Influenza is a common and highly contagious respiratory illness. In the U.S., influenza epidemics occur every year, resulting in approximately 25,000 deaths and 226,000 hospitalizations annually.1,2 Hospitalization of infants younger than 6 months of age for influenza occurs at rates greater than for other high-risk groups,3,4 and mortality attributable to this infection remains an important problem.5
The Advisory Committee on Immunization Practices recommends universal influenza vaccination for all persons 6 months of age or older.3 Infants younger than 6 months of age, therefore, are unprotected against infection through primary immunization. Immunization of pregnant women during influenza season is recommended to protect newborns by conferring transplacentally transferred maternal antibodies to them.6,7 From 1995 to 2008, influenza vaccine coverage rates during pregnancy had been less than 25%,8 and national recommendations also encouraged vaccinating women in the postpartum period if they had not received the vaccine that influenza season. From 2010 to 2011, influenza vaccine coverage rates during pregnancy were 45%.9
Influenza vaccination of preschool children has been shown to be cost-saving.10 To our knowledge, only one study has evaluated the economic effect of vaccinating pregnant women on disease prevention in the newborn, but this study also considered infection in the neonate as independent of maternal influenza.11 A recent case-control study documented a clinical benefit of prepartum or peripartum influenza vaccination in the prevention of influenza-associated hospitalization in infants younger than 6 months of age.12 No economic data have been reported to assess the cost benefit of a national postpartum vaccination strategy. We performed this study to estimate the economic burden associated with this strategy.
MATERIALS AND METHODS
To retrieve the related literature published during 1996–2011, we searched the MEDLINE database with the following key words: influenza vaccine and cost-effectiveness analysis; household transmission of influenza to infants; or direct and indirect costs of influenza. References from these publications were also retrieved, as appropriate. We used probabilities and costs derived from our review of published literature, Centers for Disease Control and Prevention (CDC) data, and expert panel recommendations. The study was exempt from institutional review board review because it relied only on publicly available secondary literature sources.
A decision analysis model was constructed to calculate the costs, benefits, and potential cost benefit of a postpartum influenza vaccination strategy during the immediate postpartum period before hospital discharge. Decision tree modeling was used in this study because it is best suited for acute care episodes (eg, seasonal influenza in general is an acute illness with a convalescent period lasting approximately 5–15 days) compared with other types of pharmacoeconomic models (eg, Markov models or discrete event simulation models).13 The provisional number of live births in the United States for June 2009–June 2010 was approximately four million.14 In this study, we only included postpartum women who had not received influenza vaccine before delivery in the influenza season, and these postpartum women would be vaccinated in the immediate postpartum period. We assumed the national rate for predelivery vaccine (ie, vaccine coverage rate in the pregnant population) to be as high as 44.8%.15 National surveillance data indicate that influenza virus activity usually begins in September, peaks in January or February, and continues to April.16 We assumed no influenza vaccine supply availability from May 1 to August 30,3,17 and thus the benefit of postpartum vaccination was not applied for women who delivered during this time period. Therefore, a cohort of 1.47 million (ie, 4 million multiplied by 55% multiplied by two-thirds) healthy postpartum mothers in the United States were included in the model assuming an influenza season beginning September 1 and ending April 30. We used the cost of trivalent injectable inactivated vaccine in this study as a conservative cost estimate, because this vaccine is more widely stocked in hospitals.3 Figure 1A depicts the overall structure of the model for a postpartum influenza vaccination strategy, and Figure 1B shows the maternal influenza subtree. In this decision tree model, there were two major arms: vaccine arm (birth mothers were vaccinated with trivalent injectable inactivated vaccine) and no vaccine arm (birth mothers received no vaccine). It was modeled that no infant younger than 6 months of age would receive the influenza vaccine, as per current national recommendations.3 Each pathway in the model was defined by probabilities an event would occur and the costs of clinical outcomes. We included four possible outcomes after the influenza virus infection in both birth mothers and infants: 1) symptomatic or asymptomatic influenza but not medically attended regardless, 2) outpatient visit only, 3) hospitalization, and 4) death.
The base-case analysis was conducted from a societal perspective, which included all estimated direct and indirect costs. We also analyzed the potential cost benefit of postpartum vaccination including direct medical costs only, which is particularly relevant for the third-party payer's perspective. The time frame was 1 year. Modeling was performed using Microsoft Excel 2007. All costs and benefits were discounted at a 3% annual discount rate. Results were reported in 2010 U.S. dollars.
