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Original Research

Adding Azithromycin to Cephalosporin for


Cesarean Delivery Infection Prophylaxis
A Cost-Effectiveness Analysis
Ashley E. Skeith, BA, Brenda Niu, MD, Amy M. Valent, DO, Methodius G. Tuuli, MD, MPH,
and Aaron B. Caughey, MD, PhD

OBJECTIVE: To investigate the cost-effectiveness of add- of venous thromboembolism, and one fewer maternal
ing azithromycin to standard cephalosporin regimens of death with azithromycin–cephalosporin. Additionally,
cesarean delivery prophylaxis by considering the mater- this strategy prevented 36 uterine ruptures and four
nal outcomes in the current and potential subsequent cesarean hysterectomies in the subsequent pregnancy.
pregnancies. Overall, the addition of azithromycin led to both lower
METHODS: A cost-effectiveness model was created costs and higher quality-adjusted life-years when com-
using TreeAge to compare the outcomes of using pared with standard cephalosporin prophylaxis. In sen-
azithromycin–cephalosporin with cephalosporin alone sitivity analysis, we found that as long as the cost of
in a theoretical cohort of 700,000 women, the approximate azithromycin remained below $930 (baseline cost $27),
number of nonelective cesarean deliveries annually in the it was cost-effective.
United States that occur during labor or after membrane CONCLUSION: For women who undergo cesarean
rupture. Outcomes examined included endometritis, delivery in labor or after membrane rupture, compared
wound infection, sepsis, venous thromboembolism, and with cephalosporin alone, the addition of azithromycin
maternal death in the current pregnancy and uterine rup- to cesarean delivery infection prophylaxis is less costly
ture, cesarean hysterectomy, and maternal death in sub- and leads to better maternal outcomes in the index
sequent pregnancies, including cost and quality-adjusted delivery and subsequent deliveries. These findings sup-
life-years for both pregnancies. Probabilities, utilities, and port the use of prophylactic azithromycin at the time of
costs were derived from the literature, and a cost- cesarean delivery.
effectiveness threshold was set at $100,000 per quality-
(Obstet Gynecol 2017;130:1279–84)
adjusted life-year. Sensitivity analyses were used to
DOI: 10.1097/AOG.0000000000002333
determine the robustness of our results.

C
RESULTS: Compared with cephalosporin alone for pro- esarean delivery is the most common surgical
phylaxis, our model showed 16,100 fewer cases of procedure in the United States1 with postcesar-
endometritis, 17 fewer cases of sepsis, eight fewer cases
ean delivery infection being a common cause of
maternal morbidity and mortality. The current rate of
From the Departments of Obstetrics and Gynecology, Oregon Health and Science infection after cesarean delivery in the United States is
University, Portland, Oregon, the University of Wisconsin, Madison, Wisconsin, 10–20 times higher than the risk with vaginal delivery.2
and Washington University in St. Louis, St. Louis, Missouri.
Cesarean deliveries performed in labor carry an even
Presented as a poster at the 37th Annual Meeting of the Society for Maternal-
Fetal Medicine, January 23–28, 2017, Las Vegas, Nevada. higher risk of postoperative infection than those per-
Each author has indicated that he or she has met the journal’s requirements for formed before the onset of labor or after membrane
authorship. rupture.3 Postoperative infection is associated with a lon-
Corresponding author: Ashley E. Skeith, Department of Obstetrics and ger length of hospitalization, higher readmission rates,
Gynecology, Oregon Health & Science University, Mail Code L466, 3181 SW and higher health care costs.4,5 Additionally, women
Sam Jackson Park Road, Portland, OR 97202; email: Skeith@ohsu.edu.
diagnosed with endometritis face an increased risk of
Financial Disclosure
The authors did not report any potential conflicts of interest.
uterine rupture in a subsequent trial of labor.5,6
Current recommendations for antibiotic prophy-
© 2017 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved. laxis in cesarean delivery include standard use of
ISSN: 0029-7844/17 a narrow-spectrum antibiotic administered before skin

