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Hospital length of stay and cost burden of HIV, tuberculosis, and HIV-tuberculosis coinfection among pregnant women in the United States
ARTICLE IN PRESS American Journal of Infection Control ■■ (2017) ■■-■■
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American Journal of Infection Control
American Journal of Infection Control
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Major Article
Hospital length of stay and cost burden of HIV, tuberculosis, and HIVtuberculosis coinfection among pregnant women in the United States Adeola Falana a, Vanessa Akpojiyovwi a, Esther Sey a, Andika Akpaffiong a, Olive Agumbah a, Samara Chienye a, Jamie Banks a, Erin Jones a, Kiara K. Spooner DrPH, MPH b, Jason L. Salemi PhD, MPH b, Omonike A. Olaleye PhD a, Sherri D. Onyiego MD, PhD b, Hamisu M. Salihu MD, PhD b,* a b
Texas Southern University, Houston, TX Department of Family & Community Medicine, Baylor College of Medicine, Houston, TX
Key Words: HIV-TB coinfection pregnancy length of stay (LOS) cost burden
Background: We sought to determine hospital length of stay (LOS) and cost burden associated with hospital admissions among pregnant women with HIV monoinfection, tuberculosis (TB) monoinfection, or HIV-TB coinfection in the United States. Methods: Analysis covered the period from 2002-2014 using data from the Nationwide Inpatient Sample. Relevant ICD-9-CM codes were used to determine HIV and TB status. Costs associated with hospitalization were calculated and adjusted to 2010 dollars using the medical care component of the Consumer Price Index. Results: We found modest annual average reduction in HIV, TB, and HIV-TB coinfection rates over the study period. The mean LOS was lowest among mothers free of HIV or TB disease and highest among those with HIV-TB coinfection. The average LOS among mothers diagnosed with TB monoinfection was 60% higher than for those with HIV monoinfection. The cost associated with pregnancy-related hospital admissions among mothers with HIV was approximately 30% higher than disease-free mothers, and the cost more than doubled among patients with TB monoinfection or HIV-TB coinfection. Conclusions: TB significantly increased hospital care cost among HIV-positive and HIV-negative pregnant women. © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
HIV and tuberculosis (TB) represent major public health problems and continue to be accountable for reduced quality and quantity of life globally.1 The 2 conditions are not uncommon and affect millions of people worldwide annually to the extent that the World Health Organization considers the 2 diseases as pandemic.2,3 An estimated 2 billion people—one-third of the global population—are infected with TB, and each year, 8.7 million people develop TB
* Address correspondence to Hamisu M. Salihu, MD, PhD, Department of Family and Community Medicine, Baylor College of Medicine, 3701 Kirby Dr, Ste 600, Houston, TX 77098. E-mail address: [email protected] (H.M. Salihu). Funding/support: Research funding support was provided by the U.S. Department of Health and Human Services, Health Resources and Services Administration for the Maternal and Child Health Pipeline Training Program: TSU-BCM Maternal and Child Health Student Training for Academic Readiness and Success (MCH STARS) Undergraduate Fellowship Program, Grant No:T16MC29831. Conflicts of interest: None to report.
disease. TB kills >1.4 million people each year and is economically devastating to families and communities worldwide.4 A number of factors are responsible for the transmission and spread of TB in the United States, including increases in the inflow of foreign-born individuals, overcrowded living conditions, the rise in TB drug resistance, health inequities such as lack of access to medical care or suboptimal quality of care, and the effects of poverty.5 TB is one of the top killers of women and is responsible for 500,000 of their deaths each year, emerging as the leading cause of death in HIV-positive individuals.4,6 As a result of the sustained public health efforts toward TB elimination over the previous 2 decades, the incidence of TB has decreased progressively and currently stands at approximately 3.0 cases per 100,000 in the general U.S. population.7 However, a recent study of TB among U.S. pregnant mothers tends to suggest an increase in TB rates associated with elevated levels of pregnancy complications.8 With increasing concerns regarding the possible rise of TB during pregnancy, especially among HIV women,8 it is unclear how this could impact the health
0196-6553/© 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajic.2017.09.016
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care costs related to the 2 conditions during pregnancy. To fill this gap, we conducted this population-based study to determine hospital length of stay (LOS) and hospitalization costs among pregnant women infected with HIV monoinfection, TB monoinfection, and HIV-TB coinfection in the United States. MATERIALS AND METHODS The analysis covered the period from January 1, 2002-December 31, 2014, using data from the Nationwide Inpatient Sample (NIS). The NIS, made available by the Healthcare Cost and Utilization Project (HCUP), currently constitutes the largest all-payer, publicly available inpatient database in the United States.9 Each year, the NIS stratifies all nonfederal community hospitals from participating states into groups according to 5 characteristics: geographic region of the United States, urban or rural location, teaching status, number of beds, and type of ownership. Within each unique stratum, a 20% sample of hospitals is drawn using a systematic random sampling approach designed to ensure the sample’s geographic representativeness.9 For each sampled hospital, all inpatient hospitalization records are included in the NIS, and the HCUP provides discharge-level sampling weights so that national frequency and prevalence estimates take into account this 2-stage cluster sampling design. The NIS contains approximately 7 million inpatient hospitalizations each year (36 million when weighted), and has grown from 22 participating states in 1998 to 44 states in 2014. Through 2011, pregnant women that delivered in selected hospitals in the United States were included based on a 2-stage cluster sampling design. Beginning in 2012, the NIS sampling strategy was changed from keeping all hospitalizations from a sample of hospitals (2 stage) to drawing a sample of hospitalizations from all hospitals (1 stage). To assess the study’s primary exposures, we scanned ICD-9-CM codes (the principal diagnosis and up to 24 secondary diagnoses) in each woman’s discharge record for an indication of HIV and TB status. HIV-affected pregnancies were those with 042, 079.53, or V08. Pregnancies affected by active TB were defined as those with 010-018.x (TB), 137.x (sequelae of TB), or 647.3 (TB complicating pregnancy or childbirth). Latent TB—defined as a documentation of V12.01 (personal history of TB) without an active TB code—was not included in this study because of the absence of symptoms that may impact pregnancy and the substantially lower rates of adverse pregnancy outcomes, LOS, and cost relative to active TB.10 Individual-level sociodemographic and behavioral characteristics were also extracted from the NIS databases. Maternal age in years was classified into 3 categories: 13-24, 25-34, and 35-49. Selfreported maternal race and ethnicity was first based on ethnicity (Hispanic or non-Hispanic), and the non-Hispanic group was further subdivided by race (white, black, or other). Median household income, which served as a proxy for socioeconomic status, was estimated using the patient’s postal code and subsequently grouped into quartiles. We classified the primary payer for hospital admission into 3 categories: government (Medicare or Medicaid), private (commercial carriers, private health maintenance organization, and preferred provider organization), and other sources (eg, self-pay, charity). Because of their strong associations with HIV infection, we also used ICD-9-CM codes to ascertain information on alcohol and drug use during pregnancy. Our definition of alcohol abuse included indications of alcohol-induced mental disorders (291.0–9), alcohol dependence syndrome (303.00–93), nondependent alcohol abuse such as binge drinking (305.00–03), alcoholic cardiomyopathy (425.5), and alcohol that has affected the fetus or newborn via the placenta or breast milk (760.71). Drug abuse included druginduced mental disorders (291.0–9), drug dependence (304.00– 93), nondependent drug abuse (305.20–93), drug dependence
complicating pregnancy or childbirth (648.30–34), suspected damage to the fetus from drugs (655.50–53), drugs affecting the fetus or newborn via the placenta or breast milk (760.72–73, 760.75), and poisoning by opiates and related narcotics (965.00–09). We also considered several hospital characteristics including teaching status (teaching vs nonteaching), location (urban vs rural), and U.S. region (Northeast, Midwest, South, or West). Joinpoint regression was then used to estimate and describe temporal changes in the rates of TB and HIV during the 13-year study period. Joinpoint regression is valuable in identifying key periods in time, marking changes in the rate of events over time.11,12 The iterative model-building process began by fitting the annual rate data to a straight line with no joinpoints, which assumed a single trend best described the data. Then a joinpoint—reflecting a change in the trend—was added to the model and a Monte Carlo permutation test assessed the improvement in model fit. The process continued until a final model with an optimal (best-fitting) number of joinpoints was selected, with each joinpoint indicating a change in the trend, and an annual percent change estimated to characterize how the rate was changing within each distinct trend segment. We calculated mean costs of hospitalization for each inpatient hospitalization and compared these charges for patients without HIV or TB diagnosis, for those with only HIV diagnosis, and for those with HIV-TB coinfections. To account for inflation, we further adjusted all costs to 2010 dollars using the medical care component of the Consumer Price Index. All statistical analyses accounted for the complex sampling design of the NIS and were weighted to facilitate the generation of national frequency and prevalence estimates. To account for NIS sampling design changes, we used the NIS Trends files, supplied by HCUP, so that trend weights and data elements would be consistently defined over time.13 Statistical tests were 2-sided with level of significance set at 5%. Because of the deidentified, publicly available nature of NIS data, the analyses performed for this study (H-36335) were considered exempt by the Baylor College of Medicine Institutional Review Board.
