America’s Insurance Industry Considers The Oral Systemic Link

Casey Hein, BSDH, MBA; Charles M. Cobb, DDS, MS, PhD; Kim A. Boggess, MD; and Robert Ostfeld, MD MSc

About a year ago, America’s Health Insurance Plans (AHIP) began to coordinate a panel of dental and medical experts to present the scientific evidence linking oral and systemic health at the 2008 AHIP Institute meeting. AHIP is the national association representing close to 1,300 health insurance companies that provide benefits (medical and dental) to more than 200 million Americans.

Introduction
About a year ago, America’s Health Insurance Plans (AHIP) began to coordinate a panel of dental and medical experts to present the scientific evidence linking oral and systemic health at the 2008 AHIP Institute meeting. AHIP is the national association representing close to 1,300 health insurance companies that provide benefits (medical and dental) to more than 200 million Americans. The annual Institute sessions comprise AHIP’s largest meeting, attracting more than 2,000 executives from the nation’s leading health plans, insurers, and their business partners. As such, this special event represented a valuable opportunity to develop a thought-provoking program with a slate of speakers who could communicate credible and compelling information about oral-systemic relationships. 
The speakers for the program included some of the most highly respected researchers, academicians, and policymakers within the scientific community. According to Tom Meyers, Executive Director of the Product Policy Department at AHIP, the program was well attended by a variety of stakeholders within the insurance industry, and the feedback regarding the relevance and impact of the presentation was excellent. There were numerous suggestions by attendees that this subject matter be considered for discussion at future AHIP Institute meetings.
This article provides a synopsis of the presentations delivered by several of the panelists at AHIP Institute’s program, entitled “Oral and Medical Health,” which was held in San Francisco in June 2008. 

Reconnecting the Mouth to the Whole Body
Introductory Discussion by Casey Hein, BSDH, MBA
The body of literature that suggests there is a relationship between oral conditions, specifically periodontal diseases and inflammatory-driven systemic disease states, is mounting, both in quantity and overall strength of evidence. This begs the question: When, how, and why did the mouth become separated from the rest of the body?
Perhaps it was in 1840, when the first dental school, the Baltimore College of Dental Surgery, was opened that this historical schism between dentistry and medicine occurred. Previously, in the earlier 1800s, most of those who proclaimed themselves as experts in dentistry had learned through trade-like apprenticeships. The debate that raged during this time centered on whether dentistry should be included as part of scholarly education or be taught in trade schools. The Doctor of Dental Surgery (DDS) degree at the Baltimore College of Dental Surgery originated from the vision of two dental practitioners, Hayden and Harris, who brought to the forefront the need for systematic formal education as the foundation for a scientific dental profession. About 20 years later, in 1867, Harvard Dental School became the first university-based dental education institution, bringing to a close the “no-man’s land”1 of the oral cavity and conferring upon dentistry the same academic status as other areas of higher education.
In 1908, Vida A. Latham, who was both a dentist and physician, wrote a compelling argument on the necessity of a medical education for dentists.2 Little did we know that Latham, considered by many as a health science pioneer, would be among the first to recognize the importance of medical education in dental education. Latham advocated that dentistry is a specialty of medicine and that basic education for dentists should be similar to that of physicians. Furthermore, Latham proposed that the practice of dentistry be a more scientific study instead of considering it merely mechanical. She also suggested that unless the dental practitioner understood systemic disease and its inception, he or she could not accurately perform as a diagnostician. As scientific investigation continues to uncover various bidirectional relationships between periodontal diseases and systemic diseases and conditions, it appears that the perspective held by Latham regarding the importance of medical education in dentistry is well supported.
Today, the body of evidence supporting these interrelationships demands the creation of new models in the delivery of dental care that place dentists and dental hygienists in key roles to screen patients for systemic diseases/conditions and to provide certain health promotion interventions.3,4 The evidence supporting periodontal-systemic relationships also must be translated into treatment planning that will require interprofessional point-of-care screening and cooperation in case management. To affect these kinds of changes in the scope of practice, many dental educators are starting to realize the need for enhanced education and training in medical sciences within dental curricula.3
Indeed, the science of oral-systemic medicine is advancing very quickly, and with it an increased awareness of the importance of medical–dental collaboration. However, a key factor in whether scientific findings become incorporated into mainstream healthcare practices will be whether there is demonstrable “buy-in” from the insurance industry. It was the hope of the experts who spoke at the AHIP Institute that the scientific evidence they presented would offer succinct information that was sufficient to facilitate greater understanding of oral-systemic relationships among those who are in a position to influence changes in healthcare policy and insurance coverage.
The evidence presented at the AHIP Institute included commentary about the epidemiology and pathogenesis of periodontitis and the biologic plausibility of the oral-systemic link, as described by Charles Cobb; the impact of oral health on maternal, fetal, and infant well-being as discussed by Kim A. Boggess; and the potential connection between atherosclerosis and periodontal diseases as elaborated on by Robert Ostfeld; among other topics (Table 1). Fundamental to a greater understanding of these oral-systemic relationships is the concept of a risk continuum that demonstrates a cascade of events linking periodontal diseases with systemic diseases driven by inflammation (Figure 1). This continuum of etiologic events begins with the bacterial challenge associated with the pathogenesis of periodontal diseases. 

