ManageMent Update
Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight Mansi Bansal, MDS,1 Manish Khatri, MDS,1 Ashish Kumar, MDS,1 Gouri Bhatia, MDS2 1 Department of Periodontics, Institute of Dental Studies & Technologies, Modinagar, Uttar Pradesh, India; 2 Department of Periodontics, Eklavya Dental College, Kotputli, Rajasthan, India
Throughout history, there has been the belief that diseases that affect the mouth, such as periodontal disease, can have an effect on the rest of the body. It is only very recently that scientists and clinicians have begun to provide an increasing body of scientific evidence suggesting that moderate untreated periodontitis may affect an individual systemically, and may contribute to cardiovascular disease, diabetes, and preterm low birth weight. Birth weight is affected by multiple factors and is considered as an outcome of a complex multifactorial system. Periodontitis is a remote gram-negative infection that may play a role in low birth weight. Periodontopathic microorganisms and their products have a wide range of effects mediated through host cytokine production in target cells. Many combined animal studies and data supporting plausible biologic mechanisms suggest that periodontal infection has a negative impact on pregnancy outcome in some women. [ Rev Obstet Gynecol. 2013;6(3/4):135-140 doi: 10.3909/riog0220]
®
© 2014 MedReviews , LLC
Key words Periodontal medicine • Preterm low birth weight • Periodontitis
P
eriodontal diseases are among the most common chronic diseases in humans, affecting 5% to 30% of the adult population. They are also among the most prevalent causes of pain, discomfort, and tooth loss in adults.1 Emerging evidence suggests that periodontitis increases the risk for certain systemic diseases such as heart disease, respiratory disease, and other conditions, such as low birth weight in infants.2 Recent research that increasingly
substantiates a role for periodontitis in affecting systemic health has brought the term periodontal medicine to the forefront and has fostered a new branch of periodontology.3
Definition
Pregnancy provides unique diagnostic and treatment challenges to the periodontal clinician. It is an opportunity to individualize care at a time when the
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight continued
TABLe 1 Prevalence of Low Birth Weight (LBW) and Mean Birth Weight (MBW) Continent Europe Asia Australia Africa South America North America patient may experience the most profound physiologic and psychologic changes in her life. Awareness exists regarding pregnancy and its effect on periodontal disease; however, recent evidence indicates an inverse relationship to systemic disease.4 The proposed link between maternal periodontitis and preterm low birth weight (PLBW) infants is particularly compelling. The World Health Organization
LBW (%)
MBW (g)
4-12 15 6 10-12 11 7
3200 2900 3200 3000 3100 3200
in South America, 10% to 12% in Africa, and 4% to 12% in Europe; the highest prevalence is in Asia, at approximately 15% (Table 1).7 A history of spontaneous preterm delivery has been identified as the most significant risk factor for preterm birth; other risk factors include preeclampsia, genitourinary tract infections, thrombophilia, low socioeconomic status, very young or old maternal age, multiparity,
The proposed link between maternal periodontitis and preterm low birth weight infants is particularly compelling.
defines preterm birth as any live birth at , 37 weeks of gestation. Delivery at , 32 weeks is termed very preterm and delivery at , 28 weeks extremely preterm. Birth weights are considered to be low if , 2500 g, very low if , 1500 g, and extremely low if , 1000 g.5 Preterm birth that occurs at , 37 weeks of gestation associated low birth weight of , 2500 g represents the major cause of neonatal morbidity and, among survivors, a major contributor to long-term disability.6
Prevalence and Risk Factors
Preterm birth has been a leading perinatal problem with increased prevalence in recent years. The prevalence of low birth weight in the United Kingdom is 6%, approximately 7% in North America, 11%
inadequate prenatal care, and the use of alcohol and tobacco. Despite extensive literature on the subject and improved antenatal care, there has been no significant decrease in the incidence of PLBW in developed countries. This has led to the belief that other factors may contribute to preterm birth, such as, environmental, genetic, obstetric, maternal, and fetal factors.8 In a landmark human study, Offenbacher and colleagues9 studied 124 pregnant or postpartum women. After controlling for a broad range of known obstetric risk factors, such as tobacco and drug use, alcohol consumption, level of prenatal care, parity, genitourinary infections, and nutrition, each subject received a periodontal examination to determine the clinical attachment level. Mothers of PLBW
infants and primiparous mothers of PLBW infants had significantly worse periodontal disease than the respective mothers of normal birth weight infants (control subjects). Multivariate logistic regression models, controlling for other risk factors and covariates, demonstrated that periodontal disease is a statistically significant risk factor for PLBW, with adjusted odds ratios of 7.9 and 7.5 for all PLBW cases and primiparous PLBW cases, respectively. The results of the study were the first to show that periodontitis was a significant risk factor for PLBW as a consequence of either preterm labor or preterm premature rupture of membranes (PPROM). Jeffcoat and colleagues10 have also shown that preexisting periodontal disease in the second trimester of pregnancy increases the risk of preterm birth. A randomized, controlled trial was undertaken by López and associates11 to further evaluate the proposed association between periodontal disease and PLBW. A total of 400 pregnant women with periodontal disease, aged 18 to 35 years, were enrolled while receiving prenatal care. They were randomly assigned to either an experimental group that received periodontal treatment before 28 weeks of gestation, or to a control group that received periodontal treatment after delivery. Previous and current pregnancies and known risk factors were obtained from patient medical records and interviews. This study showed that periodontal therapy significantly reduces the rates of PLBW in women with periodontal disease.