As noted in Figure 1A, vaccination of a birth mother will result in a limited number of potential outcomes related to protection against clinical influenza and the potential for adverse events associated with vaccination. Only those mothers who receive vaccine may experience a vaccine-related adverse event, including local or systemic reactions, anaphylaxis, and Guillain-Barré syndrome. The probabilities of experiencing such an event are derived from the published literature.18 – 20 Local reactions, which most commonly include soreness at the vaccination site lasting 2–3 days, are rarely medically attended.3 Systemic reactions most commonly include fever, headache, or myalgias. Overt anaphylaxis is rare and may manifest as respiratory difficulty, urticaria, vomiting, hypotension, decreased consciousness, or shock.3,18 Last, influenza vaccine has been previously reported to be associated with subsequent development of Guillain-Barré syndrome at a rate of approximately one additional case of Guillain-Barré syndrome per 1 million vaccines in some years.19
Each birth mother has a definable probability of development of clinical influenza, which will be lessened with receipt of vaccine. These probabilities were generated using national and regional data of disease incidence and vaccine efficacy, over several years, for adults 18–49 years of age.20 – 23 Mothers infected with influenza had a chance of hospitalization for severe disease, and we assumed only hospitalized mothers were at risk for death.20 The probability of cases not medically attended was calculated to be equal to the influenza attack rate minus the sum of the probabilities of influenza-associated outpatient visits only and hospitalizations.21
We assumed that the probability of development of influenza in newborns was, in part, dependent on the infectious status of the mother and others in the household. Previous work has shown that the infection rate among household contacts of an index case increases significantly with the number of older siblings, and the attack rate of respiratory illness among unvaccinated household contacts (aged 0–4 years of age) of children attending day care is approximately 50–69%.24,25 Thus, the probability of a newborn having development of influenza when exposed to an infected mother was estimated by multiplying the probability of maternal influenza by the attack rate in infants with maternal influenza. In this study, we assumed the base-case attack rate in infants with maternal influenza to be 59% (the midpoint of a range of 50–69%).3,24,25 The probability of development of influenza in infants born to mothers without disease was estimated by multiplying the disease probability in infants by the probability of no maternal influenza (1−probability of maternal influenza). In this pathway, the disease probability in infants is equal to the reported annual attack rate of influenza for infants.21 Rates of outpatient visits and hospitalizations attributable to influenza were based on average excess seasonal rates of outpatient visits and hospitalizations using CDC influenza surveillance data and other data from the published literature.1 – 4,17 The probability of cases not medically attended was calculated to be equal to the influenza attack rate minus the sum of the probabilities of influenza-associated outpatient visits only and hospitalizations.21 The mortality rate for infants was obtained from two previous studies.5,11 All the base-case probability inputs and their ranges for sensitivity analysis are listed in Table 1.
Direct and indirect costs for both mothers and infants are noted in Table 2. All costs in the model were adjusted for inflation to 2010 U.S. dollars using the medical care services component of the consumer price index when necessary.
Direct costs included vaccine acquisition and administration costs, vaccine-associated adverse events costs, and expenses to treat complications of clinical influenza for both mothers and infants.20,21 Vaccine costs for birth mothers were based on the CDC vaccine price list for trivalent injectable inactivated vaccine.26 The costs of adverse events with influenza vaccine were derived from a recently published economic study.20 We estimated over-the-counter medication costs using weighted mean values from published clinical trial data22,27 and used over-the-counter drug costs as the direct costs to treat cases that were not medically attended. For each outpatient case, direct medical costs included pharmaceutical claims and outpatient claims. Outpatient claims were the sum of office visits, laboratory tests, consult fees, outpatient procedures, and prescription medications.20,21 We estimated direct medical expenses of each inpatient case, including pharmaceutical, outpatient, and hospitalization costs, from published economic studies.20 – 23 In this analysis, we assumed all adults or infants who died received some treatments before death. The direct medical costs for a death included all pharmaceutical claims, outpatient, and inpatient costs based on a CDC study in which the authors estimated such costs using Medstat Marketscan health insurance claims database capturing cases from 2000 to 2004 four influenza seasons.21
Indirect costs included the unpaid opportunity costs from the mothers' or caregivers' time loss (working time and personal time) attributable to their own illnesses or their infants' diseases and the indirect societal costs of death. For influenza in infants, indirect costs sustained by caregivers were calculated by using estimates of 2 hours per office visit (including travel and waiting) and 8 hours per day for hospitalizations based on length of hospital stay published in the literature.2,21,28 For birth mothers, indirect costs were estimated to include costs of time lost from work and personal activity time lost because of adults' own influenza.3,20 – 22,27 The average compensation per hour was $29.71 in 2010, as reported by the U.S. Bureau of Labor Statistics.29 The indirect societal cost per death was based on value of statistical life estimates, which included the value of lost productivity value and the social value placed on human life.21 We assumed no additional indirect costs incurred for administration of vaccine to birth mothers, because the vaccine would likely be administered during the immediate postpartum period in the hospital, not during a separately scheduled medical visit.
