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,
and Aaron B. Caughey, MD, PhD
OBJECTIVE: To investigate the cost-effectiveness of add-
ing azithromycin to standard cephalosporin regimens of
cesarean delivery prophylaxis by considering the mater-
nal outcomes in the current and potential subsequent
pregnancies.
METHODS: A cost-effectiveness model was created
using TreeAge to compare the outcomes of using
azithromycin–cephalosporin with cephalosporin alone
in a theoretical cohort of 700,000 women, the approximate
number of nonelective cesarean deliveries annually in the
United States that occur during labor or after membrane
rupture. Outcomes examined included endometritis,
wound infection, sepsis, venous thromboembolism, and
maternal death in the current pregnancy and uterine rup-
ture, cesarean hysterectomy, and maternal death in sub-
sequent pregnancies, including cost and quality-adjusted
life-years for both pregnancies. Probabilities, utilities, and
costs were derived from the literature, and a cost-
effectiveness threshold was set at $100,000 per quality-
adjusted life-year. Sensitivity analyses were used to
determine the robustness of our results.
RESULTS: Compared with cephalosporin alone for pro-
phylaxis, our model showed 16,100 fewer cases of
endometritis, 17 fewer cases of sepsis, eight fewer cases
From the Departments of Obstetrics and Gynecology, Oregon Health and Science
University, Portland, Oregon, the University of Wisconsin, Madison, Wisconsin,
and Washington University in St. Louis, St. Louis, Missouri.
Presented as a poster at the 37th Annual Meeting of the Society for Maternal-
Fetal Medicine, January 23–28, 2017, Las Vegas, Nevada.
Each author has indicated that he or she has met the journal’s requirements for
authorship.
Corresponding author: Ashley E. Skeith, Department of Obstetrics and
Gynecology, Oregon Health & Science University, Mail Code L466, 3181 SW
Sam Jackson Park Road, Portland, OR 97202; email: Skeith@ohsu.edu.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2017 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/17
VOL. 130, NO. 6, DECEMBER 2017
Copyright ª by The American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
DO, Methodius G. Tuuli, MD, MPH,
of venous thromboembolism, and one fewer maternal
death with azithromycin–cephalosporin. Additionally,
this strategy prevented 36 uterine ruptures and four
cesarean hysterectomies in the subsequent pregnancy.
Overall, the addition of azithromycin led to both lower
costs and higher quality-adjusted life-years when com-
pared with standard cephalosporin prophylaxis. In sen-
sitivity analysis, we found that as long as the cost of
azithromycin remained below $930 (baseline cost $27),
it was cost-effective.
CONCLUSION: For women who undergo cesarean
delivery in labor or after membrane rupture, compared
with cephalosporin alone, the addition of azithromycin
to cesarean delivery infection prophylaxis is less costly
and leads to better maternal outcomes in the index
delivery and subsequent deliveries. These findings sup-
port the use of prophylactic azithromycin at the time of
cesarean delivery.
(Obstet Gynecol 2017;130:1279–84)
DOI: 10.1097/AOG.0000000000002333
C
esarean delivery is the most common surgical
procedure in the United States1 with postcesar-
ean 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 per-
formed before the onset of labor or after membrane
rupture.3 Postoperative infection is associated with a lon-
ger 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 prophy-
laxis in cesarean delivery include standard use of
a narrow-spectrum antibiotic administered before skin
OBSTETRICS & GYNECOLOGY 1279
incision, most commonly a first-generation cephalo-
sporin.7 Recently, a prospective, multicenter, random-
ized 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 azi-
thromycin 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 deliv-
ery 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 insti-
tutional review board approval.
The size of our theoretical cohort was 700,000
women, reflecting the approximate number of non-
elective 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 cephalo-
sporin 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. Addi-
tionally, our model incorporated outcomes in a poten-
tial subsequent pregnancy, comparing the difference
in uterine rupture risk and possible subsequent cesar-
ean hysterectomy in women with and without a history
of endometritis.