Putative Mechanisms Involved In Preterm Labor
Periodontitis has the potential to affect birth outcomes by a direct bacterial or inflammatory challenge originating in the periodontium.8
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight Maternal infections may produce alterations in the normal cytokineand hormone-regulated gestation, resulting in PPROM and preterm birth.11 According to Budaneli and associates12 periodontal infections may mediate PLBW through one or more of the following mechanisms: (1) contamination of the fetoplacental unit by periodontal pathogens, (2) effects of lipopolysaccharide from the periodontal reservoir on the fetoplacental unit, and (3) effects of the inflammatory mediators (interleukins [ILs], prostaglandins, tumor necrosis factor [TNF]) from the periodontal reservoir on the fetoplacental unit (Figure 1). The five common clinical findings associated with preterm labor are the normal physiologic processes that happen early: infection, inflammation, hemorrhage, placental ischemia, and stress. Local tissue damage can be caused by free radicals and lipid peroxides,
which in turn promote prostanoid production. Genitourinary tract infections have been associated with inflammation of the chorioamnion, resulting in pregnancy complications. Maternal or fetal stress can result in the release of adrenal and hypothalamic stress hormones. These are thought to promote the release of corticotrophin-releasing factor, which can increase prostanoid production. Prostaglandins and proinflammatory cytokines play a pivotal role in the initiation process. Increasing levels of maternally or fetal-derived cytokines such as TNF-α enhance amniochorionic and decidual IL-6 expression, resulting in prostanoid production. Alternatively, both polymorphonuclear leukocytes and many gram-negative organisms produce the enzyme phospholipase A2, which hydrolyzes esterified arachidonic acid, resulting in the synthesis of prostanoids, causing PPROM, preterm delivery, and low birth weight babies.7
Figure 1. Flow chart showing mechanisms of preterm low birth weight and rupture of membranes. IL, interleukin; PMN, polymorphonuclear leukocyte; TNF, tumor necrosis factor.
1. Infection
Endotoxin or gram–negative microorganisms
3. Hemorrhage
4. Placental Ischemia
2. Inflammation
Complement activation
IL-8
Macrophages
PMN (produce phospholipase A2 and hydrolyze arachidonic acid)
TNF- (increased IL-6 expression) Prostanoids
5. Stress Corticotrophin–releasing hormone Free radicals and lipid peroxidases
Contraction of uterine smooth muscle ← Proteases → Preterm rupture of membranes Premature labor
Noncausal Explanations for Correlation Between Periodontal Disease and PLBW
The association between periodontal disease and PLBW demonstrated by the studies described here does not confirm a linear causal relationship. The frequent association of spontaneous preterm labor and preterm birth with histologic infection/inflammation and elevated body fluid concentrations of inflammatory cytokines has focused investigations on single gene polymorphisms of these cytokines in both mother and fetus. The polymorphisms TNFa-308, IL-1b + 3953/3954, and IL-6-174 have been most consistently associated with spontaneous preterm labor and preterm birth. Toll-like receptors are important components of the innate immune systems, which have also been linked to spontaneous preterm labor and preterm birth. Both maternal and fetal polymorphisms of the TLR4 gene, which have been studied in periodontology, have also been associated with spontaneous preterm labor and preterm birth in certain populations.13 This suggests a possible link between periodontal diseases and PLBW, based on an individual’s genetically determined predisposition to mount a hyperinflammatory response in the presence of a bacterial challenge.
