**Abstract**

Periodontal medicine is a broad term commonly used to define the relationship between periodontitis and systemic health. Periodontitis is a highly prevalent, chronic multifactorial infectious disease, induced by the dysbiotic biofilm that triggers a persistent systemic inflammation and recurrent bacteremia. There is a growing body of scientific evidence that suggests the potential implication of periodontitis in the causation and progression of various systemic disease and conditions, such as diabetes, cardiovascular disease, pulmonary disease, adverse pregnancy outcomes and cancer. Some studies consider periodontitis as an independent risk factor for preterm birth, growth restriction, low birth-weight and preeclampsia. However not all studies support the association. Despite sparse scientific data, some studies indicate that individuals with periodontitis are at increased risk for cancer development, due to the increased inflammatory burden sustained by the presence of periodontal pathogens. This chapter emphasis the relationship between periodontitis and adverse pregnancy outcomes and the underlying mechanisms that link peridontitis to oral carcinogenesis.

**Keywords:** periodontitis, periodontal medicine, adverse pregnancy outcomes, preterm birth, malignancy, carcinogenesis, head, neck squamous cell carcinoma

#### **1. Introduction**

#### **1.1 Periodontitis - overview**

Periodontitis is a chronic disease, determined by the dysbiotic biofilm that does not merely affect the oral cavity, but also impacts the systemic health by triggering a persistent low-grade, systemic inflammation and recurrent bacteriemia. Its clinical consequences, especially in extended and severe forms, impair the overall quality of life of the individuals.

Significant progress has been made in determining the relationship between periodontitis and various systemic diseases. Some researchers consider periodontitis as an independent risk factor that mediates the development and even progression of certain systemic disease. Conversely, specific systemic diseases and conditions have a negative impact on the periodontium and can even interfere with periodontitis' progression. Valuable information are available with respect to several mechanisms underlying the correlation between periodontitis and systemic conditions. However, there are still plenty of issues, for which the scientific literature cannot currently provide specific answers, emphasizing their complexity and the need for further research in this area of interest.

#### **1.2 Information search strategy and article selection**

We conducted a search on the electronic database MEDLINE (PubMed) using MeSH terms and key words to identify relevant studies published between January 2011 and November 2020. One search strategy included the following subject terms combination: (["periodontitis"] OR ["periodontal disease"]) AND (["pregnancy outcome") OR ["preterm delivery"] OR ["birth weight"] OR ["pre-eclampsia"]). We searched another set of keywords as follows: (["periodontitis"]) OR ["periodontal disease"]) AND (["microbiota"] OR ["porphyromonas gingivalis"]) AND (["squamous cell carcinoma of head and neck"] OR ["head and neck neoplasms"] OR ["oropharyngeal neoplasms"] OR ["oral squamous cell carcinoma"] OR ["mouth neoplasms"]). Filters used were: Humans and English. A hand-search was also conducted to identify any additional related articles in Journal of Periodontology, Journal of Clinical Periodontology, and on the EFP Official Website/Gum disease & General Health Resources. Further articles of interest were searched based on reference lists of the publications where papers were available online. The presence of duplicates was assessed through Zotero version 5.0.93 software.

#### **2. The periodontal medicine concept**

Periodontitis is a highly prevalent, chronic multifactorial infectious disease, induced by the subgingival dysbiotic biofilm that produces a local immuneinflammatory response leading to the destruction of periodontal tissues. Its clinical manifestation, especially in extended and severe forms, impairs the overall quality of life, by affecting the psychosomatic, social and functional aspects of the individuals. Periodontitis also impacts the systemic health by triggering a persistent low-grade, systemic inflammation and recurrent bacteremia [1–4].

The concept of periodontal medicine was first introduced by Offenbacher [5]. Periodontal medicine is a broad term that describes an emerging branch of periodontology exploring the two way relationship between periodontal and systemic status, as well as new diagnostic tools and advanced treatment approaches that take into consideration the link between periodontitis and various systemic diseases [5]. Current evidence suggests that periodontitis acts as a biologically plausible risk factor for the development and progression of other chronic, inflammatory diseases [4].

Some associations between periodontitis and certain systemic conditions, such as diabetes mellitus, cardiovascular disease, and adverse pregnancy outcomes have been reported [6, 7]. However, there is still inconsistent information on the association between periodontitis and other systemic pathologies such as cancers, chronic renal disease, chronic obstructive pulmonary disease, minor cognitive impairment, rheumatoid arthritis, metabolic syndrome, and obesity [7, 8]. Contrarily, certain systemic diseases and conditions directly affect or worsen the periodontal status [9]. *Periodontal Medicine: Impact of Periodontal Status on Pregnancy Outcomes and Carcinogenesis DOI: http://dx.doi.org/10.5772/intechopen.96147*

Establishing the potential causal relationship between periodontitis and chronic inflammatory systemic diseases and conditions is a difficult task, because complex pathologic conditions are the consequence of multiple exposures and broad interactions of external and host-derived factors that modulate disease initiation and development [1].

