transferred embryos (1, 2, or 3 embryos) on the final treatment cycle. The average live birth rate per woman was chosen for effectiveness to normalise the data with respect to differences in the number of women in each age, ET, and cycle populations.

In summary, the variables included in the analysis comprise (a) the respective number of singleton, twin, and triplet live birth events; (b) antenatal cost of each plurality; (c) cost from delivery to the first 5 years of life; (d) total cost for each plurality; (e) total cost of each ET policy; (f) total effectiveness of each ET policy; (g) incremental cost of achieving an additional live birth event in a higher ET policy; (h) incremental effectiveness at achieving an additional live birth event with a higher ET policy; and (i) incremental cost-effectiveness expressed as the incremental cost to achieve an additional live birth event in comparative ET policies. Effectiveness ratios were expressed as the number of live birth events per woman. ICERs were subsequently mapped onto cost-effectiveness planes to graphically illustrate the within-cycle cost-effectiveness of each intervention.


Results


A total of 174,418 IVF treatment cycles occurred in the UK between 1 July 1991 and 31 December 1998. After application of exclusion criteria, 74,755 women undergoing 137,307 cycles (79 % of those registered) were analysed. These 74,755 fertility patients underwent between 1 and 23 IVF cycles where ET occurred. A total of 41,033 women underwent one cycle only, 18,275 two cycles only, and 15,447 three or more cycles. Of these 61,284 were less than 38 years of age and 13,471 were greater than 38 years of age.


SET Versus 2ET Policy



One Prior IVF Cycle


Among 3,089 women aged <38 years who underwent SET after one prior IVF cycle, there were 463 live birth events comprising 450 singletons, 11 sets of twins and 2 sets of triplets. A policy of 2ET was noted to increase the live birth rate by a factor of 2.4 (0.15 vs. 0.36 births/woman; p < 0.05), although this came at the expense of tenfold rise in multiple births (2.81 % vs. 27.32 %; p < 0.05). Correspondingly, the incremental cost per additional live birth associated with a 2ET policy was £7,728 in the nominal scenario. This value ranged from £7,450 to £8,023 in minimum and maximum scenarios, respectively.

In 1,270 women aged ≥38 years having SET after one prior IVF cycle, there were 71 live births comprising 69 singletons, 1 set of twins, and 1 set of triplets. In this group, moving from SET to 2ET increased the live birth rate by a factor of 2.7 (0.06 vs. 0.16; p < 0.05) at the expense of a fivefold increase in the incidence of multiple births (2.82 % vs. 13.89 %). The incremental cost per additional live birth in moving to a 2ET policy in the one prior cycle population was £4,663 in the nominal scenario. This value ranged from £4,537 to £4,794 in minimum and maximum scenarios, respectively.


Two Prior IVF Cycles


In 1,451 women aged <38 years with SET and two prior IVF cycles, there were 64 live births comprising 63 singletons and 1 twin delivery. A policy of 2ET increased the live birth rate by more than twofold (0.04 vs. 0.09; p < 0.05), accompanied by a ninefold increase in the risk of multiple births (1.56 vs. 14.23; p < 0.05). Whilst the proportion of multiple births to total births was slightly lower than the younger, one-cycle patients, the live birth rate was almost four times lower for two-cycle compared to one-cycle patients (0.04 vs. 0.15; p < 0.05). The incremental cost per additional live birth event in moving to a 2ET policy in this population was £5,662 in the nominal scenario, ranging from £5,464 to £5,874 in minimum and maximum scenarios, respectively.

There were 460 women aged ≥38 years who underwent SET after two prior IVF cycles, from which 10 live birth events resulted (all singleton deliveries). A policy of 2ET doubled the live birth rate (0.02 vs. 0.04; p < 0.05) at the expense of an increase in the incidence of multiple births (0 % vs. 11.76 %) including three sets of twins and one set of triplets. There were no multiple gestations in the SET group with two prior IVF cycles. The live birth rate was three times lower for women undergoing two cycles as compared to women undergoing only one cycle (0.02 vs. 0.06; p < 0.05). The incremental cost per additional live birth event in moving to a 2ET policy in this population was £8,001 in the nominal scenario. This value ranged from £7,538 to £8,535 in minimum and maximum scenarios, respectively.


Three or More Prior IVF Cycles


There were 49 live births comprising 48 singletons and 1 set of twins in 1,274 women aged <38 years with SET after ≥3 prior IVF cycles. A policy of 2ET accomplished a moderate increase in the live birth rate (0.04 vs. 0.05; p > 0.05) at the expense of a fourfold increased risk of multiple births (2.04 vs. 7.29; p < 0.05). Whilst the proportion of multiple births to total births was 30 % higher in comparison to women undergoing only two cycle attempts, the live birth rate was identical. There is an incremental cost savings (indicated by a minus sign) of (–)£6,340 in the nominal scenario per additional live birth event in moving to a 2ET policy in this population. This value ranged from (–)£3,751 to (–)£8,920 in minimum and maximum savings scenarios, respectively.

