Q U I N T E S S E N C E I N T E R N AT I O N A L
PERIODONTOLOGY
Stefano Corbella
Adverse pregnancy outcomes and periodontitis: A systematic review and meta-analysis exploring potential association Stefano Corbella, DDS, PhD1/Silvio Taschieri, MD, DDS2/Massimo Del Fabbro, BSc, PhD3/ Luca Francetti, MD, DDS4/Roberto Weinstein, MD, DDS 5/Enrico Ferrazzi, MD, OB/GYN6 Objective: The correlation between periodontal status and systemic conditions, among them pregnancy, is widely described in the scientific literature. The aim of the present systematic review of the literature was to evaluate periodontal diseases as an independent risk factor for adverse pregnancy outcomes. Data: Case-control studies reporting pregnancy outcomes and periodontal status of the subjects were included. Risk of bias evaluation was performed using a tool developed by the Cochrane Bias Methods Group. After risk of bias evaluation of included studies, a meta-analysis was performed computing the Risk Ratio (RR) for each pregnancy outcome. Sources: Electronic databases (MedLine, Embase, Cochrane Central) were searched after preparation of an appropriate
search string. Study selection: The search resulted in 422 entries that were screened. After application of inclusion and exclusion criteria, a total of 22 studies were included in the review accounting for a total of 17,053 subjects. The computed RR for periodontitis was 1.61 for preterm birth evaluated in 16 studies (P < .001), 1.65 for low birthweight evaluated in 10 studies (P < .001), and 3.44 for preterm low birthweight evaluated in four studies. Conclusion: The present systematic review reported a low but existing association between periodontitis and adverse pregnancy outcomes. This assumption is the result of proper corrections of biased methodologies and of heterogeneity of studies. (Quintessence Int 2016;47:193–204; doi: 10.3290/j.qi.a34980)
Key words: adverse pregnancy outcomes, meta-analysis, periodontal diseases, periodontitis, risk factor
Periodontal disease is a group of infectious illnesses with a high prevalence over the global population.1-3 Two main clinical forms are distinguishable: gingivitis, which is a reversible inflammation of marginal gingival tissue, and periodontitis (with its subforms), which is
characterized by a progressive and irreversible loss of alveolar bone and other tissues surrounding the tooth due to an aggressive immune response spreading from gingival connective tissue.4,5
1
Visiting Professor, University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Implantology, Milan, Italy; and IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
5
2
Academic Researcher, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; and University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Health, Milan, Italy.
Full Professor, Head of Department, University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Implantology, Milan, Italy; IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
6
Full Professor, Head of Department, University of Milan, Biomedical and Clinical Sciences School of Medicine, Department of Woman, Mother and Neonate, Buzzi Children’s Hospital, Milan, Italy.
3
Associate Professor, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; and University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Health, Milan, Italy.
4
Associate Professor, University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Implantology, Milan, Italy; and IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
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Correspondence: Dr Stefano Corbella, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi, 4, 20161 – Milan, Italy. Email: [email protected]
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Among the many risk factors and risk indicators that were identified for periodontal diseases, the presence of specific pathogenic bacterial species within the oral microbial biofilm is recognized to be the most important factor initiating and promoting periodontal inflammation, through a complex interaction with the host immune system.6,7 A wide group of bacteria were identified as putative risk factors for periodontitis and most of them were Gram-negative, facultative anaerobic species that colonize the gingival sulcus and determine the activation of the host response.8-10 Even though periodontal diseases symptoms and signs are local, such pathosis may influence the whole systemic environment through mainly three different but concurrent mechanisms. Such biologic pathways could be related to the occurrence of adverse pregnancy outcomes. First, many common daily actions, such as chewing or tooth brushing, can be responsible, and also in periodontal patients with dental plaque there can be an increase in bacteremia.11 Many dental procedures may also induce bacteremia, due to the mechanical communication between blood vessels and the oral cavity.12-14 Among these, tooth extraction is a paradigmatic macro-trauma. This situation may represent an indication for the use of antibiotic prophylaxis in particular cohorts of patients, as widely investigated in the scientific literature.15 The second mechanism of influence to systemic homeostasis is due to the observed increase of systemic inflammatory markers in periodontal patients, both in chronic and acute conditions.16,17 This particular effect of periodontal diseases is hypothesized to bear an important risk factor also into the evolution of cardiovascular disease.18 The third mechanism of influence of periodontal disease on other body systems far from the oral cavity is related to a postulated autoimmune reaction induced by oral bacteria epitopes which are recognized by the host immune system, resulting in an immune reaction against self tissue antigens.19 This extraoral pro-inflammatory condition sustained by periodontal disease is a credible candidate for possible intrusion in the delicate immune balance of pregnancy.
