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Economic Value of Seasonal and Pandemic Influenza Vaccination
During Pregnancy
Richard H. Beigi, MD, MSc1, Ann E. Wiringa, BS2,3, Rachel Bailey, MPH2,3, Tina-Marie Assi,
MPH2,3, and Bruce Y. Lee, MD, MBA2,3
1 Division of Reproductive Infectious Diseases, Department of Obstetrics, Gynecology and
Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA
2 Section of Decision Sciences and Clinical Systems Modeling, University of Pittsburgh, Pittsburgh,
PA
3 Department of Epidemiology, Graduate School of Public Health and Department of Biomedical
Informatics, University of Pittsburgh, Pittsburgh, PA
Abstract
Background—The cost-effectiveness of maternal influenza immunization against laboratory-
confirmed influenza has never been studied. The current 2009 H1N1 influenza pandemic provides
a timely opportunity to perform such analyses. The study objective was to evaluate the cost-
effectiveness of maternal influenza vaccination using both single and two-dosing strategies against
laboratory-confirmed influenza secondary to both seasonal epidemics and pandemic influenza
outbreaks.
Methods—A cost-effectiveness decision analytic model construct using epidemic and pandemic
influenza characteristics from both the societal and third-party payor perspectives. A comparison
was made between vaccinating all pregnant women in the United States versus not vaccinating
pregnant women. Probabilistic (Monte Carlo) sensitivity analyses were also performed. The main
outcome measures were incremental cost-effectiveness ratios (ICERs).
Results—Maternal influenza vaccination using either the single or two-dose strategy is a cost-
effective approach when influenza prevalence greater than or equal to 7.5% and influenza-attributable
mortality is greater than or equal to 1.05% (consistent with epidemic strains). As the prevalence of
influenza and/or the severity of the outbreak increases the incremental value of vaccination also
increases. At a higher prevalence of influenza (≥30%) the single-dose strategy demonstrates cost-
savings while the two-dose strategy remains highly cost-effective (ICER ≤ $6,787.77 per quality
adjusted life year).
Conclusions—Maternal influenza immunization is a highly cost-effective intervention at disease
rates and severity that correspond to both seasonal influenza epidemics and occasional pandemics.
These findings justify ongoing efforts to optimize influenza vaccination during pregnancy from an
economic perspective.
Corresponding author: Richard H. Beigi, MD, MSc., Department of Obstetrics, Gynecology & Reproductive Sciences, Magee-Womens
Hospital of the University of Pittsburgh, Medical Center, 300 Halket Street, Pittsburgh, PA 15213, P: (412) 641-5403, F: (412) 641-1133,
rbeigi@mail.magee.edu.
Disclosure: Richard Beigi has received honoraria for a CME lecture on maternal vaccination that was partially supported by Sanofi
Pasteur.
No other authors have any conflicts of interest to report.
NIH Public Access
Author Manuscript
Clin Infect Dis. Author manuscript; available in PMC 2010 June 18.
Published in final edited form as:
Clin Infect Dis. 2009 December 15; 49(12): 1784–1792. doi:10.1086/649013.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Keywords
Influenza; maternal vaccination; epidemic; pandemic; cost-effectiveness
Introduction
The ongoing 2009 pandemic of H1N1 swine-origin influenza A has heightened the world’s
attention to the inevitability of influenza pandemics [1]. Wide-scale efforts to improve the
understanding of the epidemiology of the current outbreak have been undertaken to temper the
extent of the current outbreak and mitigate future pandemics. Nonetheless, human cases with
this novel pandemic influenza strain have been confirmed in all areas of the world. The critical
role in global disease prevention of a strain-specific vaccine is recognized and a vaccine against
the current 2009 H1N1 influenza strain is now available and scheduled for use [2]. Uncertainty
remains for different patient populations over whether the anticipated vaccine program against
2009 H1N1 will consist of single or multiple successive doses. It is clear, however, that the
greatest benefits will be realized through implementation of wide-scale vaccination programs
that successfully immunize a critical mass of the population.
