There is emerging evidence from the dental literature that periodontal disease may be a risk factor for systemic disease such as cardiovascular disease and diabetes mellitus. In addition, several investigators report a link between periodontal infections and preterm labor. There is very little, if any, information discussing these new developments in the medical literature, particularly in obstetrics and gynecology. However, at the same time, popular scientific journals as well as women’s magazines, which focus on health issues and are read by many of our patients, all have addressed this topic. The purpose of this report is, therefore, to familiarize the reader with hypothesized or scientifically proven pathophysiological pathways that may explain the two-way relationship between periodontal disease and these systemic conditions. Although many reports were published decades ago, they represent “classic” papers and thus are included in this review.
WHAT IS PERIODONTAL DISEASE?
It is estimated that at least 35% of the adults 30 years of age and older in the U.S. have periodontitis—22% have a mild form and 13% have a moderate or severe form (1). Periodontitis is the most common cause of tooth loss in adults. Bleeding of the gums is often the first sign; with tooth mobility usually being detectable in the more severe stages of disease. In most cases, this disease is painless and asymptomatic. Gingival inflammation results from bacterial products invading the gingival epithelium, which eventually may lead to destruction of the supporting tissues. In gingivitis, the inflammatory response is limited predominantly to the gingival tissues and not accompanied by loss of alveolar bone. Periodontitis, on the other hand, is characterized by destruction of periodontal tissues, including bone and bacterial infection 5 mm or more below the surface of the gingiva (Fig. 1). Approximately 90% of the patients undergoing periodontal surgery experience bacteremia during the procedure (2). Also, simple intraoral manipulations such as tooth brushing (3, 4) and even mastication (2) result in a transient bacteremia in a significant proportion of subjects. Subsequent production of inflammatory mediators and proteolytic enzymes by monocytes are major mechanisms involved in the degradation of the periodontal tissues (5). Considerable evidence suggests that there is a genetic predisposition for severe periodontal disease. Certain polymorphisms associated with excessive interleukin-1 production might confer risk for more severe forms of periodontal disease (6). Additional risk factors are depicted in Table 1(6–11). Clinical management of periodontal disease focuses on the daily removal of all bacterial plaque. Professional care involves removal of accretions, including calculus from the crowns and root surfaces and surgical therapy to regenerate periodontal tissues and reduce plaque-retentive factors. For more information on periodontal disease, the reader is referred to an excellent review article by Williams (12).
PERIODONTAL DISEASE AND SYSTEMIC DISEASE
During the past decade, several observational studies—case-control as well as longitudinal and even the popular press— have indicated that there is a relationship between coronary heart disease and periodontal infection (13–15). These studies have adjusted for established cardiovascular risk factors such as age, gender, cholesterol, weight, smoking, diabetes, and hypertension. It seems that the associations between cardiovascular disease and periodontal disease are remarkably consistent across different populations studied and that periodontitis is an antecedent condition. The strength of this association is comparable with that of other cardiovascular risk factors such as smoking or a family history of heart disease. For example, in a cross-sectional study, male subjects less than 50 years of age with periodontitis had a relative risk (RR) of 1.72 (95% confidence interval (CI) = 1.10; 2.68) for developing cardiovascular disease (16). Similarly, in a prospective study of 1372 Pima Indians, periodontal disease conferred a RR of 2.7 (95% CI = 1.3; 5.5) for development of cardiovascular disease (17). Finally, in a 15-year longitudinal study of 1000 men in good health at baseline, those with clinically significant periodontal disease were at significantly elevated risk for subsequent development of cardiovascular disease (RR 1.5, 95% CI = 1.04; 2.14), fatal cardiovascular disease (RR 1.9, 95% CI = 1.10; 3.43) and stroke (RR 2.8, 95% CI = 1.45; 5.48) (18).
In contrast to the above mentioned associations, a recent meta-analysis (19), as well as a large and well-designed prospective cohort study published in the Journal of the American Medical Association(20), did not find convincing evidence of a causal association between periodontal disease and cardiovascular disease risk. In this study, 8032 adults with no reported history of cardiovascular disease at baseline were followed for approximately 20 years. Periodontitis was associated with a nonsignificant increased risk for cardiovascular disease event (hazard ratio of 1.14 with a 95% CI of 0.96–1.36).
It seems that the interpretation of previously reported associations is difficult. Whether they are causal or artifactual depends for the most part on study design and the inherent adjusting for possible confounding mechanisms. Incomplete adjustment for socioeconomic status, for instance, may be responsible for the observed associations, particularly as it pertains to coronary heart disease, inasmuch as many risk factors are also responsible for periodontal disease.
