Steven Offenbacher

Periodontal infection as a possible risk factor for preterm low birth weight.

Periodontal diseases are Gram-negative anaerobic infections that can occur in women of childbearing age (18 to 34 years). In the present investigation we sought to determine whether the prevalence of maternal periodontal infection could be associated with preterm low birth weight (PLBW), controlling for known risk factors and potential covariates. A case-control study of 124 pregnant or postpartum mothers was performed. PLBW cases were defined as a mother with a birth of less than 2,500 g and one or more of the following: gestational age <37 weeks, preterm labor (PTL), or premature rupture of membranes (PROM). Controls were normal birth weight infants (NBW). Assessments included a broad range of known obstetric risk factors, such as tobacco use, drug use, alcohol consumption, level of prenatal care, parity, genitourinary infections, and nutrition. Each subject received a periodontal examination to determine clinical attachment level. PLBW cases and primiparous PLBW cases (n = 93) had significantly worse periodontal disease than the respective NBW controls. Multivariate logistic regression models, controlling for other risk factors and covariates, demonstrated that periodontal disease is a statistically significant risk factor for PLBW with adjusted odds ratios of 7.9 and 7.5 for all PLBW cases and primiparous PLBW cases, respectively. These data indicate that periodontal diseases represent a previously unrecognized and clinically significant risk factor for preterm low birth weight as a consequence of either PTL or preterm PROM. J Periodontol 1996;67:1103-1113.

Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study

BACKGROUND Type 2 diabetes mellitus and atherosclerotic cardiovascular disease have common antecedents. Since markers of inflammation predict coronary heart disease and are raised in patients with type 2 diabetes, we investigated whether they predict whether people will develop type 2 diabetes. METHODS 12,330 men and women, aged 45-64 years, were followed up for a mean of 7 years. We analysed the association between different markers of acute inflammation and subsequent diagnosis of diabetes. In a subgroup of 610 individuals selected originally for an unrelated atherosclerosis case-control study, we also investigated diabetes associations with total sialic acid and orosomucoid, haptoglobin, and alpha1-antitrypsin. FINDINGS 1335 individuals had a new diagnosis of diabetes. Adjusted odds ratios for developing diabetes for quartile extremes were 1.9 (95% CI 1.6-2.3) for raised white-cell count, 1.3 (1.0-1.5) for low serum albumin, and 1.2 (1.0-1.5) for raised fibrinogen. In the subgroup analysis, individuals with concentrations of orosomucoid and sialic acid of more than the median had odds ratios of 7.9 (2.6-23.7) and 3.7 (1.4-9.8), respectively. Adjustment for body-mass index and waist-to-hip ratio lessened the associations; those for white-cell count (1.5 [1.3-1.8]), orosomucoid (7.1 [2.1-23.7]), and sialic acid (2.8 [1.0-8.1]) remained significant. INTERPRETATION Markers of inflammation are associated with the development of diabetes in middle-aged adults. Although autoimmunity may partly explain these associations, they probably reflect the pathogenesis of type 2 diabetes.

Periodontal disease and adverse pregnancy outcomes: a systematic review

Background  Recent studies suggest that periodontal disease, as a source of subclinical and persistent infection, may induce systemic inflammatory responses that increase the risk of adverse pregnancy outcomes.

Acute-phase Inflammatory Response to Periodontal Disease in the US Population

Moderate elevation of serum C-reactive protein (CRP) is a risk factor for cardiovascular disease among apparently healthy individuals, although factors that create this inflammatory response in the absence of systemic illness have not been clarified. This study aimed to: (1) evaluate associations among periodontal disease, established risk factors for elevated CRP, and CRP levels within the US population; and (2) determine whether total tooth loss is associated with reduced CRP. Data were obtained from the third National Health and Nutrition Examination Survey. A random sample of the US population was interviewed in their homes and examined at mobile examination centers. CRP was quantified from peripheral blood samples and analyzed as a continuous variable and as the prevalence of elevated CRP (≥ 10 mg/L). Some 12,949 people aged 18+ years who had periodontal examinations and an additional 1817 edentulous people aged 18+ years were included in the analysis. Dentate people with extensive periodontal disease (> 10% of sites with periodontal pockets 4+ mm) had an increase of approximately one-third in mean CRP and a doubling in prevalence of elevated CRP compared with periodontally healthy people. Raised CRP levels among people with extensive periodontal disease persisted in multivariate analyses (P < 0.01), with established risk factors for elevated CRP (diabetes, arthritis, emphysema, smoking, and anti-inflammatory medications) and sociodemographic factors controlled for. However, CRP levels were similarly raised in edentulous people. Furthermore, the established risk factors for elevated CRP modified relationships between oral status and CRP levels. Periodontal disease and edentulism were associated with systemic inflammatory response in the US population, most notably among people who had no established risk factors for elevated CRP.

