**1.3 Maternal immunological changes during pregnancy**

Previously, it was believed that there was little or no exposure of the mother to the immunologically foreign cells of the fetus. It is now clarified that there is considerable mixing of maternal and fetal cells, especially at the maternal-fetal interface.

One of the major alterations in the immune system during pregnancy is partial dampening of the mother's cell-mediated immune responses associated with T-helper type 1 (Th1) lymphocytes. Stimulated Th2 cells produce an array of cytokines, such as interleukin-4, interleukin-5, and interleukin-10, which suppress cell-mediated immune responses [13–15]. The mechanisms of this partial shift in the Th1/Th2 balance favoring Th2-mediated immune responses are not fully understood but are partly dependent on changes in progesterone, estrogen, and chorionic gonadotropin during pregnancy [8, 16].

Neutrophils in the peripheral circulation of pregnant women exhibit a significant reduction in myeloperoxidase, respiratory burst activities, and phagocytosis [8]. All of these inhibitory effects on neutrophils are most marked during the second and third trimesters [17, 18]. The postpartum readjustment of the mother's immune system occurs soon after birth, with rapid re-establishment of several Th1-associated and other proinflammatory host responses (**Table 1**). The phenomenon of return of immunological response after postpartum has been termed the "immune reconstitution syndrome" [15].

### **1.4 Gingival pyogenic granulomas in pregnancy**

Pyogenic granuloma (PG) or pregnancy tumor is a non-specific inflammatory lesion of the skin and mucous membranes. PG occurs in both males and females as inflammatory lesion on skin or mucous membrane. PG occurs approximately 0.5–2.0% of pregnant women with gingival lesions developing in interdental gingiva (**Figure 1**). They are also called pregnancy tumors or granuloma gravidarum.


**21**

*Periodontal Disease and Pregnancy Outcome DOI: http://dx.doi.org/10.5772/intechopen.84949*

**Figure 1.**

delivery, especially if local irritants are removed [8].

*Bacteroides* species, and *Campylobacter rectus* [8].

**1.5 Plaque-induced periodontal infections in pregnancy**

 The lesion frequently presents as a rapidly growing gingival mass that may bleed profusely when touched. Based on histological features, it is a highly proliferative vascular lesion resembling granulation tissue. The etiological triggers for pyogenic granuloma are unknown; most lesions are associated with the presence of local irritants or trauma [19]. The pathogenesis of the lesion has been linked to female sex hormones, which stimulate increased local synthesis of angiogenic factors such as vascular endothelial growth factor and angiopoietin-2 [8]. Clinical complaints with pregnancy-associated pyogenic granulomas include gingival bleeding, tenderness, and esthetic problems. Treatment may include surgical removal, especially if the lesion is large and symptomatic [19, 20]. However, in many cases, the lesions undergo partial or complete resolution after

*A case of pyogenic granuloma in maxillary right lateral incisor region in a 9-month pregnant woman.*

Experimental gingivitis study of women during pregnancy and at 6 months postpartum showed that there was more gingival inflammation during pregnancy despite no significant differences in plaque scores. Cross-sectional studies indicate that 100% of women develop gingivitis between 3 and 8 months of their pregnancy, with a gradual decrease after parturition [21]. In some cases, the gingival inflammation is very severe and may be accompanied by gingival tenderness and profuse bleeding. Longitudinal studies have demonstrated that, during pregnancy, probing depths increase as the gingival inflammation increases. The increase in probing depths has been attributed to movement of the gingival margin in a coronal direction because of inflammation-induced swelling of the gingiva. Most authors have found that there is usually no permanent loss of clinical attachment [22, 23]. Individuals, especially those who have chronic periodontitis prior to becoming pregnant, tend to have increased rate of progression of periodontitis. Several standard cultural microbiological studies have shown that estrogen and progesterone changes associated with pregnancy have an effect on the composition of the subgingival microbiota. Some of the periodontal pathogens that apparently blossom under the selective pressure of pregnancy-associated steroids are *Prevotella intermedia*,