Current Consensus on the Link Between PLBW and Periodontal Treatment
The association of maternal periodontitis with adverse pregnancy outcomes has been investigated for the past 20 years. As reviewed above, epidemiologic studies identified a
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight continued modest but statistically significant association between maternal periodontitis and preterm birth, low birth weight, and preeclampsia, independent of other exposures. In parallel, several studies in animals and humans contributed to a better understanding of the biologic plausibility and the mechanisms that are involved in these associations. Conversely, several wellconducted, adequately powered intervention studies over the past decade demonstrated that nonsurgical periodontal therapy delivered during the second trimester does not improve pregnancy outcomes. Possible explanations as to why periodontal treatment does not affect pregnancy outcomes, as suggested by Michalowicz and colleagues,14 in 2013 include the following: 1. Periodontitis treatment, regardless of its timing, intensity, or effectiveness, will not reduce preterm birth or low birth weight rates if the conditions are not causally linked. Although most observational studies report an association between maternal periodontitis and pregnancy outcomes, the quality of studies showing strong associations has been questioned.15 2. The treatment effect is confounded by shared risk factors. Many risk factors for both periodontitis and poor pregnancy outcomes are not addressed with periodontal treatment alone. Although such factors may be balanced between groups in randomized controlled trials (RCTs), the periodontal treatment effect on pregnancy outcomes may be mitigated if these shared risk factors are prevalent in the sample population; for example, periodontal treatment without smoking cessation may have little effect on both periodontal status and pregnancy
outcomes.16 Obesity confers a preterm birth risk comparable in magnitude to smoking.17 The mechanisms linking obesity and periodontitis with adverse pregnancy outcomes are not well defined, but adipose tissue has proinflammatory properties that increase with increasing obesity.18 Socioeconomic status (SES), including education, is associated with both adverse pregnancy outcomes and periodontitis.19 Rather than being a risk factor per se, SES is probably a marker for lifestyle factors such as care-seeking habits, diet, and exercise. Differences in SES among the RCT participants might explain some of the differences in reported periodontal treatment and pregnancy outcomes. Type 1 and 2 diabetes are associated with periodontitis and gingival inflammation, and with pregnancy outcomes such as stillbirths, perinatal mortality, and congenital
ineffective in preventing preterm birth. Targeting women prior to conception is appealing because the treatments could be more aggressive and include a longer post-treatment maintenance phase, in theory enabling any periodontitis-induced systemic inflammation to more completely resolve. The obstetric literature contains evidence that the timing of antiinfective interventions matters in reducing adverse pregnancy outcome risk. Elevated concentrations of IL-6 in the amniotic fluid at15 to 20 weeks of gestation are associated with spontaneous preterm delivery as late as 32 to 34 weeks.24 Women with an abnormal vaginal microbiota early in pregnancy continue to be at increased risk for adverse birth outcomes even if the microbiota reverts to normal.25 Moreover, antibiotics used prophylactically to treat women with abnormal genital tract flora seem to be more effective when administered early in pregnancy, before
The obstetric literature contains evidence that the timing of antiinfective interventions matters in reducing adverse pregnancy outcome risk.
malformations.20 Several RCTs have excluded women with diabetes,21 whereas others did not report the diabetes status of trial subjects.22 Differences in diabetes inclusion/ exclusion criteria also may partially explain the inconsistent results across trials.
Management of the Pregnant Patient
Providing periodontal treatment during pregnancy may be too late to reduce local and systemic inflammatory responses that lead to adverse pregnancy outcomes.23 Once the inflammatory cascade is activated, interventions targeting inflammatory pathways may be
inflammation and tissue damage have occurred. Collectively, these findings suggest that any damage caused by an abnormal microbiota or inflammation occurs early in gestation and that interventions should be administered early in pregnancy or before conception. The periodontal evaluation of the pregnant patient begins with a thorough medical history. The history should include any complications the patient has encountered in the pregnancy, any previous miscarriages, recent cramping, spotting, or pernicious vomiting. The most important objectives in planning dental treatment for the pregnant patient are to establish a healthy oral environment and to obtain
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight optimum oral hygiene levels. These are achieved by means of a good preventive dental program, consisting of nutritional counseling and rigorous plaque control measures in the dental office and at home.6 It is prudent to avoid elective dental care other than good plaque control during the first trimester and the last half of the third trimester, if possible. The first trimester is the period of organogenesis, when the fetus is highly susceptible to environmental influences. In the last half of the third trimester, there is a hazard of premature delivery because the uterus is very sensitive to external stimuli. Prolonged chair time should be avoided and the patient should be positioned on the dental chair in a left lateral supine position to avoid the development of supine hypotensive syndrome.26 Even in light of the safety of dental radiography, radiographs should be used selectively during pregnancy. A conservative approach regarding drug therapy is prudent. The dentist should prescribe only the minimum effective dose and duration absolutely essential for the
pregnant patient’s well-being and only after careful consideration of the potential side effects.6
Conclusions
Many common risk factors for PLBW are present along with periodontal diseases (eg, age, socioeconomic status, and smoking). However, because the inflammatory mediators that occur in periodontal diseases also play an important part in the initiation of labor, there can be a possible biologic mechanism that could link the two conditions. The challenge for the future is to characterize the nature of the factors that predispose a mother to give birth prematurely to infants , 2500 g and to assign relative probabilities to each. Studies are taking place in many parts of the world to determine the probability of a PLBW outcome and the interdependence of various factors that contribute to a birth event and possible causal relationships between these factors. Further, intervention studies, animal studies, and more detailed examination of the mechanisms are needed to directly correlate
periodontal diseases to PLBW babies and eliminate the confounding effects of various other risk factors. References 1.