Pregnant women and neonates less than 6 months of age represent two unique yet interrelated
patient populations that historically have been disproportionately affected by both seasonal
and pandemic outbreaks of influenza. Significantly higher morbidity and mortality (compared
to the general population) were recorded among both neonates and pregnant women during
the twentieth century influenza pandemics [3–7]. These disproportionate rates of morbidity are
also repeatedly noted for neonates and pregnant women during seasonal influenza epidemics
[4,8–11]. In addition, emerging data also suggests that the current 2009 H1N1 influenza
pandemic strain is generating higher morbidity and mortality among pregnant women
consistent with previous pandemics [12].
The Advisory Committee on Immunization Practices (ACIP) and the American College of
Obstetricians and Gynecologists (ACOG) recommend yearly influenza vaccination for all
pregnant women during influenza season [4,13]. Despite these recommendations data from the
Centers for Disease Control and Prevention (CDC) highlight poor national rates (13%) of
maternal vaccination despite demonstrated safety of the trivalent inactivated influenza vaccine
[4,14,15]. In addition, recent data suggest that reluctance exists among pregnant women to
accept vaccination using a rapidly developed pandemic avian influenza vaccine [16]. A further
barrier to influenza prevention for neonates is their exclusion from vaccination
recommendations [4].
The cost-effectiveness of maternal seasonal single-dose influenza vaccination for the
prevention of influenza-like illness (ILI) during pregnancy has been previously demonstrated
[17]. Although well-performed, this analysis quantified prevention of ILI and did not
investigate the direct value of vaccination to prevent laboratory-confirmed influenza. Neither
protection conferred to neonates by maternal vaccination nor costs associated with likely
increases in preterm birth during influenza pandemics were included. Recent data have
confirmed the previously theoretical benefit of neonatal influenza prevention following
maternal vaccination, adding greatly to the cumulative benefits of maternal influenza
immunization [18].
The goal of the current study was to assess the cost-effectiveness of universal maternal
influenza vaccination using both a single and two-dose approach during seasonal and pandemic
influenza outbreaks. It is hypothesized that immunization of pregnant women against both
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seasonal and novel pandemic influenza strains will be cost-effective regardless of number of
doses administered.
Methods
Model Structure
Using TreeAge Pro Suite 2008 (TreeAge Software, Williamstown, MA), a stochastic decision
analytic computer simulation model was constructed to simulate the decision of maternal
immunization for an influenza epidemic and/or pandemic. The model evaluated outcomes for
both mothers and neonates. Figures 1a and 1b show the overall structure of the model. The
model was run from both the third-party payor and societal perspectives, as well as with single
and two-dose approaches. The two-dose approach was included to simulate potential pandemic
vaccination scenarios.
Each pregnant woman entering the model has the option of being vaccinated against influenza
(against either seasonal or pandemic strains) during an already scheduled prenatal visit. She
then has a probability of experiencing acute side effects from the vaccine, including but not
limited to injection site irritation, fever, and myalgias. Based on the predicted efficacy of the
vaccine and the predicted prevalence of influenza, each woman has a probability of developing
influenza. Women that develop influenza have a probability of home self-treatment, a clinic
visit for evaluation and management, and/or being hospitalized for more severe illness. Only
hospitalized women have a probability of death. Gestational age at time of maternal influenza
infection determines the probability of survival for the fetus if the mother dies after
hospitalization. Twenty-four weeks of gestation was chosen as the cut-point for neonatal
survival with increasing rates of survival at later gestations consistent with national data on
preterm birth [19].
Neonatal probability of influenza was modified by maternal influenza vaccination status.
Neonates whose mothers had been vaccinated while pregnant had a decreased probability of
influenza [18]. In the baseline seasonal scenario, neonatal risk of influenza was set equal to
the estimated background risk of confirmed seasonal influenza of 0.125 (range: 0.05–0.20)
[4,20]. Development of influenza infection in the neonate was independent of maternal
influenza. Neonates who developed influenza had a chance of hospitalization for severe disease
and only hospitalized neonates were at risk for death.
Data Inputs
All cost and probability variables and their respective distributions that were included are
shown in Table 1. Triangular distributions were used for all variables except the costs of
maternal and neonatal hospitalization, and cost of lost wages, which assumed gamma
distributions. For the two-dose strategy against pandemic strains, vaccine cost and probability
of side effects were doubled, while all other parameters remained consistent with the single-
dose model. All costs were in 2009 U.S. dollars. A discount rate of 3% converted past and
future costs into 2009 dollars.