There are several proposed mechanisms by which chronic systemic Gram negative/anaerobic dental bacteremia may trigger events leading to thrombus formation, coronary artery occlusion, and, ultimately, myocardial infarction (21). Monocytes from some individuals with a “hyperinflammatory” phenotype respond to a microbial and/or lipopolysaccharide (LPS) challenge with an abnormally high production of proinflammatory mediators to include thromboxane A2 (TXA2), prostaglandin-E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1 (IL-1); each of these can initiate and exacerbate atherogenesis and thromboembolic events (6). In addition, aggregation of platelets and subsequent thrombus formation is induced by the platelet aggregation-associated protein (PAAP) expressed on bacteria present in dental plaque (22). Although these processes may explain the link between periodontal disease and heart disease, insufficient firm evidence exists to support a cause and effect relationship currently. Evidently, still larger and even better-controlled studies will be required to identify a definite association between periodontal disease and coronary heart disease.
In patients with diabetes mellitus, the prevalence, progression, and severity of periodontal disease is well recognized (23–26). Some of the most informative studies have involved the Pima Indians native to Arizona. Pima Indians are known to have a very high prevalence of type 2 diabetes (23–25) and these diabetic subjects also have a higher prevalence and severity of periodontal disease compared with nondiabetic subjects in this population. Other findings suggesting a link between diabetes and periodontal disease include the observation that teenagers with type 1 diabetes are more susceptible to destructive periodontitis (26). Similarly, diabetic patients who are poorly controlled have more severe periodontal disease (27–29), and periodontal treatment improves diabetic control by reducing insulin requirements (30, 31). Periodontitis in diabetic subjects also is associated classically with chronic recurrent abscess formation and suppuration (32). The predisposition of diabetic subjects for periodontal disease has been attributed to an impaired host response, increased insulin resistance, and vascular changes that increase susceptibility to infection (32). More specifically, it is suggested that in diabetic gingival tissue, enhanced accumulation of advanced glycation end products and increased oxidant stress are important in the pathogenesis of diabetes-associated periodontitis. In particular, advanced glycation end products can alter cellular phenotype and function by activation of cell-signaling pathways that result in activation, of the inflammatory response (33). For instance, it has been demonstrated that diabetic subjects have both an exaggerated gingival secretion of PGE2, IL-1β, and possibly TNF-α, as well as an enhanced peripheral blood monocytic response to a LPS challenge (9).
ROLE OF SEX HORMONES IN PERIODONTAL DISEASE
Several pathways exist for estrogens and progestins, as well as androgens to exacerbate gingival inflammation and promote periodontal disease. Human gingiva can function as an estrogen target tissue because it has specific high-affinity estrogen receptors (34). Elevated concentration of these sex steroids is associated with changes in microvascular topography and permeability, resulting in gingival edema and increased gingival crevicular fluid flow (35–37). Moreover, the keratinization of the gingiva is decreased under the influence of sex steroids, and this, together with an increase in epithelial glycogen, impairs the effectiveness of the gingival epithelial barrier. Sex hormones also may alter the host defense mechanisms against bacterial plaque. For example, an increased number of polymorphonuclear leukocytes and increased PGE2 production in the gingiva enhance the inflammatory response (37, 38). Elevated levels of androgens caused a downregulation of interleukin-6 production by human gingival fibroblasts in vitro, thereby reducing the normal resistance to the inflammatory challenges produced by bacteria (39). Lastly, estradiol and progesterone can promote growth of Bacteroides subspecies in the gingiva. Thus, these hormones seem to have the potential for altering the subgingival microbial ecology implicated in periodontal disease (40, 41).
A 1972 longitudinal study of 127 children between the ages of 11 and 17 first demonstrated a relationship between puberty and the development of gingivitis (42). In a more recent longitudinal study of 24 subjects progressing normally from prepuberty to puberty, there was a significant increase in gingival inflammation as well as in the proportion of specific periodontal pathogens in puberty relative to the baseline value (43). These increases were correlated with an elevation in systemic levels of estrogen and progesterone. These studies indicate a modulating role for sex hormones concerning the development of gingivitis that seemed to be independent from dental hygiene.
Studies evaluating the effect of oral contraceptive use and the development of periodontal disease are more than 20 years old. Overall, they conclude that gingival inflammation is increased in women taking oral contraceptives and is related to the duration of use (35, 37, 44–47). The greatest gingival response was seen in the first few months after oral contraceptive use, but could continue to worsen in some cases. Unfortunately, these studies evaluated women taking several different hormonal regimens. For currently marketed oral contraceptive pills, no published information is available.