VOL. 130, NO. 6, DECEMBER 2017 OBSTETRICS & GYNECOLOGY 1279

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
incision, most commonly a first-generation cephalo- delivering by cesarean treated with either cephalo-
sporin.7 Recently, a prospective, multicenter, random- sporin alone or both cephalosporin and a single dose
ized trial found that there were significantly fewer of 500 mg azithromycin for infection prophylaxis
cases of endometritis (3.8% compared with 6.1%) (Appendix 1, available online at http://links.lww.
and wound infection (2.4% compared with 6.6%) com/AOG/B25). Maternal outcomes in the model
among laboring patients who received adjunctive azi- included endometritis, wound infection, sepsis,
thromycin compared with placebo (all received venous thromboembolism, and maternal death. Addi-
a cephalosporin).8 tionally, our model incorporated outcomes in a poten-
The goal of the current study was to investigate tial subsequent pregnancy, comparing the difference
whether it is cost-effective to add azithromycin to in uterine rupture risk and possible subsequent cesar-
standard cephalosporin regimens of cesarean delivery ean hysterectomy in women with and without a history
prophylaxis in women who undergo cesarean deliv- of endometritis.
ery during labor or after membrane rupture. We Probabilities were derived from the literature
considered maternal outcomes and cost in the current (Table 1). For outcomes related to the index preg-
and potential subsequent pregnancy. nancy, the probabilities of endometritis and wound
infection with and without the addition of azithromy-
MATERIALS AND METHODS cin were derived from the recent 2016 multicenter,
We developed a decision-analytic model using randomized trial examining rates of postoperative
TreeAge Pro 2016 that compared the use of a first- infection in women undergoing nonelective cesarean
generation cephalosporin alone with cephalosporin delivery.8 The risk of sepsis in the setting of endome-
plus azithromycin given before skin incision. This tritis was estimated using a retrospective cohort of
study is a theoretic decision analytic model with no California deliveries from 2005 to 2007 and a sample
human participants and thus was exempt from insti- of national inpatient surveys from 1998 to 2008.9,10
tutional review board approval. The probability of venous thromboembolism in cesar-
The size of our theoretical cohort was 700,000 ean deliveries with and without the presence of infec-
women, reflecting the approximate number of non- tion was derived from a 2006 retrospective cohort
elective cesarean deliveries annually in the United study on venous thromboembolism during pregnancy
States that occur during labor or after membrane and the postpartum period.11 We assumed a probabil-
rupture. The model begins with a laboring woman ity of 70% of a future pregnancy and a 20%

Table 1. Outcomes, Probabilities, and Utilities for the Azithromycin Cost-Effectiveness Model

Outcome Probability Utility Reference(s)

Current pregnancy
Endometritis 0.52 25
Cephalosporin only .061 8
Cephalosporin plus azithromycin .038 8
Wound infection 0.52 25
Cephalosporin only .066 8
Cephalosporin plus azithromycin .024 8
Sepsis in the setting of endometritis .000682 0.2 9,10,25
Sepsis in the setting of wound infection .000345 0.2 9,10,25
Maternal death* 0
All cesarean .000359 15
Sepsis .0440 16
Venous thromboembolism .0062 11
Failed TOLAC .004 17
Cesarean hysterectomy .00635 15
Subsequent pregnancy
Uterine rupture
History of endometritis .028 6
No history of endometritis .007 6
Cesarean hysterectomy after uterine rupture .1167 0.81 13,19,24
TOLAC, trial of labor after cesarean.
* Probabilities for maternal death were the same in both pregnancies.