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Brown LJ, Löe H. Prevalence, extent, severity and progression of periodontal disease. Periodontol 2000. 1993;2:57-71. Scannapieco FA. Position paper of The American Academy of Periodontology: periodontal disease as a potential risk factor for systemic diseases. J Periodontol. 1998;69:841-850. Williams RC, Offenbacher S. Periodontal medicine: the emergence of a new branch of periodontology. Periodontol 2000. 2000;23:9-12. Otomo-Corgel J, Steinberg BJ. Periodontal medicine and the female patient. In: Rose LF, Genco RJ, Mealey BR, Cohen DW, eds. Periodontal Medicine. 1st ed. Hamilton, Ontario: B.C. Decker Inc; 2000:151-165. Michalowicz BS, Durand R. Maternal periodontal disease and spontaneous preterm birth. Periodontol 2000. 2007;44:103-112. Offenbacher S, Leiff S, Bogesse KA, et al. Maternal periodontitis and prematurity. Part I: Obstetric outcome of prematurity and growth restriction. Ann Periodontol. 2001;6:166-174. Williams CS, Davenport ES, Sterne J, et al. Mechanisms of risk in preterm low-birthweight infants. Periodontol 2000. 2000;23:142-150. Heimonen A, Janket S, Kaaja R, et al. Oral inflammatory burden and preterm birth. J Periodontol. 2009;80:884-891. Offenbacher S, Katz V, Fertik G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol. 1996;67(10 suppl): 1103-1113. Jeffcoat MK, Geurs NC, Reddy MS, et al. Periodontal infection and preterm birth: results of a prospective study. J Am Dent Assoc. 2001;132:875-880. López NJ, Smith PC, Gutierrez J. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: a randomized controlled trial. J Periodontol. 2002;73: 911-924.
MAIN PoINTs • Periodontal diseases are among the most common chronic diseases in humans, affecting 5% to 30% of the adult population. Emerging evidence suggests that periodontitis also increases the risk for heart disease, respiratory disease, and other conditions, such as low birth weight in infants. • A landmark human study, published in 1996, studied 124 pregnant or postpartum women. Subjects received a periodontal examination to determine the clinical attachment level; mothers of preterm low birth weight (PLBW) infants and primiparous mothers of PLBW infants had significantly worse periodontal disease than the respective mothers of normal birth weight infants. The results of the study were the first to show that periodontitis was a significant risk factor for PLBW as a consequence of either preterm labor or preterm premature rupture of membranes. • Providing periodontal treatment during pregnancy may be too late to reduce local and systemic inflammatory responses that lead to adverse pregnancy outcomes. Once the inflammatory cascade is activated, interventions targeting inflammatory pathways may be ineffective in preventing preterm birth. Targeting women prior to conception is appealing because the treatments could be more aggressive and include a longer post-treatment maintenance phase, in theory enabling any periodontitis-induced systemic inflammation to more completely resolve. Vol. 6 No. 3/4 • 2013 • Reviews in Obstetrics & Gynecology • 139
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight continued 12.