Periodontal alveolar bone loss is the major cause of tooth morbidity in the aging population. Loss of teeth may occur (47) and, in severe cases, the residual bone ridge may resorb beyond the former location of the root apices. Periodontal alveolar bone loss could be due to systemic osteoporosis, but more so to periodontal disease. Several authors have suggested that mandibular bone density may be indicative of systemic bone density (48, 49). Just recently, Jeffcoat et al. (50) presented preliminary data from the women’s health initiative oral ancillary study again demonstrating the same. It has to be recognized, however, that existing studies are preliminary in nature and cross-sectional in design. Few studies have directly evaluated the relationship between periodontal disease and its sequelae in postmenopausal women, particularly assessing the influence of hormonal replacement therapy. Two studies reported no difference in alveolar bone loss with hormone replacement therapy but demonstrated less gingival bleeding (51, 52). Two large cohort studies evaluating women taking estrogen demonstrated a significant reduction in tooth loss, where the duration of hormone replacement therapy is inversely correlated with the proportion of women with edentulism. Unfortunately, these studies may be confounded by selection bias (53, 54). Longitudinal studies could address whether the progression of periodontal disease is augmented for patients with osteoporosis compared with patients with normal bone density. Currently, it is not feasible to address this correlation from only cross-sectional studies.
Several classic papers describe the gingival condition of pregnant women. The hormonal changes seen in pregnancy are related to increased incidence and severity of gingivitis and periodontitis (38, 55–57). Symptoms of gingivitis may first appear in the second month of gestation and reach maximum severity 1 month before delivery (40, 55). It then declines and regresses after parturition (36). The greatest increase in gingivitis is usually seen in the anterior regions of the mouth but can be more generalized. A transient increase in tooth mobility has been reported (36, 57). During pregnancy, there are alterations in the subgingival microbial flora to include an increased ratio of anaerobes to aerobes and increased proportions of Prevotella intermedia and other black-pigmented species (40, 58). For instance, the relative proportions of Bacteroides species increased 55-fold in pregnancy (59). In women with marked pregnancy gingivitis, up to 107 neutrophils per minute are found in oral rinses, a 100-fold increase over the number found in subjects with healthy gingiva (Dennison, unpublished results). Immune changes associated with hormonal alterations in pregnancy include decreased neutrophil chemotaxis and phagocytosis, altered lymphocyte response, and depressed antibody production (35, 60–62). The effect of these gestational changes on the periodontal tissues is two-fold: increased gingival swelling, redness, and bleeding occur more easily and increased gingival inflammatory response to bacterial plaque (58). Septicemia due to oral pathogens also has been reported during pregnancy (63), which eventually can result in fetal death (64).
It has been demonstrated in two case-control studies, one from the United States and one from Thailand, that women who experience a preterm delivery have more severe periodontal disease (odds ratio 7.9, 95% CI = 1.95; 28.8) compared with those delivered at term (65, 66). Just recently—and not yet unpublished—preliminary results of a prospective study revealed by researchers in Alabama demonstrated similar findings irrespective of any of the well-known risk factors for preterm delivery (67). The risk for prematurity increased with periodontal disease severity. The same researchers have also begun a pilot intervention study to evaluate whether the prematurity attributable to periodontal disease can be reduced by treatment. One or several plausible biologic pathogenic mechanisms are suggested to contribute to preterm labor and low birth weight in the presence of periodontal disease. One biochemical mechanism for preterm labor is infection mediated via prostaglandins and cytokines (68). In this scenario, bacterial endotoxin stimulates macrophages to produce cytokines (69–71), which in turn stimulate prostaglandin production by decidual and chorionic cells (72–75). Indeed, gingival crevicular fluid, PGE2, and IL-1 levels have been found to be higher in women with preterm delivery and periodontal disease (76). These same women also exhibited higher gingival crevicular fluid concentrations of four specific organisms that are associated with periodontitis, as well as with systemic bacterial products such as LPS. For example, Fusobacterium nucleatum and its specific gingival subspecies, common oral organisms, are the most frequently isolated species from amniotic fluid cultures among women with preterm labor and intact membranes (77). Therefore, Gram negative anaerobic periodontal infections may serve as a chronic reservoir for hematogenous spread of bacteria and bacterial products to the fetoplacental unit. The role of the inflammatory host response seems to be a major factor of susceptibility and resultant severity of the condition (76–78). The patient with an altered inflammatory trait may be at risk for both periodontal disease and preterm birth.