Quality-adjusted life-years (QALYs), an accepted measure of disease burden, were used to
quantify the effectiveness of maternal vaccination and clinical outcomes associated with
vaccination and influenza in both mother and neonate. A QALY value of 1 was used to represent
the best possible health and was attributed to healthy newborns. A QALY value of 0 was
ascribed for death, and intermediate decrements were applied for both the natural aging process
and disease states. This model assumed that pregnant women in the model had a median age
of 27.1 years, consistent with data at the National Vital Statistics System at the Centers for
Disease Control and Prevention [28]. The QALY expectancies used for effectiveness
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calculations were 43.96 years and 72.64 years for pregnant mothers and neonates, respectively,
based on age and clinical condition-specific QALY decrements applied to projected life
expectancy estimates from the Human Mortality Database [29]. The baseline utility in QALYs
used for a 27.1 year old pregnant woman was 0.92 and 1.0 for a neonate [27,30,31].
Model assumptions were made based on previous published literature and convention for
economic analyses of influenza (4,21,32,33). Length of influenza infection (as well as side
effects from vaccination) for both mothers and neonates was 7 days (range 3–10 days). The
length of hospitalization for those admitted was 4 days. An outpatient visit for influenza
resulted in four hours of lost productivity and wages from the societal perspective. No lost
productivity and/or wages were attributed to already scheduled visits for prenatal care where
the influenza vaccine was administered. The corresponding QALYs attributed for the 7 days
of infection were: 0.5 (range: 0.38–0.63) for hospitalization, indicating that that women
hospitalized for influenza function at 50% (range: 38–63%) of their maximum expected quality
of life compared to healthy non-hospitalized women without influenza. Additional condition-
specific QALY values included 0.65 (range: 0.49–0.81) for influenza without hospitalization,
and 0.95 (range: 0.71–1.00) for the vaccine side [21,34,35].
Sensitivity Analyses
To examine the impact of altering the values of key variables probabilistic sensitivity analyses
were performed for all input parameters over the ranges noted in Table 1. Prevalence of
influenza was systematically varied from 0.001 to 0.35 to simulate a wide range of theoretical
influenza outbreaks. Maternal mortality from influenza was varied from the seasonal influenza
mortality of 0.0105 to four times this value, 0.0420, to simulate more virulent circulating strains
of influenza consistent with influenza pandemics [3–7]. Estimates of vaccine efficacy (and
ranges) were derived from values in the literature and were triangular distributions. The base
case scenario for maternal vaccine efficacy was 73% (range: 50–80%) and for neonatal efficacy
an efficacy of 63% (range: 5–85) was employed [4,18]. Vaccine efficacy also varied in both
the pregnant woman and neonate together from 25% to 50%. This variation accounted for
potential lower vaccine efficacy against novel pandemic strains given potential for less robust
immune responses.
Results
Simulation runs were conducted of 1,000 trials of 1,000 pregnant women (or 1,000,000 total
pregnant women traveling through the model) from both the societal and third-party payor
perspectives for single and two-dose strategies. All simulations used the incremental cost-
effectiveness ratio (ICER) of maternal influenza vaccination, calculated as follows:
Table 2 shows how the optimal choice of whether to vaccinate a pregnant woman for influenza
varies depending on prevalence of influenza, probability of death from influenza (severity),
and the number of doses administered. When vaccination yields cost savings as well as better
effectiveness, it “dominates” the no-vaccination option. In addition, when the ICER is ≤
$50,000/QALY (a previously established threshold) an intervention is considered cost-
effective.
Simulations run from the societal perspective with a single-dose strategy were performed first.
Table 2 lists the respective ICERs using the base-case efficacy of 73% in pregnant women and
63% in neonates and compares single to two-dose strategies. These simulations demonstrate
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that when influenza prevalence is ≥30% and the probability of death from influenza is set equal
to the expected seasonal influenza mortality, or the prevalence of influenza is ≥25%, and
mortality is 2, 3 and 4 times the seasonal rate, vaccination is the dominant strategy. Single-
dose maternal immunization was also found to be cost-effective when influenza prevalence
was as low as ≥5% and the probability of death from influenza is set equal to the expected
seasonal influenza mortality (or higher), or the prevalence of influenza is ≥2.5% and mortality
is 2, 3 and 4 times the seasonal mortality rate. Simulations run from the third-party payor
perspective (data not shown) likewise demonstrate that single-dose vaccination is the dominant
strategy when influenza prevalence is ≥30% and the probability of death from influenza is set
equal to the expected seasonal influenza mortality, or higher. Single-dose vaccination remains
cost-effective when the prevalence of influenza is ≥2.5% and the probability of influenza-
attributable mortality is greater than or equal to the expected seasonal rate.