In 288 women aged ≥38 years with SET and ≥3 prior IVF cycles, there were two live births, both singletons. In this subgroup, a policy of 2ET doubled the very low live birth rate from 0.01 to 0.02. This came at the expense of an increase in the proportion of multiple births with the extra embryo, although it is important to note that there were no multiple births observed among women undergoing SET in this category. The live birth rate was six times lower for women undergoing three or more cycles compared to women undergoing only one cycle attempt (0.01 vs. 0.06; p < 0.05). The live birth rate was half the rate for women undergoing two IVF cycles compared to those undergoing three or more IVF cycles (0.01 vs. 0.02; p < 0.05). The incremental cost per additional live birth event in moving to a 2ET policy in this population was £20,906 in the nominal scenario. This value ranged from £16,980 to £24,840 in minimum and maximum scenarios, respectively.


Two Versus Three ET Policy



One Prior IVF Cycle


Four thousand seven hundred ninety-five live births occurred among 13,260 women aged <38 years with 2ET and one prior IVF cycle, comprising of 3,485 singletons, 1,302 sets of twins, and 8 sets of triplets. A policy of 3ET increased the live birth rate by 10 % (0.36 vs. 0.40; p < 0.05) at the expense of a 50 % increase in the proportion of multiple births (27.32 vs. 40.97 %; p < 0.05). Correspondingly, the incremental cost per additional live birth event in moving to a 3ET policy in this population was £45,964 in the nominal scenario. This value ranged from £42,218 to £50,430 in minimum and maximum scenarios, respectively.

Among 2,258 women aged ≥38 years with 2ET and one prior IVF cycle, there were 360 live births comprising 310 singletons and 50 twin sets. A policy of 3ET increased the live birth rate by a factor of 1.4 (0.16 vs. 0.23; p < 0.05) at the expense of a 1.7-fold increase in the proportion of multiple births (13.89 % vs. 23.87 %; p < 0.05). The incremental cost per additional live birth event in moving to a 3ET policy in this population was £10,045 in the nominal scenario. This value ranged from £9,501 to £10,668 in minimum and maximum scenarios, respectively.


Two Prior IVF Cycles


Amidst 5,925 women aged <38 years with 2ET and two prior IVF cycles, there were 555 live births consisting of 476 singletons, 78 sets of twins, and 1 set of triplets. In this group, a policy of 3ET increased the live birth rate by approximately 50 % (0.09 vs. 0.14; p < 0.05) at the expense of 40 % increased proportion of multiple births (14.23 % vs. 19.91 %; p <0.05). Whilst the proportion of multiple births to total live birth events was approximately half the value for <38 years/1 cycle patients, the live birth rate was four times lower for two- compared to one-cycle patients (0.09 vs. 0.36; p < 0.05). The incremental cost per additional live birth event in moving to a 3ET policy in this population was £8,943 in the nominal scenario. This value ranged respectively from £8,406 to £9,570 in minimum and maximum scenarios.

In 895 women aged ≥38 years with 2ET and two prior IVF cycles, there were 34 live birth events comprising 30 singletons, 3 sets of twins, and 1 set of triplets. A policy of 3ET doubled the live birth rate (0.04 vs. 0.08; p < 0.05) with a slight decrease in the proportion of multiple births in the higher embryo category (11.76 % vs. 10.07 %). The proportion of multiple births to total births was slightly less than the value for one-cycle patients, but the twin delivery rate was higher in women receiving 3ET compared to those receiving 2ET. The live birth rate was four times lower for women with only two cycles compared with those having only one cycle (0.04 vs. 0.16; p < 0.05). The incremental cost per additional live birth event in moving to a 3ET policy in this population was £3,173 in the nominal scenario. This value ranged from £3,214 to £3,125 in the minimum and maximum scenarios, respectively.


Three or More Prior IVF Cycles


IVF for 4,853 women aged <38 with 2ET and ≥3 prior cycles resulted in 247 live births comprising 229 singletons and 18 sets of twins. A policy of 3ET increased the live birth rate by 60 % (0.05 vs. 0.08; p < 0.05) with surprisingly fewer multiple births in the higher embryo category (7.29 % vs. 6.44 %, respectively). The proportion of multiple births to total births was approximately 25 % of the value for women who received three or more cycles compared to those who received only one cycle. The proportion of multiple births was approximately half the value for women who received three or more cycles compared to those who received only two cycles. The live birth rate was approximately seven times lower for women who received three or more cycles compared to women who received only one cycle (0.05 vs. 0.36; p < 0.05), and approximately half the live birth rate of women who received only two cycles (0.05 vs. 0.09; p < 0.05). The incremental cost per additional live birth event in moving to a 3ET policy in this population was £14,016 in the nominal scenario, and ranged from £11,431 to £16,619 in minimum and maximum scenarios, respectively.

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Oct 18, 2016 | Posted by in EMBRYOLOGY | Comments Off on Cost-Effectiveness of Single Embryo Transfers Relative to Higher Embryo Transfer Policies in Clinical Practice: A Population-Based Analysis
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