Oral Health and Adverse Pregnancy Outcomes

on periodontal disease and adverse pregnancy outcomes


Introduction
Maternal health has long been recognized as an important determinant in reducing the risk for pregnancy-related complications such as preterm birth and preeclampsia. Preterm (PTB) delivery and low birth weight (LBW) are considered to be the most relevant biological determinants of newborn infant survival in both developed and developing countries. The oral changes that can occur in pregnancy have been a focus of interest for many years. Physiological changes that occur in pregnant women can adversely affect oral health. Elevations in estrogen and progesterone enhance the inflammatory response and consequently alter the gingival tissue (Mascarenhas et al., 2003). During pregnancy, the incidences of gingivitis and periodontitis are increased, and many pregnant women suffer from bleeding and spongy gums.
Periodontal disease, a persistent bacterial infection, leads to a chronic and systemic challenge with bacterial substances and host-derived inflammatory mediators that are capable of initiating and promoting systemic diseases (Williams et al., 2000;Gibbs, 2001). The mechanisms underlying this destructive process involve both direct tissue damage resulting from bacterial products and indirect damage through bacterial induction of the host inflammatory and immune responses. Even though controversy exists regarding the role of oral health as an independent contributor to abnormal pregnancy outcomes, the recognition and understanding of the importance of oral health has led to significant research into the role of maternal oral health in pregnancy outcomes . Adequate oral hygiene habits are mandatory to control the development of periopathogenic oral biofilms, which have been reported to be associated with poor obstetric outcomes (Lieff et al., 2004;Han, 2011).
The chapter will cover the following aspects on oral health and adverse pregnancy outcomes including a systematic analysis of the studies linking preterm delivery, low birth weight, preeclampsia and periodontal disease.
• Association between periodontitis and pregnancy.
• Pre term birth, low birth weight and periodontal disease.
• Biological mechanism linking periodontal disease to adverse pregnancy outcome.
• Evidence based literature analysis.
• Observational and systematic studies.
• Intervention studies on the impact of periodontal therapy • Other expected oral outcomes due to pregnancy • Early childhood caries.