RESULTS A total of 57,393,459 hospital admissions associated with pregnancy and delivery were documented during the study period. Of this number, 4,053 mothers were diagnosed with active TB, yielding a rate of 7.06 per 100,000. The prevalence of HIV in the entire population of pregnant mothers was 12.76 per 10,000 (73,223 HIVinfected mothers). Among HIV-positive mothers, 110 of them were diagnosed with active TB, equivalent to a prevalence of 150.23 per 100,000. This is 21 times as high when compared with the rate of TB in the entire population of pregnant women. Figure 1 depicts the results of the temporal trend in the prevalence of HIV and TB among pregnant women in the United States over the study period. The temporal trajectory for each of the 2 infections suggested a downward trend. From 2002-2014, we observed a 1.3% average annual reduction in HIV among pregnant women that was found to be statistically significant using a joinpoint regression analysis. Although we found a 1.2% average annual decline in the rate of TB among admissions related to pregnancy, this was not statistically significant. Figure 2 shows the trend for HIV-TB coinfection over the same study period. It is important to state that because of the extreme rarity of coinfection among pregnancyrelated admissions, we had to impute values for 3 individual years that represented the average between the rate of the preceding and the following years. During the 13-year study period, there was a tendency for declining rates of HIV-TB coinfection rates (estimated 6.7% decrease annually); however, the temporal trend did not achieve statistical significance because of the rarity of coinfection.
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Fig 1. Temporal trends in the prevalence of HIV (per 10,000 pregnancy-related hospitalizations) and TB (per 100,000 pregnancy-related hospitalizations) in the United States, 2002-2014. The x-axis represents the year of discharge, and the y-axis represents the rate of HIV (per 10,000 pregnancy-related hospitalizations) and TB (per 100,000 pregnancyrelated hospitalizations). Lines represent the trend estimated by joinpoint regression. Values represent the APC, point estimate (95% confidence interval). APC, annual percent change; TB, tuberculosis.
Fig 2. Temporal trends in the prevalence of HIV-TB coinfection (per 100,000 pregnancy-related hospitalizations) in the United States, 2002-2014. The x-axis represents the year of discharge, and the y-axis represents the rate of HIV-TB coinfection (per 100,000 pregnancy-related hospitalizations). Lines represent the trend estimated by joinpoint regression. Values represent the APC, point estimate (95% confidence interval). APC, annual percent change; TB, tuberculosis.
As summarized in Table 1, HIV monoinfection, TB monoinfection, and HIV-TB coinfection increased with ascending age and showed racial and ethnic differences. HIV and HIV-TB coinfection were most prevalent among black mothers, whereas the rate of TB was highest among Hispanics and among other non-Hispanics (not of white or black race). The proportion of HIV monoinfection, TB monoinfection, and HIV-TB coinfection was 13-, 5- and 20-fold as high among black mothers compared with their white counterparts, respectively, whereas the corresponding proportion among Hispanics was 2, 7, and 4 times as high compared with their white counterparts, respectively. Mothers in the lowest income brackets and those with public or no health insurance bore the greatest risks for HIV monoinfection, TB monoinfection, and HIV-TB coinfection. There were also notable differences in geographic distribution, with the Northeast having the highest rates for HIV monoinfection, TB monoinfection, and HIV-TB coinfection. The Western part of the United States had relatively low prevalence of HIV and HIV-TB
coinfection. The prevalence of HIV monoinfection, TB monoinfection, and HIV-TB coinfection was highest among urban teaching hospitals and lowest for hospital facilities located in rural areas. Table 1 also presents mean hospital LOS by maternal sociodemographic features across HIV and TB status. The mean LOS was lowest among mothers free of HIV or TB disease and greatest among those with HIV-TB coinfection. The average LOS among mothers diagnosed with TB monoinfection was 60% higher than for those with HIV monoinfection. Within each study subpopulation, there were no differences in mean LOS for a given sociodemographic characteristic except among those with TB monoinfection or HIV-TB coinfection. For mothers diagnosed with TB, LOS was highest in younger women, non-Hispanic blacks, those in the lowest income stratum, mothers without health insurance or with unknown health insurance status, residents of the Northeastern part of the United States, and those admitted in urban teaching health facilities. By contrast, among mothers with
4
Table 1 Rates of HIV, TB, and HIV-TB coinfections, mean hospital length of stay, and cost burden among hospital admissions of pregnant women by HIV and TB status across sociodemographic characteristics in the United States, 2002-2014 Rates of HIV, TB, and HIV-TB coinfections
Cost burden
HIV+/TB+
No HIV/no TB
HIV+
TB+
HIV+/TB+
No HIV/No TB
HIV+
TB+
HIV+/TB+
(n = 73,223)
(n = 4,053)
(n = 110)
n (%)*
Rate†
Rate‡
Rate‡
(n = 57,316,073; mean LOS, 2.67)
(n = 73,223; mean LOS, 3.70)
(n = 4,053; mean LOS, 5.85)
(n = 110; mean LOS, 6.18)
(n = 57,316,073; mean cost, $5,622)
(n = 73,223; mean cost, $8,267)
(n = 4,053; mean cost, $13,672)
(n = 110; mean cost, $11,908)
19,439,803 (33.9) 29,525,642 (51.4) 8,428,013 (14.7)
9.93 14.01 14.91
6.40 7.05 8.62
0.05 0.26 0.28
2.58 2.65 2.92
3.55 3.65 4.10
6.03 6.13 4.76
4.95 6.02 7.17
$5,355 $5,611 $6,271
$7,857 $8,013 $9,677
$13,009 $14,921 $11,382
$8,895 $12,268 $11,486
24,135,280 (42.1) 6,812,145 (11.9) 10,821,945 (18.9) 4,913,152 (8.6) 10,710,937 (18.7)
4.39 58.94 8.31 8.11 8.87
1.88 10.08 12.86 18.76 5.59
0.04 0.81 0.17 0.29 0.13
2.65 2.99 2.55 2.72 2.62
3.47 3.79 3.54 3.62 3.75
5.30 7.64 6.38 5.64 3.44
4.95 7.11 4.57 3.71 7.92
$5,475 $5,949 $5,730 $6,189 $5,405
$7,194 $8,398 $8,521 $9,493 $8,163
$13,765 $19,830 $13,634 $13,503 $7,810
$8,895 $13,596 $12,187 $8,268 $9,741
15,584,800 (27.2) 14,211,424 (24.8) 13,817,339 (24.1) 12,703,162 (22.1)
22.24 10.80 7.77 4.65
9.50 6.83 6.16 5.06
0.32 0.09 0.21 0.08
2.64 2.61 2.66 2.78
3.74 3.65 3.62 3.65
6.50 5.06 5.74 5.84
8.66 3.64 3.88 6.00
$5,383 $5,499 $5,647 $5,974
$8,272 $7,948 $8,236 $7,961
$15,392 $10,337 $13,019 $15,875
$14,618 $10,149 $8,587 —–
24,692,937 (43.0) 28,950,519 (50.4) 3,750,002 (6.5)
21.57 4.75 16.56
10.29 3.30 14.83
0.30 0.08 0.36
2.65 2.71 2.52
3.73 3.75 3.68
6.02 5.21 6.22
6.95 4.83 4.37
$5,618 $5,651 $5,423
$8,387 $7,886 $8,092
$13,844 $12,323 $14,985
$13,288 $10,184 $6,688
9,466,428 (16.5) 12,181,788 (21.2) 21,737,645 (37.9) 14,007,597 (24.4)
19.39 7.85 19.12 2.68
10.37 5.98 6.44 6.73
0.35 0.08 0.27 0.06
2.91 2.64 2.68 2.53
3.71 3.93 3.62 3.93
7.71 3.95 5.30 6.24
4.01 3.49 8.32 3.00
$6,405 $5,514 $5,002 $6,149
$9,570 $8,664 $7,404 $10,281
$20,301 $8,195 $9,551 $16,921
$9,882 $9,235 $14,214 $10,702
6,443,608 (11.2) 23,149,046 (40.3) 27,556,758 (48.0)
3.75 5.30 21.12
3.01 3.48 10.99
0.07 0.08 0.32
2.26 2.52 2.89
2.65 3.44 3.80
2.29 4.29 6.51
3.00 4.60 6.67
$5,479 $5,269 $5,957
$6,024 $7,199 $8,601
$5,521 $9,530 $15,399
$8,653 $12,921 $11,989
LOS, length of stay; NH, non-Hispanic; TB, tuberculosis. *Weighted to estimate national frequency; sum of all groups may not add up to the total because of missing data. †Rate per 10,000 persons. ‡Rate per 100,000 persons.
