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The effects of periodontaltreatment on pregnancy

outcomes

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. doi: 10.1111/jcpe.12081.

Abstract

Background: Preterm infants are at greater risk than term infants for physical

and developmental disorders. Morbidity and mortality increases as gestational

age at delivery decreases. Observational studies indicate an association between

poor periodontal health and risk for preterm birth or low birthweight, making

periodontitis a potentially modifiable risk factor for prematurity.

Aim: To identify randomized controlled trials (RCTs) published between January

2011 and July 2012 and discuss all published RCTs testing whether periodontal

therapy reduces rates of preterm birth and low birthweight.

Methods: Search of databases including PubMed, ISI Web of Science and Coch-

rane Library.

Results: The single RCT identified showed no significant effect of periodontal

treatment on birth outcomes.

Discussion: All published trials included non-surgical periodontal therapy; onlytwo included systemic antimicrobials as part of test therapy. The trials varied

substantially in terms of sample size, obstetric histories of subjects, study pre-

term birth rates and the periodontal treatment response. The largest trials – also

judged to be high-quality and at low risk of bias – have yielded consistent

results, and indicate that treatment does not alter rates of adverse pregnancy

outcomes.

Conclusion: Non-surgical periodontal therapy, scaling and root planing, does not

improve birth outcomes in pregnant women with periodontitis.

Bryan S. Michalowicz1,

Anders Gustafsson2,

Vivek Thumbigere-Math3 and

Kare Buhlin2

1Department of Developmental and Surgical

Sciences, University of Minnesota School of

Dentistry, Minneapolis, Minnesota, USA;2Department of Periodontology, Karolinska

Institute, Stockholm, Sweden; 3Adjunct

Faculty, Department of Developmental and

Surgical Sciences, University of Minnesota

School of Dentistry, Minneapolis, Minnesota,

USA

Key words: low birthweight; periodontitis;preterm birth; randomized controlled trials;

therapy

Accepted for publication 14 November 2012

The proceedings of the workshop were jointly

and simultaneously published in the Journal

of Clinical Periodontology and Journal of

Periodontology.

Epidemiology

Preterm birth, defined as a live birth

before 37 weeks of gestation, is theleading cause of infant mortality indeveloped countries (Saigal & Doyle

2008). Just under half of all pretermbirths occur following spontaneouspreterm labour; the remainder occur

following premature rupture of membranes (~ 30 – 35%) or earlyinduction of labour or caesarean sec-tion due to foetal distress or mater-nal medical conditions (i.e. are“indicated”) (Goldenberg et al.2008). Despite extensive research andpublic health efforts, the pretermbirth rate in the United States hasincreased from about 9% to 12%over the last three decades (Martinet al. 2011). Most of the increase hasbeen attributed to multiple births

and the rate for singleton births inthe United States has declinedrecently, to 10.4% (Hamilton et al.

2011). Rates in Europe and otherdeveloped countries are lower, around5-9% (Goldenberg et al. 2008). None-theless, preterm birth remains a publichealth concern worldwide given itsassociated morbidity, mortality, socie-tal and economic costs (Slattery &Morrison 2002).

Risk factors for spontaneouspreterm birth are many, includingbut not limited to smoking, alcoholconsumption, black race, lowsocio-economic status, low or high

Conflict of interest and source of

funding statement

The authors declare no conflict of

interest. The workshop was funded by

an unrestricted educational grant from

Colgate-Palmolive to the European

Federation of Periodontology and the

American Academy of Periodontology.

© 2013 European Federation of Periodontology and American Academy of Periodontology S195

J Clin Periodontol 2013; 40 (Suppl. 14): S195–S208 doi: 10.1111/jcpe.12081

http://onlinelibrary.wiley.com/doi/10.1111/jcpe.12081/abstracthttp://onlinelibrary.wiley.com/doi/10.1111/jcpe.12081/abstracthttp://www.joponline.org/doi/abs/10.1902/jop.2013.1340014http://www.joponline.org/doi/abs/10.1902/jop.2013.1340014http://onlinelibrary.wiley.com/doi/10.1111/jcpe.12081/abstracthttp://onlinelibrary.wiley.com/doi/10.1111/jcpe.12081/abstracthttp://www.joponline.org/doi/abs/10.1902/jop.2013.1340014http://www.joponline.org/doi/abs/10.1902/jop.2013.1340014

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maternal body mass index, stress,previous preterm birth, short inter-pregnancy interval, advanced mater-nal age and short cervix (Slattery &Morrison 2002, Goldenberg et al.2008, Djelantik et al. 2012). Uro-genital and other infections (e.g.

appendicitis, pneumonia and peri-odontal disease) also are associatedwith preterm birth (Goepfert et al.2004, Goldenberg & Culhane 2006).

Bacterial infections and risk for

adverse pregnancy outcomes

Although there are many theoriesregarding the aetiology of pretermbirth, the most popular one involvespremature decidual activation. Mater-nal infections are an important causeof preterm delivery (Hillier et al. 1995,Goldenberg et al. 2000, Lockwood2002) and an estimated 50% of spon-taneous preterm births are associatedwith ascending genital tract infections(Lockwood 2002). Bacteria within theuterine cavity may elicit a pro-inflam-matory cytokine response from mono-cytes, which subsequently releasemetalloproteinases and prostaglandins(Goldenberg et al. 2002). Whereasprostaglandins and cytokines stimu-late smooth muscle contractions,metalloproteinases and other prote-ases weaken the membranes and causepremature cervical ripening. For these

reasons, researchers have explored therole of other maternal infections,including periodontitis, in the aetiol-ogy of preterm birth (Goepfert et al.2004).

