This study was designed as a cost-utility analysis, and a decision tree model was constructed using TreeAge Pro 2022 software. The cost-utility of using cefazolin alone versus cefazolin combined with azithromycin for preventing nonselective post-cesarean infections was evaluated from a societal perspective in China.
2.1 Model Structure
The decision tree model (shown in Fig. 1) begins with completing maternal cesarean delivery. Maternal outcomes are divided into current cesarean delivery outcomes and potential outcomes for future pregnancies. Two studies, a retrospective study by Chen Zhifang in China and a case-control study by Shipp's team, have shown that endometritis or pelvic inflammatory disease is associated with an increased risk of uterine rupture during a potential future trial of labor after cesarean (TOLAC) [17, 18]. Thus, setting potential pregnancy event outcomes and exploring the impact of having a history of endometritis on the overall maternal quality of life level. Current cesarean delivery outcomes may include endometritis, wound infection, sepsis, venous thromboembolism, and maternal mortality. Potential outcomes of a pregnancy event may include elective repeat cesarean delivery, TOLAC, vaginal birth after cesarean (VBAC), cesarean delivery after unsuccessful TOLAC, uterine rupture, hysterectomy, and maternal mortality.
2.2.1 Cost parameters
Drug costs were determined based on the azithromycin dosing regimen of 0.5 g and the cefazolin dosing regimen of 2 g, which were used in the Tita study and recommended by the Guidelines for Clinical Use of Antimicrobial Drugs (2015 edition) [15, 19], respectively. The costs of cefazolin sodium and azithromycin drugs were obtained from www.yaozh.com and the median price in each province in China since 2022 was used.
The outcome of maternal mortality in terms of the opportunity cost of lost maternal years of work was calculated using the following formula: national per capita disposable income × (female retirement age - average female childbearing age). The average female childbearing age was 28.61 years, the female retirement age was 50, and the national per capita disposable income was set to ¥32,188.8 [20-23]. The average female childbearing age was obtained by taking a weighted average of the age data for having one, two, three, and more children from the China Fertility Report.
Other costs related to maternal outcomes include the expenses associated with treating endometritis, wound infections, sepsis, and venous thromboembolism, as reported in the literature [24-27]. The costs in Table 1 were adjusted to 2020 price levels using the Consumer Price Index (CPI) for Medical Services and the CPI for Traditional Chinese Medicine and Healthcare Supplies, as published by the National Bureau of Statistics of China (S1) [23]. Endometritis and venous thromboembolism treatment costs were divided into pharmaceutical and nonpharmaceutical costs. They were therefore adjusted according to the CPI for medical services and the CPI for Traditional Chinese Medicine and Healthcare Supplies. In contrast, the costs of treating sepsis and wound infections were not differentiated and were adjusted solely based on the Consumer Price Index (CPI) for medical services. All other costs related to maternal outcomes were obtained from the "Notice on Announcing the Prices of Some Medical Service Items and Other Related Issues in Provincial Public Hospitals" published by the Medical Security Bureau of Fujian Province, China, in 2022 [28]. The time frame for potential pregnancy events was set to three years later, representing the age difference between women with multiple children and those with only one child in 2020. The cost of treatment for the desired outcome was discounted at the recommended annual rate of 5% according to Chinese pharmacoeconomic evaluation guidelines [20, 21]. The specific cost parameters are presented in Table 1.
The range of parameters for the univariate sensitivity analysis was set to ±20% of the baseline value or based on the range reported in the literature.
Table 1 Cost parameters in the model (¥)
Cost parameters
|
Source Year
|
Baseline value (adjusted)
|
Sensitivity analysis range
|
Source
|
Azithromycin for injection
|
2022
|
13.76
|
7.36~20.21
|
www.yaozh.com
|
Cefazolin sodium for injection
|
2022
|
57.22
|
18.02~73.41
|
www.yaozh.com
|
maternal mortality
|
2020
|
688518.43
|
550814.74-826222.12
|
[20-23]
|
primary cesarean delivery
|
2022
|
1343.7
|
1215-1620
|
[28]
|
secondary cesarean
|
2022
|
1330.31
|
1261.20-1399.42
|
[28]
|
secondary cesarean section plus TOLAC
|
2022
|
1740.63
|
1649.93-1831.36
|
[28]
|
cesarean hysterectomy
|
2022
|
1442.61
|
1364.86-1520.35
|
[28]
|
Uterine repair
|
2022
|
885.43
|
837.92-932.94
|
[28]
|
Treatment of endometritis
|
2013
|
13137.53
|
10510.02-15765.03
|
[24]
|
Treatment of Sepsis
|
2018
|
24466.72
|
14312.10-49409.48
|
[25]
|
Treatment of venous thromboembolism
|
2013
|
18772.63
|
15018.10-22527.15
|
[26]
|
Treatment of wound infection
|
2013
|
11232.82
|
8986.25-13479.38
|
[27]
|
TOLAC, trial of labor after cesarean.