Noncommunicable diseases account for seven of ten worldwide deaths. In 2016, approximately 71% of the 56.9 million worldwide deaths were due to noncommunicable diseases and around 80% were due to cancers, cardiovascular diseases, chronic respiratory diseases and diabetes [10]. Since periodontitis is a potential, independent risk factor for many of these diseases, further investigations might bring additional benefits in improving the overall health status of the population and downsizing the socioeconomic burden at the same time.

### **3. Pathophysiological link between periodontitis and systemic diseases**

Today there is increasing recognition that inflammation is a common molecular pathway that underlies the pathogenesis of diverse human diseases, ranging from infection to immune-mediated disorders, cardiovascular pathology, diabetes, metabolic syndrome, neurodegeneration, and cancer. Two pathogenic mechanisms might be involved in the activation of the pathways driving to development of pathologies at distant sites [11, 12].

The direct mechanism relies on the translocation of periodontal pathogens via systemic blood circulation, causing colonization and inflammation at a distance from the diseased periodontium. This mechanism corresponds to the concept of the "mobile oral microbiome" [13]. Moderate and severe periodontitis are characterized by deep periodontal pockets, with an ulcerated internal gingival epithelium, providing direct access for periodontal pathogens and their toxic by-products into the blood flow [12, 14]. Periodontal treatment, as well as daily tooth brushing cause episodic injuries to the periodontal tissues, which further leads to recurrent, transient bacteremia and endotoxinemia [11, 14]. On the other hand, bacterial and endotoxin dissemination may be enabled by macrophages and dendritic cells, serving as carriers for the pathogens [13, 15].

The indirect mechanism is defined by the systemic inflammatory response towards periodontal pathogens or as a result of metastatic periodontal inflammation [12, 13]. Systemic dissemination of periodontal pathogens triggers the activation of acute phase proteins in the liver, which amplify the systemic inflammatory response in order to provide protection against the bacterial threat. Acute phase protein production and the following events, as a response to periodontal infection, may affect the physiological functionality of other organs and systems. Moreover, cytokines play critical roles in orchestrating the effective immune response of leukocytes and parenchymal cells towards systemic bacteremia. Leukocytes are the major source of innate cytokine responses. A healthy immune system has the capacity to effectively eliminate pathogens and restore homeostasis. However, a dysfunctional immune response and an ineffective clearance will eventually lead to the initiation and progression of inflammatory diseases [11, 13, 14].

#### **4. The relationship between periodontitis and pregnancy outcomes**

#### **4.1 The influence of hormonal variations in pregnancy on the periodontium**

Pregnancy is characterized by significant fluctuations in the levels of progesterone and estrogen hormones reaching up to 30 times higher plasma levels, by

the end of the third trimester. Various types of periodontal cells display receptors for these hormones [16, 17], which could explain the functional changes in the periodontal cells consecutive to fluctuating hormone levels during gestation, as well as microcirculatory system alterations [18]. These modifications are triggering an increased periodontal inflammatory manifestation, even in the presence of low levels of dental plaque, especially in the second and third trimesters of pregnancy. A gradual decrease of inflammatory manifestations after parturition has been reported [16–18].

Major alterations in the maternal immune system occur during pregnancy, which could favor periodontal infection and consecutive inflammation. Pregnant women have a reduction in phagocytosis and bactericidal activities of peripheral neutrophils and changes in the monocytes stimulated secretion of proinflammatory mediators after the contact with bacterial endotoxines [16].

Pregnancy not only impacts periodontal inflammation and host immune response, but also induces an increase in the oral microbial load and modifications in the oral microbiological profiles, as a consequence of elevated levels of steroid hormones [16, 18]. Significant changes in the subgingival microbiota with increases in the proportion of some periodontal pathogens such as *Bacteroides melaninogenicus*, *Prevotella intermedia*, and *Porphyromonas gingivalis* have been described [16].

Pregnancy increases the risk of new-onset periodontal disease, but it can also activate preexisting periodontitis leading to an infectious and inflammatory load similar to new-onset periodontitis. Maternal periodontitis may reflect an intrinsic inflammatory or innate immunity trait that places the woman at risk for severe forms of periodontal disease, as well as for the common terminal biochemical inflammatory cascade associated with adverse pregnancy outcomes [19].

#### **4.2 Epidemiological associations between periodontitis and adverse pregnancy outcomes**

Many studies have associated adverse pregnancy outcomes, such as low birth weight, preterm birth and preeclampsia, with maternal periodontitis. The first case–control study referring to the relationship between periodontitis and pretermbirth reported a 7.5 higher risk ratio for preterm births for the group of women with periodontitis as compared to the periodontal healthy control group [19]. Other studies have indicated oral maternal infections, including chronic periodontitis, as potential independent risk factors for various complications throughout the pregnancy. A systematic review including case–control, cohort case-control and controlled trials, confirmed the positive association between periodontitis and adverse pregnancy outcomes [20]. A meta-analysis reported a significant association between periodontitis and preterm birth, with an odds ratio of 1.38 [21]. A more recent meta-analyses including 10.215 women, indicates that periodontitis doubles the risk for preterm delivery, the calculated odds ratio being of 2.01 (95% CI 1.71–2.36) [22]. However, the level of association is mostly modest, mainly due to the high degree of heterogeneity between the studies, particularly with respect to the diversity of periodontitis disease case definitions [23].