Probabilities were derived from the literature
(Table 1). For outcomes related to the index preg-
nancy, the probabilities of endometritis and wound
infection with and without the addition of azithromy-
cin 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 endome-
tritis 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 cesar-
ean deliveries with and without the presence of infec-
tion was derived from a 2006 retrospective cohort
study on venous thromboembolism during pregnancy
and the postpartum period.11 We assumed a probabil-
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-
AC) 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 endo-
metritis 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 Con-
sumer Price Index from January to April and taken
from the societal perspective. The cost of azithromy-
cin 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 attrib-
utable to infection for women with endometritis or
wound infection for inpatient, outpatient, and emer-
gency readmission to the hospital 30 days after sur-
gery, 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 hys-
terectomy, 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
Table 2. Costs for the Cost-Effectiveness Model
Amount Reference
Cost ($) (s)
Azithromycin (per dose) 27 18,33
Endometritis (attributable cost) 3,956 5
Wound infection (attributable cost) 3,529 5
Sepsis 40,901 34
Venous thromboembolism 19,538 35
Uterine rupture 1,003 19
Cesarean hysterectomy 2,331 19
Maternal death 2,168,746 20–22
VOL. 130, NO. 6, DECEMBER 2017 Skeith et al Cost-Effectiveness of Azithromycin for Cesarean Prophylaxis
Copyright ª by The American College of Obstetricians
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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 calcu-
lated using maternal utilities from the literature
(Table 1). Utilities are quality-of-life measures for var-
ious 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 theo-
retical cohort delivered by cesarean, and 0 for mater-
nal 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 hysterec-
tomy.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 g 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 com-
mon to medical costs. A wide SD (50%) was used to
approximate the large variation in medical costs and b
distributions with a SD of 20% were used for proba-
bility estimates.
1281
RESULTS
Maternal outcomes were estimated for a theoretical
cohort of 700,000 women undergoing cesarean
deliveries in the United States, comparing cephalo-
sporin alone with the addition of azithromycin
(Table 3). The addition of azithromycin decreased
all maternal outcomes, including endometritis,
wound infection, sepsis, and venous thromboembo-
lism 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 hysterec-
tomy were decreased in a potential subsequent preg-
nancy. 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 preg-
nancy. The baseline cost-effectiveness analysis re-
sults in our theoretical cohort demonstrate that the
addition of azithromycin is less expensive at $7.5
billion compared with $8.1 billion with cephalospo-
rin 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
Table 3. Summary of Results in a Theoretical
Cohort of 700,000 Cesarean Deliveries
Azithromycin
Plus Cephalosporin
Cephalosporin Only
Endometritis 26,600 42,700
Wound infection 16,800 46,200
Sepsis 22 39
Venous thromboembolism 2,532 2,540
Subsequent uterine rupture 573 609
Cesarean hysterectomy 67 71
Maternal death 474 475
Cost (in millions) $7,504 $8,129
QALYs (in 1,000s) 18,668.08 18,668.03
QALYs, quality-adjusted life-years.
1282 Skeith et al Cost-Effectiveness of Azithromycin for Cesarean Prophylaxis
Copyright ª by The American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
the model, which have been verified in a multicenter
trial.8 After varying cost of azithromycin, at a willing-
ness-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 azithromy-
cin 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 azi-
thromycin 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).
DISCUSSION
We found that the addition of azithromycin to
cephalosporin cesarean delivery infection prophy-
laxis 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 postcesar-
ean delivery infection and a recent study compared
costs associated with this intervention.8,28–31 How-
ever, 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 expen-
sive and led to improved outcomes in the setting of
infection prophylaxis for cesarean delivery.
OBSTETRICS & GYNECOLOGY
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
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 admin-
istration 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 out-
comes, and utilities. The findings from studies used to
populate this model were vulnerable to bias, low
external validity, and the possibility of being under-
powered. 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 im-
proves maternal outcomes. Now that there are several
clinical studies with demonstrated benefit and poten-
tial cost savings related to the reduction in complica-
tions, 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 sub-
sequent deliveries. These findings lend further support
to the use of prophylactic azithromycin at the time of
cesarean delivery.
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