From the societal perspective, the average cost in the vaccine administration and no vaccine arms were estimated at $328.45 and $341.02 per mother, respectively. Each term includes annual expected costs associated with the mother and her infants. For example, the expected cost per unvaccinated mother was calculated by summation of (probability of each potential outcome associated with maternal or infantile influenza multiplied by its cost, respectively). In the base case, our analysis suggests an expected net societal benefit of $12.57 per postpartum vaccinated mother compared with no vaccination. In our hypothetical cohort of 1.47 million birth mothers in the United States, the overall expected net benefit was calculated by the following equation: overall expected net societal benefit in the cohort=($12.57)×(1.47 million)×(vaccination coverage rate). Here, we assumed the coverage rate for postpartum influenza vaccination to vary from 20% to 80% (Yeh SH, et al. Effectiveness of hospital-based procedures on postpartum vaccination with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis and seasonal influenza. 49th Annual Meeting of the Infectious Diseases Society of America, October 20–23, 2011), and then the overall annual expected net societal benefit in the cohort of U.S. birth mothers was estimated to be $3.69 to $14.75 million.
From the third-party payer perspective (direct medical costs only), the average costs in vaccine and control arms were predicted to be $197.6 and $183.9 per birth mother, respectively. The expected net societal benefit value of −$13.70 per vaccinated mother indicates that postpartum vaccination would not generate net savings in this case compared with no vaccination.
From year to year, the circulating influenza virus strains may change, which usually significantly alters the disease incidence, clinical morbidity, vaccine efficacy, or other variables we have included in our model. As such, we performed one-way sensitivity analyses on selected variables. Ranges were selected based on the high and low values from previously reported studies. A tornado diagram in Figure 2 shows the effect of varying model estimates on expected net societal benefit per vaccinated mother from a societal perspective. The variables that elicit the greatest effect on the model are the annual attack rate in birth mothers and vaccine efficacy, both of which affect the direct and indirect costs. For example, a 70% decrease in attack rate among mothers (adults) results in a 120% decrease in expected net societal benefit per mother. If vaccine virus does not match the circulating strain, then vaccine efficacy may in fact approach zero; our base case assumes a match between the vaccine strain and the strain that circulates in any given year, resulting in vaccine efficacy of 50–86%.4 For example, a change from the base case of 73% efficacy to 50% efficacy nearly eliminates the expected net benefit from $12.6 to $1.7 per mother. The third variable that exhibits significant effect on the model is vaccine acquisition and administration cost per dose, which affects the direct costs only. Other parameters, such as mortality rate, nonmedical costs of cases that are not medically attended, indirect societal cost per death, and incidence of influenza-associated hospitalization among birth mothers also influence the expected net societal benefit per vaccine (Fig. 2). Percent change in outcome (expected net societal benefit per mother) divided by percent change in each key parameter, representing elasticity, are reported in Table 1 in the Appendix (available online at http://links.lww.com/AOG/A277). Similarly, one-way sensitivity analyses on key variables also were performed from a third-party payer perspective with a tornado diagram showing in Figure 1 in the Appendix (http://links.lww.com/AOG/A277).
Because the timing, severity, and length of the influenza epidemic can vary substantially from season to season, the attack rate in birth mothers could range higher than 10% in some years when influenza viruses mismatch the vaccine strain. Two-way sensitivity analyses were performed using 2–20% attack rates in birth mothers and 50% compared with 80% efficacies for influenza vaccine, with other parameters remaining unchanged in the base-case values. The results are presented in Table 3. From the societal perspective in which all direct and indirect costs were included, assuming 50% vaccine efficacy, the resulting expected net societal benefit per vaccinated mother ranged from −$8.7 to $31.6 and the attack rate ranged from 2% to 20%. If we assumed 80% vaccine efficacy, then the resulting expected net societal benefit per vaccinated mother ranged from −$0.6 to $63.9 and the attack rate ranged from 2% to 20%. From the third-party perspective, the trends were similar but most of the expected net societal benefits per mother were negative values, indicating that the average cost per vaccinated mother exceeded the average cost per unvaccinated mother.