2.2.2 Probability parameters
Most of the probabilities for each outcome in the decision tree model were obtained from relevant literature published in Chinese and English databases. Due to the limited research on the effectiveness of cefazolin and cefazolin combined with azithromycin in preventing cesarean infections in China, the study by Tita's team was used to determine their preventive effects [15]. Data from international research were used to calculate the probability of maternal endometritis or wound infection in conjunction with sepsis, as these conditions are rare in China [29, 30]. Maternal mortality rates associated with cesarean delivery were obtained from a retrospective study that analyzed the mode of delivery [31]. The probability of death resulting from sepsis was derived from an epidemiological study conducted in Beijing [25]. The probability of venous thromboembolism was investigated in an observational study on the risk of maternal venous thromboembolism in Hong Kong, China [32]. The probability of maternal death resulting from venous thromboembolism was obtained from a retrospective study that utilized a risk assessment model for patients who experienced combined venous thromboembolism during pregnancy and postpartum [33]. The probability of a woman having another pregnancy was 54.2% based on the proportion of one child versus multiple births in 2020 [20]. For specific potential pregnancy outcomes, the probability of TOLAC from an analysis of maternal outcomes of the vaginal trial of labor after cesarean delivery [34]. The probability of maternal death resulting from cesarean delivery after a failed trial of labor after cesarean (TOLAC) was assumed to be zero [35, 36]. This decision was based on multiple sources in the literature that reported no instances of maternal mortality. The probability of uterine rupture during a trial of labor after cesarean [TOLAC] in pregnant women, with or without a history of endometritis, was determined through a retrospective study that examined the factors influencing complications after secondary cesarean delivery [18]. The probability of needing a hysterectomy after uterine rupture was derived from a multicenter analysis of uterine rupture outcomes in China [37]. The probability of maternal death resulting from hysterectomy was determined based on five retrospective studies, as there is a lack of research on maternal outcomes in women who undergo hysterectomy, and the sample sizes in individual studies are small [38-42]. The probability of VBAC was derived from a retrospective study on factors associated with pregnancy outcomes and uterine rupture [43]. The probability of maternal death for this outcome was assumed to be 0, considering no maternal complications after VBAC.
The parameter range for the univariate sensitivity analysis of each outcome probability was determined based on the range reported in the literature or set to a baseline value of ±20%. As the probability of maternal death resulting from cesarean delivery after failed TOLAC and maternal death after successful vaginal birth was set to zero, it was not feasible to establish the parameter range to the baseline value ± 20%. Therefore, the upper limit of the parameter range for the former was determined based on the maternal mortality rate (13.16/100,000) from a Meta-analysis on maternal and infant safety of TOLAC, and the upper limit of the parameter range for the latter was set to the maternal mortality rate in 2021 (16.1/100,000). The lower limit for both was zero [35, 44]. The probability parameters for specific outcomes are presented in Table 2.
Table 2 Probability of maternal outcomes
Probability parameters
|
Baseline value
|
Sensitivity analysis range
|
Source
|
Endometritis: cefazolin
|
0.061
|
0.05-0.1
|
[15]
|
Endometritis: cefazolin azithromycin
|
0.038
|
0.02-0.06
|
[15]
|
Wound infection: cefazolin
|
0.066
|
0.05-0.1
|
[15]
|
Wound infection: cefazolin azithromycin
|
0.024
|
0.02-0.07
|
[15]
|
Probability of endometritis combined with sepsis
|
0.000682
|
0-0.033
|
[29, 30]
|
Probability of wound infection combined with sepsis
|
0.000345
|
0-0.000345
|
[29, 30]
|
Probability of venous thromboembolism
|
0.0004
|
0-0.00138
|
[32]
|
Maternal mortality due to cesarean delivery
|
0.0004
|
0.00032-0.00048
|
[31]
|
Maternal mortality due to sepsis
|
0.174
|
0.1392-0.2088
|
[25]
|
Maternal mortality due to venous thromboembolism
|
0.007
|
0.0056-0.0084
|
[33]
|
Probability of potential pregnancy
|
0.542
|
0.4336-0.6504
|
[20]
|
Probability of TOLAC
|
0.2962
|
0.2381-0.3939
|
[34]
|
Maternal mortality due to cesarean delivery after failed TOLAC
|
0
|
0-0.0001316
|
[35, 36]
|
Probability of uterine rupture during TOLAC in pregnant women with a history of endometritis
|
0.1379
|
0.1103-0.1655
|
[18]
|
Probability of uterine rupture during TOLAC in pregnant women without a history of endometritis
|
0.02193
|
0.01754-0.02632
|
[18]
|
Probability of needing hysterectomy after uterine rupture
|
0.071
|
0.0568-0.0852
|
[37]
|
Maternal mortality due to hysterectomy
|
0.05115
|
0.04092-0.06138
|
[38-42]
|
Probability of VBAC
|
0.05656
|
0-0.0641
|
[43]
|
Maternal mortality after VBAC
|
0
|
0-0.0000161
|
[44]
|
TOLAC, trial of labor after cesarean; VBAC, vaginal birth after cesarean.