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Budaneli N, Baylas H, Budaneli E, et al. Periodontal infections and pre-term low birth weight: a case-control study. J Clin Periodontol. 2005;32:174-181. Varner MW, Esplin MS. Current understanding of genetic factors in preterm birth. BJOG. 2005;112(suppl 1):28-31. Michalowicz BS, Gustafsson A, Thumbigere-Math V, Buhlin K. The effects of periodontal treatment on pregnancy outcomes. J Clin Periodontol. 2013;40(suppl 14):S195-S208. Vergnes JN, Sixou M. Preterm low birth weight and maternal periodontal status: a meta-analysis. Am J Obstet Gynecol. 2007;196:135.e1-135.e7. Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res. 2004;6(suppl 2):S125-S140. Djelantik AA, Kunst AE, van der Wal MF, et al. Contribution of overweight and obesity to the occurrence of adverse pregnancy outcomes in a
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multi-ethnic cohort: population attributive fractions for Amsterdam. BJOG. 2012;119:283-290. Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol. 2010;314:1-16. Boillot A, El Halabi B, Batty GD, et al. Education as a predictor of chronic periodontitis: a systematic review with meta-analysis population-based studies. PLoS One. 2011; 6:e21508. Novak MJ, Novak KF, Hodges JS, et al. Periodontal bacterial profiles in pregnant women: response to treatment and associations with birth outcomes in the obstetrics and periodontal therapy (OPT) study. J Periodontol. 2008;79:1870-1879. Oliveira AM, de Oliveira PA, Cota LO, et al. Periodontal therapy and risk for adverse pregnancy outcomes. Clin Oral Investig. 2011;15:609-615. Macones GA, Parry S, Nelson DB, et al. Treatment of localized periodontal disease in pregnancy does not reduce the occurrence of preterm birth: results
23.
24.
25.
26.
from the Periodontal Infections and Prematurity Study (PIPS). Am J Obstet Gynecol. 2010;202:147. e1-147.e8. Xiong X, Buekens P, Goldenberg RL, et al. Optimal timing of periodontal disease treatment for prevention of adverse pregnancy outcomes: before or during pregnancy? Am J Obstet Gynecol. 2011;205:111.e1-111.e6. Wenstrom KD, Andrews WW, Hauth JC, et al. Elevated second-trimester amniotic fluid interleukin-6 levels predict preterm delivery. Am J Obstet Gynecol. 1998;178:546-550. Rosenstein IJ, Morgan DJ, Lamont RF, et al. Effect of intravaginal clindamycin cream on pregnancy outcome and on abnormal vaginal microbial flora of pregnant women. Infect Dis Obstet Gynecol. 2000;8:158-165. Otomo-Corgel J. Periodontal therapy in the female patient. In: Newman MG, Takei H, Klokkevold PR, Carranza FA, eds. Carranza’s Clinical Periodontology. 10th ed. St. Louis, MO: Saunders Elsevier; 2006: 636-650.
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight Mansi Bansal, MDS,1 Manish Khatri, MDS,1 Ashish Kumar, MDS,1 Gouri Bhatia, MDS2 1 Department of Periodontics, Institute of Dental Studies & Technologies, Modinagar, Uttar Pradesh, India; 2 Department of Periodontics, Eklavya Dental College, Kotputli, Rajasthan, India
Throughout history, there has been the belief that diseases that affect the mouth, such as periodontal disease, can have an effect on the rest of the body. It is only very recently that scientists and clinicians have begun to provide an increasing body of scientific evidence suggesting that moderate untreated periodontitis may affect an individual systemically, and may contribute to cardiovascular disease, diabetes, and preterm low birth weight. Birth weight is affected by multiple factors and is considered as an outcome of a complex multifactorial system. Periodontitis is a remote gram-negative infection that may play a role in low birth weight. Periodontopathic microorganisms and their products have a wide range of effects mediated through host cytokine production in target cells. Many combined animal studies and data supporting plausible biologic mechanisms suggest that periodontal infection has a negative impact on pregnancy outcome in some women. [ Rev Obstet Gynecol. 2013;6(3/4):135-140 doi: 10.3909/riog0220]
®
© 2014 MedReviews , LLC
Key words Periodontal medicine • Preterm low birth weight • Periodontitis
P
eriodontal diseases are among the most common chronic diseases in humans, affecting 5% to 30% of the adult population. They are also among the most prevalent causes of pain, discomfort, and tooth loss in adults.1 Emerging evidence suggests that periodontitis increases the risk for certain systemic diseases such as heart disease, respiratory disease, and other conditions, such as low birth weight in infants.2 Recent research that increasingly
substantiates a role for periodontitis in affecting systemic health has brought the term periodontal medicine to the forefront and has fostered a new branch of periodontology.3
Definition
Pregnancy provides unique diagnostic and treatment challenges to the periodontal clinician. It is an opportunity to individualize care at a time when the
Vol. 6 No. 3/4 • 2013 • Reviews in Obstetrics & Gynecology • 135
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03/04/14 11:02 AM
Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight continued
TABLe 1 Prevalence of Low Birth Weight (LBW) and Mean Birth Weight (MBW) Continent Europe Asia Australia Africa South America North America patient may experience the most profound physiologic and psychologic changes in her life. Awareness exists regarding pregnancy and its effect on periodontal disease; however, recent evidence indicates an inverse relationship to systemic disease.4 The proposed link between maternal periodontitis and preterm low birth weight (PLBW) infants is particularly compelling. The World Health Organization
LBW (%)
MBW (g)
4-12 15 6 10-12 11 7
3200 2900 3200 3000 3100 3200
in South America, 10% to 12% in Africa, and 4% to 12% in Europe; the highest prevalence is in Asia, at approximately 15% (Table 1).7 A history of spontaneous preterm delivery has been identified as the most significant risk factor for preterm birth; other risk factors include preeclampsia, genitourinary tract infections, thrombophilia, low socioeconomic status, very young or old maternal age, multiparity,
The proposed link between maternal periodontitis and preterm low birth weight infants is particularly compelling.