Diverse array of pathogens that have the potential to cause periodontal tissue damage have been found in pregnant and parous women through microbiological studies using DNA probes [24, 25]. Several types of spirochetes, including *Treponema denticola*, as well as numerous gram-positive and gram-negative putative periodontal pathogens, are found in pregnant and nonpregnant women. Prominent gram-positive bacteria in this group are *Streptococcus intermedius*, *Parvimonas micra*

#### **Table 1.**

*Innate and adaptive immunity changes during pregnancy [8]*

*Periodontal Disease and Pregnancy Outcome DOI: http://dx.doi.org/10.5772/intechopen.84949*

**Figure 1.**

*Gingival Disease - A Professional Approach for Treatment and Prevention*

Previously, it was believed that there was little or no exposure of the mother to the immunologically foreign cells of the fetus. It is now clarified that there is considerable mixing of maternal and fetal cells, especially at the maternal-fetal interface. One of the major alterations in the immune system during pregnancy is partial

Neutrophils in the peripheral circulation of pregnant women exhibit a significant reduction in myeloperoxidase, respiratory burst activities, and phagocytosis [8]. All of these inhibitory effects on neutrophils are most marked during the second and third trimesters [17, 18]. The postpartum readjustment of the mother's immune system occurs soon after birth, with rapid re-establishment of several Th1-associated and other proinflammatory host responses (**Table 1**). The phenomenon of return of immunological response after postpartum has been termed the "immune reconstitution syndrome" [15].

Pyogenic granuloma (PG) or pregnancy tumor is a non-specific inflammatory lesion of the skin and mucous membranes. PG occurs in both males and females as inflammatory lesion on skin or mucous membrane. PG occurs approximately 0.5–2.0% of pregnant women with gingival lesions developing in interdental gingiva

Effect on cellular immunity via enhanced phagocytosis and superoxide anion

progesterone-induced blocking factor and IL-10; decreased IFN-c production

of complement regulatory proteins including membrane cofactor protein (CD46),

Effect on humoral immunity via increased levels of acute-phase reactants (e.g.,

Effect on humoral immunity via increased T cell-dependent immunoglobulin

IL, interleukin; IFN, interferon; Th1, T-helper type 1 lymphocytes; Th2, T-helper

generation (respiratory burst); increased expression of CD14

Complement Effect on humoral immunity by increased C3, C4, and C1q levels and elevated levels

T cells Effect on cellular immunity via enhanced Th2 (e.g., IL-4, IL-10) and Th3 (i.e., TGF-

type 2 lymphocytes; TGF, transforming growth factor *IL, interleukin; IFN, interferon; Th1, T-helper type 1 lymphocytes; Th2, T-helper type 2 lymphocytes; TGF,* 

(**Figure 1**). They are also called pregnancy tumors or granuloma gravidarum.

Natural killer cells Effect on cellular immunity via downregulation of cytotoxic activity by

decay accelerating factor (CD55), and CD59

b) and suppressed Th1 (IFN-c, IL12) responses

B cells Effect on cellular immunity via increased Th2-induced B-cell activity

fibrinogen and ceruloplasmin)

production

*Innate and adaptive immunity changes during pregnancy [8]*

dampening of the mother's cell-mediated immune responses associated with T-helper type 1 (Th1) lymphocytes. Stimulated Th2 cells produce an array of cytokines, such as interleukin-4, interleukin-5, and interleukin-10, which suppress cell-mediated immune responses [13–15]. The mechanisms of this partial shift in the Th1/Th2 balance favoring Th2-mediated immune responses are not fully understood but are partly dependent on changes in progesterone, estrogen, and chorionic

**1.3 Maternal immunological changes during pregnancy**

gonadotropin during pregnancy [8, 16].

**1.4 Gingival pyogenic granulomas in pregnancy**

**Components Changes in host response**

Innate immunity Monocytes and neutrophils

Acute-phase reactants

Adaptive immunity

*transforming growth factor.*

**20**

**Table 1.**

*A case of pyogenic granuloma in maxillary right lateral incisor region in a 9-month pregnant woman.*

 The lesion frequently presents as a rapidly growing gingival mass that may bleed profusely when touched. Based on histological features, it is a highly proliferative vascular lesion resembling granulation tissue. The etiological triggers for pyogenic granuloma are unknown; most lesions are associated with the presence of local irritants or trauma [19]. The pathogenesis of the lesion has been linked to female sex hormones, which stimulate increased local synthesis of angiogenic factors such as vascular endothelial growth factor and angiopoietin-2 [8]. Clinical complaints with pregnancy-associated pyogenic granulomas include gingival bleeding, tenderness, and esthetic problems. Treatment may include surgical removal, especially if the lesion is large and symptomatic [19, 20]. However, in many cases, the lesions undergo partial or complete resolution after delivery, especially if local irritants are removed [8].