Many investigators have reportedan association between periodontaldisease and adverse pregnancy out-comes, including preterm birth, lowbirthweight, foetal growth restric-tion, preeclampsia and perinatalmortality (Eide and Papapanou,2013). The exact mechanisms bywhich periodontal disease can

adversely affect these outcomes,however, remain unclear. Periodon-tal inflammation is theorized toaffect pregnancy outcomes throughtwo mechanisms (Gibbs 2001).Women with periodontitis may expe-rience more frequent and severe bac-teremias than periodontally healthywomen, increasing the chance theuterus will become exposed to oralbacteria or their by-products. Oncebacteria reach the maternal – foetalunit, they can elicit an inflammatory

cascade leading to preterm labour. Asecond putative mechanism involvescytokines generated within thediseased periodontal tissues enteringthe systemic circulation, where theypromote systemic inflammation,again leading to preterm labour.

Boggess et al. (2005) suggested thatthe preterm labour risk is highestwhen the foetus is exposed to peri-odontal bacteria and generates aninflammatory response. To date, thespecific ways in which the womanand foetus respond to periodontalpathogens and inflammation toadversely affect pregnancy outcomeshave not been fully elucidated. Thishas complicated efforts to define rel-evant and modifiable risk exposuresfor targeting in clinical trials.

Updated review of the literature

Numerous meta-analyses and sys-tematic reviews of periodontitistreatment and pregnancy outcomeshave been published in the recentpast, including at least eight since2010 (Pimentel Lopes De Oliveiraet al. 2010, Polyzos et al. 2010,Uppal et al. 2010, Chambrone et al.2011, Fogacci et al. 2011, Georgeet al. 2011, Xiong et al. 2011, Kimet al. 2012). Notably, these reviewshave included most of same ran-domized controlled trials (RCTs)

published in 2011 or earlier (Lopezet al. 2002, 2005, Jeffcoat et al.2003, 2011b, Michalowicz et al.2006, Offenbacher et al. 2006, 2009,Sadatmansouri et al. 2006, Taran-num & Faizuddin 2007, Newnhamet al. 2009, Radnai et al. 2009, Ma-cones et al. 2010, Oliveira et al.2011). Although each reviewincluded a slightly different set of RCTs, all RCTs have been includedin at least one review. Thus, ourgoal was not to conduct yet anothersystematic review; the reader is

referred to two recent and compre-hensive reviews (Chambrone et al.2011, Kim et al. 2012). Rather, wesearched the literature from January2011 through July 2012 to identifyRCTs published since the latestreviews. We limited our search toRCTs comparing periodontal treat-ment to either no treatment, oralhygiene instruction alone or superfi-cial debridement (prophylaxis). Wefocused on preterm birth and lowbirthweight as trial outcomes and

considered pre-eclampsia as a preg-nancy complication rather than anoutcome per se. We do not reportneonatal outcomes because many of these (e.g. neonatal intensive careadmissions, neonatal deaths, AP-GAR scores) are strongly correlated

with gestational age at delivery orbirthweight and were not reportedin most RCTs.

We searched PubMed, ISI Web of Science and the Cochrane Libraryusing the terms “periodontal disease”or “periodontal therapy,” and “preg-nancy” or “preterm birth.” Thesesame search terms identified in Pub-Med all RCTs cited in previous sys-tematic reviews. Our search yielded amaximum of 98 citations in PubMed,78 in ISI Web of Science and one inthe Cochrane Library. We did notsearch non-peer reviewed materials(e.g. government reports or unpub-lished theses or dissertations). Two of the authors (BSM and VTM)reviewed all titles and abstracts, manyof which were duplicated in the firsttwo search engines. Three papersreported clinical trials (Jeffcoat et al.2011a, Sant’Ana et al. 2011, Weidlichet al. 2012), two of which wereexcluded (Jeffcoat et al. 2011a, San-t’Ana et al. 2011) because the inter-vention was not randomly allocated.

The lone RCT (Weidlich et al.2012) we identified randomized 303

Brazilian women 18 to 35 years of agewith a gestational age 20 weeks.Randomization was stratified onsmoking. All women, regardless of their periodontal status, received com-prehensive non-surgical treatment (testgroup: oral hygiene instruction, scal-ing and root planing, and at leastmonthly follow-up visits) or supragin-gival scaling and oral hygiene instruc-tion (control group). Birth outcomeswere available for 299 (98.7%)women. Despite statistically significantand substantial improvements in clini-

cal periodontal measures with treat-ment (e.g. bleeding on probing (BOP)was reduced from 50% to 11%), therewere no significant differences betweentest and control groups in pretermbirth rates at

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teristics of all published RCTs, includ-ing Weidlich et al. (2012).

Features of RCTs

Clinical trials should be instituted atthe appropriate point during thestudy of a putative risk factor.Neaton & Mugglin (2006) cautionedagainst conducting trials before criti-cal exposure levels and appropriateoutcomes are defined. While RCTsto date have defined preterm birthrisk in terms of clinical periodontalmeasures, others have suggested that

risk may be better defined by themicrobial profile of the woman orthe foetal inflammatory and immuneresponse (Boggess et al. 2005, Linet al. 2007). The literature, however,is equivocal regarding associationsbetween specific oral microbes andpreterm birth. While some groupsreported associations between Por- phyromonas gingivalis and Tannerella forsythia or BANA-positive speciesand preterm birth (Lin et al. 2007,Chan et al. 2010), others found asso-ciations with Eikenella corrodens but

not P. gingivalis and T. forsythia(Santa Cruz et al. 2012). Still othersfound no associations with individ-ual bacterial species (Noack et al.2005). RCTs to date have recruitedwomen based on periodontitis asdefined clinically because it is howthe relevant risk had been defined inmost supporting case-control orcohort studies.

Below, we briefly discuss impor-tant issues in clinical trial researchand how published RCTs have

addressed or managed these issues.Table 3 summarizes some of thisinformation.