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Preterm delivery represents one of the major obstetric adverse outcomes, affecting from 7% to 17% of pregnancies worldwide. The identification, quantification, and removal of risk factors is still a major aim of clinical and epidemiologic research. Inflammation appears to be a common pathway for risk factors leading to preterm delivery. Periodontal disease represents a paradigm of mucosal bacteria-related inflammation able to activate the release of a cascade of biologic factors that might interfere with myometrium and placental membrane growth and homeostasis. In fact, the role of periodontal disease in abnormal pregnancy outcome has been investigated by systematic reviews20,21 that add to the many studies on other areas of diseases characterized by chronic low-grade inflammation such as diabetes and cardiovascular disease.22-27 However, studies with different designs have been pooled in those papers, which might represent a bias somehow affecting the reliability of the outcomes. Moreover, in recent years, there was a significant increase in the number of studies evaluating the entity of the correlation between periodontal diseases and adverse pregnancy outcomes. Newly published data could add new information about such a hypothetical link. The aim of this systematic review of published case-control and prospective cohort studies was to evaluate the evidence of periodontal diseases as a risk factor for adverse pregnancy outcomes such as preterm birth and low birthweight.
METHOD AND MATERIALS Eligibility criteria This systematic review included all case-control studies and prospective cohort studies according to the following inclusion criteria: • publications in any language dealing with periodontal disease in relation to pregnancy outcomes • retrospective or prospective study designs with the exception of case reports and case series
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Q U I N T E S S E N C E I N T E R N AT I O N A L Corbella et al
•
•
clear definition of periodontal disease, providing the clinical parameters used to define the illness (or health) status prospective studies in which a clear data extrapolation regarding pregnancy outcomes is possible by distinguishing cases (adverse pregnancy outcomes) and control (regular delivery) groups.
When papers from the same group of authors were identified, with very similar databases of patients, materials, methods and outcomes, the authors were contacted to clarify whether the pool of patients was indeed the same. In case of multiple publications relative to consecutive phases of the same study only the most recent data (those with the longer follow-up) were considered.
Search strategy An electronic search was conducted via MEDLINE (Pubmed), Scopus, EMBASE, and the Cochrane Library in the dental literature to select only human studies published from 1965 to January 2015. The search string used with PubMed was: ([“periodontal disease*”] OR [“periodontitis”] OR [“gingivitis”] OR [“periodontal”]) AND ([“preterm birth”] OR [“low birth weight”] OR [“obstetrical complication*”] OR [“preterm low birth weight”] OR [“PTB”] OR [“PTLBW”] OR [“LBW”]) This string was adapted to be used with other electronic databases. A manual forward and backward search was performed of the bibliographies of selected articles and of related articles resulting from the electronic search. In addition a hand search of issues from 1965 to January 2015 was undertaken of the following journals: Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, International Journal of Periodontics and Restorative Dentistry, Journal of Dentistry, Community Dentistry and Oral Epidemiology, Journal of the American Dental Association, Obstetrics and Gynecology, American Journal of Obstetrics and Gynecology, Journal of Perinatology, Clinical Perinatology, American Journal of Perinatology. No language restriction was posed.
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Selection of the studies Two reviewers (SC and ST) independently screened the abstracts and, in case of doubts, the full-texts of the retrieved articles for possible inclusion. Any disagreement was resolved by discussion.
Data extraction and risk of bias evaluation An ad hoc designed data extraction form was filled independently by two authors. Demographic data (number of patients, mean age, country) were recorded for each of the studies. Definition of periodontal disease was extrapolated from the study and reported. Number of cases (patients who experienced preterm birth, low birthweight or both) and healthy controls were extracted. For each group the number of patients affected by periodontal disease and the number of periodontally healthy subjects were also recorded. Risk of bias evaluation for included case-control studies was performed by two authors (SC and EF) using the proper tool developed by the Cochrane Bias Methods Group.28 Items from this tool were chosen according to the instructions provided. Five items (in the form of questions) were chosen and the possible answers were only “yes” or “no”. The questions were: 1. Was selection of exposed and non-exposed cohorts drawn from the same population? 2. Can we be confident in the assessment of exposure? 3. Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these prognostic variables? 4. Can we be confident in the assessment of the presence or absence of prognostic factors? 5. Can we be confident in the assessment of outcome? If all the questions could be answered with “yes” the study was judged at low risk of bias. If only one question could be answered with “no” the study was considered at moderate risk. In any other case the study was judged at high risk and not included in the review.