#### **1.5 Plaque-induced periodontal infections in pregnancy**

Experimental gingivitis study of women during pregnancy and at 6 months postpartum showed that there was more gingival inflammation during pregnancy despite no significant differences in plaque scores. Cross-sectional studies indicate that 100% of women develop gingivitis between 3 and 8 months of their pregnancy, with a gradual decrease after parturition [21]. In some cases, the gingival inflammation is very severe and may be accompanied by gingival tenderness and profuse bleeding. Longitudinal studies have demonstrated that, during pregnancy, probing depths increase as the gingival inflammation increases. The increase in probing depths has been attributed to movement of the gingival margin in a coronal direction because of inflammation-induced swelling of the gingiva. Most authors have found that there is usually no permanent loss of clinical attachment [22, 23]. Individuals, especially those who have chronic periodontitis prior to becoming pregnant, tend to have increased rate of progression of periodontitis. Several standard cultural microbiological studies have shown that estrogen and progesterone changes associated with pregnancy have an effect on the composition of the subgingival microbiota. Some of the periodontal pathogens that apparently blossom under the selective pressure of pregnancy-associated steroids are *Prevotella intermedia*, *Bacteroides* species, and *Campylobacter rectus* [8].

Diverse array of pathogens that have the potential to cause periodontal tissue damage have been found in pregnant and parous women through microbiological studies using DNA probes [24, 25]. Several types of spirochetes, including *Treponema denticola*, as well as numerous gram-positive and gram-negative putative periodontal pathogens, are found in pregnant and nonpregnant women. Prominent gram-positive bacteria in this group are *Streptococcus intermedius*, *Parvimonas micra*

(formerly *Micromonas micros* and *Peptostreptococcus micros*), *Peptostreptococcus anaerobius*, *Staphylococcus aureus*, and *Actinomyces odontolyticus*. Frequently detected gram-negative organisms include *Porphyromonas gingivalis*, *Tannerella forsythia*, *C. rectus*, *P. intermedia*, *Prevotella nigrescens*, *Fusobacterium nucleatum*, *Eikenella corrodens*, *Selenomonas noxia*, *Enterococcus faecalis*, *Pseudomonas aeruginosa*, *Haemophilus influenzae*, and *Aggregatibacter actinomycetemcomitans*. [8] As the immunological changes associated with pregnancy include an increased susceptibility to intracellular pathogens, it is not surprising that survival of locally invasive bacteria such as *P. intermedia* and A. actinomycetemcomitans is enhanced during pregnancy [8].

Gingivitis and periodontitis are plaque-induced periodontal diseases, which are multifactorial infections involving innate and adaptive immune responses of the host toward tooth-associated microbial biofilms (plaque). Pregnant women undergo a lot of physiological and immunological changes during pregnancy. These changes in pregnancy have profound effects on the host-parasite interactions found in microbial infections. The exact mechanisms responsible for the increased gingival inflammation during pregnancy are not fully understood. It is clear that perturbations in neutrophil function, modifications in cellular and humoral immunity, hormone-induced changes in cellular physiology, and local effects on microbial ecology all play crucial roles [8].

#### **1.6 Periodontal infections and gestational diabetes mellitus**

Gestational diabetes mellitus (GDM) refers to the detection of glucose intolerance or raised blood glucose level, for the first time during pregnancy in a woman. Gestational diabetes occurs in approximately 7% of women during pregnancy, and it is a multifactorial disease. GDM has been associated with a long list of risk factors [26]. The increased blood sugar levels make the pregnant woman more susceptible for periodontal diseases.