defines preterm birth as any live birth at , 37 weeks of gestation. Delivery at , 32 weeks is termed very preterm and delivery at , 28 weeks extremely preterm. Birth weights are considered to be low if , 2500 g, very low if , 1500 g, and extremely low if , 1000 g.5 Preterm birth that occurs at , 37 weeks of gestation associated low birth weight of , 2500 g represents the major cause of neonatal morbidity and, among survivors, a major contributor to long-term disability.6
Prevalence and Risk Factors
Preterm birth has been a leading perinatal problem with increased prevalence in recent years. The prevalence of low birth weight in the United Kingdom is 6%, approximately 7% in North America, 11%
inadequate prenatal care, and the use of alcohol and tobacco. Despite extensive literature on the subject and improved antenatal care, there has been no significant decrease in the incidence of PLBW in developed countries. This has led to the belief that other factors may contribute to preterm birth, such as, environmental, genetic, obstetric, maternal, and fetal factors.8 In a landmark human study, Offenbacher and colleagues9 studied 124 pregnant or postpartum women. After controlling for a broad range of known obstetric risk factors, such as tobacco and drug use, alcohol consumption, level of prenatal care, parity, genitourinary infections, and nutrition, each subject received a periodontal examination to determine the clinical attachment level. Mothers of PLBW
infants and primiparous mothers of PLBW infants had significantly worse periodontal disease than the respective mothers of normal birth weight infants (control subjects). Multivariate logistic regression models, controlling for other risk factors and covariates, demonstrated that periodontal disease is a statistically significant risk factor for PLBW, with adjusted odds ratios of 7.9 and 7.5 for all PLBW cases and primiparous PLBW cases, respectively. The results of the study were the first to show that periodontitis was a significant risk factor for PLBW as a consequence of either preterm labor or preterm premature rupture of membranes (PPROM). Jeffcoat and colleagues10 have also shown that preexisting periodontal disease in the second trimester of pregnancy increases the risk of preterm birth. A randomized, controlled trial was undertaken by López and associates11 to further evaluate the proposed association between periodontal disease and PLBW. A total of 400 pregnant women with periodontal disease, aged 18 to 35 years, were enrolled while receiving prenatal care. They were randomly assigned to either an experimental group that received periodontal treatment before 28 weeks of gestation, or to a control group that received periodontal treatment after delivery. Previous and current pregnancies and known risk factors were obtained from patient medical records and interviews. This study showed that periodontal therapy significantly reduces the rates of PLBW in women with periodontal disease.
Putative Mechanisms Involved In Preterm Labor
Periodontitis has the potential to affect birth outcomes by a direct bacterial or inflammatory challenge originating in the periodontium.8
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight Maternal infections may produce alterations in the normal cytokineand hormone-regulated gestation, resulting in PPROM and preterm birth.11 According to Budaneli and associates12 periodontal infections may mediate PLBW through one or more of the following mechanisms: (1) contamination of the fetoplacental unit by periodontal pathogens, (2) effects of lipopolysaccharide from the periodontal reservoir on the fetoplacental unit, and (3) effects of the inflammatory mediators (interleukins [ILs], prostaglandins, tumor necrosis factor [TNF]) from the periodontal reservoir on the fetoplacental unit (Figure 1). The five common clinical findings associated with preterm labor are the normal physiologic processes that happen early: infection, inflammation, hemorrhage, placental ischemia, and stress. Local tissue damage can be caused by free radicals and lipid peroxides,
which in turn promote prostanoid production. Genitourinary tract infections have been associated with inflammation of the chorioamnion, resulting in pregnancy complications. Maternal or fetal stress can result in the release of adrenal and hypothalamic stress hormones. These are thought to promote the release of corticotrophin-releasing factor, which can increase prostanoid production. Prostaglandins and proinflammatory cytokines play a pivotal role in the initiation process. Increasing levels of maternally or fetal-derived cytokines such as TNF-α enhance amniochorionic and decidual IL-6 expression, resulting in prostanoid production. Alternatively, both polymorphonuclear leukocytes and many gram-negative organisms produce the enzyme phospholipase A2, which hydrolyzes esterified arachidonic acid, resulting in the synthesis of prostanoids, causing PPROM, preterm delivery, and low birth weight babies.7
Figure 1. Flow chart showing mechanisms of preterm low birth weight and rupture of membranes. IL, interleukin; PMN, polymorphonuclear leukocyte; TNF, tumor necrosis factor.
