Cesarean delivery is the most common surgical procedure in the United States1 with postcesarean delivery infection being a common cause of maternal morbidity and mortality. The current rate of infection after cesarean delivery in the United States is 10–20 times higher than the risk with vaginal delivery.2 Cesarean deliveries performed in labor carry an even higher risk of postoperative infection than those performed before the onset of labor or after membrane rupture.3 Postoperative infection is associated with a longer length of hospitalization, higher readmission rates, and higher health care costs.4,5 Additionally, women diagnosed with endometritis face an increased risk of uterine rupture in a subsequent trial of labor.5,6
Current recommendations for antibiotic prophylaxis in cesarean delivery include standard use of a narrow-spectrum antibiotic administered before skin incision, most commonly a first-generation cephalosporin.7 Recently, a prospective, multicenter, randomized trial found that there were significantly fewer cases of endometritis (3.8% compared with 6.1%) and wound infection (2.4% compared with 6.6%) among laboring patients who received adjunctive azithromycin compared with placebo (all received a cephalosporin).8
The goal of the current study was to investigate whether it is cost-effective to add azithromycin to standard cephalosporin regimens of cesarean delivery prophylaxis in women who undergo cesarean delivery during labor or after membrane rupture. We considered maternal outcomes and cost in the current and potential subsequent pregnancy.
MATERIALS AND METHODS
We developed a decision-analytic model using TreeAge Pro 2016 that compared the use of a first-generation cephalosporin alone with cephalosporin plus azithromycin given before skin incision. This study is a theoretic decision analytic model with no human participants and thus was exempt from institutional review board approval.
The size of our theoretical cohort was 700,000 women, reflecting the approximate number of nonelective cesarean deliveries annually in the United States that occur during labor or after membrane rupture. The model begins with a laboring woman delivering by cesarean treated with either cephalosporin alone or both cephalosporin and a single dose of 500 mg azithromycin for infection prophylaxis (Appendix 1, available online at http://links.lww.com/AOG/B25). Maternal outcomes in the model included endometritis, wound infection, sepsis, venous thromboembolism, and maternal death. Additionally, our model incorporated outcomes in a potential subsequent pregnancy, comparing the difference in uterine rupture risk and possible subsequent cesarean hysterectomy in women with and without a history of endometritis.
Probabilities were derived from the literature (Table 1). For outcomes related to the index pregnancy, the probabilities of endometritis and wound infection with and without the addition of azithromycin were derived from the recent 2016 multicenter, randomized trial examining rates of postoperative infection in women undergoing nonelective cesarean delivery.8 The risk of sepsis in the setting of endometritis was estimated using a retrospective cohort of California deliveries from 2005 to 2007 and a sample of national inpatient surveys from 1998 to 2008.9,10 The probability of venous thromboembolism in cesarean deliveries with and without the presence of infection was derived from a 2006 retrospective cohort study on venous thromboembolism during pregnancy and the postpartum period.11 We assumed a probability of 70% of a future pregnancy and a 20% probability that a trial of labor after cesarean (TOLAC) would be attempted for that delivery.12,13 For outcomes in a subsequent pregnancy, the probability of uterine rupture in a TOLAC with a history of endometritis originated from a 2003 nested case–control study in a cohort of all women undergoing TOLAC.6 The risk of a cesarean hysterectomy after uterine rupture comes from a 2000 retrospective study of maternal outcomes after uterine rupture in labor.14
Probabilities of maternal death were estimated for various outcomes in both the index and potential subsequent pregnancies, including maternal death in the setting of sepsis, venous thromboembolism, or failed TOLAC in the index pregnancy and maternal death in the setting of cesarean hysterectomy, vaginal birth after cesarean delivery, or elective cesarean delivery in a subsequent pregnancy.11,15–17