Association between periodontitis and pregnancy
Several studies have revealed the role and influence of periodontitis on adverse pregnancy outcomes. During pregnancy, the changes in hormone levels promote an inflammatory response that increases the risk of developing gingivitis and periodontitis. Even with good plaque control, 50%-70% of all women will develop gingivitis during their pregnancy, commonly referred to as pregnancy gingivitis, due to the variations in hormone levels. Pregnancy gingivitis generally manifests during the second and eighth months of pregnancy and is considered a consequence of the observed increased levels of the hormones progesterone and estrogen, which can effect small blood vessels of the gingiva, making it more permeable (Jensen et al., 1981; Barak et al., 2003).
Research suggests that the presence of maternal periodontitis has been associated with adverse pregnancy outcomes such as preterm birth (Offenbacher et al., 1996;Jeffcoat et al., 2001;Offenbacher et al., 2001), preeclampsia (Boggess et al., 2003), gestational diabetes (Xiong et al., 2006), delivery of a small-for-gestational-age infant, and fetal loss (Moore et al., 2004;. These increased risks suggest that periodontitis may be an independent risk factor for adverse pregnancy outcomes. a birth weight of less than 2,500 grams (WHO, 1984). The primary cause of LBW is PTB delivery or premature rupture of membranes. Preterm infants who are born with a low birth weight are termed preterm low birth weight (PLBW). PTB and LBW are considered to be the most relevant biological determinants of newborn infants survival, both in developed and in developing countries. Preterm birth is a major cause of infant mortality and morbidity and poses considerable medical and economic burdens on society (Alves and Ribeiro, 2006). The rate of preterm birth appears to be increasing worldwide, and efforts to prevent or reduce its prevalence have been largely unsuccessful. The importance of PTB and LBW deliveries comes from their capacity to predict the increased risk of mortality among infants born with this condition. Preterm births account for 75% of perinatal mortality and more than half of longterm morbidity . Moreover, one of the targets of the World Health Organization is to reduce the number of births in which the child weighs less than 2,500 g because this is a known predictor of childhood morbidity and mortality (Cruz et al., 2005).
Microbiological studies suggest that intrauterine infection might account for 25-40% of preterm births. Microorganisms can gain access to the amniotic cavity by (1) ascending from the vagina and the cervix; (2) hematogenous dissemination through the placenta; (3) accidental introduction during invasive procedures; and (4) retrograde spreading through the fallopian tubes (Goldenberg et al., 2000). It has been suggested that spontaneous preterm labor is commonly associated with bacterial vaginosis, a vaginal condition characterized by the prevalence of anaerobes (Gibbs, 2001). This has been shown to elicit an inflammatory burden that results in placental damage and distress and, hence, fetal growth restriction. In addition, the cascade of disordered cytokine response can lead to the stimulation of prostaglandin synthesis and the release of matrix metalloproteinases (MMPs), which account for the uterine contractions and membrane rupture, respectively, and lead to the induction of labor (Romero et al., 1992;Winkler et al., 1998). This suggests that distant sites of infection (oral cavity) or sepsis may target the placental membranes. The maternal susceptibility to oral infections during pregnancy increases the sensitivity of the gingiva to the pathogenic bacteria found in dental biofilms (Barak et al., 2003). Studies have reported the presence of higher levels of Porphyromonas gingivalis, Bacteroides forsythus, Actinobacillus actinomycetemcomitans and Treponema denticola, organisms normally associated with periodontal disease, in mothers of PTB and LBW babies as compared to normal controls (Offenbacher et al., 1996). Approximately 25% of PLBW deliveries occur without any of the risk factors discussed in this section, which emphasizes the limited understanding of the causes and pathophysiology of the problem (McGaw, 2002).
In 1996, researchers first reported a relationship between maternal periodontal disease and the delivery of a preterm infant. The 1996 study by Offenbacher and colleagues suggested that maternal periodontal disease could lead to a seven-fold increased risk of delivering a PLBW infant. Since then, researchers have investigated these possible associations for over a decade. It is important to understand the underlying biologic mechanisms for the relationship between periodontal disease and adverse pregnancy outcomes such as preterm birth to provide a rationale for therapeutic interventions and exploration of other methods that may be used as adjuncts to the standard treatment. These authors concluded that approximately 18% of PLBW cases might be attributable to periodontal disease (Offenbacher et al., 1996).

Preeclampsia and periodontal disease
Preeclampsia is a complication recognized by gestational hypertension and proteinuria. It is one of the most significant health problems during pregnancy and affects 8% to 10% of all pregnancies (Roberts et al., 2003). Intravascular inflammation and endothelial cell dysfunction with altered placental vascular development is believed to be central to the pathogenesis of preeclampsia. To prevent fetal morbidity due to preeclampsia, preterm delivery is induced . Maternal clinical periodontal disease at delivery has been associated with an increased risk for the development of preeclampsia (Canakci et al., 2007). Boggess et al. (2003) were the first investigators to report an association between maternal clinical periodontal infection and the development of preeclampsia. In this longitudinal study, they found a two-fold increased risk for preeclampsia among women with periodontal disease during pregnancy compared with controls. A few other studies also reported an association between preeclampsia and periodontal disease (Table). Canakci et al. (2007) reported that women with preeclampsia were three times more likely to have periodontal infections than healthy women and that periodontal disease also affects the severity of preeclampsia. Barak and colleagues (2007) also found that women with preeclampsia experienced more severe periodontitis than healthy controls. They found a significant elevation in the gingival crevicular fluid levels of PGE-2, interleukin (IL)-1 P, and tumor necrosis factor alpha (TNF-a). In their study, Contreras et al. (2006) found more severe periodontal infections in pregnant women with preeclampsia with the presence of P. gingivalis, T. forsythensis, and E. corrodens than in controls.