1. Infection
Endotoxin or gram–negative microorganisms
3. Hemorrhage
4. Placental Ischemia
2. Inflammation
Complement activation
IL-8
Macrophages
PMN (produce phospholipase A2 and hydrolyze arachidonic acid)
TNF- (increased IL-6 expression) Prostanoids
5. Stress Corticotrophin–releasing hormone Free radicals and lipid peroxidases
Contraction of uterine smooth muscle ← Proteases → Preterm rupture of membranes Premature labor
Noncausal Explanations for Correlation Between Periodontal Disease and PLBW
The association between periodontal disease and PLBW demonstrated by the studies described here does not confirm a linear causal relationship. The frequent association of spontaneous preterm labor and preterm birth with histologic infection/inflammation and elevated body fluid concentrations of inflammatory cytokines has focused investigations on single gene polymorphisms of these cytokines in both mother and fetus. The polymorphisms TNFa-308, IL-1b + 3953/3954, and IL-6-174 have been most consistently associated with spontaneous preterm labor and preterm birth. Toll-like receptors are important components of the innate immune systems, which have also been linked to spontaneous preterm labor and preterm birth. Both maternal and fetal polymorphisms of the TLR4 gene, which have been studied in periodontology, have also been associated with spontaneous preterm labor and preterm birth in certain populations.13 This suggests a possible link between periodontal diseases and PLBW, based on an individual’s genetically determined predisposition to mount a hyperinflammatory response in the presence of a bacterial challenge.
Current Consensus on the Link Between PLBW and Periodontal Treatment
The association of maternal periodontitis with adverse pregnancy outcomes has been investigated for the past 20 years. As reviewed above, epidemiologic studies identified a
Vol. 6 No. 3/4 • 2013 • Reviews in Obstetrics & Gynecology • 137
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03/04/14 11:02 AM
Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight continued modest but statistically significant association between maternal periodontitis and preterm birth, low birth weight, and preeclampsia, independent of other exposures. In parallel, several studies in animals and humans contributed to a better understanding of the biologic plausibility and the mechanisms that are involved in these associations. Conversely, several wellconducted, adequately powered intervention studies over the past decade demonstrated that nonsurgical periodontal therapy delivered during the second trimester does not improve pregnancy outcomes. Possible explanations as to why periodontal treatment does not affect pregnancy outcomes, as suggested by Michalowicz and colleagues,14 in 2013 include the following: 1. Periodontitis treatment, regardless of its timing, intensity, or effectiveness, will not reduce preterm birth or low birth weight rates if the conditions are not causally linked. Although most observational studies report an association between maternal periodontitis and pregnancy outcomes, the quality of studies showing strong associations has been questioned.15 2. The treatment effect is confounded by shared risk factors. Many risk factors for both periodontitis and poor pregnancy outcomes are not addressed with periodontal treatment alone. Although such factors may be balanced between groups in randomized controlled trials (RCTs), the periodontal treatment effect on pregnancy outcomes may be mitigated if these shared risk factors are prevalent in the sample population; for example, periodontal treatment without smoking cessation may have little effect on both periodontal status and pregnancy
outcomes.16 Obesity confers a preterm birth risk comparable in magnitude to smoking.17 The mechanisms linking obesity and periodontitis with adverse pregnancy outcomes are not well defined, but adipose tissue has proinflammatory properties that increase with increasing obesity.18 Socioeconomic status (SES), including education, is associated with both adverse pregnancy outcomes and periodontitis.19 Rather than being a risk factor per se, SES is probably a marker for lifestyle factors such as care-seeking habits, diet, and exercise. Differences in SES among the RCT participants might explain some of the differences in reported periodontal treatment and pregnancy outcomes. Type 1 and 2 diabetes are associated with periodontitis and gingival inflammation, and with pregnancy outcomes such as stillbirths, perinatal mortality, and congenital
ineffective in preventing preterm birth. Targeting women prior to conception is appealing because the treatments could be more aggressive and include a longer post-treatment maintenance phase, in theory enabling any periodontitis-induced systemic inflammation to more completely resolve. The obstetric literature contains evidence that the timing of antiinfective interventions matters in reducing adverse pregnancy outcome risk. Elevated concentrations of IL-6 in the amniotic fluid at15 to 20 weeks of gestation are associated with spontaneous preterm delivery as late as 32 to 34 weeks.24 Women with an abnormal vaginal microbiota early in pregnancy continue to be at increased risk for adverse birth outcomes even if the microbiota reverts to normal.25 Moreover, antibiotics used prophylactically to treat women with abnormal genital tract flora seem to be more effective when administered early in pregnancy, before
The obstetric literature contains evidence that the timing of antiinfective interventions matters in reducing adverse pregnancy outcome risk.