Modulation of Host PGE2 Secretion as a Determinant of Periodontal Disease Expression

An increasing body of evidence supports the concept that host-produced PGE2 mediates much of the tissue destruction that occurs in periodontal disease. PGE2 levels within the crevicular fluid can serve as a static assessment of ongoing disease activity; i.e., rate of attachment loss and bone resorption. New insights into the mechanisms that regulate PGE2 synthesis provide an altered paradigm of periodontal disease which places the emphasis on host response, rather than the bacterial etiology, as the principal determinant of disease expression. We describe a PGE2 host response model as a hypothetical framework to discuss new, possible explanations for host susceptibility to periodontal disease. J Periodontol 1993;64:432-444.

Periodontal Disease and Coronary Heart Disease A Reappraisal of the Exposure

Background—Results from studies relating periodontal disease to cardiovascular disease have been mixed. Residual confounding by smoking and use of clinical measures of periodontal disease rather than measures of infection have been 2 major criticisms. The aims of this study were to investigate relationships between prevalent coronary heart disease (CHD) and 2 exposures, (1) clinical periodontal disease and (2) IgG antibodies to 17 oral organisms, and to evaluate the role of smoking in these relationships. Methods and Results—Our study is based on a subset of participants in the Atherosclerosis Risk in Communities (ARIC) Study, who received a complete periodontal examination during visit 4 (1996–1998). The exposures were periodontal status and serum IgG antibody levels against 17 periodontal organisms, and the outcome was prevalent CHD at visit 4. Multivariable analyses indicate that periodontal status is not significantly associated with CHD in either ever smokers or never smokers. Similar analyses evaluating antibodies indicate that high antibodies (above the median) to Treponema denticola (odds ratio [OR]=1.7; 95% CI, 1.2 to 2.3), Prevotella intermedia (OR=1.5; 95% CI, 1.1 to 2.0), Capnocytophaga ochracea (OR=1.5; 95% CI, 1.1 to 2.1), and Veillonella parvula (OR=1.7; 95% CI, 1.2 to 2.3) are significantly associated with CHD among ever smokers, whereas Prevotella nigrescens (OR=1.7; 95% CI, 1.1 to 2.6), Actinobacillus actinomycetemcomitans (OR=1.7; 95% CI, 1.2 to 2.7), and Capnocytophaga ochracea (OR=2.0; 95% CI, 1.3 to 3.0) were associated with CHD among never smokers. Conclusions—Clinical signs of periodontal disease were not associated with CHD, whereas systemic antibody response was associated with CHD in ever smokers and never smokers. These findings indicate that the quality and quantity of the host response to oral bacteria may be an exposure more relevant to systemic atherothrombotic coronary events than clinical measures.

Systemic effects of periodontitis: epidemiology of periodontal disease and cardiovascular disease.

There have been 42 published studies describing associations between oral conditions and cardiovascular diseases. In the absence of randomized controlled trials, the 16 longitudinal studies represent the highest level of evidence available. However, two databases produced eight of the 16 studies. There also is extensive variability in definitions of the oral exposure that include salivary flow, reported periodontal disease, number of teeth, oral organisms, antibodies to oral organisms, Total Dental Index, Community Periodontal Index of Treatment Needs, plaque scores, probing depth, attachment loss, and bone level. Variability also exists in the cardiovascular outcomes that include atherosclerosis measures and events, such as hospitalization for coronary heart disease (CHD), chronic CHD, fatal CHD, total stroke, ischemic stroke, and revascularization procedures. One of the criticisms of this research is that the exposure has not been represented by measures of infection. To begin to address this concern, we present new data showing that patterns of high and low levels of eight periodontal pathogens and antibody levels against those organisms are related to clinical periodontal disease as well as other characteristics of the individuals, such as age, race, gender, diabetic status, atherosclerosis, and CHD. As others before us, we conclude that the cumulative evidence presented above supports, but does not prove, a causal association between periodontal infection and atherosclerotic cardiovascular disease or its sequelae. A number of legitimate concerns have arisen about the nature of the relationship and, indeed, the appropriate definitions for periodontal disease when it is thought to be an exposure for systemic diseases. There is still much work needed to identify which aspects of the exposure are related to which aspects of the outcome. Principal component analyses illustrate the complexity of the interactions among risk factors, exposures, and outcomes. These analyses provide an initial clustering that describes and suggests the presence of specific syndromes.