Biological mechanism linking periodontal disease to adverse pregnancy outcomes
Two potential mechanisms have been put forward to explain the underlying link between oral health and adverse pregnancy outcomes (Han, 2011). First, periodontal disease causes systemic abnormal immunological changes, leading to pregnancy complications. The elevated systemic inflammation leads to elevated C-reactive protein (CRP) levels, which increase the risk for preeclampsia. Translocation of oral bacteria into the placenta has been demonstrated in animal models of both chronic and acute infections (Lin et al., 2003b;Han et al., 2004). The biological mechanisms proposed to explain the link between maternal periodontitis and PLBW involve the translocation of either inflammatory mediators such as IL-1 β, TNFα and PGE 2 or periodontal bacteria and their products from the periodontal tissues to the fetalplacental unit via the systemic circulation, thereby triggering preterm labor (Hillier et al., 1988). Increased levels of interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α, beta-glucuronidase (β-glucuronidase), prostaglandin E2 (PGE2), aspartate aminotransferase (AST), and metalloproteinase-8 (MMPT-8) and decreased levels of osteoprotegerin (OPG) have been detected not only in the gingival tissues, gingival crevicular fluid (GCF), and saliva but also in the serum/plasma of patients affected by periodontal disease (Lin et  Cytokines such as IL-1, IL-6, and TNF-α are all potent inducers of both prostaglandin synthesis and labor, and the levels of these cytokines have been found to be elevated in the amniotic fluid of patients with amniotic fluid infections in preterm labor (Romero et al., 2006). The intraamniotic levels of PGE 2 and TNF-α rise steadily throughout pregnancy until a critical threshold is reached to induce labor, cervical dilation, and delivery (Offenbacher et al., 1996). Lipo poly sacchrides (LPS), one of the microbial components, can activate macrophages and other cells to synthesize and secrete a wide array of molecules, including the cytokines IL-16, TNF-α, and IL-6, PGE2 and matrix metalloproteinases (Darveau et al., 1997).
The second hypothesis suggests that oral bacteria directly colonize the placenta, causing a localized inflammatory response that results in prematurity and other adverse outcomes. The ratio of anaerobic gram-negative bacterial species to aerobic species increases in dental plaques during the second trimester of pregnancy (Kornman and Loesche, 1980), which may lead to increased cytokine production. If these bacteria escape into the general circulation and cross the placental barrier, they could augment the physiologic levels of PGE 2 and TNF-α in the amniotic fluid and induce premature labor. Animal studies have shown that chronic maternal exposure to the periodontal pathogen P. gingivalis results in systemic dissemination, transplacental passage, and fetal exposure (Lin et al., 2003b;Boggess et al., 2005). Studies in murine models have shown that P. gingivalis infection compromises normal fetal development by systemic dissemination and direct targeting of the fetal-placental unit.

Observational studies
The increasing number of case control studies investigating a link between periodontal disease and various adverse pregnancy outcomes in humans has produced conflicting findings ( Table  1, 2, 3). Several studies suggest a significant association between maternal periodontal disease and pregnancy complications, including premature delivery, low birth weight and preeclampsia. Periodontal disease and progression during pregnancy appear to confer risk for preterm delivery, and the strength of the association increases at earlier gestational deliveries. However, not all studies supported this contention. Differences in the ethnicity and levels of periodontal disease in patients have been proposed as possible reasons for the conflicting findings reported in these studies. Periodontal disease is twice as prevalent among African-Americans, and this might possibly explain the observed increased risk in preterm delivery and fetal growth restriction among African-Americans .Adverse pregnancy outcome and periodontal disease share a number of common risk factors, including age, ethnicity, socioeconomic status and smoking. The majority of studies investigating this association have used a dichotomous definition based on the number of teeth or sites with predefined levels of probing depth and attachment loss. Other studies have employed a range of continuous variables to reflect periodontal status, including probing depth, attachment loss and bleeding on probing. Several studies focused on the clinical measures of periodontal disease, which may not adequately reflect the infectious/ inflammatory burden present in pregnant women. The effect of periodontal disease on adverse pregnancy outcome suggests that periodontal infection as a risk factor but the evidence is insufficient to establish a cause and effect relationship.