In the past few decades, major advances have been made in the elucidation of the etiology, pathogenesis, and treatment of periodontal disease. Basic scientific data continue to be collected to enhance our knowledge of the host response. Although the findings currently available suggest a strong association among a number of systemic diseases, certain hormonal states, and periodontal disease, further rigorous randomized, controlled clinical trials are needed to establish causality and benefits of treatment. These developments will be of importance to the obstetrician and gynecologist as periodontal disease may become a potential modifiable risk factor for several systemic conditions, including pregnancy complications encountered in daily practice.
1. Albandar JM, Brunelle JA, Kingman A. Destructive periodontal disease in adults 30 years of age and older in the United States, 1988–1994. J Periodontol 1999:70:13–29.
2. Durack DT. Prevention of infective endocarditis. N Engl J Med 1995; 332: 38–44.
3. Silver JG, Martin AW, McBride BC. Experimental transient bacteremias in human subjects with varying degrees of plaque accumulation and gingival inflammation. J Clin Periodontol 1977; 4: 92–99.
4. Sconyers JR, Crawford JJ, Moriarty JD. Relationship of bacteremia and tooth brushing in patients with periodontitis. J Am Dent Assoc 1973; 87: 616–622.
5. Genco RJ, Slots J. Host responses in periodontal disease. J Dent Res 1984; 63: 441–451.
6. Kornman KS, Crane A, Wang HY et al. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997; 24: 72–77.
7. Salvi GE, Lawrence HP, Offenbacher S et al. Influence of risk factors on the pathogenesis of periodontitis. Periodontol 2000 1997; 14: 173–201.
8. Papapanou PN. Periodontal diseases: Epidemiology. Ann Periodontol 1996; 1: 1–36.
9. Salvi GE, Beck JD, Offenbacher S. PGE2
, IL-1βb, and TNF-αa responses in diabetics as modifiers of periodontal disease expression. Ann Periodontol 1998; 3: 40–50.
10. Grossi SG, Zambon JJ, Ho AW et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994; 65: 260–267.
11. Grossi SG, Genco RJ, Machtei EE et al. Assessment of risk for periodontal disease. II Risk indicators for alveolar bone loss. J Periodontol 1995; 66: 23–29.
12. Williams RC. Periodontal disease. N Engl J Med 1990; 322: 373–382.
13. Beck JD, Slade G, Offenbacher S. Oral disease, cardiovascular disease, and systemic inflammation. Periodontology 2000; 23: 110–120.
14. Genco RJ. Periodontal disease and risk for myocardial infarction and cardiovascular disease. Cardiovasc Rev Rep 1998:34–40.
15. Holden C. Healthy gums for a happy heart. Science 1997; 276: 203.
16. DeStefano F, Anda RF, Kahn HS et al. Dental disease and risk of coronary heart disease and mortality. Br J Med 1993; 306: 688–691.
17. Genco R, Chadda S, Grossi S et al. Periodontal disease is a predictor of cardiovascular disease in a native American population [Abstract 3158]. J Dent Res 1997;(Suppl)76:408.
18. Beck JD, Barcia R, Heiss G et al. Periodontal disease and cardiovascular disease. J Periodontol 1996; 67: 1123–1137.
19. Danesh J. Coronary heart disease, Helicobacter pylori
, dental disease, Chlamydia pneumoniae
, and cytomegaly virus. Am Heart J 1999; 138: S434–S437.
20. Hujoel PP, Drangsholt M, Spiekerman C et al. Periodontal disease and coronary heart disease risk. JAMA 2000; 284: 1406–1410.
21. Kinane DF, Lowe GDO. How periodontal disease may contribute to cardiovascular disease. Periodontology 2000> 2000;23:121–126.
22. Herzberg MC, Meyer MW. Effects of oral flora on platelets: Possible consequences in cardiovascular disease. J Periodontol 1996; 67: 1138–1142.
23. Shlossman M, Knowler WC, Pettitt DJ et al. Type 2 diabetes mellitus and periodontal disease. J Am Dent Assoc 1990; 121: 531–536.
24. Emrich LJ, Shlosmann M, Genco RJ. Periodontal disease in non-insulin-dependent diabetes mellitus. J Periodontol 1991; 62: 123–130.
25. Nelson RG, Shlossman M, Budding LM et al. Periodontal disease and NIDDM in Pima Indians. Diabetes Care 1990; 13: 836–840.