malformations.20 Several RCTs have excluded women with diabetes,21 whereas others did not report the diabetes status of trial subjects.22 Differences in diabetes inclusion/ exclusion criteria also may partially explain the inconsistent results across trials.
Management of the Pregnant Patient
Providing periodontal treatment during pregnancy may be too late to reduce local and systemic inflammatory responses that lead to adverse pregnancy outcomes.23 Once the inflammatory cascade is activated, interventions targeting inflammatory pathways may be
inflammation and tissue damage have occurred. Collectively, these findings suggest that any damage caused by an abnormal microbiota or inflammation occurs early in gestation and that interventions should be administered early in pregnancy or before conception. The periodontal evaluation of the pregnant patient begins with a thorough medical history. The history should include any complications the patient has encountered in the pregnancy, any previous miscarriages, recent cramping, spotting, or pernicious vomiting. The most important objectives in planning dental treatment for the pregnant patient are to establish a healthy oral environment and to obtain
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Relationship Between Maternal Periodontal Status and Preterm Low Birth Weight optimum oral hygiene levels. These are achieved by means of a good preventive dental program, consisting of nutritional counseling and rigorous plaque control measures in the dental office and at home.6 It is prudent to avoid elective dental care other than good plaque control during the first trimester and the last half of the third trimester, if possible. The first trimester is the period of organogenesis, when the fetus is highly susceptible to environmental influences. In the last half of the third trimester, there is a hazard of premature delivery because the uterus is very sensitive to external stimuli. Prolonged chair time should be avoided and the patient should be positioned on the dental chair in a left lateral supine position to avoid the development of supine hypotensive syndrome.26 Even in light of the safety of dental radiography, radiographs should be used selectively during pregnancy. A conservative approach regarding drug therapy is prudent. The dentist should prescribe only the minimum effective dose and duration absolutely essential for the
pregnant patient’s well-being and only after careful consideration of the potential side effects.6
Conclusions
Many common risk factors for PLBW are present along with periodontal diseases (eg, age, socioeconomic status, and smoking). However, because the inflammatory mediators that occur in periodontal diseases also play an important part in the initiation of labor, there can be a possible biologic mechanism that could link the two conditions. The challenge for the future is to characterize the nature of the factors that predispose a mother to give birth prematurely to infants , 2500 g and to assign relative probabilities to each. Studies are taking place in many parts of the world to determine the probability of a PLBW outcome and the interdependence of various factors that contribute to a birth event and possible causal relationships between these factors. Further, intervention studies, animal studies, and more detailed examination of the mechanisms are needed to directly correlate
periodontal diseases to PLBW babies and eliminate the confounding effects of various other risk factors. References 1.
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MAIN PoINTs • Periodontal diseases are among the most common chronic diseases in humans, affecting 5% to 30% of the adult population. Emerging evidence suggests that periodontitis also increases the risk for heart disease, respiratory disease, and other conditions, such as low birth weight in infants. • A landmark human study, published in 1996, studied 124 pregnant or postpartum women. Subjects received a periodontal examination to determine the clinical attachment level; mothers of preterm low birth weight (PLBW) infants and primiparous mothers of PLBW infants had significantly worse periodontal disease than the respective mothers of normal birth weight infants. The results of the study were the first to show that periodontitis was a significant risk factor for PLBW as a consequence of either preterm labor or preterm premature rupture of membranes. • Providing periodontal treatment during pregnancy may be too late to reduce local and systemic inflammatory responses that lead to adverse pregnancy outcomes. Once the inflammatory cascade is activated, interventions targeting inflammatory pathways may be ineffective in preventing preterm birth. Targeting women prior to conception is appealing because the treatments could be more aggressive and include a longer post-treatment maintenance phase, in theory enabling any periodontitis-induced systemic inflammation to more completely resolve. Vol. 6 No. 3/4 • 2013 • Reviews in Obstetrics & Gynecology • 139
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