Interventional studies
Several studies have examined the effects of periodontal treatment on preterm birth and low birth weight outcomes with conflicting findings (Table.4). Studies showed that periodontal therapy provided to women with periodontitis or gingivitis during pregnancy reduced the incidence of preterm low birth weight compared to those whose treatment was delayed until after birth ( Another study reported that significantly reduced rates of preterm births and low birth weight infants were observed for pregnant women who received plaque control instructions and scaling and root planing (Tarannum and Faizuddin, 2007). A three-year retrospective examination of a large insurance company database suggested that receiving preventive dental treatment is associated with a lower incidence of adverse birth outcomes compared with instances in which no dental services are delivered (Albert et al., 2011). However, a large multicenter study that included over 800 patients reported that periodontal treatment had no effect on pregnancy outcomes, recording the occurrence of preterm birth as 12% in the treatment group and 12.8% in the control group (Michalowicz et al., 2006).
Notably, the incidence of adverse birth outcomes from the various studies was lower among women who received some dental care and more so among those who received post-delivery periodontal care or those who received prophylactic treatment compared with those who received no dental care. The beneficial effect of dental care during the gestation period among these health-conscious and care-seeking women might also represent a coincidence. Good oral hygiene practices, however, can minimize gingival disease during pregnancy (Gibbs, 2001). Therefore, it has been recommended that all women should have a dental examination and appropriate dental hygiene care at least once during their pregnancy (Lieff et al., 2004). The American Academy of Periodontology recommends that women considering pregnancy or who are pregnant undergo a periodontal examination and receive the appropriate preventive and/or therapeutic services, if indicated.

Conclusions from the meta-analysis
The association between maternal periodontitis with adverse pregnancy outcomes such as low birthweight, pre-term birth and pre-eclampsia has been investigated for the past 20 years.
Several systematic reviews and meta-analysis has been conducted on various aspect of the association (Table 5). However, the strength of the observed associations based on clinical parameters is modest and seems to vary according to the population studied, the method used to assess periodontal diseases (Ide and Papapanou, 2013) Khader and Ta'ani (2005) conducted a meta-analysis of periodontal disease in relation to the risk of preterm birth/low birth weight (PTB/LBW) based on two case-control studies and three prospective cohort studies. The sample sizes in the studies ranged from 80 to 1,313 women, with an age range between 12 and 40 years old. The odds ratio in these studies ranged from 3.5 to 7.5. Pregnant women with periodontal disease had an overall adjusted odds ratio of preterm birth that was 4.28 times higher than the odds ratio for healthy subjects (95% CI: 2.62 to 6.99; P < 0.005). They concluded that periodontal disease in pregnant mothers significantly increases the risk of subsequent preterm births or low birth weights.
Based on the meta-analysis, Xiong et al. (2006) concluded that periodontal disease might be associated with an increased risk of adverse pregnancy outcomes. They analyzed 44 studies (26 case-control studies, 13 cohort studies, and five controlled trials). The authors observed that the findings from observational studies yielded inconsistent conclusions on the relationship between periodontal disease and various pregnancy outcomes. Of the 39 observational studies, 25 studies (16 case-control and nine cohort) suggested that periodontal disease was associated with an increased risk of adverse pregnancy outcomes. Several studies demonstrated a direct relationship between the intensity of the periodontal disease and the risk of adverse pregnancy outcomes.
Vergnes and Sixou (2007) too echoed the same association when they reviewed 17 observational studies (11 case/controls, four cohorts, and two cross-sectionals) resulting in preterm low birth weight with an OR = 2.83 (95% CI: 1.95-4.10, P < 0.0001) and low birth weight with OR = 4.03 (95% CI: 2.05-7.93, P < 0.0001) Though most of the studies have focused on the pregnancy outcome and periodontitis, very few studies have addressed the effect of periodontal treatment on adverse pregnancy outcome. One such review (Michalowicz et al., 2013) analyzed the same and resulted in a lone study on 303 Brazilian women 18 to 35 years of age with a gestational age ≤20 weeks. Randomization was stratified on smoking. All women, regardless of their periodontal status, received comprehensive non-surgical treatment (test group: oral hygiene instruction, scaling and root planing, and at least monthly follow-up visits) or supragingival scaling and oral hygiene instruction (control group).Despite statistically significant and substantial improvements in clinical periodontal measures with treatment (e.g. bleeding on probing (BOP) was reduced from 50% to 11%), there were no significant differences between test and control groups in preterm birth rates at <37 weeks (11.7 versus 9.1%, respectively, p = 0.57) or at <35 weeks (5.5% versus 5.8%, p = 0.99), or in fractions of infants weighing <2500 g (5.6% versus 4.1%,p = 0.59).
In a meta-analysis of the seven randomized trials, Polyzos and colleagues (2009) summarized that overall treatment of periodontal problems substantially reduced the rate of preterm delivery. They evaluated seven randomized controlled trials (n=2,663). There was a statistically significant reduction in incidence of preterm birth (OR 0.55, 95% CI 0.35 to 0.86, p<0.05) and low birth weight (OR 0.48, 95% CI 0.23 to 1.00, p<0.05) in women who received periodontal treatment compared to those who did not. The review findings suggested that treatment of periodontal disease during pregnancy reduced the rate of preterm birth and may reduce the incidence of low birth weight in infants.  Polyzos et al (2010) examined whether treatment of periodontal disease with scaling and root planing during pregnancy is associated with a reduction in the preterm birth rate in random-ized controlled trials. Of the 11 trials (with 6558 women), five trials were considered to be of high methodological quality (low risk of bias), whereas the rest were low quality (high or unclear risk of bias). It is noteworthy to see that the results among low and high quality trials were consistently diverse; low quality trials supported a beneficial effect of treatment, and high quality trials provided clear evidence that no such effect exists (odds ratio 1.15, 95% confidence interval 0.95 to 1.40; P=0.15). Cariogenic bacteria can be transmitted from mother to child by behaviors that directly pass saliva such as sharing a spoon when tasting baby food, cleaning a dropped pacifier by mouth or wiping the baby's mouth with saliva (Berkowitz, 2003). Reducing the transmission of cariogenic bacteria can be accomplished by reducing the maternal reservoir, avoiding vectors, and increasing the child's resistance to colonization (Li et al., 2003). Studies have demonstrated the effectiveness of a primary prevention program initiated during pregnancy to significantly improve the oral health of mothers and their children (Gunay et al., 1998;Soderling et al., 2001). Hence, comprehensive dental care for pregnant women is imperative to safeguard their oral and general health, as well as to reduce their children's caries risk (Brambilla et al., 1998;Boggess and Edelstein, 2006).

