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2006;137;7S-13SJ Am Dent Assoc

Steven OffenbacherYiorgos A. Bobetsis, Silvana P. Barros and

complicationsperiodontal disease and pregnancyExploring the relationship between

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Background. Increasing evidence suggests that

maternal gingivitis and periodontitis may be a risk

factor for preterm birth and other adverse pregnancyoutcomes.

Types of Studies Reviewed. To clarify the

possible mechanisms behind the association between

periodontal disease and preterm delivery, the authors reviewed studies of

the effect of infection with periodontal pathogens in animal models on preg-

nancy outcomes including fetal growth, placental structural abnormalities

and neonatal health. After the first report, in 1996, of a potential associa-

tion between maternal periodontal disease and delivery of a preterm/low-

birth-weight infant in humans, many case control and prospective studies

were published. This review summarizes these, as well as early studies

involving periodontal intervention to reduce risk.

Results. Although there are some conflicting findings and potential prob-lems regarding uncontrolled underlying risk factors, most of the clinical

studies indicate a positive correlation between periodontal disease and

preterm birth. Recent studies also have shown that there are microbiologic

and immunological findings that strongly support the association. The

studies indicate that periodontal infection can lead to placental-fetal expo-

sure and, when coupled with a fetal inflammatory response, can lead to

preterm delivery. Data from animal studies raise the possibility that

maternal periodontal infections also may have adverse long-term effects on

the infants development.

Clinical Implications. Education for patients and health care providers

regarding the biological plausibility of the association and the potential risks

is indicated, but there is insufficient evidence at this time for health carepolicy recommendations to provide maternal periodontal treatments for the

purpose of reducing the risk of adverse pregnancy outcomes.

Key Words. Periodontal disease; preterm birth; risk factor.

JADA 2006;137(10 supplement):7S-13S.

I

n the last two decades, the sci-entific community has demon-strated a growing interest indetermining whether peri-odontal disease is associated

with pregnancy complications. Inpart, this concern derives from thefact that despite the advances inprenatal care and increased publicawareness, adverse pregnancy out-comes still present a major publichealth problem worldwide. In fact,in the United States, approximately12 percent of pregnancies are com-plicated by a preterm birth (gesta-tion that lasts less than 37 weeks).1

Preterm infants are immature and

small, factors that contribute to theincreased risk of neonatal mortalityand morbidity. Low birth weight(LBW)a weight less than5 pounds 8 ounces (2.5 kilograms)may be used as a surrogate forpreterm birth in developing nationswhere adequate ultrasound tech-nology for dating of gestation is notreadily available. Infants also maybe born small for gestational age(SGA), a condition usually defined

as birth weight of less than the 10thpercentile of normal weight for ges-tational age. Thus, even full-terminfants may be SGA, reflecting poorintrauterine growth and develop-ment. Finally, miscarriage and pre-eclampsia (increased maternalblood pressure with proteinuriaduring pregnancy) also are commonadverse pregnancy outcomes.Approximately one-third of allpreterm births occur as a result of

ABSTRACT

ARTICLE

1

Dr. Bobetsis is a postdoctoral fellow, Center for Oral and Systemic Diseases, Department of

Periodontology, School of Dentistry, University of North Carolina at Chapel Hill.

Dr. Barros is a research associate professor, Center for Oral and Systemic Diseases, Department of

Periodontology, School of Dentistry, University of North Carolina at Chapel Hill.

Dr. Offenbacher is director, Center for Oral and Systemic Diseases, Department of Periodontology,

School of Dentistry, University of North Carolina at Chapel Hill, CB #7455, DRC Room 222, Chapel Hill,

N.C. 27599-7455, e-mail [email protected]. Address reprint requests to Dr. Offenbacher.

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Exploring the relationship betweenperiodontal disease and pregnancy

complications

Yiorgos A. Bobetsis, DDS, PhD; Silvana P. Barros, DDS, PhD; Steven Offenbacher, DDS, PhD, MMSc

JADA, Vol. 137 http://jada.ada.org October 2006 7S

Copyright 2006 American Dental Association. All rights reserved.