Biological Plausibility for a Link Between Periodontal Diseases and Systemic Diseases
A Discussion by Charles M. Cobb, DDS, MS, PhD
The oral microflora colonizes exposed tooth surfaces, the gingival crevice and/or periodontal pocket, and all mucous membranes of the oral cavity and oropharynx. The microbes grow as complex, mixed, interdependent colonies in biofilms and may achieve considerable thickness, achieving a thickness of 1 mm within 96 hours, if left undisturbed.5 Oral biofilms (dental plaque), like all microbial biofilms, exhibit a successional colonization, with gram-positive aerobic Streptococci species being the initial colonizers, followed in sequence by Actinomyces species, Veillonella species, and then a variety of gram-negative anaerobic microbes, such as Treponema species, Fusobacterium species, Porphyromonas species, Prevotella species, and Tannerella species.6
As oral biofilms mature, the percentage of gram-negative anaerobic microbes increases. Specific complexes of such microbes commonly cohabit subgingival sites and consistently are associated with inflammatory periodontal diseases.6 These putative microbial pathogens include Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola.6 Infection with these and other gram-negative anaerobes is accompanied by the release of en-
dotoxins, leukotoxins, collagenase, gellatinase, elastase, fibrinolysins, and other proteolytic enzymes.7 Obviously, such bacterial toxins and enzymes are tissue irritants and/
or cytotoxic and viewed by the host immune system as foreign proteins. Taken as an aggregate cellular/tissue insult, the host immune system is activated locally and perceived at a clinical level as inflammation with all the inherent gingival changes.8
Locally, bacteria and their metabolic by-products stimulate a cellular immune response represented by a dense infiltration of neutrophils, macrophages, and lymphoid cells. These cells and host connective-tissue cells within the inflammatory lesion are stimulated to synthesize and release proinflammatory cytokines, prostanoids, and proteolytic enzymes (eg, interleukin [IL]-1, IL-6, IL-8, tumor necrosis factor [TNF]-a, prostaglandin E2 [PGE2], and matrix metalloproteinases [MMPs]).8 It is this immune-inflammatory reaction that ultimately leads to the clinical signs of gingivitis and chronic periodontitis and their characteristic features of fibrous connective-tissue degradation, resorption of tooth-supporting alveolar bone, and periodontal pocket formation (Figure 2 and Figure 3).
The epithelial lining of the periodontal pocket lacks the strata corneum and granulosum. Consequently, the pocket epithelium is easily ulcerated and breached by invasive subgingival pathogenic bacteria9 that, in turn, have access to the underlying lamina propria and gingival vasculature, leading to bacteremia and endotoxemia. In addition, there is considerable evidence that locally produced proinflammatory cytokines and prostanoids also gain access to the circulatory system.10-12 Thus, the biologic potential is present for a link between the inflammatory periodontal diseases and the induction of a host systemic inflammatory response.
Based on this understanding and numerous research initiatives, the relationship between poor oral hygiene and the presence and severity of periodontal diseases and the incidence of bacteremia has been well established.13-15 Given the evidence that bacteremia, endotoxemia, and elevated systemic levels of inflammatory mediators are associated with moderate and advanced chronic periodonti-
tis,4,10-12,16 it is not surprising that the presence of viable oral bacteria or bacterial antibodies in atheromas and/or the tunica intima/media of vessels exhibiting atherosclerotic lesions has been reported.17-21 Furthermore, given the invasive potential of oral pathogenic microbes, the potential for bacteremia, endotoxemia, and the systemic influx of locally generated inflammatory mediators, one might predict an acute-phase protein response from the liver. Indeed, there is evidence suggesting that chronic periodontitis is associated with elevated levels of acute-phase proteins, particularly C-reactive protein (CRP).22-27 Furthermore, it appears that the treatment of periodontal diseases can decrease levels of CRP.26-30
Evidence for associations between inflammatory periodontal diseases and a variety of systemic responses continues to accumulate. Recent reports have confirmed the potential for such a relationship and include such systemic conditions as atherosclerosis,30-32 cardiovascular disease,29,30,33-35 ischemic stroke,35-38 and cancer,39 as well as a bidirectional relationship between periodontitis and diabetes and between periodontitis and adverse pregnancy outcomes.25,40,41