Cost data were derived through literature review (Table 2). All costs were inflated to 2017 dollars using an average of the medical component of the Consumer Price Index from January to April and taken from the societal perspective. The cost of azithromycin in the model accounts for the cost of the drug itself, medication preparation, and administration.18 The attributable costs of endometritis and wound infection were derived from a 2010 retrospective cohort study of 1,605 women who delivered by low transverse cesarean.5 This study included costs attributable to infection for women with endometritis or wound infection for inpatient, outpatient, and emergency readmission to the hospital 30 days after surgery, including sepsis and venous thromboembolism. Thus, independent costs for these infection sequelae were excluded from our model to avoid double-counting. Costs for outcomes related to a subsequent pregnancy include uterine rupture and cesarean hysterectomy, which were derived from a 2001 cost-effectiveness study of TOLAC.19 The cost of maternal death includes the opportunity cost of lost working years and was calculated using data inputs from the Centers for Disease Control and Prevention (life expectancy), the Bureau of Labor Statistics (wage), and the Center for Retirement Research (retirement age).20–22
Quality-adjusted life-years (QALYs) were calculated using maternal utilities from the literature (Table 1). Utilities are quality-of-life measures for various states of well-being that range from 0 for death and 1 for optimal health. The baseline parameters for maternal utility in this model are set at 0.996 for a cesarean delivery,23 because all women in the theoretical cohort delivered by cesarean, and 0 for maternal death. These utilities are combined with estimates of maternal life expectancy to calculate the QALYs. The time horizon for this analysis was the patient's lifetime after delivery.
We used a maternal utility of 0.7 for maternal infection, 0.2 for sepsis, and 0.81 for cesarean hysterectomy.19,24,25,26 The utility for hysterectomy was applied to the remaining years of maternal fertility, which was estimated to be 20 additional years, assuming delivery at an average age of 25 years. The utilities for infection and sepsis were applied to the mean attributable hospital stay for each condition.25,26 An annual discount rate of 3% was applied to cost and utility values according to the Panel on Cost-Effectiveness in Health Medicine recommendations.27
Total costs and QALYs were calculated for each strategy to determine the incremental cost-effectiveness ratio of adding azithromycin to current cephalosporin regimens of cesarean delivery infection prophylaxis. The cost-effectiveness threshold was set at $100,000 per QALY. Additionally, we calculated clinical outcomes for each strategy, including those related to a subsequent pregnancy such as uterine rupture and cesarean hysterectomy.
Sensitivity analysis was performed to allow for the variation of model inputs such as cost of azithromycin and rate of cesarean delivery and measurement of how this variation would change results. For this model, univariate sensitivity analyses were performed on each input in the model to determine a threshold value beyond which the intervention would not be cost-effective. A Monte Carlo simulation analysis was performed to simulate the outcome of 10,000 women delivering by cesarean. We assumed a γ distribution for costs in this simulation, which is comparable with a normal distribution but with a left skew. This was done to approximate the upper range outliers common to medical costs. A wide SD (50%) was used to approximate the large variation in medical costs and β distributions with a SD of 20% were used for probability estimates.
Maternal outcomes were estimated for a theoretical cohort of 700,000 women undergoing cesarean deliveries in the United States, comparing cephalosporin alone with the addition of azithromycin (Table 3). The addition of azithromycin decreased all maternal outcomes, including endometritis, wound infection, sepsis, and venous thromboembolism in the index pregnancy. Additionally, as a result of the prevention of endometritis and thus lower population risk of uterine rupture in a subsequent trial of labor, uterine rupture and cesarean hysterectomy were decreased in a potential subsequent pregnancy. Compared with cephalosporin alone for prophylaxis, our model showed 16,100 fewer cases of endometritis, 29,400 cases of wound infection, 17 fewer cases of sepsis, and eight fewer cases of venous thromboembolism with azithromycin–cephalosporin. Additionally, this strategy prevented 36 uterine ruptures, four cesarean hysterectomies, and one maternal death in the subsequent pregnancy. The baseline cost-effectiveness analysis results in our theoretical cohort demonstrate that the addition of azithromycin is less expensive at $7.5 billion compared with $8.1 billion with cephalosporin alone and more effective demonstrated by higher QALYs at 18,668,076 compared with 18,668,032 with cephalosporin alone (Table 3). With lower costs and higher QALYs, the addition of azithromycin is the dominant strategy.