Simulations using the two-dose strategy from societal perspective were subsequently
performed using the same efficacy above (Table 2). A two-dose strategy also demonstrated
cost-effectiveness when influenza prevalence is ≥7.5% and the probability of death from
influenza is set equal to the expected seasonal influenza mortality and 2 times this rate, and
when the prevalence of influenza is ≥5% and influenza-attributable mortality is 3 or 4 times
the expected seasonal rate. Compared to the single-dose approach, cost-effectiveness at
baseline vaccine efficacy is realized for the two-dose approach at a slightly higher prevalence
of influenza (≥5% for 2-dose vs. ≥2.5% for 1-dose). This is noted for all levels of vaccine
efficacy and mortality. A two-dose strategy, however, never dominates the no-vaccination
approach.
Sensitivity analyses testing lower vaccine efficacies (25% and 50% for both maternal and
neonatal efficacy) were performed from the societal perspective using both the single and two-
dose strategies At the lowest presumed vaccine efficacy of 25%, vaccination remained cost-
effective at influenza prevalence levels ≥ 7.5% for single-dose immunization at all levels of
influenza-attributable mortality. Cost-effectiveness was realized for a two-dose immunization
strategy when the prevalence of influenza is ≥ 12.5% (expected seasonal value) and the
probability of mortality due to influenza is equal to expected seasonal influenza mortality, or
when influenza prevalence is ≥ 10% and the probability of influenza-attributable mortality is
2, 3, or 4 times the expected seasonal mortality rate.
Increasing the vaccine efficacy to 50% demonstrates that a single-dose vaccination strategy is
cost-effective when influenza prevalence is ≥ 5% and the probability of death from influenza
is set equal to the expected seasonal influenza mortality, or higher. Cost-effectiveness is also
realized for a two-dose approach when the prevalence of influenza is ≥ 10% and the influenza-
attributable mortality rate is equal to the expected seasonal rate or twice that, or when
prevalence of influenza is ≥ 7.5% and the probability of death from influenza is 3 or 4 times
the expected seasonal mortality rate.
Figure 2(a–c) highlights the findings of a single-dose approach, comparing different vaccine
efficacies and influenza prevalence, in addition to increasing levels of mortality (severity of
infection). The two key factors noted to impact cost-effectiveness of both dosing strategies to
the greatest extent are influenza prevalence and severity of illness.
Figure 3 shows the acceptability curves for different influenza prevalence levels when vaccine
efficacy is 73% in the mother and 63% in the neonate and the probability of death from
influenza is 1.05%. These curves demonstrate that when influenza prevalence is 12.5% and
the maximum willingness-to-pay is $50,000, vaccinating pregnant women for influenza is cost-
effective approximately 90% of the time. As the prevalence of influenza increases, the same
probability of maternal vaccination yielding cost-effectiveness is achieved at lower
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willingness-to-pay thresholds (approximately $30,000 at 15% prevalence, $20,000 at 20%, and
$15,000 at 25%).
Discussion
These results demonstrate the clear cost-effectiveness of maternal influenza vaccination at
disease prevalence rates consistent with both seasonal influenza epidemics and the occasional
influenza pandemic. This comes during an active influenza pandemic when novel vaccine and
mass-vaccination protocols are under development and implementation. Importantly, the
results of this study remain robust regardless of whether a single or two-dose strategy is
adopted. The cost-effectiveness of maternal vaccination also becomes increasingly more
pronounced as the clinical severity and prevalence of influenza increase in the population,
which is characteristic of influenza pandemics such as 2009 H1N1. It is also important to
highlight that even with more mild outbreaks typical of a seasonal influenza (lower prevalence
and/or severity of infection), cost-effectiveness of maternal vaccination remains.