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TB+
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Characteristic Age (y) 13-24 25-34 35-49 Race and ethnicity NH white NH black Hispanic Other Missing Income Lowest Second Third Highest Payer Public Private Other or none Region Northeast Midwest South West Hospital type Rural Urban, nonteaching Urban, teaching
Mean hospital LOS (d)
HIV+
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Table 2 Adjusted estimates for the associations between hospital length of stay, cost burden, and pregnancy and delivery hospital admissions in mothers with HIV monoinfection, TB monoinfection, or HIV-TB coinfection diagnosis in the United States, 2002-2014 Hospital length of stay Adjusted RR (95% CI) Infection Status No HIV, no TB HIV monoinfection TB monoinfection HIV-TB coinfection
Cost burden Adjusted RR (95% CI)
Adjusted RR (95% CI)
Adjusted RR (95% CI)
Crude RR (95% CI)
Model 1
Model 2
Crude RR (95% CI)
Model 1
Model 2
Referent 1.38 (1.37-1.30) 2.19 (2.11-2.27) 2.29 (1.85-2.84)
Referent 1.30 (1.28-1.31) 2.17 (2.09-2.25) 2.13 (1.72-2.54)
Referent 1.27 (1.26-1.28) 2.04 (1.97-2.11) 2.06 (1.67-2.53)
Referent 1.47 (1.45-1.48) 2.41 (2.32-2.52) 2.13 (1.66-2.72)
Referent 1.42 (1.41-1.43) 2.27 (2.18-2.37) 2.02 (1.58-2.58)
Referent 1.38 (1.37-1.40) 2.09 (2.01-2.18) 1.92 (1.52-2.44)
NOTE. Model 1 adjusts for age group, race and ethnicity, household income, insurance status, and hospital census region. Model 2 adjusts for everything in model 1 plus a composite indicator of pregnancy complications (encompassing preeclampsia, eclampsia, placenta accrete, placental abruption, placenta previa, other antepartum hemorrhage, postpartum hemorrhage, sepsis, or anemia). CI, confidence interval; RR, rate ratio (eg, ratio of length of stay, ratio of costs).
HIV-TB coinfection, the highest LOS was among older women, those with missing information on race and ethnicity, mothers covered by public health insurance, and residents of the Southern part of the United States. There was concordance in both TB monoinfected and HIV-TB coinfected subpopulations regarding mothers in the lowest income group and those admitted to urban teaching health facilities bearing the highest LOS in their respective sociodemographic categories. The cost burden associated with HIV, TB, and HIV-TB coinfections by sociodemographic characteristics is also described in Table 1. Overall, the mean cost of hospital admissions was highest for mothers hospitalized with TB and lowest for those free of TB and HIV infections. Across all sociodemographic characteristics, infectionfree mothers (ie, no HIV, no TB) had the lowest cost burden related to hospital admissions. Mothers admitted with a TB monoinfection diagnosis experienced the highest cost burden except for hospital admissions among older mothers, those with missing information on race and ethnicity, and those with hospital admissions in the Midwest and South. In these exceptional instances, the cost burden was highest in mothers with HIV-TB coinfection. We did not observe consistent temporal changes in the LOS or inflation-adjusted direct costs of medical care for any of the HIV or TB subgroups. Table 2 provides crude and adjusted estimates for the association between infection status and LOS and cost burden, respectively, using disease-free mothers as referent. The LOS among individuals with HIV was approximately 30% higher than disease-free mothers, and the LOS more than doubled among patients with TB monoinfection or HIV-TB coinfection. A similar pattern of association was observed for cost burden, which further confirmed the direct relationship between extended hospital stay and increasing cost. DISCUSSION Worldwide, TB remains a major public health issue with an estimated 10.4 million newly emerging active TB cases in 2016.14 Among HIV coinfected patients, TB is the leading infectious cause of death.6,15 Concurrent TB infection is also a significant contributing factor to maternal mortality in HIV-infected pregnant women.16 To our knowledge this is the first HIV-TB coinfection populationbased study among pregnant women from the United States. Our study confirmed the known heightened risk of TB among HIVpositive individuals.6,17 We observed the prevalence of TB among HIV-positive pregnant women to be >20 times that of their HIVnegative counterparts. These findings are consistent with the literature. The increased susceptibility of HIV-positive patients to TB has biological plausibility. Among HIV-positive individuals, the immune responses to contain TB disease may not be effective as a
result of underlying HIV-induced immunologic dysfunction which undermines effector immune responses.18,19 Studies on immune phenotyping have reported that peripheral CD4+T cells from a subset of HIV-positive patients on antiretroviral therapy regimens still continue to display features of elevated cellular exhaustion,20 turnover21 and senescence.22 These immunologic aberrations will explain the increased likelihood of TB disease and reactivation of latent TB in HIV-positive pregnant mothers as found in this study. We observed a 1.3% average annual reduction in HIV among pregnant women that was found to be statistically significant using a joinpoint regression analysis. Similarly, we found a 1.2% average annual decline in the rate of TB among these women; however, this failed to reach statistical significance. Data published from the Centers for Disease Control and Prevention on annual trends in the diagnosis of HIV in the general population showed an estimated annual percentage decrease over the decade from 2002-2011 of approximately 4% on average.23 Our findings among pregnant women are consistent with reports from the Centers for Disease Control and Prevention and other sources of a downward trend in TB incidence in the general U.S. population over the period of the study.24-26 However, a recent publication using the same dataset as ours suggested a rise in TB prevalence among U.S. pregnant women in the period 2003-2011.8 The authors reported a 9.8% increase in the TB rate each year, a finding that is starkly in contrast with consistent and reputable reports of a persistent decline in TB rates in the United States as a result of enhanced TB control nationwide. As pointed out in a letter to the editor reacting to that publication,10 the major flaw in that article is the way the authors defined TB, which encompassed both clinically confirmed and unconfirmed self-reported patients’ history of TB. Inclusion of the latter (using ICD-9-CM code V12.01) results in gross overestimation of both the prevalence and temporal trends in TB infection among pregnant women in the United States. That explains why that study remains an outlier. To our knowledge, this is the first study that reports findings relative to cost burden across the 3 infection states (ie, HIV, TB, HIVTB coinfection). In our analysis, we noted considerable disparity in mean LOS. The mean LOS was lowest among mothers free of HIV or TB disease and greatest among those with HIV-TB coinfection. Adjusted estimates confirmed that the LOS among HIV-positive mothers was approximately 30% higher than that for disease-free mothers, whereas the LOS was more than doubled among patients with TB monoinfection or HIV-TB coinfection. The same magnitude of association was observed between infection status and cost burden, which further demonstrates that extended LOS mediates increasing health care cost. The relationship patterns also showed that TB disease was the main driver for hospitalization cost during pregnancy. It is well established that TB is associated with elevated risk for pregnancy complications,8 and this could explain the excess costs