Univariate sensitivity analysis was conducted on all probabilities, costs, and utilities. The included tornado diagram (Fig. 1) of simultaneous univariate sensitivity analyses suggests that the probability of endometritis and wound infection after the addition of azithromycin are the most critical probabilities in the model, which have been verified in a multicenter trial.8 After varying cost of azithromycin, at a willingness-to-pay threshold of $100,000 per QALY, the addition of azithromycin was cost-effective as long as the cost of the drug did not exceed $930 and cost-saving as long as the drug did not exceed $924, far above the baseline cost assumption of azithromycin in the model of $27. This model was also robust when the probability of endometritis with the addition of azithromycin was varied up to 6.07%, which nears the probability of endometritis with cephalosporin alone, given as 6.10% in this model. Our findings were similar for wound infection, demonstrating robustness when the probability of wound infection with the addition of azithromycin was varied up to 6.41%, which nears the probability of wound infection with cephalosporin alone, given as 6.60% in this model. These results indicate that the addition of azithromycin would be cost-effective even with a much more modest reduction in rates of endometritis and wound infection than predicted.
Based on a Monte Carlo simulation of 10,000 random women delivering by cesarean, a willingness-to-pay acceptability curve demonstrated a 97.0% probability that the addition of azithromycin to cephalosporin cesarean delivery prophylaxis would be cost-effective at a cost-effectiveness threshold of $100,000 per QALY (Appendix 2, available online at http://links.lww.com/AOG/B25).
We found that the addition of azithromycin to cephalosporin cesarean delivery infection prophylaxis in laboring women is cost-effective as long as the cost of the drug remains below $930 and as long as the probability of endometritis and wound infection with the addition of azithromycin was below that of cephalosporin alone. Several studies have examined the efficacy of adding azithromycin to cephalosporin prophylaxis to prevent postcesarean delivery infection and a recent study compared costs associated with this intervention.8,28–31 However, no studies thus far have compared overall quality-of-life measures or specific costs related to a potential subsequent pregnancy. This study found similar results to prior studies in findings related to maternal outcomes, particularly rates of sepsis, venous thromboembolism, and uterine rupture in a potential subsequent pregnancy. Considering the downstream costs related to infectious morbidity, the addition of azithromycin was both less expensive and led to improved outcomes in the setting of infection prophylaxis for cesarean delivery.
Notably, the theoretical cohort for our model was limited to women undergoing cesarean delivery in labor or after membrane rupture. Additionally, our model did not account for neonatal outcomes. A recent multicenter study demonstrated that adverse neonatal outcomes did not increase with the administration of azithromycin before skin incision for cesarean delivery and it is unclear what effect the addition of a single dose of azithromycin might have on the neonatal and childhood microbiome.8,36
Like with any cost-effectiveness study, the model is subject to unreliable inputs of costs, health outcomes, and utilities. The findings from studies used to populate this model were vulnerable to bias, low external validity, and the possibility of being underpowered. With sensitivity analysis and Monte Carlo simulations, however, the variability in our data was scrutinized and the model was determined to be robust. Thus, despite limitations, our findings suggest that the addition of azithromycin to current regimens of cesarean delivery prophylaxis costs less and improves maternal outcomes. Now that there are several clinical studies with demonstrated benefit and potential cost savings related to the reduction in complications, prophylactic azithromycin at the time of cesarean delivery may be not just a clinical improvement, but may be one of the rare items in health care that helps meet the triple aim of improving quality of care, improving access to care, and lowering costs.32
In conclusion, the addition of azithromycin to cesarean delivery prophylaxis is less costly and leads to better maternal outcomes in the index and subsequent deliveries. These findings lend further support to the use of prophylactic azithromycin at the time of cesarean delivery.
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