Periodontitis and diabetes are both risk to each other, and studies have proved that increased diabetes was correlated with increased severity of periodontitis. Studies have been conducted on association of microorganisms and gestational diabetes, and contradictory results are obtained. Several study groups concluded that there appears to be an association between periodontal disease and gestational diabetes mellitus, but prospective studies with large enough sample sizes are required to confirm a relationship [8].

#### **1.7 Preeclampsia in pregnant woman and periodontal infections**

Preeclampsia is a condition characterized by hypertension, with blood pressure higher than 140/90 mmHg, and the patient also suffers from peripheral edema and proteinuria (i.e., urinary excretion of ±300 mg protein in 24 h) [27, 28]. Eclampsia occurs when there is a failure to control physiological abnormalities in a pregnant woman leading to convulsions, coma, and death of the mother.

Multiple factors are involved in the etiology of preeclampsia including infection, genetic susceptibility, immune responses, abnormal placentation secondary to hypoxia and impaired arterial remodeling, and a markedly enhanced systemic inflammatory burden. Increased risk of preeclampsia is seen with elevated serum levels of C-reactive protein; periodontal infections contribute to the increased C-reactive protein level [29, 30]. Therefore, it is biologically plausible that periodontal infections could play a part in the multifactorial etiology of preeclampsia. The link between periodontal disease and risk of preeclampsia is proved only in few populations and has not been confirmed in all populations [8].

**23**

the amnion [8, 33] (**Figure 2**).

*Periodontal Disease and Pregnancy Outcome DOI: http://dx.doi.org/10.5772/intechopen.84949*

tious diseases like periodontal infection.

gingival environment.

**1.8 Two-way relationship between periodontitis and pregnancy**

Periodontal disease (PD) per se causes little clinical features and goes unnoticed until late in disease status. The tissue destruction is characterized by the formation of periodontal pocket that acts as reservoirs for bacterial colonization in the dento-

Multiple factors have been associated with preterm baby (PB) and/or LBW such as smoking, drug use, high or low maternal age, low socioeconomic strata, inadequate prenatal care, low maternal body mass index (BMI), hypertension, genitourinary tract infections, cervical incompetence, diabetes, low nutritional status, stress, and multiple pregnancies [31]. However, more than 50% of the cases do not show the presence of these risk factors and are still affected by PB and/or LBW [15]. The search continues for other causes including the presence of the chronic infec-

The hypothesis that infection remote from the fetal-placental unit may influence PLBW has led to an increased awareness of the potential role of chronic bacterial infections elsewhere in the body. Periodontal disease is associated with a "chronic gram-negative infection" of the periodontal tissues which results in long-term local elevation of pro-inflammatory prostaglandins and cytokines [8] and an increase in the systemic levels of some of these inflammatory mediators [20]. Hence, periodontal disease has a potential to influence PLBW through an indirect mechanism, involving inflammatory mediators or a direct bacterial assault on the amnion [28]. Multiple factors have been associated with the delivery of preterm and low birth weight infants. The evidence suggests that an infectious etiology is the main cause for a large percentage of cases for preterm birth. Genitourinary tract infections, such as bacterial vaginosis, and inflammatory mediators resulting from such infections have been considered a biologically plausible pathway for preterm labor and premature rupture of the membranes. Alternatively, it was hypothesized that preterm low birth weight may be indirectly mediated through distant infections resulting in translocation of bacterial vesicles and lipopolysaccharide (LPS) in the systemic circulation. However, the exact mechanisms for the proposed relationship remain unclear. The periodontal infection is initiated by predominantly gram-negative, anaerobic, and microaerophilic bacteria that colonize the subgingival area. Host defense mechanisms play integral role in the pathogenesis of periodontal disease. It has been postulated that the association between periodontal disease and preterm low birth weight (PLBW) may have similar pathogenic mechanisms as other maternal infections [32]. Inflamed periodontal tissues produce significant amounts of pro-inflammatory cytokines, mainly interleukin 1 (IL-1b), IL-6, prostaglandin E2, and tumor necrosis factor-alpha (TNF-α), which may have systemic effects on the host, leading to premature rupture of membrane. Hence, periodontal disease has the potential to influence preterm low birth weight through an indirect mechanism involving inflammatory mediators or a direct bacterial assault on