1280 Skeith et al Cost-Effectiveness of Azithromycin for Cesarean Prophylaxis OBSTETRICS & GYNECOLOGY

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
probability that a trial of labor after cesarean (TOL- Centers for Disease Control and Prevention (life
AC) would be attempted for that delivery.12,13 For expectancy), the Bureau of Labor Statistics (wage),
outcomes in a subsequent pregnancy, the probability and the Center for Retirement Research (retirement
of uterine rupture in a TOLAC with a history of endo- age).20–22
metritis originated from a 2003 nested case–control Quality-adjusted life-years (QALYs) were calcu-
study in a cohort of all women undergoing TOLAC.6 lated using maternal utilities from the literature
The risk of a cesarean hysterectomy after uterine rupture (Table 1). Utilities are quality-of-life measures for var-
comes from a 2000 retrospective study of maternal ious states of well-being that range from 0 for death
outcomes after uterine rupture in labor.14 and 1 for optimal health. The baseline parameters for
Probabilities of maternal death were estimated for maternal utility in this model are set at 0.996 for
various outcomes in both the index and potential a cesarean delivery,23 because all women in the theo-
subsequent pregnancies, including maternal death in retical cohort delivered by cesarean, and 0 for mater-
the setting of sepsis, venous thromboembolism, or nal death. These utilities are combined with estimates
failed TOLAC in the index pregnancy and maternal of maternal life expectancy to calculate the QALYs.
death in the setting of cesarean hysterectomy, vaginal The time horizon for this analysis was the patient’s
birth after cesarean delivery, or elective cesarean lifetime after delivery.
delivery in a subsequent pregnancy.11,15–17 We used a maternal utility of 0.7 for maternal
Cost data were derived through literature review infection, 0.2 for sepsis, and 0.81 for cesarean hysterec-
(Table 2). All costs were inflated to 2017 dollars using tomy.19,24,25,26 The utility for hysterectomy was applied
an average of the medical component of the Con- to the remaining years of maternal fertility, which was
sumer Price Index from January to April and taken estimated to be 20 additional years, assuming delivery at
from the societal perspective. The cost of azithromy- an average age of 25 years. The utilities for infection and
cin in the model accounts for the cost of the drug sepsis were applied to the mean attributable hospital stay
itself, medication preparation, and administration.18 for each condition.25,26 An annual discount rate of 3%
The attributable costs of endometritis and wound was applied to cost and utility values according to the
infection were derived from a 2010 retrospective Panel on Cost-Effectiveness in Health Medicine
cohort study of 1,605 women who delivered by low recommendations.27
transverse cesarean.5 This study included costs attrib- Total costs and QALYs were calculated for each
utable to infection for women with endometritis or strategy to determine the incremental cost-
wound infection for inpatient, outpatient, and emer- effectiveness ratio of adding azithromycin to current
gency readmission to the hospital 30 days after sur- cephalosporin regimens of cesarean delivery infection
gery, including sepsis and venous thromboembolism. prophylaxis. The cost-effectiveness threshold was set
Thus, independent costs for these infection sequelae at $100,000 per QALY. Additionally, we calculated
were excluded from our model to avoid double- clinical outcomes for each strategy, including those
counting. Costs for outcomes related to a subsequent related to a subsequent pregnancy such as uterine
pregnancy include uterine rupture and cesarean hys- rupture and cesarean hysterectomy.
terectomy, which were derived from a 2001 cost- Sensitivity analysis was performed to allow for the
effectiveness study of TOLAC.19 The cost of maternal variation of model inputs such as cost of azithromycin
death includes the opportunity cost of lost working and rate of cesarean delivery and measurement of
years and was calculated using data inputs from the how this variation would change results. For this
model, univariate sensitivity analyses were performed
on each input in the model to determine a threshold
Table 2. Costs for the Cost-Effectiveness Model value beyond which the intervention would not be
Amount Reference
cost-effective. A Monte Carlo simulation analysis was
Cost ($) (s) performed to simulate the outcome of 10,000 women
delivering by cesarean. We assumed a g distribution
Azithromycin (per dose) 27 18,33 for costs in this simulation, which is comparable with
Endometritis (attributable cost) 3,956 5
a normal distribution but with a left skew. This was
Wound infection (attributable cost) 3,529 5
Sepsis 40,901 34 done to approximate the upper range outliers com-
Venous thromboembolism 19,538 35 mon to medical costs. A wide SD (50%) was used to
Uterine rupture 1,003 19 approximate the large variation in medical costs and b
Cesarean hysterectomy 2,331 19 distributions with a SD of 20% were used for proba-
Maternal death 2,168,746 20–22
bility estimates.