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preterm premature rupture of membranes(PPROM) and one-third because of preterm labor(uterine contraction); the remaining proportionincludes all other complications, includinginduced labor (of which pre-eclampsia is the

major indication).Complicated pregnancies impose a risk not only

to the mother, but also, and primarily, to the off-spring. The majority of very preterm infants (bornat less than 32 weeks gestation) enter theneonatal intensive care unit (NICU) owing to anincreased risk of perinatal mortality, especiallywith impaired lung development and function.Fortunately, new modalities in perinatal care,such as the use of lung surfactant treatments andmothers receiving steroid injections to hastenfetal lung development, have improved the sur-

vival rates of preterm infants. However, pretermand LBW infants who survive the neonatal periodface a higher risk of developing neurodevelop-mental problems (cerebral palsy, blindness, deaf-ness), respiratory problems(asthma, lower respiratory infec-tions, bronchopulmonary dysplasia,chronic lung disease), behavioralproblems (attention deficit hyperac-tivity disorder), learning problems,cardiovascular disease and meta-bolic abnormalities (obesity, type 2

diabetes mellitus).2-8

As a result, theobstetric complications not only area significant health care expense(estimated at more than $5.5 billionannually), but also affect the well-being of the affected infants throughout life.

Research has been conducted to further theunderstanding of the etiology and mechanisms ofobstetric complications that lead to prematurityand growth restriction. However, not all of thecontributing factors have been identified, andmore than 25 percent of all complicated pregnan-

cies occur without any known reason. Reportedrisk factors for preterm delivery include smokingand alcohol consumption, race, parity (number ofbirths), short cervical length, low maternalweight, older (older than 34 years) and younger(younger than 17 years) maternal age, high phys-ical and psychological stress, low socioeconomicstatus and education, and poor maternal nutri-tion. Genitourinary infections also are consideredmajor contributors to preterm deliveries and areresponsible for 30 to 50 percent of all cases.9

These infections occur in close proximity to the

fetal-placental unit, and they induce the release ofhigh amounts of inflammatory mediators such asinterleukin 1 (IL-1), tumor necrosis factor alpha(TNF-) and prostaglandin E2 (PGE2), whichtrigger preterm labor, PPROM and LBW. How-

ever, other more generalized systemic infections,such as viral respiratory infections, diarrhea andmalaria, also may lead to preterm deliveries.

PERIODONTAL DISEASE: INFLAMMATORYRESPONSE

Periodontal disease also represents an infectiousdisease affecting more than 23 percent of womenbetween the ages of 30 and 54 years.10 In theabsence of adequate oral hygiene, periodontalbacteria accumulate in the gingival crevice of theteeth and form an organized structure known as

a bacterial biofilm. In mature biofilms, the bac-teria possess a plethora of virulence factors,including lipopolysaccharide (LPS), that maycause direct destruction to the periodontal tissues

or stimulate the host to activate alocal inflammatory response that,although intended to eliminate theinfection, also may lead to furtherloss of periodontal structures.11

Moreover, bacteria and/or theirshed virulence factors may enterthe bloodstream, disseminate

throughout the body and triggerthe induction of systemic inflamma-tory responses and/or ectopicinfections.

The ability of periodontalpathogens and their virulence factors to dissemi-nate and induce both local and systemic inflam-matory responses in the host has led to thehypothesis that periodontal disease may haveconsequences beyond the periodontal tissuesthemselves. Interestingly, this concept wasreported by Miller12 in 1891 when he published

the theory of focal infection. On the basis of thistheory, oral foci of infection were consideredresponsible for a number of regional and systemicdiseases, such as tonsillitis, pneumonia, endo-carditis and septicemia. However, the lack ofscientific evidence condemned this theory todormancy.

It was 100 years later, in the early 1990s, thatCollins and colleagues13,14 hypothesized that oralinfection, such as periodontitis, could act as asource of bacteria and inflammatory mediatorsthat could disseminate systemically to the fetal-

8S JADA, Vol. 137 http://jada.ada.org October 2006

Obstetric

complications not

only are a significant

health care expense,

but also affect the

well-being of theaffected infants

throughout life.