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Main outcome Preterm birth cases, low birthweight cases, and preterm low birthweight cases were extracted from each study and analyzed independently and pooled. Other adverse pregnancy outcomes such as abortions and stillbirths were not considered in this review because of their extremely low prevalence.
18 additional records identified through other sources
Screening
422 records after duplicates removed
422 records screened
397 records excluded
Eligibility
If less than five of the cited parameters were not controlled or the control was not reported the study was judged at low risk of bias as regard as confounding factors; if more than four parameters but less than eight were not controlled or the control was not reported the study was judged at moderate risk; otherwise the study was judged at high risk. Studies with high risk of bias were considered as not adequately responding to the third question in the overall risk of bias evaluation.
415 records identified through electronic searching
25 full-text articles assessed for eligibility
3 full-text articles excluded because of unclear definition of periodontal disease
Included
The control of the following confounding factors served to assess one of the items of risk of bias evaluation: • age • marital status • educational level • socioeconomic status • previous preterm birth • parity • history of abortion • smoking • alcohol • drug abuse • diabetes • Body Mass Index (BMI).
Identification
Corbella et al
Fig 1
22 studies included in qualitative and quantitative synthesis
Flowchart of article selection process.
A subgroup analysis was performed on the basis of the evaluated risk of bias.
Statistical analysis The analysis was performed using the software Review Manager (RevMan) Version 5.0 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). A random-effect meta-analysis using the Mantel-Haenszel method, based on Risk Ratios (RRs) and 95% confidence intervals (CIs), was adopted. The results were graphically presented by means of forest plots and funnel plots.
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RESULTS The last electronic search was conducted on 30 January 2015. A total of 422 articles were retrieved and screened. Figure 1 is a flowchart that summarizes the article selection process. After title and abstract examination, 397 articles were excluded because of not following the inclusion criteria. Of the 25 full-texts
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Table 1
Characteristics of included studies
ID
Study
Year
Country
Total
Mean age (SD) (cases in age intervals)
Definition of periodontal disease
1
Rakoto-Alson et al32
2010
Madagascar
204
25.6 (5.6)
≥ 3 sites from different teeth with CAL loss ≥ 4 mm
2
Ryu et al33
2010
Korea
172
32.0
> 2 teeth with CAL loss > 3.5 mm
3
Guimaraes et al34
2010
Brazil
1,207
4
Vogt et al35
2010
Brazil
327
123 < 25 y; 204 ≥ 25 y
≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 4 mm ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm, BOP ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm, BOP
Def. 1: ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 4 mm; Def. 2: ≥ 1 site with PD and CAL ≥ 4 mm
5
Cruz et al36
2009
Brazil
548
212 13–20 y; 305 21–35 y; 30 36–48 y
6
Nabet et al37
2010
France
2,202
321 < 25 y; 1,368 25–34 y; 513 ≥ 35 y
7
Goepfert et al38
2004
United States
103
≥ 1 site in any one sextant with CAL loss ≥ 5 mm ≥ 5 sites with CAL loss ≥ 3 mm
39
8
Jarjoura et al
2005
United States
203
9
Radnai et al40
2004
Hungary
85
10
Radnai et al41
2006
Hungary
161
28 (5)
11
Siqueira et al42
2007
Brazil
1,305
779 < 30 y; 263 ≥ 30 y; ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm
12
Wood et al43
2006
Canada
151
13
Mumghamba and Manji44
2007
Tanzania
373
106 ≤ 19 y; 267 > 19 y
14
Agueda et al45
2008
Spain
1,296
29.6
≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm
15
Lopez et al46
2002
Chile
639
24.1 (4.6); 27.1 (4.3)
≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm
16
Marin et al47
2005
Brazil
152
23.3 (5.7)
≥ 1 sites with PD ≥ 5 mm and ≥ 2 teeth with CAL ≥ 6 mm
17
Offenbacher et al48
2006
United States
1,020
28.2 (6.6)
≥ 4 sites with PD ≥ 5 mm and ≥ 4 sites with CAL loss ≥ 2 mm
18
Guimaraes et al49
2012
Brazil
1,686
19
50
Santa Cruz et al
2012
Spain
170
31.9 (4.0)
≥ 15 sites with CAL ≥ 3 mm
20
Ali et al53
2012
Malaysia
73
29.1
≥ 2 teeth with PD ≥ 5 mm and CAL ≥ 3 mm
51
21
Abati et al
2013
Italy
750
22
Macedo et al52
2013
Brazil
296
≥ 1 site with PD and CAL ≥ 4 mm and BOP ≥ 1 side with PD ≥ 4 mm and BOP 50% teeth
≥ 5% sites with CAL loss ≥ 3 mm ≥ 4 sites with PD ≥ 4 mm and BOP in ≥ 30% sites
≥ 1 tooth with PD and CAL ≥ 4 mm
≥ 1 site with CAL ≥ 4 mm 27.9 (7.2)
Def. 1: ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 4 mm; Def. 2: ≥1 site with PD and CAL ≥ 4 mm
BOP, bleeding on probing; CAL, clinical attachment loss; Def., definition; PD, probing depth; SD, standard deviation.