RCTs should define a primary outcome

The primary outcome is the principalmeasure by which groups are com-pared and trial inferences made. Inobstetrics, researchers frequently usegestational age at delivery or birth-weight as the primary outcome. Com-posite outcomes (e.g. preterm birthand/or low birthweight) are notcommon in prematurity research.

Although gestational age and birth-weight are correlated, the risk profilesdiffer somewhat (Wessel et al. 1996,Panaretto et al. 2006) and the use of outcomes that combine elements of preterm birth, low birthweight and foe-tal growth restriction may confoundthe results for individual outcomes.

Published RCTs differ in terms of how they analysed non-live births(i.e. spontaneous abortions or still-births). Two trials (Michalowiczet al. 2006, Offenbacher et al. 2009)considered all events occurring

before 37 weeks gestation [spontane-ous abortions, stillbirths and sponta-neous and medically indicated(induced) live preterm births] as theprimary outcome. Both trials alsocompared rates of live preterm birthsonly between study groups. Otherstrials considered spontaneous abor-tions and stillbirths after randomiza-tion as separate events (Maconeset al. 2010) or variably excludedsuch events from the analyses(Newnham et al. 2009). Still others

excluded all “non-live” events (Lo-pez et al. 2002, 2005, Tarannum &Faizuddin 2007, Oliveira et al. 2011).Finally, several trials (Jeffcoat et al.2003, Offenbacher et al. 2006, Rad-nai et al. 2009) did not report spon-taneous abortions or stillbirths,making it impossible to determine if these events were not observed orsimply excluded from the analyses.

Excluding select pregnancy out-comes may mast deleterious or bene-ficial effects of the intervention. Forexample, the intervention itself mayelicit host responses associated with

adverse outcomes, causing a womanat risk for preterm delivery to experi-ence an earlier or more severe event(e.g. a spontaneous abortion or still-birth). Thus, it is important to countall pregnancy outcomes, not just livepreterm births. To address this issue,Michalowicz et al. (2006) added acompeting risks analysis, wherebylive and non-live pregnancy out-comes were considered separate butcompeting events.

Clinical trials should allocate

interventions randomly

Randomization eliminates treatmentallocation bias by balancing betweenstudy groups known and unknownprognostic factors (i.e. factors affect-ing trial outcomes). Randomizationalso permits the use of probabilitytheory to express the likelihood thatobserved group differences merelyreflect chance (Moher et al. 2010). Afew non-randomized trials have beenpublished (Mitchell-Lewis et al. 2001,

Table 1. Bias Risk* for Weidlich et al. (2012)

Entry Judgement Description

Adequate sequence generation? Yes “Women were randomly allocated to the experimental groups…”

Allocation concealment? Yes Used a computer-generated random numbers concealed in opaque, sealed,

serially numbered envelopes.

Blinding? (Primary outcome

assessments)

No No mention of blinding of primary outcome assessments. Primary outcomes

not “pre-specified,” but were likely to have been. OB/GYN reviewed medical record

to estimate gestational age at delivery. If non-blinded assessment, high risk for bias.If birthweight abstracted from medical record (not specified), non-blinded recorder

likely unbiased.

Blinding? (Periodontal

measures)

No No mention of blinding of calibrated clinical examiners

Incomplete outcome data addressed? Yes Primary trial outcomes unavailable for 1.3% of randomized women, 2 per group.

Free of selective reporting? Yes Both preterm birth and low birthweight fractions reported and compared. Fractions of

preterm births computed as a fraction of all pregnancies, not all live births.

Free of other bias? No Sample size based on unrealistic expected reduction in preterm birth associated with

periodontal treatment (10.7% to 2%); Enrolled all otherwise eligible women,

not only those with periodontitis.

*According to the Cochrane Collaboration’s tool for assessing risk of bias (http://www.cochrane.org/, accessed July 23, 2012).

© 2013 European Federation of Periodontology and American Academy of Periodontology

Periodontal therapy and pregnancy outcomes S197

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Cruz et al. 2010, Sant’Ana et al.2011), all reporting improved out-comes in pregnant women whoreceived periodontal treatment com-pared to those who needed buteither refused or did not seek suchcare. At face value, these results sug-

gest that periodontal treatment mayimprove pregnancy outcomes. Analternative explanation, however, isthat health care-seeking behavioursduring pregnancy, possibly indepen-dent of periodontal treatment per se,may be associated with improved out-comes. This alternative is not incon-sistent with results from high-qualityRCTs (see below) and is one of sev-eral reasons why random allocationof treatment, if ethical, is highly desir-able. Importantly, randomizationtends to balance prognostic factorsbetween groups only if the trial issufficiently large (>~ 400 subjects)(Kernan et al. 1999). Given the num-ber of risk factors for adverse preg-nancy outcomes, important groupimbalances may remain in small trialseven with randomization.

RCTs must ensure an adequate number of

events are observed, allowing treatment

effects to be estimated with reasonable

precision

Smaller trials, even ones that reportstatistically significant treatment

effects, often have broad confidenceintervals for the statistics of interest,resulting in a range of estimated effectsthat spans from marginal to striking.Wide confidence intervals for treat-ment effects can befuddle cliniciansand the public alike. For example, onetrial’s (Sadatmansouri et al. 2006)confidence interval indicated that peri-odontal treatment was associated withsomewhere between a 100-fold reduc-tion and a 2.5-fold increase in the oddsof delivering a preterm infant (Polyzoset al. 2010). Sample sizes of published