Oral Health: Impact on Maternal, Fetal, and Infant Well-Being
A Discussion by Kim A. Boggess, MD
The presence of maternal periodontal infection has been associated with adverse pregnancy outcomes, such as preterm birth,42-44 preeclampsia,45 gestational diabetes,46 delivery of a small-for-gestational-age infant,47 and fetal loss.48 In 1996, Offenbacher et al42 first reported an association between maternal periodontal infection and delivery of a preterm/low-birth-weight infant. Two prospective cohort studies44,49 subsequently found that moderate/severe maternal periodontal infection identified early in pregnancy is associated with an increased risk for spontaneous preterm birth, independent of other traditional risk factors.44 A recent meta-analysis of the association between maternal periodontal diseases and preterm birth examined 17 studies and reported a pooled estimate odds ratio for preterm birth of 2.27 (1.06–4.85).50
While there is data suggesting a relationship between maternal periodontal infection and preterm birth, several studies have failed to demonstrate such an association.49,51-54 The reasons for conflicting data have yet to be defined. There is significant variation among studies in the clinical definition of periodontal diseases, and none of the definitions have been validated. Clinical markers of periodontal diseases may be late manifestations of the local infection, such that bacterial exposure may have occurred already, with subsequent downstream deleterious effects. Several studies48,52,53 that found no association between maternal periodontal diseases and adverse pregnancy outcomes did not control for potential confounders. However, it remains uncertain whether the observed association between maternal periodontal diseases and adverse pregnancy outcomes represents a causal relationship or is caused by the confounding effects of other variables, therefore the importance of these study differences is unclear. Another potential reason for the disparate findings among studies is the differences in populations studied. Differential access to insurance, dental care, and prenatal care may confound the relationship between maternal periodontal diseases and adverse pregnancy outcomes and explain some of the conflicting data.
Despite this controversy, several investigators have reported that periodontal treatment during pregnancy leads to a reduction in preterm birth risk.53,55,56 Lopez et al55 found almost a five-fold reduction in preterm birth among women treated during pregnancy. In a pilot trial of periodontal treatment, Offenbacher et al49 found a trend toward reduced preterm birth among women treated during pregnancy compared with those who delayed therapy until postpartum. This study demonstrated significant improvement in oral health measures and also a reduction in oral pathogen burden among women treated during pregnancy. Because periodontal infection is both preventable and treatable, these data are encouraging. There would be significant public health interest if a cause-effect relationship between periodontal infection and preterm birth can be demonstrated.
In contrast, Michalowicz et al57 found no reduction in preterm births < 37 weeks’ gestation among women treated for periodontal infection during pregnancy. However, there were twice as many deliveries at < 32 weeks’ gestation among women in the control group compared with treated women. While not statistically significant, this is suggestive evidence that periodontal disease treatment may benefit women at risk for the earliest and most morbid preterm births.
There are also data on the role of maternal periodontal infection and other adverse pregnancy outcomes. Evidence suggests a role for inflammation and endothelial activation in the pathophysiology of preeclampsia;58,59 periodontal infection is one of many potential stimuli for these host responses. A two-fold increased risk for preeclampsia among women with periodontal infection diagnosed at delivery (Figure 4) has been reported45 and confirmed by others.60,61 A recent meta-analysis examining the role of maternal infection in the development of preeclampsia concluded that maternal periodontal infection was one of only two potential infectious exposures associated with preeclampsia (urinary tract infection was the second).62
While it remains inconclusive whether maternal periodontal treatment improves pregnancy outcome, it is clear that periodontal treatment during pregnancy is safe and improves maternal oral health.49,56 In several studies of periodontal treatment during pregnancy, oral health parameters improved following therapy.49,57
Conflicting observational and treatment effect data demonstrate that significant gaps in knowledge of the relationship between maternal periodontal diseases and adverse pregnancy outcomes remain. Further studies are needed to better understand the mechanism of periodontal disease-associated adverse outcomes. Education for patients and healthcare providers regarding the potential association and risks is indicated, and an understanding of their ability to prevent and manage oral diseases should be promoted. Given the relationship between maternal and infant oral health, and periodontal infection and general health and well-being, oral healthcare should be a goal in its own right for all individuals. 