While this investigation is timely for 2009 H1N1, it is acknowledged that vaccine acceptance
is a key component related to the effectiveness of large immunization programs and maternal
seasonal influenza immunization efforts suffer from poor acceptance [14]. Moreover, the
recently reported reticence among the obstetric community to accept a rapidly developed
pandemic influenza vaccine may pose challenges among this vulnerable population [16].
Strong support for maternal immunization exists when one considers the combination of
demonstrated safety in pregnancy, ethical obligations for protecting vulnerable populations,
and the favorable economics delineated herein. Although vaccine acceptance has many
influential factors, it is hoped that these data strengthen ongoing efforts and improve acceptance
overall, particularly against 2009 H1N1.
Previous investigators have demonstrated the cost-effectiveness of seasonal maternal influenza
vaccine for the prevention of ILI [17]. The most important difference is that the model presented
herein directly assesses the cost-effectiveness of maternal influenza vaccination against rates
of laboratory-confirmed cases, not self-reported influenza-like illness. This is a noteworthy
difference because the point estimates and prevalence ranges used for ILI represent much
higher estimations of influenza-attributable outcomes than those used in the current
investigation. Thus, an overestimation of the true level of potential influenza-specific disease
prevention is possible when considering ILI. The current model includes conferral of protection
from vaccinated mother to fetus, and also acknowledges increased rates of preterm birth and
the associated economic burden that have been demonstrated in previous influenza pandemics
[5,7,8,18,19}. Another important distinction is that the current model simulates both single-
dose and two-dose mass vaccination approaches. The current model thus strives to provide
wider-ranging influenza scenarios and produce economic projections that approximate the
fluctuating characteristics of influenza disease more directly.
Analysis of the cost-effectiveness of influenza immunization for seasonal outbreaks among
healthy adult populations has yielded mixed results. Nichol et al. demonstrated many
significant clinical benefits of vaccination that translated into an approximate cost-savings of
$46.85 per person vaccinated [36]. A subsequent investigation failed to show robust yearly
cost savings [37]. These authors attributed their non-robust yearly findings to fluctuations
between vaccine and seasonal strain compatibility. The higher rates of untoward influenza-
associated outcomes noted among pregnant women and neonates plus the additional
measurable neonatal protection from maternal vaccination provides a basis for the robust nature
of our findings [3–7,9–11,18].
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Vaccine safety is always an important consideration when contemplating widespread use. The
safety profile used for the current investigation was modeled with the same high level of safety
noted in pregnancy using the seasonal trivalent inactivated influenza vaccine given identical
manufacturing technology (4,15). It is acknowledged that safety of future vaccines are never
known until widespread use. Thus, any arising safety concerns noted with a pandemic influenza
vaccine could impact these results in an economically disadvantageous manner. Likewise, the
decision not to include Guillain-Barré Syndrome (GBS) as a side-effect of influenza
vaccination may have underestimated the overall costs associated with vaccination. The
decision to omit GBS as a clinical outcome was made given the paucity of data clearly linking
GBS and current influenza vaccination and the fact that most cases of Guillain-Barré appear
to come from natural infections, including influenza. Thus, GBS could also occur in increased
frequency (thus generating costs) if the vaccine was not administered [38,39].
It is also important to consider that all computer simulation models are simplifications of real
life and cannot represent every possible event that may result from influenza infection or
vaccination. For example, mass vaccination “clinics” (and any associated costs) were not
factored into this model given regional variability in immunization methods. The data inputs
for this model also come from studies of varying quality, and computer models are subject to
their respective assumptions. However, frequently referenced sources were used and thus
represent the current best approximations of these values.
Nonetheless, clear cost-effectiveness against influenza prevalence rates noted during yearly
epidemics and during pandemic outbreaks is demonstrated. Maternal immunization becomes
increasingly cost-effective (generating actual cost-savings) as the prevalence and/or severity
of influenza increases. These findings economically justify ongoing efforts to maximize
maternal influenza immunization under all disease scenarios.
Acknowledgments
Work partially supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences
(NIGMS) Models of Infectious Disease Agent Study (MIDAS) research network.
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Figure 1.
A General model structure B Maternal and neonatal influenza subtrees.
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Figure 2.