RCTs vary dramatically, from 30 to1806 randomized women. Five peri-odontitis trials (Lopez et al. 2002,Michalowicz et al. 2006, Newnhamet al. 2009, Offenbacher et al. 2009,Macones et al. 2010) randomized 400or more women whereas one gingivitistrial randomized 870 (Lopez et al.2005). Trial size has been linked totrial quality or bias risk, as severalreviews consistently rated the largesttrials as being of highest quality or atlowest risk for bias (Polyzos et al. T

a b l e 2 . S e l e c t e d f e a t u r e s o f p u b l i s h e d R C T s *

F i r s t a u t h o r , y e a r

C o u n t r y

N u m b e r

r a n d o m i z e d

P e r i o d o n t a l e n r o l m e n t c r i t e r i a

P r e v i o u s

P T B ( % ) †

T e s t t r e a t m e n t

C o n t r o l t r e a

t m e n t

N u m b e r

a n a l y s e d

L o p e z ( 2 0 0 2 )

C h i l e

4 0 0

4 t e e t h w i t h P D

4 m m

&

C A L

3 m m a t s a m e s i t e

6 . 0

S R P +

0 . 1 2 %

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m a i n t e n a n c e

q 2 - 3 w e e k s . 2

7 r e c e i v e d A M O X + M E T

N o T X

3 5 1

J e f f c o a t ( 2 0 0 3 )

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3 s i t e s w i t h C A L

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S R P +

p l a c e b o

, S R P +

M E T

P X S +

p l a c e b o

3 6 6

L o p e z ( 2 0 0 5 )

C h i l e

8 7 0

2 5 %

s i t e s w i t h B O P , n o s i t e s w i t h

C A L >

2 m m

4 . 8

S c a l e a n d p o l i s h +

0 . 1 2 %

C H X +

O H I +

m a i n t e n a n c e q 2 - 3 w e e k s

N o T X

8 3 1

O f f e n b a c h e r ( 2 0 0 6 )

U S A

1 0 9

2 s i t e s w i t h P D

5 m m

&

1 s i t e s

w i t h C A L 1 - 2 m m a t

1 s

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8 1 . 1

S R P +

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p o w e r e d t o o t h b r u s h

S u p r a g i n g i v

a l

d e b r i d e m e n t

6 7 ( f o r b i r t h

o u t c o m e s )

M i c h a l o w i c z ( 2 0 0 6 )

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8 2 3


4 m m

& C A L

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m a i n t e n a n c e q 4 w e e k s

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8 1 2 ( f o r b i r t h

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0 . 2 %

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e v a l u a t i o n

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3 0

T a r a n n u m ( 2 0 0 7 )

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o f s i t e s w i t h C A L

2 m m

5 8 . 5

S R P +

0 . 2 % C

H X +

O H I +


q 3 - 4 w e e k s

O H I

1 8 8

N e w n h a m ( 2 0 0 9 )

A u s t r a l i a

1 0 8 7

1 2 s i t e s w i t h P D >

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1 2 . 2

S R P +

0 . 1 2 %

C H X +

O H I +


a s n e e d e d

N o T X

1 0 7 8

O f f e n b a c h e r ( 2 0 0 9 )

U S A

1 8 0 6


3 m m

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S R P +

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N o T X

1 7 6 0

R a d n a i ( 2 0 0 9 )

H u n g a r y

8 9

1 s i t e w i t h P D

4 m m &

5 0 %

o f s i t e s w i t h B O P

N S

S R P +

O H I a t ~ 3 2 w e e k s g e s t a t i o n

N o T X

8 3

M a c o n e s ( 2 0 1 0 )

U S A

7 5 6


3 m m

1 2 . 3

S R P


a l

s c a l i n g

7 1 3

O l i v e i r a e t a l . 2 0 1 1 ,

B r a z i l

2 4 6


4 m m & C A L


N S

M e c h a n i c a l d e

b r i d e m e n t +

P X S +

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N o T X

2 2 5

W e i d l i c h ( 2 0 1 2 )

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3 0 3

N o n e

1 3 . 4

S R P +

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m a i n t e n a n c e q 1 m o n t h


a l

s c a l i n g + O

H I

2 9 9

* J e f f c o a t e t a l . ( 2 0 1 1 b ) n o t i n c l u d e d b

e c a u s e a n u n k n o w n n u m b e r o f p a r t i c i p a n t s w e r e a l s o i n c l u d e d i n M a c o n e s e t a l . ( 2 0 1 0 ) r e p o r t .

† V a r i a b l y r e p o r t e d a s a p e r c e n t a g e o f

a l l w o m e n o r w o m e n w i t h a p r e v i o u s l i v e b i r t h .

P D , p r o b i n g d e p t h ; C A L , c l i n i c a l a t t a c h m e n t l o s s ; B O P , b l e e d i n g o n p r o b i n g ;

S R P , s c a l i n g a n d r o o t p l a n i n g ; C H X , c h l o r h e x i d i n e m o u t h r i n s e ; A M O X , a m o x i c i l l i n ; M E T , m e t r o n i d a z o l e ;

P X S , p r o p h y l a x i s ; O H I , o r a l h y g i e n e

i n s t r u c t i o n ; N S , n o t s p e c i fi e d ; T X , t r e a t m e n t ; P T B , p r e t e r m b i r t h .


S198 Michalowicz et al.

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2010, Uppal et al. 2010, Chambroneet al. 2011). Again, smaller trials areat risk for being imbalanced in termsof measured and unmeasured prog-nostic factors.