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placental unit, via the blood circulation, andinduce pregnancy complications.

In a series of landmark animal studies inwhich pregnant hamsters were injected with theperiodontal pathogen Porphyromonas gingivalis,

Collins and colleagues13 found that infection ledto smaller fetuses (approximately 20 percentreduction in weight) and to an increase of inflam-matory mediators (TNF- and PGE2) at the siteof infection and in the amniotic fluid. In subse-quent experiments, in which periodontal diseasewas induced in pregnant hamsters, the investiga-tors found similar results in terms of fetalgrowth.14 These were the first proof-of-principleexperiments to suggest a possible association ofperiodontal disease with adverse pregnancy out-comes. Since then, many investigators have tried

to elucidate whether this association also is pres-ent in humans. In an era of evidence-based den-tistry, several different experimental designshave been used, including epidemiologic studies,intervention studies, microbial studies and exper-iments with animal models.

PERIODONTAL DISEASE AND ADVERSEPREGNANCY OUTCOMES

Clinical evidence. The published epidemiologicstudies can be grouped in two categories: case-control studies and cohort studies. In case-control

studies, mothers with adverse pregnancy out-comes are identified and their past exposure toperiodontal disease is compared with that ofhealthy control subjects. Among the 13 studiesavailable, six found an association between peri-odontal disease and pregnancy complications,15-20

three concluded that this association may be pre-sent21-23 and four demonstrated no association.24-27

The diversity in results among these studiescould be explained by differences in the samplesizes studied or by racial and socioeconomic dif-ferences among the populations. African-

Americans and populations of low socioeconomicstatus demonstrate a higher risk of pregnancycomplications and of more severe periodontal dis-ease. Furthermore, not all populations may nec-essarily be at risk of experiencing adverse preg-nancy outcomes related to periodontal disease,such as was found in a study of Londoners origi-nally from Bangladesh.24 Moreover, among thesestudies, there was significant variation in the cri-teria used to define periodontal disease as themeasure of exposure. For example, some studiesused the Community Periodontal Index of Treat-

ment Needs28 score, others used bleeding onprobing and the majority of studies used pocketdepths or attachment loss levels. Finally, not allstudies assessed the same outcomes; severalinvestigators evaluated the association of peri-

odontal disease with LBW, while others evaluatedthe association with preterm births, preterm LBWor even pre-eclampsia. The results of the studiesthat showed a positive association demonstratedthat pregnant women with periodontal diseaseare up to 7.5 times more likely to have a preg-nancy complication than are their disease-freecounterparts. However, one should exercise cau-tion when using these estimates of the magnitudeof the risk, as case-control study designs can over-estimate odds ratios.

In cohort studies, researchers follow women

over time to see whether those with periodontaldisease will demonstrate a higher incidence ofadverse pregnancy outcomes than will pregnantwomen without periodontal disease. From the 10published studies in this group, six29-34 indicatedan association between periodontal disease andpregnancy complications, one35 suggested thatthis association may be present and three36-38

revealed no association. As with the case-controlstudies, the cohort studies also varied in samplesize, diversity of populations, definition criteriafor periodontal disease and pregnancy outcomes.

In these studies, the risk that women with peri-odontal disease would have an obstetric complica-tion was reported to be as high as 20 timesgreater than that of healthy women.