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RESULTS the model, which have been verified in a multicenter
Maternal outcomes were estimated for a theoretical trial.8 After varying cost of azithromycin, at a willing-
cohort of 700,000 women undergoing cesarean ness-to-pay threshold of $100,000 per QALY, the
deliveries in the United States, comparing cephalo- addition of azithromycin was cost-effective as long
sporin alone with the addition of azithromycin as the cost of the drug did not exceed $930 and
(Table 3). The addition of azithromycin decreased cost-saving as long as the drug did not exceed $924,
all maternal outcomes, including endometritis, far above the baseline cost assumption of azithromy-
wound infection, sepsis, and venous thromboembo- cin in the model of $27. This model was also robust
lism in the index pregnancy. Additionally, as a result when the probability of endometritis with the addition
of the prevention of endometritis and thus lower of azithromycin was varied up to 6.07%, which nears
population risk of uterine rupture in a subsequent the probability of endometritis with cephalosporin
trial of labor, uterine rupture and cesarean hysterec- alone, given as 6.10% in this model. Our findings
tomy were decreased in a potential subsequent preg- were similar for wound infection, demonstrating
nancy. Compared with cephalosporin alone for robustness when the probability of wound infection
prophylaxis, our model showed 16,100 fewer cases with the addition of azithromycin was varied up to
of endometritis, 29,400 cases of wound infection, 6.41%, which nears the probability of wound infection
17 fewer cases of sepsis, and eight fewer cases of with cephalosporin alone, given as 6.60% in this
venous thromboembolism with azithromycin– model. These results indicate that the addition of azi-
cephalosporin. Additionally, this strategy prevented thromycin would be cost-effective even with a much
36 uterine ruptures, four cesarean hysterectomies, more modest reduction in rates of endometritis and
and one maternal death in the subsequent preg- wound infection than predicted.
nancy. The baseline cost-effectiveness analysis re- Based on a Monte Carlo simulation of 10,000
sults in our theoretical cohort demonstrate that the random women delivering by cesarean, a willingness-
addition of azithromycin is less expensive at $7.5 to-pay acceptability curve demonstrated a 97.0%
billion compared with $8.1 billion with cephalospo- probability that the addition of azithromycin to
rin alone and more effective demonstrated by higher cephalosporin cesarean delivery prophylaxis would
QALYs at 18,668,076 compared with 18,668,032 be cost-effective at a cost-effectiveness threshold of
with cephalosporin alone (Table 3). With lower costs $100,000 per QALY (Appendix 2, available online at
and higher QALYs, the addition of azithromycin is http://links.lww.com/AOG/B25).
the dominant strategy.
Univariate sensitivity analysis was conducted on DISCUSSION
all probabilities, costs, and utilities. The included We found that the addition of azithromycin to
tornado diagram (Fig. 1) of simultaneous univariate cephalosporin cesarean delivery infection prophy-
sensitivity analyses suggests that the probability of laxis in laboring women is cost-effective as long as
endometritis and wound infection after the addition the cost of the drug remains below $930 and as long
of azithromycin are the most critical probabilities in as the probability of endometritis and wound
infection with the addition of azithromycin was
below that of cephalosporin alone. Several studies
Table 3. Summary of Results in a Theoretical have examined the efficacy of adding azithromycin
Cohort of 700,000 Cesarean Deliveries to cephalosporin prophylaxis to prevent postcesar-
ean delivery infection and a recent study compared
Azithromycin costs associated with this intervention.8,28–31 How-
Plus Cephalosporin ever, no studies thus far have compared overall
Cephalosporin Only quality-of-life measures or specific costs related to
Endometritis 26,600 42,700 a potential subsequent pregnancy. This study found
Wound infection 16,800 46,200 similar results to prior studies in findings related to
Sepsis 22 39 maternal outcomes, particularly rates of sepsis,
Venous thromboembolism 2,532 2,540 venous thromboembolism, and uterine rupture in
Subsequent uterine rupture 573 609
Cesarean hysterectomy 67 71 a potential subsequent pregnancy. Considering the
Maternal death 474 475 downstream costs related to infectious morbidity,
Cost (in millions) $7,504 $8,129 the addition of azithromycin was both less expen-
QALYs (in 1,000s) 18,668.08 18,668.03 sive and led to improved outcomes in the setting of
QALYs, quality-adjusted life-years. infection prophylaxis for cesarean delivery.

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Fig. 1. Incremental cost-effectiveness ratio (ICER) tornado diagram, univariate sensitivity analysis. The vertical axis displays the
ICER. Each column represents the changes in the ICER while varying the input probability or cost listed beside the column. The
light gray vertical line is the cost per quality-adjusted life-year (QALY) (2$14,230,000) less the ICER under baseline assumptions.
This demonstrates that, at baseline, the addition of azithromycin is a cost-saving strategy. VTE, venous thromboembolism.
Skeith. Cost-Effectiveness of Azithromycin for Cesarean Delivery Prophylaxis. Obstet Gynecol 2017.

Notably, the theoretical cohort for our model was tions, prophylactic azithromycin at the time of
limited to women undergoing cesarean delivery in cesarean delivery may be not just a clinical
labor or after membrane rupture. Additionally, our improvement, but may be one of the rare items in
model did not account for neonatal outcomes. A health care that helps meet the triple aim of
recent multicenter study demonstrated that adverse improving quality of care, improving access to care,
neonatal outcomes did not increase with the admin- and lowering costs.32
istration of azithromycin before skin incision for In conclusion, the addition of azithromycin to
cesarean delivery and it is unclear what effect the cesarean delivery prophylaxis is less costly and leads
addition of a single dose of azithromycin might have to better maternal outcomes in the index and sub-
on the neonatal and childhood microbiome.8,36 sequent deliveries. These findings lend further support
Like with any cost-effectiveness study, the model to the use of prophylactic azithromycin at the time of
is subject to unreliable inputs of costs, health out- cesarean delivery.
comes, and utilities. The findings from studies used to
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and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.