RCTs should recruit subjects from diverse

populations

Recruiting subjects from diversepopulation helps ensure that resultsare broadly applicable, or generaliz-able, to all women at risk foradverse pregnancy outcomes. If theputative deleterious exposure is peri-odontitis, all women with diseasecould benefit from treatment andshould be included in a trial.Although the periodontitis-preterm

birth association appears strongestin women from low socio-economicstrata (Xiong et al. 2006), there areno compelling biological reasonswhy the deleterious effects of peri-odontitis should vary by income sta-

tus or race or ethnicity.Trials that recruit from a singlegroup raise concerns about the trial’sgeneralizability. Several trials havereported preterm birth rates that aremuch higher than seen in similar,non-study populations (Tarannum &Faizuddin 2007, Radnai et al. 2009,Jeffcoat et al. 2011b). For example,Tarannum & Faizuddin (2007)reported that periodontal treatmentsignificantly reduced preterm birthrates, from 74.4% in untreated con-

trols to 53.5% in treated women.These are strikingly high rates in bothgroups considering the reported pre-term birth rate in the same populationis

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that treatment is effective only in thehighest risk groups (Kim et al. 2012),the applicability of these results tobroader patient groups might bequestioned.

RCTs are designed to test a specific

hypothesis and their methods are largelyprescribed

RCTs are not exploratory in nature,or hypothesis-generating exercises.Investigators must pre-specify mostaspects of the trial, including the sam-ple size, statistical power, test andcontrol interventions, primary andsecondary outcomes and data analy-sis plans, including subgroup analy-ses. Trials that propose subgroupanalyses (or that perform multipleinterim data analyses) must makeappropriate adjustments for multiple

comparison testing. Subgroup analy-ses should preserve the randomiza-tion process. Post hoc analyses thatviolate the randomization processhave the same shortcomings thatobservational studies do; they cannotcontrol for potential confounders(measured and unmeasured) and bias(Di Mario et al. 2011).

Trial outcomes must be assessed

accurately and with little or no ambiguity

Most obstetrics trials estimate gesta-

tional age early in pregnancy usingself-reported last menstrual perioddates and ultrasound data (Careyet al. 2000). Establishing gestationalage later in pregnancy or at delivery isless precise and confounded by differ-ences in growth rates and factors thatrestrict foetal growth. Birthweight isnot subject to such errors and for thisreason is a common outcome inobstetrics research. Published RCTsvary according to the methods usedto estimate gestational age. Seven tri-als (Lopez et al. 2002, 2005, Jeffcoat

et al. 2003, Michalowicz et al. 2006,Radnai et al. 2009, Oliveira et al.2011, Weidlich et al. 2012) used acombination of last menstrual perioddates and data from ultrasoundsobtained early in pregnancy. One trial(Offenbacher et al. 2009) used onlydata from ultrasounds obtained priorto 16 weeks, and another (Tarannum& Faizuddin 2007) from ultrasoundsobtained between 9 and 32 weeks.Three trials (Offenbacher et al. 2006,Sadatmansouri et al. 2006, Newnham

et al. 2009) did not specify themethod while two (Macones et al.2010, Jeffcoat et al. 2011b) abstractedinformation from medical recordswithout describing the method usedby practitioners.

RCTs should have few losses to follow-upand drop outs

Investigators should make all reason-able attempts to assess the primaryoutcome in randomized participants.Too many losses to follow-up canproduce biased results and diminishthe trial’s credibility (Hulley 2007). Ingeneral, published RCTs have hadretention rates >90%, and only two – both of which reported a significanttreatment effect – lost >10% of ran-domized participants [14.5% (Taran-num & Faizuddin 2007) and 38.5%

(Offenbacher et al. 2006)].Investigators may impute rather

than ignore missing data. In theMOTOR Trial (Offenbacher et al.2009), study groups were comparedusing two approaches – both usingobserved birth outcomes only and“imputing” preterm births for miss-ing observations. Both approachesyielded the same result – no signifi-cant periodontal treatment effect onpreterm birth rates. The obstetricsand periodontal therapy (OPT) Trial(Michalowicz et al. 2006) handled

missing data differently. Becausegroups were compared using survivalanalysis (using “time to end of preg-nancy” as the event), a woman’s datawere included in the analysis until shewas lost to follow-up, underwentan elective abortion, experienced aspontaneous abortion or stillbirth, ordelivered a live preterm infant. In thismanner, data from all randomizedwomen contributed to the trial’sstatistical power.

Meta-analyses and systematic

reviews

Numerous systematic reviews havebeen published in the recent past. Ourgoal is not to provide a “review of reviews,” although several themes canbe gleaned from these publicationsand deserve mention. Notably, conclu-sions from published meta-analysesdiffer according to how the compo-nent RCTs were rated and grouped.Most reviews rated study quality orbias level (low, high or unclear).

Recent reviews (each including 10 ormore RCTs) that segregated trialsaccording to judged quality or biasconcluded that there is no significanteffect of non-surgical periodontaltreatment on rates of preterm birth orlow birthweight (Polyzos et al. 2010,

Uppal et al. 2010, Chambrone et al.2011, Kim et al. 2012). Others com-bined the component RCTs regardlessof their judged quality and reportedmixed findings. Three reported no sig-nificant treatment effect on pretermbirth and low birthweight (Fogacciet al. 2011, Xiong et al. 2011, Kimet al. 2012), whereas two others con-cluded that treatment significantlyreduced rates of these outcomes (Pi-mentel Lopes De Oliveira et al. 2010,George et al. 2011).

Most reviews have recognized theheterogeneity among the RCTs andspeculated on possible causes. Theseinclude differences in baseline diseaselevels or disease definitions, pretermbirth risk, the extent of treatment ormagnitude of treatment response orsample size. Notably, results from thefour largest trials (Michalowicz et al.2006, Newnham et al. 2009, Offenb-acher et al. 2009, Macones et al.2010) – each reporting birth outcomesfrom >700 participants – are remark-ably consistent, with none showing asignificant treatment effect on pre-term birth rates. Thus, sample size

differences, more than any other fac-tor, seem to explain the heterogeneityamong studies. Moreover, Kim et al.(2012) concluded “no small studiesreport[ed a] lack of effect, indicatingsome likely reporting bias or othersmall study bias effect.”