26. Ciancola LJ, Park BH, Bruck E et al. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes). J Am Dent Assoc 1982; 104: 653–660.
27. Safkan-Seppala B, Ainamo J. Periodontal conditions in insulin-dependent diabetes mellitus. J Clin Periodontol 1992; 19: 24–29.
28. Taylor GW, Burt BA, Becker MP et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus. J Periodontol 1996; 67: 1085–1093.
29. Taylor GW, Burt BA, Becker MP et al. Glycemic control and alveolar bone loss progression in type 2 diabetes. Ann Periodontol 1998; 3: 30–39.
30. Miller LS, Manwell MA, Newbold D et al. The relationship between reduction in periodontal inflammation and diabetes control: A report of 9 cases. J Periodontol 1992; 63: 843–848.
31. Grossi SG, Genco RJ. Periodontal disease and diabetes mellitus: A two-way relationship. Ann Periodontol 1998; 3: 51–61.
32. Dennison DK, Gottsegen R, Rose LF. Diabetes and periodontal diseases. J Periodontol 1996; 67: 166–176.
33. Lalla E, Lamster IB, Drury S et al. Hyperglycemia, glycoxidation, and receptor for advanced glycation endproducts: Potential mechanisms underlying diabetic complications, including diabetes-associated periodontitis. Periodontology 2000 2000; 23: 50–63.
34. Vittek J, Hernandez MR, Wenk EJ et al. Specific estrogen receptors in human gingiva. J Clin Endocrinol Metab 1982; 54: 608–612.
35. Sooriyamoorthy M, Gower DB. Hormonal influences on gingival tissue: Relationship to periodontal disease. J Clin Periodontol 1989; 16: 201–208.
36. Amar S, Chung KM. Influence of hormonal variation on the periodontium in women. Periodontology 2000 1994; 6: 79–87.
37. Kalkwarf KL. Effect of oral contraceptive therapy on gingival inflammation in humans. J Periodontol 1978; 49: 560–563.
38. Miyazaki H, Yamashita Y, Shirahama R et al. Periodontal condition of pregnant women assessed by CPTIN. J Clin Periodontol 1991; 18: 751–754.
39. Gornstein RA, Lapp CA, Bustos-Valdes SM et al. Androgens modulate interleukin-6 production by gingival fibroblasts in vitro. J Periodontol 1999; 70: 604–609.
40. Kornman KS, Loesche WJ. The subgingival microbial flora during pregnancy. J Periodont Res 1980; 15: 111–122.
41. Kornman KS, Loesche WJ. Effects of estradiol and progesterone on Bacteroides melanogenicus
and Bacteroides gingivalis
. Infect Immun 1982; 35: 256–263.
42. Sutcliffe P. A longitudinal study of gingivitis and puberty. J Periodont Res 1972; 7: 52–58.
43. Nakagawa S, Fujii H, Machida Y et al. A longitudinal study from prepuberty to puberty of gingivitis. J Clin Periodontol 1994; 21: 658–665.
44. El-Ashiry GM, El-Kafrawy AH, Nasr MF et al. Effects of oral contraceptives on the gingiva. J Periodontol 1971; 42: 273–275.
45. Lindhe J, Attstrom R. Gingival exudation during the menstrual cycle. J Periodont Res 1967; 2: 194–198.
46. Pankhurst CL, Waite IM, Hicks KA et al. The influence of oral contraceptive therapy on the periodontium—Duration of drug therapy. J Periodontol 1981; 52: 617–620.
47. Jeffcoat MK, Chestnut CH. Systemic osteoporosis and oral bone loss: evidence show increased risk factors. J Am Dent Assoc 1993; 124: 49–56.
48. Von Wowern N, Klausen B, Kollerup G. Osteoporosis: A risk factor in periodontal disease. J Periodontol 1994; 65: 1134–1138.
49. Jeffcoat MK. Osteoporosis. A possible modifying factor in oral bone loss. Ann Periodontol 1998; 3: 312–321.
50. Jeffcoat MK, Lewis CE, Reddy MS et al. Postmenopausal bone loss and its relationship to oral bone loss. Periodontology 2000 2000; 23: 94–103.
51. Norderyd OM, Grossi SG, Machtei EE et al. Periodontal status of women taking postmenopausal estrogen supplementation. J Periodontol 1993; 64: 957–962.