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associated with TB. To test this hypothesis, we built an adjusted model that included not only sociodemographic characteristics, but also frequently reported pregnancy complications (encompassing preeclampsia, eclampsia, placenta accrete, placental abruption, placenta previa, other antepartum hemorrhage, postpartum hemorrhage, sepsis, or anemia). There was a slight reduction in the magnitude of the association between infection status and hospitalization cost which was not significant (model 2). This illustrates that pregnancy complications could be a confounding, but not a mediating, variable between infection status and hospital costs. This finding is intriguing and does indicate that the observed 2-fold elevation of hospital costs among TB mono-infected and HIV-TB coinfected mothers were not mediated by pregnancy complications, but rather by other unmeasured variables. It is known in the literature that women of low socioeconomic status tend to have poor access to adequate health care, including treatment of their conditions, so most likely, these cases were captured as a result of their visits to health facilities, which might have been triggered by their pregnancy condition. Diagnostic tests for detection and follow-up and instituted treatment during pregnancy may lead to extended hospital stays and increased costs. This represents mere speculation at this stage because we lack the kind of itemized microcosting data that could provide us with comprehensive information to adequately test our hypothesis. We think additional and more refined studies are warranted to determine the cost mechanisms that could explain TB cost elevation during pregnancy. Because of the deidentified nature of the NIS database and the inability to link hospitalizations for the same patient longitudinally, our LOS and cost estimates are per hospitalization, and not per deduplicated pregnant woman. The actual costs of hospitalization associated with TB monoinfection and HIV-TB coinfection may be underestimated because of the limited information on the aggregate cost data in the national database of hospital admissions. Moreover, despite its widespread use for epidemiologic and clinical research, the NIS databases rely on ICD-9-CM codes to identify medical conditions (eg, HIV, TB) and procedures, and these codes are expected to have imperfect accuracy and reliability. The database has also some limitation with respect to ascertainment of certain quality metrics concerning the care received by the various groups across infection status. Information on the quality of care received could determine the reasons for the elevated costs associated with TB mono- and coinfection, especially across sociodemographic categories. Another limitation in our cost analysis is its confinement to payer’s rather than societal perspective, the latter being a better measure for cost burden on society than the former. Nonetheless, the study bears a number of strengths, including being the largest population-based study to offer cost estimates for pregnancy and delivery hospitalizations associated with HIV monoinfection, TB monoinfection, and HIV-TB coinfection. It is noteworthy that understanding determinants of cost is important; this is because it could potentially facilitate tailoring appropriate interventions to reduce costs and elevate affordability and sustainability of care that will improve both quantity and quality of life for affected mothers. The public health implications of our findings are significant. The elimination of TB from the United States is a major policy issue supported by a dynamic strategy articulation and monitoring by the Centers for Disease Control and Prevention. This strategic plan led to the formation of the Advisory Council for the Elimination of Tuberculosis and the publication of a national TB elimination plan in 1987, defining elimination as achieving a TB case rate of 1 per 1 million persons per year.27,28 The plan is comprehensive and seeks to address enabling and disabling factors for TB disease, including costs. The consideration of cost of care for TB is of great significance for the following reasons: (1) TB is a neglected disease that
attracts minimal budgetary allocation, a rate-limiting factor in the efforts to eliminate TB; and (2) ongoing health care reforms in the United States are cost-driven, and neglected diseases such as TB that disproportionately impact the poor will progressively get inadequate insurance coverage in the future given the current congressional inclination to limit Medicaid funding. Such an inevitable situation will threaten ongoing efforts for the elimination of TB in the United States. Therefore, these findings have the potential to once again move TB to the forefront as a public health issue and boost our struggle toward TB elimination nationwide. References 1. Sugarman J, Colvin C, Moran AC, Oxlade O. Tuberculosis in pregnancy: an estimate of the global burden of disease. Lancet Glob Health 2014;2:e710-6. 2. UNAIDS. 2006 report on the global AIDS epidemic. 2006. Available from: http://data.unaids.org/pub/report/2006/2006_gr_en.pdf. Accessed July 1, 2010. 3. World Health Organization. 2007 tuberculosis facts. 2007. Available from: http://www.who.int/tb/publications/2007/factsheet_2007.pdf. Accessed July 1, 2010. 4. U.S. Agency for International Development. The twin epidemics: HIV and TB coinfection. 2014. Available from: https://www.usaid.gov/news-information/ fact-sheets/twin-epidemics-hiv-and-tb-coinfection. Accessed April 4, 2017. 5. Schneider E, Castro KG. Tuberculosis trends in the United States, 1992-2001. Tuberculosis (Edinb) 2003;83:21-9. 6. World Health Organization. Global tuberculosis report 2015. 2015. Available from: http://who.int/tb/publications/global_report/en/. Accessed April 4, 2017. 7. Salinas JL, Mindra G, Haddad MB, Pratt R, Price SF, Langer AJ. Leveling of tuberculosis incidence—United States, 2013-2015. MMWR Morb Mortal Wkly Rep 2016;65:273-8. 8. El-Messidi A, Czuzoj-Shulman N, Spence AR, Abenhaim HA. Medical and obstetric outcomes among pregnant women with tuberculosis: a population-based study of 7.8 million births. Am J Obstet Gynecol 2016;215:797.e1-6. 9. Healthcare Cost and Utilization Project (HCUP). Introduction to the HCUP Nationwide Inpatient Sample (NIS) 2011. 2015. Available from: http://www.hcup-us.ahrq.gov/db/nation/nis/NIS_Introduction_2011.pdf. Accessed January 1, 2016. 10. Salemi JL, Salihu HM. The prevalence of active tuberculosis infection among pregnant women is not increasing in the United States. Am J Obstet Gynecol 2017;217:490-1. 11. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med 2000;19:335-51. 12. National Cancer Institute. Joinpoint regression program, version 4.2.0.2, statistical methodology and applications branch, surveillance research program. 2016. Available from: http://surveillance.cancer.gov/joinpoint/. Accessed January 4, 2015. 13. Houchens RL, Elixhauser A. Using the HCUP nationwide inpatient sample to estimate trends (updated for 1988-2004). HCUP methods series Report # 2006-05 online. Available from: http://www.hcup-us.ahrq.gov/reports/methods/ 2006_05_NISTrendsReport_1988-2004.pdf. Accessed January 1, 2016. 14. World Health Organization. Global tuberculosis report 2016. 2016. Available from: http://who.int/tb/publications/global_report/en/. Accessed April 4, 2017. 15. Hesseling AC, Rabie H. Tuberculosis and HIV remain major causes of death in African children. Int J Tuberc Lung Dis 2016;20:996-7. 16. Ribeiro PS, Jacobsen KH, Mathers CD, Garcia-Moreno C. Priorities for women’s health from the Global Burden of Disease study. Int J Gynaecol Obstet 2008;102:82-90. 17. Holmquist L, Russo CA, Elixhauser A. Tuberculosis stays in U.S. hospitals, 2006. Rockville (MD): Agency for Healthcare Research and Quality; 2008. 18. Girardi E, Sabin CA, d’Arminio Monforte A, Hogg B, Phillips AN, Gill MJ, et al. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005;41:1772-82. 19. Sutherland JS, Young JM, Peterson KL, Sanneh B, Whittle HC, Rowland-Jones SL, et al. Polyfunctional CD4(+) and CD8(+) T cell responses to tuberculosis antigens in HIV-1-infected patients before and after anti-retroviral treatment. J Immunol 2010;184:6537-44. 20. Grabmeier-Pfistershammer K, Steinberger P, Rieger A, Leitner J, Kohrgruber N. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J Acquir Immune Defic Syndr 2011;56:118-24. 21. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis 2011;204:1217-26. 22. Vivar N, Ruffin N, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Survival and proliferation of CD28- T cells during HIV-1 infection relate to the amplitude of viral replication. J Infect Dis 2011;203:1658-67. 23. Johnson AS, Hall HI, Hu X, Lansky A, Holtgrave DR, Mermin J. Trends in diagnoses of HIV infection in the United States, 2002-2011. JAMA 2014;312:432-4. 24. Hill AN, Becerra J, Castro KG. Modelling tuberculosis trends in the USA. Epidemiol Infect 2012;140:1862-72.
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25. Nnadi CD, Anderson LF, Armstrong LR, Stagg HR, Pedrazzoli D, Pratt R, et al. Mind the gap: TB trends in the USA and the UK, 2000-2011. Thorax 2016;71:35663. 26. Schmit KM, Wansaula Z, Pratt R, Price SF, Langer AJ. Tuberculosis - United States, 2016. MMWR Morb Mortal Wkly Rep 2017;66:289-94.