Most reviews examined treatmenteffects in various post hoc studygroups. George et al. (2011) reportedthat trials enrolling women with lowrates of previous preterm birth( 5%) showed a positive treatmenteffect, whereas Kim et al. (2012)

found that RCTs with high rates of preterm study births showed a posi-tive treatment effect. Somewhatcounter-intuitively, George et al.(2011) found a significant combinedtreatment effect in two studies thatenrolled women with less extensiveor severe baseline periodontitis.

Conducting subgroup analyses inmeta-analyses poses the same risk asmultiple comparisons testing in asingle study. As these analyses havebeen performed using essentially the



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same set of published RCTs, the riskis real that some findings from thesesubgroup analyses are falsely posi-tive. Unfortunately, there is littlechance that results from these sub-group analyses can be confirmed inindependent sets of RCTs.

Possible explanations why

periodontal treatment does not affect

pregnancy outcomes

The largest and highest quality RCTsto date have consistently shown noeffect of non-surgical, mechanicaltreatment on preterm birth and birth-weight. The only RCT publishedsince the latest systematic reviews(Weidlich et al. 2012) also reportedno significant treatment effect. Theremay be many reasons why periodon-tal treatment has not been shown toreduce risk for adverse pregnancyoutcomes. We discuss a few of thesebelow. None of these reasons havebeen “proven” or refuted with clinicaltrials data nor should any be viewedas having strong or moderate sup-porting evidence (for example, Level Ior II-1evidence according to Newmanet al. 2003). Instead, we raise theseissues for the sake of discussion.

Periodontal disease is not causally linked

to preterm birth or low birthweight

Periodontitis treatment, regardless of its timing, intensity or effectiveness,will not reduce preterm birth or lowbirthweight rates if the conditions arenot causally linked. Although mostobservational studies report an associ-ation between maternal periodontitisand pregnancy outcomes, the qualityof studies showing strong associationshas been questioned (Vergnes & Sixou2007). In addition, several large obser-vational studies (both cross-sectionaland prospective) failed to detect anassociation between maternal peri-

odontitis and risk for preterm or lowbirthweight delivery (Davenport et al.2002, Moore et al. 2004, 2005, Vettoreet al. 2008, Lohsoonthorn et al. 2009,Srinivas et al. 2009). Vettore et al.(2008) reported evidence that increas-ing levels of disease were associatedwith progressively lower risks for lowbirthweight, suggesting that maternalperiodontitis was protective, in a dose-dependent manner, against infantlow birthweight. Thus, researcherscontinue to debate the magnitude of

the association between periodontalhealth and birth outcomes.

The treatment effect is confounded by

shared risk factors

Many risk factors for both periodon-

titis and poor pregnancy outcomesare not addressed with periodontaltreatment alone. Although such fac-tors may be balanced betweengroups in RCTs, the periodontaltreatment effect on pregnancy out-comes may be mitigated if theseshared risk factors are prevalent inthe sample population. Smoking isone example (Cnattingius 2004).Periodontal treatment without smok-ing cessation may have little effecton both periodontal status and preg-nancy outcomes.

Obesity confers a preterm birthrisk comparable in magnitude tosmoking (Djelantik et al. 2012). Themechanisms linking obesity and peri-odontitis with adverse pregnancy out-comes are not well defined, butadipose tissue has pro-inflammatoryproperties that increase with increas-ing obesity (Maury & Brichard 2010).Six of the 13 published RCTs do notdescribe maternal body weight mea-sures. Trials addressing maternalweight gain with diet and/or exercisehave shown an effect on maternalweight but not on pregnancy out-

comes (Muktabhant et al. 2012).Socio-economic status (SES),

including education, is associatedwith both adverse pregnancy out-comes and periodontitis (Blumen-shine et al. 2010, Boillot et al. 2011).Rather than being a risk factor perse, SES is probably a marker for lifestyle factors such as care-seekinghabits, diet and exercise. Differencesin SES among the RCTs mightexplain some of the differences inreported periodontal treatment andpregnancy outcomes.

Type 1 and 2 diabetes are associ-ated with periodontitis and gingivalinflammation (Novak et al. 2006,Lalla et al. 2007, Mealey & Ocampo2007) and with pregnancy outcomes,mainly stillbirths, perinatal mortalityand congenital malformations (Dun-ne et al. 2003). Several RCTs haveexcluded women with diabetes (Lo-pez et al. 2002, Offenbacher et al.2006, 2009, Sadatmansouri et al.2006, Tarannum & Faizuddin 2007,Oliveira et al. 2011), whereas others

did not report the diabetes status of trial subjects (Jeffcoat et al. 2003,2011b, Radnai et al. 2009, Maconeset al. 2010). Differences in diabetesinclusion/exclusion criteria also maypartially explain the inconsistentresults across trials.

Periodontal therapy is effective at

reducing early preterm births, which

studies have been underpowered to

detect

Most preterm births are “late,” mean-ing they occur close to 37 weeks gesta-tion. Preterm birth rates decreaseprecipitously at earlier gestationalages. For example, in the USA in2009, the rate of singleton birthsoccurring at

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studies, however, have examinedhow disease definitions affect theobserved association between peri-odontal disease and birth outcomes.Gomes-Filho et al. (2007) found theassociation was consistent acrossvarious disease definitions that

included probing depth. Vettoreet al. (2008) and Lohsoonthorn et al.(2009) tested for associations using15 and 7 published disease defini-tions, respectively, in case-controlstudies of 542 and 934 women. Nei-ther study found a positive associa-tion between periodontitis andpreterm birth using any disease defi-nition. As mentioned earlier, Vettoreet al. (2008) found an inverse relation-ship between maternal periodontaldisease levels and low birthweight.More recently, Al Habashneh et al.(2012) reported that preterm birthcases and controls differed signifi-cantly in terms of mean clinicalattachment loss (CAL) and the per-centage of sites with CAL 5 mmand 6 mm, but not in terms of probing depth (PD) measures or theextent of CAL at lower thresholds.Given these equivocal findings, it isnot possible to identify from the exist-ing literature a disease definition thatis consistently and strongly associatedwith preterm birth risk and that couldbe used to define eligibility in futureRCTs.