Gingival overgrowth related to pregnancy
Hormonal changes during pregnancy have been associated with varying types of gingival enlargement. These changes can potentiate the effects of local irritants on gingival connective tissue. Localized gingival overgrowth (pregnancy gingival tumor) is found in 0.2-0.5% of pregnant females. It occurs as a benign, rapidly growing lesion, usually in the 1st trimester of pregnancy and extending up to 3rd trimester. A pregnancy gingival tumor is a smooth or lobulated exophytic lesion with a pedunculated or sessile base (Srivastava et al., 2013) ( Figure  3.). Several theories and speculations have been suggested to explain its occurrence during pregnancy, and meticulous maintenance of oral hygiene during pregnancy is important in reducing its incidence and the severity of gingival inflammation. Hormonal factors might play a role in aggravating gingivitis and gingival overgrowth (Oettinger- Barak

Conclusion
Birth weight is considered to be an important determinant of the chances that an infant survives, grows, and matures. Maternal risk factors include age, height, weight, socioeconomic status, ethnicity, smoking, alcohol use, nutritional status, and stress (Copper et  The hypothesis that infection elsewhere in the body may influence PLBW has led to an increased awareness of the potential role of chronic bacterial infections. Periodontal disease is associated with a chronic Gram-negative infection of the periodontal tissues that results in a long-term local elevation of pro-inflammatory prostaglandins and cytokines and an increase in systemic levels of some of these inflammatory mediators (Page and Kornman, 1997). The evidence suggests that periodontitis can have a significant effect on systemic health. Periodontal disease is associated with many adverse pregnancy outcomes such as preterm delivery Several common risk factors are responsible for PLBW, such as age, socioeconomic status, and smoking, along with periodontal diseases. Because the inflammatory mediators that occur in periodontal diseases also play an important part in the initiation of labor, it is possible that a biological mechanism links the two conditions. Furthermore, intervention studies, animal studies, and more detailed mechanistic examinations are needed to directly correlate periodontal diseases to PLBW babies and eliminate the confounding effects of various other risk factors.