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27. Centers for Disease Control and Prevention. A strategic plan for the elimination of tuberculosis in the United States. MMWR Morb Mortal Wkly Rep 1989;38:269-72. 28. Reves RR, Nolan CM. Tuberculosis elimination in the United States: an achievable goal or an illusion? Am J Respir Crit Care Med 2012;186:i-iii.
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
j o u r n a l h o m e p a g e : w w w. a j i c j o u r n a l . o r g
Major Article
Hospital length of stay and cost burden of HIV, tuberculosis, and HIVtuberculosis coinfection among pregnant women in the United States Adeola Falana a, Vanessa Akpojiyovwi a, Esther Sey a, Andika Akpaffiong a, Olive Agumbah a, Samara Chienye a, Jamie Banks a, Erin Jones a, Kiara K. Spooner DrPH, MPH b, Jason L. Salemi PhD, MPH b, Omonike A. Olaleye PhD a, Sherri D. Onyiego MD, PhD b, Hamisu M. Salihu MD, PhD b,* a b
Texas Southern University, Houston, TX Department of Family & Community Medicine, Baylor College of Medicine, Houston, TX
Key Words: HIV-TB coinfection pregnancy length of stay (LOS) cost burden
Background: We sought to determine hospital length of stay (LOS) and cost burden associated with hospital admissions among pregnant women with HIV monoinfection, tuberculosis (TB) monoinfection, or HIV-TB coinfection in the United States. Methods: Analysis covered the period from 2002-2014 using data from the Nationwide Inpatient Sample. Relevant ICD-9-CM codes were used to determine HIV and TB status. Costs associated with hospitalization were calculated and adjusted to 2010 dollars using the medical care component of the Consumer Price Index. Results: We found modest annual average reduction in HIV, TB, and HIV-TB coinfection rates over the study period. The mean LOS was lowest among mothers free of HIV or TB disease and highest among those with HIV-TB coinfection. The average LOS among mothers diagnosed with TB monoinfection was 60% higher than for those with HIV monoinfection. The cost associated with pregnancy-related hospital admissions among mothers with HIV was approximately 30% higher than disease-free mothers, and the cost more than doubled among patients with TB monoinfection or HIV-TB coinfection. Conclusions: TB significantly increased hospital care cost among HIV-positive and HIV-negative pregnant women. © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
HIV and tuberculosis (TB) represent major public health problems and continue to be accountable for reduced quality and quantity of life globally.1 The 2 conditions are not uncommon and affect millions of people worldwide annually to the extent that the World Health Organization considers the 2 diseases as pandemic.2,3 An estimated 2 billion people—one-third of the global population—are infected with TB, and each year, 8.7 million people develop TB
* Address correspondence to Hamisu M. Salihu, MD, PhD, Department of Family and Community Medicine, Baylor College of Medicine, 3701 Kirby Dr, Ste 600, Houston, TX 77098. E-mail address: [email protected] (H.M. Salihu). Funding/support: Research funding support was provided by the U.S. Department of Health and Human Services, Health Resources and Services Administration for the Maternal and Child Health Pipeline Training Program: TSU-BCM Maternal and Child Health Student Training for Academic Readiness and Success (MCH STARS) Undergraduate Fellowship Program, Grant No:T16MC29831. Conflicts of interest: None to report.
disease. TB kills >1.4 million people each year and is economically devastating to families and communities worldwide.4 A number of factors are responsible for the transmission and spread of TB in the United States, including increases in the inflow of foreign-born individuals, overcrowded living conditions, the rise in TB drug resistance, health inequities such as lack of access to medical care or suboptimal quality of care, and the effects of poverty.5 TB is one of the top killers of women and is responsible for 500,000 of their deaths each year, emerging as the leading cause of death in HIV-positive individuals.4,6 As a result of the sustained public health efforts toward TB elimination over the previous 2 decades, the incidence of TB has decreased progressively and currently stands at approximately 3.0 cases per 100,000 in the general U.S. population.7 However, a recent study of TB among U.S. pregnant mothers tends to suggest an increase in TB rates associated with elevated levels of pregnancy complications.8 With increasing concerns regarding the possible rise of TB during pregnancy, especially among HIV women,8 it is unclear how this could impact the health
0196-6553/© 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajic.2017.09.016
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care costs related to the 2 conditions during pregnancy. To fill this gap, we conducted this population-based study to determine hospital length of stay (LOS) and hospitalization costs among pregnant women infected with HIV monoinfection, TB monoinfection, and HIV-TB coinfection in the United States. MATERIALS AND METHODS The analysis covered the period from January 1, 2002-December 31, 2014, using data from the Nationwide Inpatient Sample (NIS). The NIS, made available by the Healthcare Cost and Utilization Project (HCUP), currently constitutes the largest all-payer, publicly available inpatient database in the United States.9 Each year, the NIS stratifies all nonfederal community hospitals from participating states into groups according to 5 characteristics: geographic region of the United States, urban or rural location, teaching status, number of beds, and type of ownership. Within each unique stratum, a 20% sample of hospitals is drawn using a systematic random sampling approach designed to ensure the sample’s geographic representativeness.9 For each sampled hospital, all inpatient hospitalization records are included in the NIS, and the HCUP provides discharge-level sampling weights so that national frequency and prevalence estimates take into account this 2-stage cluster sampling design. The NIS contains approximately 7 million inpatient hospitalizations each year (36 million when weighted), and has grown from 22 participating states in 1998 to 44 states in 2014. Through 2011, pregnant women that delivered in selected hospitals in the United States were included based on a 2-stage cluster sampling design. Beginning in 2012, the NIS sampling strategy was changed from keeping all hospitalizations from a sample of hospitals (2 stage) to drawing a sample of hospitalizations from all hospitals (1 stage). To assess the study’s primary exposures, we scanned ICD-9-CM codes (the principal diagnosis and up to 24 secondary diagnoses) in each woman’s discharge record for an indication of HIV and TB status. HIV-affected pregnancies were those with 042, 079.53, or V08. Pregnancies affected by active TB were defined as those with 010-018.x (TB), 137.x (sequelae of TB), or 647.3 (TB complicating pregnancy or childbirth). Latent TB—defined as a documentation of V12.01 (personal history of TB) without an active TB code—was not included in this study because of the absence of symptoms that may impact pregnancy and the substantially lower rates of adverse pregnancy outcomes, LOS, and cost relative to active TB.10 Individual-level sociodemographic and behavioral characteristics were also extracted from the NIS databases. Maternal age in years was classified into 3 categories: 13-24, 25-34, and 35-49. Selfreported maternal race and ethnicity was first based on ethnicity (Hispanic or non-Hispanic), and the non-Hispanic group was further subdivided by race (white, black, or other). Median household income, which served as a proxy for socioeconomic status, was estimated using the patient’s postal code and subsequently grouped into quartiles. We classified the primary payer for hospital admission into 3 categories: government (Medicare or Medicaid), private (commercial carriers, private health maintenance organization, and preferred provider organization), and other sources (eg, self-pay, charity). Because of their strong associations with HIV infection, we also used ICD-9-CM codes to ascertain information on alcohol and drug use during pregnancy. Our definition of alcohol abuse included indications of alcohol-induced mental disorders (291.0–9), alcohol dependence syndrome (303.00–93), nondependent alcohol abuse such as binge drinking (305.00–03), alcoholic cardiomyopathy (425.5), and alcohol that has affected the fetus or newborn via the placenta or breast milk (760.71). Drug abuse included druginduced mental disorders (291.0–9), drug dependence (304.00– 93), nondependent drug abuse (305.20–93), drug dependence
complicating pregnancy or childbirth (648.30–34), suspected damage to the fetus from drugs (655.50–53), drugs affecting the fetus or newborn via the placenta or breast milk (760.72–73, 760.75), and poisoning by opiates and related narcotics (965.00–09). We also considered several hospital characteristics including teaching status (teaching vs nonteaching), location (urban vs rural), and U.S. region (Northeast, Midwest, South, or West). Joinpoint regression was then used to estimate and describe temporal changes in the rates of TB and HIV during the 13-year study period. Joinpoint regression is valuable in identifying key periods in time, marking changes in the rate of events over time.11,12 The iterative model-building process began by fitting the annual rate data to a straight line with no joinpoints, which assumed a single trend best described the data. Then a joinpoint—reflecting a change in the trend—was added to the model and a Monte Carlo permutation test assessed the improvement in model fit. The process continued until a final model with an optimal (best-fitting) number of joinpoints was selected, with each joinpoint indicating a change in the trend, and an annual percent change estimated to characterize how the rate was changing within each distinct trend segment. We calculated mean costs of hospitalization for each inpatient hospitalization and compared these charges for patients without HIV or TB diagnosis, for those with only HIV diagnosis, and for those with HIV-TB coinfections. To account for inflation, we further adjusted all costs to 2010 dollars using the medical care component of the Consumer Price Index. All statistical analyses accounted for the complex sampling design of the NIS and were weighted to facilitate the generation of national frequency and prevalence estimates. To account for NIS sampling design changes, we used the NIS Trends files, supplied by HCUP, so that trend weights and data elements would be consistently defined over time.13 Statistical tests were 2-sided with level of significance set at 5%. Because of the deidentified, publicly available nature of NIS data, the analyses performed for this study (H-36335) were considered exempt by the Baylor College of Medicine Institutional Review Board.