The relationship between periodontitis and adverse pregnancy outcomes was investigated also by means of surrogate markers defining both conditions. Many studies indicate a positive association between gingival crevicular fluid, inflammatory mediators and adverse pregnancy outcomes [23, 24].

An umbrella review which analyzed systematic reviews and meta-analysis showed that non-surgical periodontal therapy with or without antibiotic therapy has low to moderate positive effects on reducing the frequency of the common pregnancy complications related to periodontitis [25]. The large heterogeneity of

#### *Periodontal Medicine: Impact of Periodontal Status on Pregnancy Outcomes and Carcinogenesis DOI: http://dx.doi.org/10.5772/intechopen.96147*

the outcomes of the interventional studies is due to variations in periodontitis case definition, sample particularities, follow-up period, control of confounding factors, as well as the therapy moment throughout the pregnancy [14, 25]. The nonsurgical periodontal therapy may be ineffective in reducing inflammatory cascade once activated and thus eventually lead to preterm birth [14].

#### **4.3 Medical impact of adverse pregnancy outcomes**

Preterm birth is defined as the birth prior to 37 weeks of gestation [26]. Complications of preterm birth are a leading cause of infant deaths worldwide raising the neonatal mortality risk rate up to 11.4 [27, 28]. The prevalence of preterm birth ranges from 5 to 7% in high-income countries, and is generally higher in low-income ones [29]. In 2014, the estimated global preterm birth rate was 10.6%, the equivalent of about 14.84 million preterm births from a total number of 139.95 million livebirths [30]. Therefore, prematurity is considered a major public health issue and the identification of any potential risk factor is of tremendous importance [27, 28, 30].

Low birth weight is defined as a birth weight below 2500 g regardless of gestational age of live infants [31, 32]. Various maternal factors such as extremes of maternal age, multiple pregnancies, obstetric complications, chronic maternal conditions like hypertensive disorders, and nutritional status or environmental exposures such as tobacco and drug use, can contribute to the low birth weight of the neonate. The estimates rate of global low birth weight for 2015 was 14.6% [31].

Maternal mortality is another important adverse outcome during pregnancy and is considered the death of a woman during pregnancy, within 42 days post-partum or during an abortion, as a consequence of any pregnancy associated pathological condition or complication [33]. The yearly number of global maternal deaths decreased from 532.000 in 1990, to 303.000 in 2015 [34]. Between 1990 and 2015, 10.7 million women worldwide died from various causes related to the evolution of pregnancy. Among the main risk factors of maternal mortality, pre-eclampsia and eclampsia are still in leading positions. Strategies aiming to reduce the number of deaths related to eclampsia showed a relatively low efficacy, which indicates the need to turn the attention to other potential risk factors in order to significantly lower mortality rates associated to eclampsia [33].

### **4.4 Pathophysiological link between periodontitis and adverse pregnancy outcomes**

Hematogenous dissemination of periodontal bacteria is suspected to cause adverse pregnancy outcomes, by genitourinary tract and fetal–maternal unit colonization [16, 35]. Recent research indicates the presence of bacteria derived from supra- and subgingival biofilms in the placental microbiome. Moreover, some studies suggest that placental microbial profiles are closer to the oral microbial profiles than to the gut microbiome [36–38]. However, there is no general agreement on the bacterial translocation concept. The presence of oral bacteria in the placenta could be the consequence of an external contamination [39].

Although maternal infection is considered a major contributor of adverse pregnancy outcomes, a critical factor which can trigger the preterm birth might be rather the persistent inflammation generated by chronic periodontal infections. Inflammatory mediators that are abundantly produced at the affected sites determine periodontal tissue breakdown [14]. From a clinical point of view, deep periodontal pockets indicate the magnitude of the periodontal inflammation [39]. Chronic, long-term periodontal inflammation will eventually lead to a continuous passage of cytokines, chemokines, and gingival-derived C-reactive protein from the affected periodontal tissues into the bloodstream inducing a systemic acute-phase reaction and also maintaining a chronic, systemic inflammatory status [11, 12, 14]. High levels of C reactive protein over longer periods of time increases the risk for premature birth, but also of diabetes, and cardiovascular disease [13, 40].

Local and systemic accumulations of pro-inflammatory mediators, such as prostaglandins E2, interleukins, tumor necrosis factor α (TNF- α) and metalloproteinase (MMP) can stimulate the labor [41]. It is likely that spontaneous preterm parturition is induced by a high level of inflammation in the early stage of pregnancy [39]. However, the exact role of periodontal inflammation and the potential biological mechanisms that link periodontal disease with adverse pregnancy outcomes is not fully understood.

## **4.5 Clinical indications for pregnant women**

European Federation of Periodontology guidelines for oral-health professionals provides the following recommendations [42]:


*Periodontal Medicine: Impact of Periodontal Status on Pregnancy Outcomes and Carcinogenesis DOI: http://dx.doi.org/10.5772/intechopen.96147*