Progressive Periodontal Disease and Risk of Very Preterm Delivery

OBJECTIVE: The goal was to estimate whether maternal periodontal disease was predictive of preterm (less than 37 weeks) or very preterm (less than 32 weeks) births. METHODS: A prospective study of obstetric outcomes, entitled Oral Conditions and Pregnancy (OCAP), was conducted with 1,020 pregnant women who received both an antepartum and postpartum periodontal examination. Predictive models were developed to estimate whether maternal exposure to either periodontal disease at enrollment (less than 26 weeks) and/or periodontal disease progression during pregnancy, as determined by comparing postpartum with antepartum status, were predictive of preterm or very preterm births, adjusting for risk factors including previous preterm delivery, race, smoking, social domain variables, and other infections. RESULTS: Incidence of preterm birth was 11.2% among periodontally healthy women, compared with 28.6% in women with moderate-severe periodontal disease (adjusted risk ratio [RR] 1.6, 95% confidence interval [CI] 1.1–2.3). Antepartum moderate-severe periodontal disease was associated with an increased incidence of spontaneous preterm births (15.2% versus 24.9%, adjusted RR 2.0, 95% CI 1.2–3.2). Similarly, the unadjusted rate of very preterm delivery was 6.4% among women with periodontal disease progression, significantly higher than the 1.8% rate among women without disease progression (adjusted RR 2.4, 95% CI 1.1–5.2). CONCLUSION: The OCAP study demonstrates that maternal periodontal disease increases relative risk for preterm or spontaneous preterm births. Furthermore, periodontal disease progression during pregnancy was a predictor of the more severe adverse pregnancy outcome of very preterm birth, independently of traditional obstetric, periodontal, and social domain risk factors. LEVEL OF EVIDENCE: II-2

Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2

Bone wound healing requires osteoinductive signals that are attributed to (the) bone morphogenetic proteins (BMPs). The cellular origin of such osteoinductive signals has only been partially elucidated. Because of the central role of the macrophage in cutaneous wound healing, we hypothesized that the macrophage could play a similar role in osseous healing. It was the aim of the present investigation to examine the possible expression of BMP by the macrophage, and to evaluate the contribution of macrophage products to an early step of bone formation modeled in an in vitro culture system. The synthesis of BMP-2 and BMP-6 by cultured human and murine macrophages was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). When human mesenchymal stem cells (hMSCs) were grown in conditioned media from J774A.1 cells, alkaline phosphatase expression increased. This induction was blocked by anti-BMP-2 antibody and by anti-transforming growth factor-beta1 (TGF-beta1) antibody. Modeling of the macrophage expression of osteoinductive signals by potential physiological situations was evaluated by treatments with lipopolysaccharide (LPS) or macrophage chemotactic peptide-1 (MCP-1). Macrophage BMP-2 expression was reduced by proinflammatory LPS stimulation (which was confirmed to induce release of the proinflammatory cytokine, TNF-alpha), and conditioned media from LPS-treated macrophages had no ability to increase alkaline phosphatase activity in hMSCs. This first study of macrophage BMP-2 expression indicates that the macrophage is capable of physiological regulation consistent with a key role in osteoinduction for osseous wound healing.

Dental infections and atherosclerosis

In most countries, coronary heart disease is one of the leading causes of morbidity and death. This report reviews the current evidence indicating that oral conditions (specifically periodontitis) may be a risk factor for atherosclerosis and its clinical manifestations and provides new preliminary data. This review is done in the context of the research indicating that inflammation plays a central role in atherogenesis and that there is a substantial systemic microbial and inflammatory burden associated with periodontal disease. Our review concentrates on 5 longitudinal studies that show oral conditions being associated with the onset of coronary heart disease while controlling for a variety of established coronary heart disease risk factors. In addition to published evidence, preliminary findings from our Dental Atherosclerosis Risk in Communities study also indicate that periodontal disease is associated with carotid intimal-medial wall thickness, a measure of subclinical atherosclerosis, adjusting for factors known to be associated with both conditions.