Interestingly, because periodontal disease ischaracterized by periods of exacerbation andremission, one recent cohort study evaluatedwhether the presence of active disease poses agreater risk to pregnancy.34 The investigators inthis study concluded that women with progressingperiodontal disease during pregnancy indeed aremore likely to have very preterm deliveries com-

pared with women whose disease does notprogress.34

It is important to note that case-control andcohort studies demonstrate association, in thatboth conditions exist in the same patients. Fur-thermore, cohort studies have demonstrated tem-porality in that periodontal disease precedes thepregnancy complication and is not a consequenceof it. This association is both strong and statisti-cally significant, with relative risks increasedtwofold after traditional risk factors (includingprevious preterm birth and smoking) are adjusted

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for. Although this finding is consistent withcausality, such studies cannot fully exclude thepossibility that other underlying risk factors thatcontribute to both conditionsincluding bothknown and unknown risksmay, in part, explain

the association.In the past five years, studies have been per-

formed to determine whether periodontal diseaseis a potentially reversible cause of adverse preg-nancy outcomes. The design of these studies wasto randomly divide women with periodontal dis-ease into two groups. One group received peri-odontal treatment during pregnancy and theother did not. Hence, the investigators evaluatedwhether periodontal therapy leads to a decreasein the incidence of pregnancy complications andthus determined whether periodontal disease is

an independent risk factor for obstetriccomplications.

So far, only three randomized interventionstudies have been published.39-41 In all of thesestudies, the intervention consisted of scaling androot planing of all teeth with or without the useof a chlorhexidine mouthrinse or metronidazole.One of the studies reported a 28 percent reduc-tion in preterm LBW births in the periodontallytreated group, but this difference was not statisti-cally significant.39 The second study indicatedthat periodontal disease is an independent risk

factor for preterm LBW,40

and the third studyconcluded that scaling and root planing mayreduce preterm deliveries.41 Hence, all threestudies point toward the same direction: peri-odontal treatment resulted in a significant reduc-tion in the rate of preterm delivery and anincrease in birth weight. However, the resultswere not always significant, perhaps because ofthe small sample size. Interestingly also, themajority of women participating in these studieswere black and/or of low socioeconomic status,both of which characteristics are significant risk

factors for periodontal disease and preterm birth.Therefore, the data may not be generalizable tothe entire maternal population. However, theycertainly appear promising for those at greatestrisk, in whom the burden of disease and compli-cations of pregnancy are greatest.

Microbiological studies. A third line of evi-dence that sheds light on the possible associationof periodontal disease with adverse pregnancyoutcomes has been a result of microbiologicalstudies. As mentioned earlier, periodontal diseaseis an infectious disease caused mainly by anaer-

obic gram-negative bacteria. Socransky and col-leagues42 divided these bacteria into microbialcomplexes or clusters and assigned to each one acolor designation for the convenience of discus-sion. The blue, green, yellow and purple

clusters include mainly bacteria that colonize theperiodontal sulcus in the early stages of dentalplaque formation. As the biofilm matures andbecomes more pathogenic, organisms of theorange cluster (Campylobacter rectus, Fusobac-terium nucleatum, Peptostreptococcus micros, Pre-

votella intermedia and Prevotella nigrescence)appear and provide the necessary habitat for thesubsequent colonization and establishment of themore aggressive bacteria of the red cluster (Por-phyromonas gingivalis, Tannerella forsythensis

and Treponema denticola). Although the exact

role of each of these bacterial species in the pro-gression of periodontal disease is not fully under-stood, it is clear that the presence of a large groupof bacteria somehow is necessary for the overallpathogenic effect.

As periodontal disease progresses, the hostsimmune system responds by producing antibodiesagainst the various bacterial species. Madianosand colleagues43 examined the prevalence ofvarious periodontal bacteria along with thematernal and fetal antibody response againstthese organisms in 400 pregnant women and

tried to correlate the results with pregnancy out-comes. They concluded that there was a higherrate of preterm deliveries among mothers withouta protective immunoglobulin (Ig) G responseagainst the bacteria of the red cluster. More-over, the fetal IgM response against periodontalpathogens of the orange cluster was stronger inpreterm neonates than in full-term neonates.43

Since this first report, more studies have con-firmed these results and further revealed thatfrom the fetuses with a robust IgM response toperiodontal pathogens, the risk of preterm birth

is greatest among those that also demonstrate aninflammatory response, as indicated by theincrease in cord serum levels of C-reactive pro-tein, IL-1, IL-6, TNF-, PGE2 and 8-isoprostane.44 These studies indicate that whenthere is both fetal exposure to maternal oral bac-teria and an inflammatory response, the relativerisk of preterm delivery is huge, with a risk ratioof 4:7. Together, these findings support the con-cept that maternal periodontal infection in theabsence of a protective maternal antibodyresponse is associated with systemic dissemina-



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tion of oral organisms that translocate to thefetus and result in preterm deliveries. It alsoraises the possibility that in the future, maternalimmunization may help provide protectionagainst fetal exposures during pregnancy.