Atherosclerosis and Periodontal Disease: Is There a Connection?
A Discussion by Robert Ostfeld, MD, MSc
Cardiovascular disease is the leading cause of death for adult men and adult women in the United States.63 Approximately 2,600 Americans die of cardiovascular disease every day, accounting for, on average, one death every 34 seconds.63 By 2020, cardiovascular disease is predicted to claim 25 million lives annually.64
According to the Framingham Heart Study, the chance of developing symptomatic coronary heart disease in men and women after the age of 40 years is 49% and 32%, respectively.63 However, the prevalence of subclinical atherosclerosis may be significantly higher, with 69% of adoles-
cents showing early signs of atherosclerosis.65
Nearly 50% of all myocardial infarctions and cerebrovascular events occur in individuals with cholesterol levels deemed “normal” by current guidelines,64 emphasizing the importance of treating other risk factors, including hypertension, smoking, and physical inactivity. Additionally, the growing epidemic of obesity and diabetes will likely increase the burden of cardiovascular diseases by placing patients at even greater risk and further straining the healthcare system.
Periodontal disease is also common, present in approximately 60 million Americans.66 To date, there is a growing body of evidence that links the presence of periodontal disease with atherosclerosis.67 Although intriguing, it is important to reinforce that this association has been derived largely from observational data. Hence, confounders cannot be excluded and causality is not clear. We will briefly discuss some pathophysiologic mechanisms that may account for this association, epidemiologic evidence supporting this association, how treating periodontal disease may ameliorate atherosclerosis, and how these common diseases present an opportunity for physicians and dentists to work together.
Atherosclerosis is an inflammatory disease.64 Inflammation promotes all aspects of atherosclerosis, from its initiation to its progression and its potential culmination in an atherothrombotic event.
Periodontal diseases cause an increase in inflammatory markers in what appears to be a dose-dependent manner.67 Interestingly, an increasing burden of periodontal diseases also is associated with an increasing burden of atherosclerosis. This suggests that periodontal diseases may have a dose-dependent relationship with atherosclerosis, which is mediated by inflammation. Accordingly, when compared with patients without periodontal diseases, patients with periodontal diseases had increased markers of systemic inflammation, such as CRP, fibrinogen, and IL-6.16
Alternatively, bacterial translocation from the mouth into the atherosclerotic plaque with subsequent promotion of atherosclerosis has been postulated and is supported by a number of studies.4,16,20 Nevertheless, it appears to be less embraced as a potential pathophysiologic mechanism.68
Interestingly, Papapanagiotou et al69 recently reported that periodontal disease is associated with platelet activation. Because platelet activation is associated with both increased inflammation70 and increased risk of acute coronary syndromes,70 including myocardial infarctions, periodontal disease ultimately may be found to increase atherosclerotic risk via multiple means (Figure 5).
Numerous epidemiologic studies4,20,68,71 have demonstrated a modest association between the presence of periodontal diseases and the presence of atherosclerosis. One meta-analysis72 found a 19% increase in the risk of future cardiovascular events, such as myocardial infarction and stroke, in patients with periodontal disease vs those without disease. Other studies have further supported the association between periodontal disease, myocardial infarction,73 and stroke.74 In addition, because atherosclerosis is a systemic disease, it is not surprising that periodontal disease also has been associated with peripheral vascular disease.75
Desvarieux and colleagues76 found that carotid intimal medial thickness, a marker of atherosclerosis, is increased in patients with periodontal disease vs those without disease. Amabile et al77 reported that the presence of periodontal disease is correlated directly to the burden of atherosclerosis found on cardiac catheterization. Interestingly, Janket et al72 found that the association between periodontal disease and atherothrombotic events is greatest in those under the age of 65, suggesting that earlier detection and treatment may have the greatest benefit. This relationship with age has been supported in other work,34 as well.
A number of studies have suggested that by treating periodontal disease, markers of both local and systemic inflammation may decrease.4 Given that atherosclerosis is an inflammatory disease, such treatment also may benefit the cardiovascular system. In a randomized prospective trial of 120 patients with severe periodontal disease, Tonetti et al32 found that intensive periodontal treatment vs community-based periodontal care was associated with improved endothelial function, a marker of arterial health, 6 months after treatment (Figure 6). Further studies are needed to determine whether improved endothelial function will translate into a reduction in cardiovascular events.
Given the wide prevalence of periodontal disease, atherosclerosis, and their frequent coexistence in the same patient, the need for dentists and physicians to work together when treating patients is clear. Promoting oral and systemic health across multiple disciplines within the healthcare system is a desirable goal. Increasing awareness across specialties ultimately will serve the patient better, as dentists reinforce cardiovascular disease prevention and physicians reinforce the importance of oral health. 