Incremental cost - effectiveness ratio (ICERs) for vaccinating pregnant women for influenza
at different vaccine efficacies and influenza prevalence (single vaccine dose). Probabilities of
mortality were 1.05%, 2.10%, and 4.20% for panels A–C, respectively. *12.5% is the most
likely value from the Centers for Disease Control and Prevention annual influenza prevalence
estimate. QALY, quality - adjusted life year.
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Figure 3.
Acceptability curves at different influenza prevalence levels for base case vaccine efficacy and
influenza - attributable mortality from a societal perspective (single vaccine dose). *12.5% is
the most likely value from the Centers for Disease Control and Prevention annual influenza
prevalence estimate. Base case vaccine efficacy, 73% for mothers and 63% for neonates; base
case influenza - attributable mortality, 1.05%.
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Table 1
Cost and Probability Inputs
Description Value Reference(s)
Cost, US$
Death
Mother 5000.00 [21]
Neonate 5000.00 [21]
Home treatment of influenza
Mother 15.61 (11.70–19.51) [22]
Neonate 15.61 (11.70–19.51) [22]
Home treatment of vaccine - related adverse effects 0.76 (0.68–3.82) [22]
Hospitalization for influenza
Mother 3526 ± 302.10 [23]
Neonate 2323.84 ± 262.38 [23]
Influenza vaccine, per dose 15.00 (10.00–20.00) [22]
Preterm birth
Third - party payor perspective 37,366.89 [19]
Societal perspective 58,076.25 [19]
Productivity loss for outpatient visit for illnessa64.08 ± 5.04 [24]
Probabilities
Death due to influenza
Hospitalized mother 0.0105 [20]
Neonate 0.0000088 (0.0000052–0.0000139) [4,25]
Preterm neonate 0.02 (0.0088–0.151) [4]
Hospitalization
Mother 0.004 (0.001–0.007) [20]
Neonate 0.0048 (0.0024–0.0072) [20]
Influenza
Mother 0.125 (0.05–0.20) [20]
Neonate 0.125 (0.05–0.20) [20]
Preterm birth 0.12 ± 0.1 [19,26]
Adverse effects of vaccination, per dose 0.05 [27]
Vaccine efficacy
Mother 0.73 (0.50–0.80) [20]
Neonate 0.63 (0.05–0.85) [18]
NOTE. Data are mean ± standard deviation or mean (95% confidence interval).
aOnly applied for societal perspective simulations; assumes 4 h of lost wages.
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Table 2
Incremental Cost - Effectiveness Ratios (ICERs) for Single - and 2 - Dose Maternal Influenza Vaccination using 73% and 63% Efficacy for Mothers and
Neonates, Respectively (Societal Perspective)
Prevalence of influenza
Probability of death (severity of influenza strain)a
Single - dose option Two - dose option
0.0105 0.021 (2×) 0.0315 (3×) 0.042 (4×) 0.0105 0.021 (2×) 0.0315 (3×) 0.042 (4×)
0.025 76,835.47 35,049.72 31,080.77 30,929.89 138,012.76 101,747.98 236,745.07 122,145.75
0.05 26,307.67 30,903.57 30,591.51 14,708.87 71,032.61 77,562.47 47,330.25 43,318.68
0.1 9165.78 11,506.89 7061.17 9933.36 27,079.08 31,931.70 22,240.58 21,130.45
0.125b7718.32 6543.38 6090.59 4350.15 19,527.97 26,221.96 17,400.19 10,148.43
0.15 5019.41 4059.41 3721.89 3634.95 18,068.06 15,808.83 14,158.94 8899.62
0.25 603.42 Vaccinate Vaccinate Vaccinate 9284.22 6490.86 5394.14 4581.31
0.3 Vaccinate Vaccinate Vaccinate Vaccinate 6787.77 4223.76 3057.21 2597.23
0.35 Vaccinate Vaccinate Vaccinate Vaccinate 4499.38 2387.32 2516.00 1657.27
NOTE. Data are ICERs in US$ per quality - adjusted life year. Boldface font indicates scenarios that were cost - effective (ICER, ≤ $50,000 per quality - adjusted life year). Underlined entries in boldface font
are scenarios in which vaccination was the dominant strategy (ie, maternal vaccination was less costly and more effective than no maternal vaccination).
aRepresents base case probability of maternal death from influenza strain among hospitalized women.
bRepresents base case influenza prevalence
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