In addition, neonates who have elevated IgMantibody to both P. gingivalis and C. rectus aretwice as likely to be admitted to the NICU andthree times as likely to stay within the NICU formore than seven days. Hence, the high preva-lence of elevated fetal IgM to these organismsamong preterm infants raises the possibility thatthese specific maternal oral pathogens may serveas a primary fetal infectious agent, thus elicitingpregnancy complications. Thesemicrobiological and immunologicalstudies in humans provide mecha-

nistic insight as well as a strongargument for the biological plausi-bility of association by causality.

The mechanistic aspect of thepossible association of periodontaldisease with pregnancy complica-tions has been explored in severalexperimental animal models. Inmost models, periodontal bacteria(P. gingivalis or C. rectus) are injected in a smallchamber that previously had been implanted sub-cutaneously in the pregnant animals (hamsters,

mice, rabbits).13,14,45-49

The purpose of these experi-ments is to create a site of infection distant to thefetal-placental unit, mimicking, in a simplifiedand reproducible manner, a periodontal infection.

The results of these studies reveal thatmaternal infection with periodontal pathogenshas a deleterious effect on fetal growth and via-bility. Specifically, both P. gingivalis and C.rectus have the capacity to disseminate from thesubcutaneous chamber toward not only maternalorgans (liver, uterus) but, most importantly, toplacental and fetal tissues. This translocation is

accompanied by an increase in inflammatorymediators in the placenta. Moreover, the infec-tion with periodontal pathogens induces a signifi-cant alteration in the architecture of the pla-centa, especially in areas that are critical for theexchange of nutrients between the mother andthe fetus. Furthermore, maternal exposure toP. gingivalis or C. rectus results in a decrease inthe size of the fetuses (preterm deliveries do notoccur in mice). The reduced size of the fetuses isnot the only complication, since the newbornsdemonstrate a higher risk of experiencing peri-

natal death, similarly to preterm LBW humaninfants. Finally, pups that survive the perinatalperiod appear to have an increase in inflamma-tory cytokines (interferon IFN-) in the brain tis-sues along with ultrastructural alterations in the

hippocampal region of the brain. Interestingly,these changes in the neonatal brain occur in amanner analogous to the effect of maternal infec-tion on white-matter damage seen in humans.Taken together, these findings suggest that thethreat of maternal infection with periodontalpathogens during pregnancy may not be limitedto the duration of gestation, but also may affectperinatal neurological growth and development.

THE IMPACT OFINFLAMMATION ONDEVELOPMENT

On the basis of the current evi-dence from both animal and humanstudies, a hypothetical model of theassociation between maternal peri-odontal inflammation and fetaldevelopment may be proposed.

Periodontal bacteria and theirvirulence factors, found in the peri-

odontal pockets, induce a local periodontal host-immune response that includes mainly the pro-duction of inflammatory cytokines (IL-1, PGE2,

TNF- and so forth) and antibodies against thebacteria. If this immune response and the neu-trophils are not capable of keeping the infectionlocalized (such as low maternal IgG response tobacteria), then the bacteria and/or their virulencefactors and the inflammatory cytokines may gainaccess systemically via the blood circulation. Thiswould be particularly evidenced clinically bysigns of bleeding on probing and increased pock-eting during pregnancy. The presence of the bac-teria in the blood circulation will trigger the hostto elicit a second round of inflammatory response,

systemic this time, mainly by the production ofmore inflammatory cytokines and acute-phasereactants such as C-reactive protein from theliver. Eventually, bacteria and/or their virulencefactors and inflammatory cytokines appear toreach the placenta, as about 40 percent of allpregnancies are associated with some fetal IgMantibody response to organisms of maternal oralorigin. This will create another site of bacterialchallenge and possibly placental infection,leading to a new inflammatory response, localizedat the fetal-placental interface this time, with the