RESULTS A total of 57,393,459 hospital admissions associated with pregnancy and delivery were documented during the study period. Of this number, 4,053 mothers were diagnosed with active TB, yielding a rate of 7.06 per 100,000. The prevalence of HIV in the entire population of pregnant mothers was 12.76 per 10,000 (73,223 HIVinfected mothers). Among HIV-positive mothers, 110 of them were diagnosed with active TB, equivalent to a prevalence of 150.23 per 100,000. This is 21 times as high when compared with the rate of TB in the entire population of pregnant women. Figure 1 depicts the results of the temporal trend in the prevalence of HIV and TB among pregnant women in the United States over the study period. The temporal trajectory for each of the 2 infections suggested a downward trend. From 2002-2014, we observed a 1.3% average annual reduction in HIV among pregnant women that was found to be statistically significant using a joinpoint regression analysis. Although we found a 1.2% average annual decline in the rate of TB among admissions related to pregnancy, this was not statistically significant. Figure 2 shows the trend for HIV-TB coinfection over the same study period. It is important to state that because of the extreme rarity of coinfection among pregnancyrelated admissions, we had to impute values for 3 individual years that represented the average between the rate of the preceding and the following years. During the 13-year study period, there was a tendency for declining rates of HIV-TB coinfection rates (estimated 6.7% decrease annually); however, the temporal trend did not achieve statistical significance because of the rarity of coinfection.
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Fig 1. Temporal trends in the prevalence of HIV (per 10,000 pregnancy-related hospitalizations) and TB (per 100,000 pregnancy-related hospitalizations) in the United States, 2002-2014. The x-axis represents the year of discharge, and the y-axis represents the rate of HIV (per 10,000 pregnancy-related hospitalizations) and TB (per 100,000 pregnancyrelated hospitalizations). Lines represent the trend estimated by joinpoint regression. Values represent the APC, point estimate (95% confidence interval). APC, annual percent change; TB, tuberculosis.
Fig 2. Temporal trends in the prevalence of HIV-TB coinfection (per 100,000 pregnancy-related hospitalizations) in the United States, 2002-2014. The x-axis represents the year of discharge, and the y-axis represents the rate of HIV-TB coinfection (per 100,000 pregnancy-related hospitalizations). Lines represent the trend estimated by joinpoint regression. Values represent the APC, point estimate (95% confidence interval). APC, annual percent change; TB, tuberculosis.
As summarized in Table 1, HIV monoinfection, TB monoinfection, and HIV-TB coinfection increased with ascending age and showed racial and ethnic differences. HIV and HIV-TB coinfection were most prevalent among black mothers, whereas the rate of TB was highest among Hispanics and among other non-Hispanics (not of white or black race). The proportion of HIV monoinfection, TB monoinfection, and HIV-TB coinfection was 13-, 5- and 20-fold as high among black mothers compared with their white counterparts, respectively, whereas the corresponding proportion among Hispanics was 2, 7, and 4 times as high compared with their white counterparts, respectively. Mothers in the lowest income brackets and those with public or no health insurance bore the greatest risks for HIV monoinfection, TB monoinfection, and HIV-TB coinfection. There were also notable differences in geographic distribution, with the Northeast having the highest rates for HIV monoinfection, TB monoinfection, and HIV-TB coinfection. The Western part of the United States had relatively low prevalence of HIV and HIV-TB
coinfection. The prevalence of HIV monoinfection, TB monoinfection, and HIV-TB coinfection was highest among urban teaching hospitals and lowest for hospital facilities located in rural areas. Table 1 also presents mean hospital LOS by maternal sociodemographic features across HIV and TB status. The mean LOS was lowest among mothers free of HIV or TB disease and greatest among those with HIV-TB coinfection. The average LOS among mothers diagnosed with TB monoinfection was 60% higher than for those with HIV monoinfection. Within each study subpopulation, there were no differences in mean LOS for a given sociodemographic characteristic except among those with TB monoinfection or HIV-TB coinfection. For mothers diagnosed with TB, LOS was highest in younger women, non-Hispanic blacks, those in the lowest income stratum, mothers without health insurance or with unknown health insurance status, residents of the Northeastern part of the United States, and those admitted in urban teaching health facilities. By contrast, among mothers with
4
Table 1 Rates of HIV, TB, and HIV-TB coinfections, mean hospital length of stay, and cost burden among hospital admissions of pregnant women by HIV and TB status across sociodemographic characteristics in the United States, 2002-2014 Rates of HIV, TB, and HIV-TB coinfections
Cost burden
HIV+/TB+
No HIV/no TB
HIV+
TB+
HIV+/TB+
No HIV/No TB
HIV+
TB+
HIV+/TB+
(n = 73,223)
(n = 4,053)
(n = 110)
n (%)*
Rate†
Rate‡
Rate‡
(n = 57,316,073; mean LOS, 2.67)
(n = 73,223; mean LOS, 3.70)
(n = 4,053; mean LOS, 5.85)
(n = 110; mean LOS, 6.18)
(n = 57,316,073; mean cost, $5,622)
(n = 73,223; mean cost, $8,267)
(n = 4,053; mean cost, $13,672)
(n = 110; mean cost, $11,908)
19,439,803 (33.9) 29,525,642 (51.4) 8,428,013 (14.7)
9.93 14.01 14.91
6.40 7.05 8.62
0.05 0.26 0.28
2.58 2.65 2.92
3.55 3.65 4.10
6.03 6.13 4.76
4.95 6.02 7.17
$5,355 $5,611 $6,271
$7,857 $8,013 $9,677
$13,009 $14,921 $11,382
$8,895 $12,268 $11,486
24,135,280 (42.1) 6,812,145 (11.9) 10,821,945 (18.9) 4,913,152 (8.6) 10,710,937 (18.7)
4.39 58.94 8.31 8.11 8.87
1.88 10.08 12.86 18.76 5.59
0.04 0.81 0.17 0.29 0.13
2.65 2.99 2.55 2.72 2.62
3.47 3.79 3.54 3.62 3.75
5.30 7.64 6.38 5.64 3.44
4.95 7.11 4.57 3.71 7.92
$5,475 $5,949 $5,730 $6,189 $5,405
$7,194 $8,398 $8,521 $9,493 $8,163
$13,765 $19,830 $13,634 $13,503 $7,810
$8,895 $13,596 $12,187 $8,268 $9,741
15,584,800 (27.2) 14,211,424 (24.8) 13,817,339 (24.1) 12,703,162 (22.1)
22.24 10.80 7.77 4.65
9.50 6.83 6.16 5.06
0.32 0.09 0.21 0.08
2.64 2.61 2.66 2.78
3.74 3.65 3.62 3.65
6.50 5.06 5.74 5.84
8.66 3.64 3.88 6.00
$5,383 $5,499 $5,647 $5,974
$8,272 $7,948 $8,236 $7,961
$15,392 $10,337 $13,019 $15,875
$14,618 $10,149 $8,587 —–
24,692,937 (43.0) 28,950,519 (50.4) 3,750,002 (6.5)
21.57 4.75 16.56
10.29 3.30 14.83
0.30 0.08 0.36
2.65 2.71 2.52
3.73 3.75 3.68
6.02 5.21 6.22
6.95 4.83 4.37
$5,618 $5,651 $5,423
$8,387 $7,886 $8,092
$13,844 $12,323 $14,985
$13,288 $10,184 $6,688
9,466,428 (16.5) 12,181,788 (21.2) 21,737,645 (37.9) 14,007,597 (24.4)
19.39 7.85 19.12 2.68
10.37 5.98 6.44 6.73
0.35 0.08 0.27 0.06
2.91 2.64 2.68 2.53
3.71 3.93 3.62 3.93
7.71 3.95 5.30 6.24
4.01 3.49 8.32 3.00
$6,405 $5,514 $5,002 $6,149
$9,570 $8,664 $7,404 $10,281
$20,301 $8,195 $9,551 $16,921
$9,882 $9,235 $14,214 $10,702
6,443,608 (11.2) 23,149,046 (40.3) 27,556,758 (48.0)
3.75 5.30 21.12
3.01 3.48 10.99
0.07 0.08 0.32
2.26 2.52 2.89
2.65 3.44 3.80
2.29 4.29 6.51
3.00 4.60 6.67
$5,479 $5,269 $5,957
$6,024 $7,199 $8,601
$5,521 $9,530 $15,399
$8,653 $12,921 $11,989
LOS, length of stay; NH, non-Hispanic; TB, tuberculosis. *Weighted to estimate national frequency; sum of all groups may not add up to the total because of missing data. †Rate per 10,000 persons. ‡Rate per 100,000 persons.