Concluding Remarks
by Casey Hein, BSDH, MBA
Understanding the risk continuum that links periodontal diseases with systemic diseases driven by inflammation and the concept of “systemic periodontitis” is fundamental in appreciating the potential whole-body benefit of prevention and aggressive treatment of periodontal diseases. This concept was demonstrated in a number of recently reported studies,27,29,32,79 as well as by the presentations offered during the AHIP Institute and summarized here. Proposed intervention strategies must be considered as the insurance industry begins to calculate the cost savings associated with the prevention and treatment of periodontal diseases and secondary prevention of complications of interrelated systemic diseases and conditions. 

About the Authors
• Casey Hein, BSDH, MBA, is President of PointPerio, LLC. She also serves as Assistant Professor, Division of Periodontics, and Project Director of Interprofessional Oral-Systemic Curriculum Development in the Faculty of Dentistry at the University of Manitoba in Winnipeg, Canada and as Assistant Professor in Craniofacial Biology, and Associate Professor in Dental Hygiene at the University of Colorado School of Dental Medicine in Denver, Colorado.   

• Charles M. Cobb, DDS, MS, PhD, is Professor Emeritus, Department of Periodontics, School of Dentistry, University of Missouri-Kansas City. 

•  Kim A. Boggess, MD, is an Associate Professor, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of North Carolina at Chapel Hill.  •  Robert Ostfeld, MD, MSc, is an Associate Professor of Clinical Medicine, Albert Einstein College of Medicine, Montefiore Medical Center.  n

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Figure 1 The risk continuum linking periodontal diseases with inflammatory-driven disease states (courtesy of Casey Hein).	Figure 2 Human cadaver specimen showing the characteristic histologic features of chronic periodontitis, dense inflammatory infiltrate, loss of connective tissue, and bone resorption (H and E stain, original magnification x25).	Figure 3 Magnification of an area from Figure 2 showing osteoclastic mediated resorption of crestal alveolar bone (H and E stain, original magnification x250)
Figure 4 Preeclampsia rate by periodontal infection status.	Figure 5 Potential mechanisms linking periodontal diseases with atherosclerosis.	Figure 6 The potential positive effects of treating periodontal disease.