Table 4 lists selected clinical char-acteristics of study participantsaccording to the RCT’s reportedtreatment effect on preterm birth.Few publications summarized peri-odontal measures in the same man-ner, making it is difficult to comparedisease levels among the RCTs.Nonetheless, it appears that trialsshowing a treatment effect tended toenrol women with more extensive andsevere disease than “negative” ones.In contrast, a recent meta-analysisconcluded that RCTs enrolling

women with less extensive or severedisease showed significant treatmenteffects whereas trials enrolling morediseased women did not (Georgeet al. 2011). No trial has randomizedonly women with advanced periodon-titis or reported treatment effects insubgroups with advanced disease.

To date, there is no strong evidenceindicating that the magnitude of theperiodontal treatment effect (on preg-nancy outcomes) in RCTs variesaccording to baseline disease levels.

Two recent systematic reviews (Poly-zos et al. 2010, Chambrone et al.2011) also concluded it was unlikelythat the absence of a periodontal treat-ment effect on pregnancy outcomeswas attributable to inter-trial differ-ences in disease definitions.

Periodontal treatment alone,however, may not improve preg-nancy outcomes in the presence of other oral, non-periodontal infec-tions. Three trials (Lopez et al. 2002,Michalowicz et al. 2006, Weidlichet al. 2012) provided dental care toall women with abscessed or badlydecayed teeth, while three others(Offenbacher et al. 2006, 2009, Jeff-coat et al. 2011b) excluded womenwith extensive treatment needs. Theremaining trials (Jeffcoat et al. 2003,Sadatmansouri et al. 2006, Taran-num & Faizuddin 2007, Newnhamet al. 2009, Radnai et al. 2009, Ma-cones et al. 2010, Oliveira et al.2011) did not specify how patientswith non-periodontal dental treat-ment needs were managed.

Interventions tested to date have been

inadequate to affect birth outcomes

All published RCTs have includednon-surgical treatment with or with-out follow-up care. Although scalingand root planing improves clinicalperiodontal measures even in

advanced disease, it is possible thatmore aggressive therapies (that fur-ther reduce pocketing and inflamma-tion) are needed to consistentlyimprove pregnancy outcomes. Asevidence, positive RCTs tend to havemore pronounced clinical periodon-tal treatment responses than negativeones (Table 4).

Such concerns were first raised inregards to the OPT Trial (Mich-alowicz et al. 2006). Armitage (2008)argued that more pronounced reduc-tions in BOP, as was achieved in

earlier positive trials (Lopez et al.2002, Offenbacher et al. 2006), maybe necessary to affect pregnancy out-comes. Subgroup analyses in OPT,however, found no treatment effect(on pregnancy outcomes) amongthose with the most favourable treat-ment responses (Michalowicz et al.2006). The largest trial to date, whichshowed no treatment effect, reporteda rather weak clinical treatmentresponse (Offenbacher et al. 2009).Excluding this trial substantially

improves the average clinical responseamong the remaining negative trials(Table 4). For example, the weightedaverage absolute reduction in BOPwith treatment increases from 22.2%to 32.9% without this trial, which isnearly identical to the weighted aver-

age change reported in positive trials.Three other RCTs that achievedgreater BOP reductions than OPTalso reported no significant treatmenteffects on preterm birth and birth-weight (Newnham et al. 2009, Olive-ira et al. 2011, Weidlich et al. 2012).The remaining large negative trial didnot report changes in periodontalmeasures (Macones et al. 2010). Itappears unlikely that OPT, or theother negative trials, failed to demon-strate a treatment effect because of their periodontal treatment response.No RCT enrolled women based onthe presence of specific periodontalpathogens and none targetedpathogen elimination as an aim of therapy.

Concerns regarding the variableclinical treatment responses amongRCTs reflect a broader concernregarding the lack of establishedtreatment endpoints, or criteria thatdefine an acceptable response and sig-nify an end to active treatment (Ar-mitage 2008). Treatment protocols inRCTs typically define treatmentaccording to the number and timing

of procedures, rather than whether aparticular endpoint is achieved, forexample, some pre-specified percent-age reduction in BOP or pathologi-cally deepened pockets. Althoughmany RCTs included a maintenancephase that allowed for re-instrumen-tation and reinforcement of oralhygiene instructions, others did not(Table 2). The need for supportiveperiodontal therapy and behaviourreinforcement and the notion thattreatment should be adapted to thepatient’s individual needs are tenets

of clinical periodontal care. Nonethe-less, just as the research communitycontinues to struggle with the devel-opment of uniform disease defini-tions, it has yet to build a consensusdefinition of “successful” periodontaltreatment. Future studies addressingthe effects of periodontal diseasetreatment on general health measureswould benefit mightily from thedevelopment and harmonization of specific disease criteria and treatmentendpoints.



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No RCT included periodontal sur-gery, which tends to produce largerreductions in PD when compared tonon-surgical approaches. The inclu-sion of surgical care, however, couldreduce a trial’s public health impactbecause of the added expense and

because many pregnant women maybe unwilling to undergo such treat-ments. A call for more aggressivetreatments might be justified if thetreatment effect (on pregnancy out-comes) was found to be smallest inwomen with the most advanced dis-ease, that is, in those who might bene-fit most from surgical interventions.George et al. (2011) provided somesupport for this theory by reporting asignificant overall treatment effect intrials that enrolled women with lessextensive – although not necessarilyless severe – disease. A recent study,however, questions whether adversepregnancy outcomes are associatedwith advanced or aggressive forms of periodontitis (Schenkein et al. 2012).