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production of more inflammatory cytokines. As inperiodontal tissues, these cytokines, althoughproduced with the intention to combat the infec-tion, also may cause tissue destruction. Becausethe structural integrity of the placenta is vital for

the normal exchange of nutrients between themother and the fetus, this placental tissuedamage may contribute to impaired fetal growth,which may lead to LBW. Also, structural damagein the placenta may disrupt the normal blood flowbetween the mother and the fetus, affecting thematernal blood pressure and leading to pre-eclampsia. The increase in the production ofinflammatory cytokines such as IL-1 and PGE2also may contribute to preterm rupture of themembranes and uterine contraction and lead tomiscarriage or preterm delivery. Finally, peri-

odontal bacteria and/or their virulence factorsand inflammatory cytokines may cross the pla-centa and enter the fetal circulation. There, theymay trigger a new fetal-host immune response, asevidenced by the observed elevated levels of fetalIgM to periodontal pathogens. If the fetus cannotcontrol the infection, the bacteria and/or their vir-ulence factors may gain access to various tissuesand initiate local inflammatory responses and,consequently, structural damage to the fetal tis-sues and organ systems. Depending on the extentof this damage, the newborn may or may not sur-

vive the perinatal period. However, survivors maypossess deficiencies that may compromise theirquality of life, even throughout adulthood.

It is obvious that many parts of this modelneed further confirmation and in-depth investi-gation. Many questions still remain partiallyunanswered or completely unresolved:dCan preventing or treating periodontal diseasereduce the rate of pregnancy complications?dWhich periodontal bacterial species induceadverse pregnancy complications, or must agroup of bacteria be present?d

After infection with periodontal pathogens, arethe biological events occurring in animals similarto those occurring in humans, especially withregard to effects on the neonate?dWhat is the best treatment for pregnantwomen with periodontal disease, and whenshould it be provided?

CLINICAL IMPLICATIONS

Despite the growing volume of data generated byhuman studies and the experimental animalmodels, the clinical application of this informa-

tion to the practice of dentistry needs to be care-fully delineated. Although most of the studies todate indicate a positive correlation, it is still tooearly to attribute a cause-and-effect relationship.The questions posed here emphasize the need for

more research, especially intervention trials inhumans.

Results from multicenter randomized con-trolled intervention trials are believed to providethe highest level of evidence to support the con-cept that periodontal disease is a possiblereversible cause of adverse pregnancy outcomes.If the results of the studies that are under wayare encouraging, additional research will beneeded to determine the optimal treatmentstrategy. However, since periodontal disease is apreventable and treatable condition, it should be

the dentists responsibility to diagnose and treatit properly in women who are pregnant or plan-ning to become pregnant.

CONCLUSION

It is important to note that all of the studies todate that have involved treating periodontal dis-ease in pregnant women (usually in the secondtrimester of pregnancy) suggest that periodontaltreatment is safe for both the mother and thechild. Therefore, treatments can be providedsafely during pregnancy to improve the oral

health of the mother. What we do not yet know iswhether this treatment also significantlyimproves the pregnancys outcome. Nor can wetell pregnant women that treating their gingivalcondition will improve their pregnancy orneonatal outcomes. We will have to wait for theresults of the multicenter trials sponsored by theNational Institute of Dental and CraniofacialResearch that are in progress before we have anopportunity to answer this critical question.

Nonetheless, it is the responsibility of the den-tist and the profession to inform patients about

the biological plausibility that untreated peri-odontal disease may increase the risk not only ofunfavorable pregnancy outcomes, but also ofdeveloping conditions that may affect the well-being of the offspring. There is no evidence of adown-side to providing care to mothers, whichsuggests that such treatment actually may bebeneficial for two. s

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