2.2.3 Utility parameters
Health outcomes were measured using utility values to adjust life years for health-related quality of life, resulting in quality-adjusted life years (QALYs). We used a maternal utility of 0.6309 for Hysterectomy, 0.52 for maternal infection, 0.2 for maternal infection combined with sepsis, and 0.96 for Venous thromboembolism [45-48]. The health utility values for the combined states were obtained by multiplying the health utility values of each state.
Life cycle by status from China Bureau of Statistics data, a prospective study of menopausal status in Chinese women, and a retrospective study on treatment duration by outcome status [24, 25, 27, 48-50]. The length of hospital stay for the combined state outcomes was determined by taking the most extended mean length of stay from both groups. These parameters were obtained from published studies. The specific utility parameters are presented in Table 3.
Table 3 Utility values for each outcome
Utility Parameters
|
Baseline Value
|
Sensitivity analysis range
|
Source
|
Health utility value
|
|
|
|
Hysterectomy
|
0.6309
|
0.5507-0.8100
|
[45]
|
Endometritis
|
0.52
|
0.416-0.624
|
[46]
|
Wound infection
|
0.52
|
0.416-0.624
|
[46]
|
Wound infection or endometritis combined with sepsis
|
0.2
|
0.16-0.24
|
[46, 47]
|
Maternal death
|
0
|
-
|
-
|
Venous thromboembolism
|
0.96
|
0.768-1
|
[48]
|
Sepsis combined with venous thromboembolism
|
0.192
|
0.1536-0.2304
|
[47, 48]
|
Endometritis or wound infection combined with venous thromboembolism
|
0.4492
|
0.3594-0.5390
|
[46, 48]
|
Time parameters for each endpoint (years)
|
|
|
|
mean length of hospital stay for endometritis
|
0.01671
|
0.01370-0.01973
|
[24]
|
mean length of hospital stay for sepsis
|
0.03013
|
0.01644-0.04932
|
[25]
|
mean length of hospital stay for wound infection
|
0.03789
|
0.02896-0.04682
|
[27]
|
mean length of hospital stay for venous thromboembolism
|
0.01370
|
0.01-0.0174
|
[48]
|
remaining years of childbearing
|
9.59
|
5.19-13.99
|
[49]
|
maternal remaining life expectancy
|
52.27
|
41.816-62.724
|
[50]
|
"-" means not set.
The QALYs for each outcome were set as follows:
QALYs for maternal hysterectomy = 1 × (maternal remaining life expectancy - remaining years of childbearing) + hysterectomy utility value × remaining years of childbearing (remaining years of childbearing = mean female menopause - mean female childbearing age, with the health utility value of hysterectomy discounted at an annual rate of 5%).
QALYs for maternal sepsis combined with venous thromboembolism = 1 × (maternal remaining life expectancy - mean length of hospital stay for sepsis combined with venous thromboembolism) + utility value for sepsis combined with venous thromboembolism × mean length of hospital stay.
QALYs for maternal wound infection or endometritis combined with sepsis = 1 × (maternal life remaining - mean length of hospital stay for wound infection or endometritis combined with sepsis) + utility value for wound infection or endometritis combined with sepsis × mean length of hospital stay.
QALYs for maternal endometritis or wound infection combined with venous thromboembolism = 1 × (maternal life remaining - mean length of hospital stay for endometritis or wound infection combined with venous thromboembolism) + utility value for endometritis or wound infection combined with venous thromboembolism × mean length of hospital stay.
QALYs for maternal venous thromboembolism = 1 × (maternal life remaining - mean length of hospital stay for venous thromboembolism) + venous thromboembolism utility value × mean length of hospital stay.
QALYs for successful maternal pregnancy with no complications = 1 × remaining maternal life expectancy.
2.3 Analysis method
This study constructed a cost-utility model using TreeAge Pro 2022 software. The collected model parameters were utilized to conduct a cost-utility analysis. First, a basic analysis was conducted to estimate the lifetime health output (measured in QALYs), total cost, and incremental cost-effectiveness ratio (ICER) of using a prophylactic regimen consisting of cefazolin combined with azithromycin and cefazolin alone. Second, the aim is to estimate the cesarean section outcomes for 800,000 women by calculating the incidence of each outcome. Approximately 800,000 women undergo nonselective cesarean deliveries during labor and delivery in China each year. This estimate is based on the following formula: the number of public hospital discharges for cesarean delivery in 2021 [44] × proportion of nonselective cesarean to total cesarean deliveries (54.90%, as reported in the literature) [7-14]. Third, a one-way sensitivity analysis was conducted to evaluate the influence of uncertainty in each parameter on cost utility. The parameter range was obtained from the literature or set to baseline values with a variation of ±20% interval. Fourth to conduct probabilistic sensitivity analysis, we generated 1000 iterations for all variables with uncertainty within the 95% confidence interval (CI). The cost parameters were assumed to follow a Gamma distribution, while the probability and quality of life parameters followed a Beta distribution. The standard deviation was fixed at 25%. The willingness-to-pay cost was determined using the World Health Organization's recommended cost-utility acceptability threshold of ¥257,094, three times the 2022 GDP per capita (¥85,698) [51].