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Characteristic Age (y) 13-24 25-34 35-49 Race and ethnicity NH white NH black Hispanic Other Missing Income Lowest Second Third Highest Payer Public Private Other or none Region Northeast Midwest South West Hospital type Rural Urban, nonteaching Urban, teaching
Mean hospital LOS (d)
HIV+
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Table 2 Adjusted estimates for the associations between hospital length of stay, cost burden, and pregnancy and delivery hospital admissions in mothers with HIV monoinfection, TB monoinfection, or HIV-TB coinfection diagnosis in the United States, 2002-2014 Hospital length of stay Adjusted RR (95% CI) Infection Status No HIV, no TB HIV monoinfection TB monoinfection HIV-TB coinfection
Cost burden Adjusted RR (95% CI)
Adjusted RR (95% CI)
Adjusted RR (95% CI)
Crude RR (95% CI)
Model 1
Model 2
Crude RR (95% CI)
Model 1
Model 2
Referent 1.38 (1.37-1.30) 2.19 (2.11-2.27) 2.29 (1.85-2.84)
Referent 1.30 (1.28-1.31) 2.17 (2.09-2.25) 2.13 (1.72-2.54)
Referent 1.27 (1.26-1.28) 2.04 (1.97-2.11) 2.06 (1.67-2.53)
Referent 1.47 (1.45-1.48) 2.41 (2.32-2.52) 2.13 (1.66-2.72)
Referent 1.42 (1.41-1.43) 2.27 (2.18-2.37) 2.02 (1.58-2.58)
Referent 1.38 (1.37-1.40) 2.09 (2.01-2.18) 1.92 (1.52-2.44)
NOTE. Model 1 adjusts for age group, race and ethnicity, household income, insurance status, and hospital census region. Model 2 adjusts for everything in model 1 plus a composite indicator of pregnancy complications (encompassing preeclampsia, eclampsia, placenta accrete, placental abruption, placenta previa, other antepartum hemorrhage, postpartum hemorrhage, sepsis, or anemia). CI, confidence interval; RR, rate ratio (eg, ratio of length of stay, ratio of costs).
HIV-TB coinfection, the highest LOS was among older women, those with missing information on race and ethnicity, mothers covered by public health insurance, and residents of the Southern part of the United States. There was concordance in both TB monoinfected and HIV-TB coinfected subpopulations regarding mothers in the lowest income group and those admitted to urban teaching health facilities bearing the highest LOS in their respective sociodemographic categories. The cost burden associated with HIV, TB, and HIV-TB coinfections by sociodemographic characteristics is also described in Table 1. Overall, the mean cost of hospital admissions was highest for mothers hospitalized with TB and lowest for those free of TB and HIV infections. Across all sociodemographic characteristics, infectionfree mothers (ie, no HIV, no TB) had the lowest cost burden related to hospital admissions. Mothers admitted with a TB monoinfection diagnosis experienced the highest cost burden except for hospital admissions among older mothers, those with missing information on race and ethnicity, and those with hospital admissions in the Midwest and South. In these exceptional instances, the cost burden was highest in mothers with HIV-TB coinfection. We did not observe consistent temporal changes in the LOS or inflation-adjusted direct costs of medical care for any of the HIV or TB subgroups. Table 2 provides crude and adjusted estimates for the association between infection status and LOS and cost burden, respectively, using disease-free mothers as referent. The LOS among individuals with HIV was approximately 30% higher than disease-free mothers, and the LOS more than doubled among patients with TB monoinfection or HIV-TB coinfection. A similar pattern of association was observed for cost burden, which further confirmed the direct relationship between extended hospital stay and increasing cost. DISCUSSION Worldwide, TB remains a major public health issue with an estimated 10.4 million newly emerging active TB cases in 2016.14 Among HIV coinfected patients, TB is the leading infectious cause of death.6,15 Concurrent TB infection is also a significant contributing factor to maternal mortality in HIV-infected pregnant women.16 To our knowledge this is the first HIV-TB coinfection populationbased study among pregnant women from the United States. Our study confirmed the known heightened risk of TB among HIVpositive individuals.6,17 We observed the prevalence of TB among HIV-positive pregnant women to be >20 times that of their HIVnegative counterparts. These findings are consistent with the literature. The increased susceptibility of HIV-positive patients to TB has biological plausibility. Among HIV-positive individuals, the immune responses to contain TB disease may not be effective as a
result of underlying HIV-induced immunologic dysfunction which undermines effector immune responses.18,19 Studies on immune phenotyping have reported that peripheral CD4+T cells from a subset of HIV-positive patients on antiretroviral therapy regimens still continue to display features of elevated cellular exhaustion,20 turnover21 and senescence.22 These immunologic aberrations will explain the increased likelihood of TB disease and reactivation of latent TB in HIV-positive pregnant mothers as found in this study. We observed a 1.3% average annual reduction in HIV among pregnant women that was found to be statistically significant using a joinpoint regression analysis. Similarly, we found a 1.2% average annual decline in the rate of TB among these women; however, this failed to reach statistical significance. Data published from the Centers for Disease Control and Prevention on annual trends in the diagnosis of HIV in the general population showed an estimated annual percentage decrease over the decade from 2002-2011 of approximately 4% on average.23 Our findings among pregnant women are consistent with reports from the Centers for Disease Control and Prevention and other sources of a downward trend in TB incidence in the general U.S. population over the period of the study.24-26 However, a recent publication using the same dataset as ours suggested a rise in TB prevalence among U.S. pregnant women in the period 2003-2011.8 The authors reported a 9.8% increase in the TB rate each year, a finding that is starkly in contrast with consistent and reputable reports of a persistent decline in TB rates in the United States as a result of enhanced TB control nationwide. As pointed out in a letter to the editor reacting to that publication,10 the major flaw in that article is the way the authors defined TB, which encompassed both clinically confirmed and unconfirmed self-reported patients’ history of TB. Inclusion of the latter (using ICD-9-CM code V12.01) results in gross overestimation of both the prevalence and temporal trends in TB infection among pregnant women in the United States. That explains why that study remains an outlier. To our knowledge, this is the first study that reports findings relative to cost burden across the 3 infection states (ie, HIV, TB, HIVTB coinfection). In our analysis, we noted considerable disparity in mean LOS. The mean LOS was lowest among mothers free of HIV or TB disease and greatest among those with HIV-TB coinfection. Adjusted estimates confirmed that the LOS among HIV-positive mothers was approximately 30% higher than that for disease-free mothers, whereas the LOS was more than doubled among patients with TB monoinfection or HIV-TB coinfection. The same magnitude of association was observed between infection status and cost burden, which further demonstrates that extended LOS mediates increasing health care cost. The relationship patterns also showed that TB disease was the main driver for hospitalization cost during pregnancy. It is well established that TB is associated with elevated risk for pregnancy complications,8 and this could explain the excess costs