We performed threshold sensitivity analyses from the societal perspective (using expected net societal benefit per vaccinated mother=$0) to determine the break-even point for the variables noted to most influence the results in our one-way sensitivity analysis (annual attack rate in birth mothers, vaccine efficacy, and vaccine acquisition and administration cost per dose). Our results suggest that this strategy would be cost-saving (expected net societal benefit more than $0 per mother), holding all other variables to the base case, if the annual attack rate among birth mothers exceeds 2.8%, influenza vaccine efficacy is more than 47%, and vaccination acquisition and administration costs per dose are less than $32.78.
This study evaluates the cost benefit of a hospital-based postpartum influenza vaccination strategy. Our model included data-driven vaccine coverage estimates, and the concept that influenza virus infection in newborns is at least partially dependent on the infectious status of their mothers. The results suggest that from a societal perspective, immediate postpartum (or postpartum vaccination before discharge) of birth mothers is likely to be cost-beneficial if key parameters are within reasonable ranges, which in a typical influenza year is highly likely. When compared with no influenza vaccination, our base-case data suggest an expected net societal benefit of $12.57 per vaccinated mother from the societal perspective and an expected net societal benefit of −$13.70 from the third-party perspective. Others have shown the potential for clinical benefit of this vaccination strategy,12 and current CDC recommendations endorse vaccination in the postpartum period if the preferred strategy of vaccination during pregnancy was not followed.3 We believe our analysis provides a useful and timely economic assessment for its implementation as well.
Previous work indicated cost-effectiveness of influenza vaccination in pregnant women,7,11 when rates of influenza vaccine coverage were low (approximately 25%).8 A CDC survey completed in November 2010 found that mid-season influenza vaccination coverage among pregnant women was 44.8%.15 Although recent CDC data revealed a sustained coverage rate of 44% in pregnancy for the 2010–2011 influenza season, studies have shown that provider recommendation, public awareness, the intensity of the annual epidemic, and concerns about vaccine safety are strong predictors of vaccination in other adult populations.29,30 When predelivery vaccine rates vary from 25% to 45%, a range of 1.47 to 2.0 million healthy postpartum women would be eligible for the postpartum strategy. This would realize an overall annual societal cost savings of $3.69 to $20.11 million, depending on the influenza vaccine coverage rates in pregnant and postpartum populations.
The postpartum period provides an opportunity for targeted vaccination that can be easily incorporated into postpartum routine care. This avoids the indirect costs associated with waiting and transportation time incurred for a separate health care visit.8 Previous work indicated that the average recipient time lost to receive influenza vaccine in the doctor's office setting was 1.24 hours.20,22 In our model, adding this cost reveals vaccination to be cost-incurring, with an expected net societal benefit of −$24.3 per vaccinated mother, using an average compensation of $29.71 per hour in 2010.29
The biggest driver of our model from the societal perspective was the annual attack rate of influenza in birth mothers. In the base case, we derived the annual attack rate of influenza of 6.6% among adults from published randomized controlled trial data,22 with a range of 2–10% in the one-way sensitivity analyses from CDC-reported data.3,21 However, circulating influenza virus strains may change from year to year, as do attack rates and clinical morbidity. We therefore evaluated a wider range for the attack rate (2–20%) in two-way sensitivity analyses and performed threshold sensitivity analyses. We found that the postpartum influenza vaccination strategy would generate net savings, with an expected net societal benefit more than $0 per vaccine, if the annual attack rate among birth mothers exceeds 2.8% with other parameters remaining unchanged in the base-case scenario.
We acknowledge that we lack precision with some of the point estimates in our model. For example, few data exist for estimating maternal disease incidence and disease complications in the months after a child's birth; we used available data from the general population for women of childbearing age. We may have underestimated the potential cost savings if postpartum women are more susceptible to influenza or serious influenza-associated complications than we assumed.6 In addition, viral virulence and the duration of the annual epidemics can vary substantially from year to year. We therefore used combined data over several years and assigned broad ranges for the key parameters, such as disease attack rate and vaccine efficacy in the sensitivity analyses. Except for the annual attack rate in birth mothers, no reasonable variation in these parameters decreased the expected net societal benefit per vaccine less than $0 in one-way sensitivity analyses (Fig. 2). Future work may further clarify these issues, but our model was robust to wide ranges of parameter values in the sensitivity analyses.
The primary approach for prevention of influenza disease in young infants currently is maternal vaccination during pregnancy. Our analysis of a national in-hospital postpartum influenza vaccination strategy, however, indicates cost benefit, which we believe could be helpful to decision-makers and may encourage use of influenza vaccine in the postpartum period to complement current prepartum vaccination efforts.
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