52. Reinhardt RA, Payne JB, Maze CA et al. Influence of estrogen and osteopenia/osteoporosis on clinical periodontitis in postmenopausal women. J Periodontol 1999; 70: 823–828.
53. Grodstein F, Colditz G, Stampfer M. Post-menopausal hormone use and tooth loss: A prospective study. J Am Dent Assoc 1996; 127: 370–377.
54. Paganini-Hill A. The benefits of estrogen replacement therapy on oral health: The Leisure World Cohort. Arch Intern Med 1995; 155: 2325–2329.
55. Loe H, Silness J. Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odont Scand 1963; 21: 533–551.
56. Cohen DW, Friedman L, Shapiro J et al. A longitudinal investigation of the periodontal changes during pregnancy and 15 months postpartum. J Periodontol 1971; 42: 563–570.
57. Rateitschak KH. Tooth mobility changes in pregnancy. J Periodont Res 1967; 2: 199–206.
58. Raber-Durlacher JE, van Steenbergen TJM, van der Velden U et al. Experimental gingivitis during pregnancy and postpartum: Clinical, endocrinological, and microbiological aspects. J Clin Periodontol 1994; 21: 549–558.
59. Jensen J, Liljemark W, Bloomquist C. The effect of female sex hormones on subgingival plaque. J Periodontol 1981; 52: 599–602.
60. Raber-Durlacher JE, Zeijlemaker WP, Meinesz AAP et al. CD4 to CD8 ratio and in vitro lymphoproliferative responses during experimental gingivitis in pregnancy and postpartum. J Periodontol 1991; 62: 663–667.
61. Raber-Durlacher JE, Leene W, Palmer-Bouva CCR et al. Experimental gingivitis during pregnancy and postpartum: Immunohistochemical aspects. J Periodontol 1993; 64: 211–218.
62. O’Neil TCA. Maternal T lymphocyte response and gingivitis in pregnancy. J Periodontol 1979; 50: 178–182.
63. Shalini S, Ganesh P, Anand AR. Actinobacillus actinomycetemcomitans
septicemia during pregnancy. Int J Gynaecol Obstet 1995; 51: 57–58.
64. Bendon RW, Bornstein S, Faye-Petersen OM. Two fetal deaths associated with maternal sepsis and with thrombosis of the intervillous space of the placenta. Placenta 1998; 19: 385–389.
65. Offenbacher S, Katz V, Fertik G et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996; 67: 1103–1113.
66. Dasanayake AP. Poor periodontal health of the pregnant woman as a risk factor for low birth weight. Ann Periodontol 1998; 3: 206–212.
67. Marwick C. Periodontal disease may pose one risk for premature birth. JAMA 2000; 283: 2922.
68. Bejar R, Curbelo V, Davis C et al. Premature labor. II. Bacterial sources of phospholipase. Obstet Gynecol 1981; 57: 479–482.
69. Gibbs RS, Romero R, Hillier SL et al. A review of premature births and subclinical infection. Am J Obstet Gynecol 1992; 166: 1515–1528.
70. Beutler B, Krohin N, Milsark IW et al. Control of cachectin (TNF) synthesis: Mechanism of endotoxin resistance. Science 1986; 232: 977–980.
71. Michie HR, Manogue RR, Spriggs DR et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481–1486.
72. Pollard JK, Thai D, Mitchell MD. Evidence for a common mechanism of action of interleukin 1-beta5, tumor necrosis factor-alpha, and epidermal growth factor on prostaglandin production in human chorion cells. Am J Reprod Immunol 1993; 30: 146–153.
73. Romero R, Mazor M, Wu YK et al. Bacterial endotoxin and tumor necrosis factor stimulate prostaglandin production by human decidua. Prostaglandins Leukot Essent Fatty Acids 1989; 37: 183–186.
74. Curebelo V, Bejar R, Benirschke K et al. Premature labor. I. Prostaglandin precursors in human placental membrane. Obstet Gynecol 1981; 57: 473–478.
75. Casey ML, MacDonald PC, Mitchell MD. Characterization of prostaglandin formation by human amnion cells in monolayer culture. Prostaglandin 1984; 27: 421–427.
76. Offenbacher S, Jared HL, O’Reilly PG et al. Potential pathogenic mechanisms of periodontitis-associated pregnancy complications. Ann Periodontol 1998; 3: 233–250.
77. Hill GB. Preterm birth: Associations with genital and possible oral microflora. Ann Periodontol 1998; 3: 222–232.
78. Offenbacher S. Periodontal diseases: Pathogenesis. Ann Periodontol 1996; 1: 821–878.