Systemic or locally delivered anti-microbials are useful adjuncts in thetreatment of periodontitis (Cioncaet al. 2009), particularly aggressiveperiodontitis (Mombelli et al. 2011).Only two trials (Lopez et al. 2002,Jeffcoat et al. 2003) used systemicantibiotics in some participants,excluding rescue treatments. Becauseantibiotics can resolve non-oral, bacte-

rial infections, their use makes it diffi-cult to attribute changes in birthoutcomes to periodontal improve-ments alone. Jeffcoat et al. (2003) con-ducted a three-arm pilot trial in whichone group received systemic metroni-dazole along with scaling and rootplaning. Consistent with studies of antibiotic use in pregnant women withbacterial vaginosis or Trichomonasvaginalis (Okun et al. 2005), use of adjunctive metronidazole in the Jeff-coat et al. (2003) study did not signifi-cantly reduce preterm birth rates.

Lopez et al. (2002) providedamoxicillin and metronidazole towomen with aggressive periodontitis,who comprised 18% of their test subjects. The effect of these drugs inresolving non-oral infection con-founded the periodontal treatmenteffect and birth outcomes were notreported in this subgroup alone. Notrial has included locally delivered an-timicrobials, several of which arecommercially available and approvedas adjuncts to scaling and root T

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planing. Although locally deliveredmetronidazole and chlorhexidineproducts are not contraindicated foruse in pregnant women, two others(AtridoxTM; Zila, Inc., Fort Collins,CO, USA and ArestinTM; OraPharma,Inc., Horsham, PA, USA) are tetra-

cycline derivatives, which are contra-indicated in pregnant women.More recently, Jeffcoat et al.

(2011b) reported that rates of pre-term birth (

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Suggestions for future research

In the preceding sections, we dis-cussed a variety of issues surroundingthe existing clinical trials research.The preponderance of evidence sug-gests that non-surgical treatment doesnot alter rates of adverse pregnancyoutcomes. Nonetheless, some mightargue that additional trials are war-ranted given the remaining knowl-edge gaps. Researchers planningfuture RCTs should consider the fol-lowing design issues:

• The relevant periodontal risk expo-sure (i.e. the clinical, microbiologi-cal, serological/ immunologicalcharacteristic, or by combinationsof the above, along with the thresh-olds for each component) shouldbe precisely defined for each

adverse pregnancy outcome of interest. For example, if risk isdefined solely on clinical periodon-tal status, then the minimum extentand/or severity of disease should bedefined based on validated evi-dence from observational studies.To date, a variety to disease criteriahave been used to define trial eligi-bility. Standardizing the enrolmentcriteria across trials would maketrials more directly comparable,which would assist those conduct-ing systematic reviews and meta-

analyses. To date, however, vali-dated definitions and thresholdsare not available.

• Clinical trials protocols shouldpre-specify evidence-based treat-ment endpoints or clinical criteriafor judging treatment success. Byevidence based, we mean end-points for which there is corrobo-rated evidence that women withperiodontal conditions notexceeding these threshold are atlittle or no increased risk for theadverse outcome of interest. Such

clinical endpoints have not beenidentified to date.

• Researchers should consider ran-domized trials that provide peri-odontal treatment to women whoare planning to become pregnant.Alternatively, trials should com-pare the effects of periodontalinterventions at varying timesduring gestation. Only throughsuch study designs will it be pos-sible to determine the ideal tim-ing, if any, of periodontal

treatment as a means of improv-ing pregnancy outcomes.

Conclusions

Many but certainly not all observa-

tional studies suggest that womenwho deliver preterm or low birth-weight infants have poorer periodon-tal health than those with term ornormal birthweight deliveries. Thenature of this association and theeffect of periodontal treatment onthese outcomes continue to be stud-ied and debated. To date, large,high-quality RCTs suggest thatnon-surgical periodontal therapy,delivered early in pregnancy, doesnot alter rates of preterm births andlow birthweight deliveries. Meta-analyses limited to high-quality orlow-bias risk RCTs (Polyzos et al.2010, Uppal et al. 2010, Chambroneet al. 2011) have yielded summaryodds ratios of 1.05 and 1.15 favour-ing no treatment. Had these analysessuggested that treatment was associ-ated with an intriguing but not-yet-significant reduction in pretermbirth risk, additional RCTs testingnon-surgical periodontal treatmentsmight be warranted to improve theprecision of the estimated treatmenteffect. Composite results from high-quality RCTs, however, do not sup-

port the need for additional similartrials.

It is not known if more intensivetreatment, treatment delivered beforeconception or treatments that targetspecific components of inflammationor oral pathogens [such as Fusobacte-rium nucleatum (Han et al. 2010)] canreduce these adverse outcomes. Nota-bly, only one RCT (the OPT Study)reported microbiological findings instudy participants (Novak et al. 2008).Scaling and root planing significantlyreduced levels of seven selected peri-

odontal bacteria, although all targetedspecies remained detectable in plaquefollowing treatment. It is possible thatpregnancy outcomes can be improvedonly if one or more microbial patho-gens are dramatically reduced or elimi-nated from the oral cavity.

If more intensive or sophisticatedtreatments are proposed and ulti-mately shown effective in improvingpregnancy outcomes, the professionand public policymakers must addressconcerns regarding patient compli-

ance, cost and access to a workforcecapable of providing advanced treat-ments for the large, culturally, raciallyand geographically diverse group of women at risk for preterm birth. Cur-rent evidence from RCTs does notsupport the provision of periodontal

therapy to improve pregnancy out-comes. It may be time to focus onother aetiologies and methods toreduce the rate of adverse pregnancyoutcomes, including preterm birth(Srinivas & Parry 2012).

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