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associated with TB. To test this hypothesis, we built an adjusted model that included not only sociodemographic characteristics, but also frequently reported pregnancy complications (encompassing preeclampsia, eclampsia, placenta accrete, placental abruption, placenta previa, other antepartum hemorrhage, postpartum hemorrhage, sepsis, or anemia). There was a slight reduction in the magnitude of the association between infection status and hospitalization cost which was not significant (model 2). This illustrates that pregnancy complications could be a confounding, but not a mediating, variable between infection status and hospital costs. This finding is intriguing and does indicate that the observed 2-fold elevation of hospital costs among TB mono-infected and HIV-TB coinfected mothers were not mediated by pregnancy complications, but rather by other unmeasured variables. It is known in the literature that women of low socioeconomic status tend to have poor access to adequate health care, including treatment of their conditions, so most likely, these cases were captured as a result of their visits to health facilities, which might have been triggered by their pregnancy condition. Diagnostic tests for detection and follow-up and instituted treatment during pregnancy may lead to extended hospital stays and increased costs. This represents mere speculation at this stage because we lack the kind of itemized microcosting data that could provide us with comprehensive information to adequately test our hypothesis. We think additional and more refined studies are warranted to determine the cost mechanisms that could explain TB cost elevation during pregnancy. Because of the deidentified nature of the NIS database and the inability to link hospitalizations for the same patient longitudinally, our LOS and cost estimates are per hospitalization, and not per deduplicated pregnant woman. The actual costs of hospitalization associated with TB monoinfection and HIV-TB coinfection may be underestimated because of the limited information on the aggregate cost data in the national database of hospital admissions. Moreover, despite its widespread use for epidemiologic and clinical research, the NIS databases rely on ICD-9-CM codes to identify medical conditions (eg, HIV, TB) and procedures, and these codes are expected to have imperfect accuracy and reliability. The database has also some limitation with respect to ascertainment of certain quality metrics concerning the care received by the various groups across infection status. Information on the quality of care received could determine the reasons for the elevated costs associated with TB mono- and coinfection, especially across sociodemographic categories. Another limitation in our cost analysis is its confinement to payer’s rather than societal perspective, the latter being a better measure for cost burden on society than the former. Nonetheless, the study bears a number of strengths, including being the largest population-based study to offer cost estimates for pregnancy and delivery hospitalizations associated with HIV monoinfection, TB monoinfection, and HIV-TB coinfection. It is noteworthy that understanding determinants of cost is important; this is because it could potentially facilitate tailoring appropriate interventions to reduce costs and elevate affordability and sustainability of care that will improve both quantity and quality of life for affected mothers. The public health implications of our findings are significant. The elimination of TB from the United States is a major policy issue supported by a dynamic strategy articulation and monitoring by the Centers for Disease Control and Prevention. This strategic plan led to the formation of the Advisory Council for the Elimination of Tuberculosis and the publication of a national TB elimination plan in 1987, defining elimination as achieving a TB case rate of 1 per 1 million persons per year.27,28 The plan is comprehensive and seeks to address enabling and disabling factors for TB disease, including costs. The consideration of cost of care for TB is of great significance for the following reasons: (1) TB is a neglected disease that
attracts minimal budgetary allocation, a rate-limiting factor in the efforts to eliminate TB; and (2) ongoing health care reforms in the United States are cost-driven, and neglected diseases such as TB that disproportionately impact the poor will progressively get inadequate insurance coverage in the future given the current congressional inclination to limit Medicaid funding. Such an inevitable situation will threaten ongoing efforts for the elimination of TB in the United States. Therefore, these findings have the potential to once again move TB to the forefront as a public health issue and boost our struggle toward TB elimination nationwide. References 1. Sugarman J, Colvin C, Moran AC, Oxlade O. Tuberculosis in pregnancy: an estimate of the global burden of disease. Lancet Glob Health 2014;2:e710-6. 2. UNAIDS. 2006 report on the global AIDS epidemic. 2006. Available from: http://data.unaids.org/pub/report/2006/2006_gr_en.pdf. Accessed July 1, 2010. 3. World Health Organization. 2007 tuberculosis facts. 2007. Available from: http://www.who.int/tb/publications/2007/factsheet_2007.pdf. Accessed July 1, 2010. 4. U.S. Agency for International Development. The twin epidemics: HIV and TB coinfection. 2014. Available from: https://www.usaid.gov/news-information/ fact-sheets/twin-epidemics-hiv-and-tb-coinfection. Accessed April 4, 2017. 5. Schneider E, Castro KG. Tuberculosis trends in the United States, 1992-2001. Tuberculosis (Edinb) 2003;83:21-9. 6. World Health Organization. Global tuberculosis report 2015. 2015. Available from: http://who.int/tb/publications/global_report/en/. Accessed April 4, 2017. 7. Salinas JL, Mindra G, Haddad MB, Pratt R, Price SF, Langer AJ. Leveling of tuberculosis incidence—United States, 2013-2015. MMWR Morb Mortal Wkly Rep 2016;65:273-8. 8. El-Messidi A, Czuzoj-Shulman N, Spence AR, Abenhaim HA. Medical and obstetric outcomes among pregnant women with tuberculosis: a population-based study of 7.8 million births. Am J Obstet Gynecol 2016;215:797.e1-6. 9. Healthcare Cost and Utilization Project (HCUP). Introduction to the HCUP Nationwide Inpatient Sample (NIS) 2011. 2015. Available from: http://www.hcup-us.ahrq.gov/db/nation/nis/NIS_Introduction_2011.pdf. Accessed January 1, 2016. 10. Salemi JL, Salihu HM. The prevalence of active tuberculosis infection among pregnant women is not increasing in the United States. Am J Obstet Gynecol 2017;217:490-1. 11. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med 2000;19:335-51. 12. National Cancer Institute. Joinpoint regression program, version 4.2.0.2, statistical methodology and applications branch, surveillance research program. 2016. Available from: http://surveillance.cancer.gov/joinpoint/. Accessed January 4, 2015. 13. Houchens RL, Elixhauser A. Using the HCUP nationwide inpatient sample to estimate trends (updated for 1988-2004). HCUP methods series Report # 2006-05 online. Available from: http://www.hcup-us.ahrq.gov/reports/methods/ 2006_05_NISTrendsReport_1988-2004.pdf. Accessed January 1, 2016. 14. World Health Organization. Global tuberculosis report 2016. 2016. Available from: http://who.int/tb/publications/global_report/en/. Accessed April 4, 2017. 15. Hesseling AC, Rabie H. Tuberculosis and HIV remain major causes of death in African children. Int J Tuberc Lung Dis 2016;20:996-7. 16. Ribeiro PS, Jacobsen KH, Mathers CD, Garcia-Moreno C. Priorities for women’s health from the Global Burden of Disease study. Int J Gynaecol Obstet 2008;102:82-90. 17. Holmquist L, Russo CA, Elixhauser A. Tuberculosis stays in U.S. hospitals, 2006. Rockville (MD): Agency for Healthcare Research and Quality; 2008. 18. Girardi E, Sabin CA, d’Arminio Monforte A, Hogg B, Phillips AN, Gill MJ, et al. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005;41:1772-82. 19. Sutherland JS, Young JM, Peterson KL, Sanneh B, Whittle HC, Rowland-Jones SL, et al. Polyfunctional CD4(+) and CD8(+) T cell responses to tuberculosis antigens in HIV-1-infected patients before and after anti-retroviral treatment. J Immunol 2010;184:6537-44. 20. Grabmeier-Pfistershammer K, Steinberger P, Rieger A, Leitner J, Kohrgruber N. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J Acquir Immune Defic Syndr 2011;56:118-24. 21. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis 2011;204:1217-26. 22. Vivar N, Ruffin N, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Survival and proliferation of CD28- T cells during HIV-1 infection relate to the amplitude of viral replication. J Infect Dis 2011;203:1658-67. 23. Johnson AS, Hall HI, Hu X, Lansky A, Holtgrave DR, Mermin J. Trends in diagnoses of HIV infection in the United States, 2002-2011. JAMA 2014;312:432-4. 24. Hill AN, Becerra J, Castro KG. Modelling tuberculosis trends in the USA. Epidemiol Infect 2012;140:1862-72.
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25. Nnadi CD, Anderson LF, Armstrong LR, Stagg HR, Pedrazzoli D, Pratt R, et al. Mind the gap: TB trends in the USA and the UK, 2000-2011. Thorax 2016;71:35663. 26. Schmit KM, Wansaula Z, Pratt R, Price SF, Langer AJ. Tuberculosis - United States, 2016. MMWR Morb Mortal Wkly Rep 2017;66:289-94.
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