The inflammation and infection caused during the periodontal disease is not just limited to the oral cavity but also enters the systemic circulation. The systemic immune response gets activated due to the episodes of bacteraemia and dissemination of endotoxins from periodontal pockets. Systemic circulation may induce pro-inflammatory cytokine production due to the presence of bacteria or bacterial endotoxins in the systemic circulation. IL-6 and C-reactive protein that are released during chronic lowgrade inflammation are further activated due to presence of cytokines in the systemic circulation. The endothelial dysfunction may result due to inflammatory response of endothelial cells. The immune response plays a pivotal role in maintaining a healthy equilibrium between the mother and fetus, during pregnancy. The specific immune response is shifted toward a Th2-type immune response, and the inflammatory

*Gingival Disease - A Professional Approach for Treatment and Prevention*

**1.6 Periodontal infections and gestational diabetes mellitus**

**1.7 Preeclampsia in pregnant woman and periodontal infections**

woman leading to convulsions, coma, and death of the mother.

populations and has not been confirmed in all populations [8].

pregnancy [8].

ecology all play crucial roles [8].

for periodontal diseases.

required to confirm a relationship [8].

(formerly *Micromonas micros* and *Peptostreptococcus micros*), *Peptostreptococcus anaerobius*, *Staphylococcus aureus*, and *Actinomyces odontolyticus*. Frequently detected gram-negative organisms include *Porphyromonas gingivalis*, *Tannerella forsythia*, *C. rectus*, *P. intermedia*, *Prevotella nigrescens*, *Fusobacterium nucleatum*, *Eikenella corrodens*, *Selenomonas noxia*, *Enterococcus faecalis*, *Pseudomonas aeruginosa*, *Haemophilus influenzae*, and *Aggregatibacter actinomycetemcomitans*. [8] As the immunological changes associated with pregnancy include an increased susceptibility to intracellular pathogens, it is not surprising that survival of locally invasive bacteria such as *P. intermedia* and A. actinomycetemcomitans is enhanced during

Gingivitis and periodontitis are plaque-induced periodontal diseases, which are multifactorial infections involving innate and adaptive immune responses of the host toward tooth-associated microbial biofilms (plaque). Pregnant women undergo a lot of physiological and immunological changes during pregnancy. These changes in pregnancy have profound effects on the host-parasite interactions found in microbial infections. The exact mechanisms responsible for the increased gingival inflammation during pregnancy are not fully understood. It is clear that perturbations in neutrophil function, modifications in cellular and humoral immunity, hormone-induced changes in cellular physiology, and local effects on microbial

Gestational diabetes mellitus (GDM) refers to the detection of glucose intolerance or raised blood glucose level, for the first time during pregnancy in a woman. Gestational diabetes occurs in approximately 7% of women during pregnancy, and it is a multifactorial disease. GDM has been associated with a long list of risk factors [26]. The increased blood sugar levels make the pregnant woman more susceptible

Periodontitis and diabetes are both risk to each other, and studies have proved that increased diabetes was correlated with increased severity of periodontitis. Studies have been conducted on association of microorganisms and gestational diabetes, and contradictory results are obtained. Several study groups concluded that there appears to be an association between periodontal disease and gestational diabetes mellitus, but prospective studies with large enough sample sizes are

Preeclampsia is a condition characterized by hypertension, with blood pressure higher than 140/90 mmHg, and the patient also suffers from peripheral edema and proteinuria (i.e., urinary excretion of ±300 mg protein in 24 h) [27, 28]. Eclampsia occurs when there is a failure to control physiological abnormalities in a pregnant

Multiple factors are involved in the etiology of preeclampsia including infection, genetic susceptibility, immune responses, abnormal placentation secondary to hypoxia and impaired arterial remodeling, and a markedly enhanced systemic inflammatory burden. Increased risk of preeclampsia is seen with elevated serum levels of C-reactive protein; periodontal infections contribute to the increased C-reactive protein level [29, 30]. Therefore, it is biologically plausible that periodontal infections could play a part in the multifactorial etiology of preeclampsia. The link between periodontal disease and risk of preeclampsia is proved only in few

**22**