retrieved, three were excluded from the qualitative and quantitative analysis because of the lack of a clear definition of periodontal disease.29-31 A total of 22 studies fulfilled all inclusion criteria and were included in the review.32-53 A total of 17,053 subjects were included in the review. Table 1 shows demographic data of the studies considered in the meta-analysis. All included studies were published between 2002 and 2014. They reported data of women from different countries. The mean age in the included studies ranged from 13 to 48 years.
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Periodontal criteria used to determine if a subject was exposed to the analyzed risk factor (periodontal disease) or not are shown in Table 1. Most of the used definitions referred to the Armitage classification of periodontal disease published in 1999.54 Control of confounders was evaluated for each study (Table 2). In two studies the confounding factors were controlled between periodontally healthy subjects and periodontally compromised ones.46,47 Only one study reported a significantly different mean age between case and control group.48 A history of previous preterm
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Table 2
Control of possible confounders
Study ID
132
233
334
435
536
637
738
839
940 1041 1142 1243 1344 1445 1546 1647 1748 1849 1950 2051 2152 2253
Age
+
+
+
+
+
+
+
+
+
+
+
+
+
+
/
/
-
-
/
/
+
+
Marital status
+
/
-
+
/
-
/
/
/
/
+
/
-
/
/
/
-
+
/
/
/
+
Educational level
+
/
+
+
+
-
+
/
+
+
-
-
+
+
/
/
/
-
/
/
+
+
Socioeconomic status
/
/
/
/
/
/
/
/
/
/
/
+
/
+
/
/
/
/
/
/
/
+
Previous preterm birth
+
+
+
/
/
/
+
-
/
/
-
/
+
-
-
/
-
+
/
/
/
+
Parity
+
+
+
+
+
+
+
+
/
/
-
+
+
+
/
/
+
-
/
/
/
+
History of abortion
/
+
+
/
/
/
/
/
/
/
-
/
+
/
/
/
/
+
/
/
/
+
Smoking
/
/
+
+
-
-
+
+
-
-
+
-
+
+
/
/
+
-
/
/
+
/
Alcohol
/
+
+
+
-
/
/
/
+
/
+
/
+
/
/
/
+
+
/
/
/
/
Drug abuse
/
/
+
/
/
/
/
/
/
/
+
/
/
/
/
/
+
/
/
/
/
/
Diabetes
/
/
+
/
+*
/
/
/
+*
+*
+
/
+*
+
/
/
/
+
+
/
/
/
BMI
/
/
/
+
/
-
/
+
/
/
/
/
/
-
/
/
/
/
+
/
/
/
Risk of bias
M
M
L
M
H
H
M
H
H
H
M
H
L
M
H
H
H
M
H
H
H
M
+, controlled confounder; -, uncontrolled confounder; /, not reported; *, subjects with diabetes were excluded.
birth was controlled in seven studies,32-34,38,44,49,52 in ten studies it was not reported,35-37,40,41,43,47,50,51,53 while in five studies there was a statistically significant difference of women with previous preterm birth between cases and controls.39,42,45,46,48 Significant differences between study groups were reported considering marital status in four studies,34,37,44,48 educational level in three studies,37,42,43 parity in one study,42 history of abortion in one study,42 smoking status in five studies,36,37,40,41,43 and alcohol misuse in one study.36 In four studies, subjects with diabetes were excluded.36,40,41,44 In two studies, BMI was significantly different between cases and controls.37,45 After risk of bias analysis (Table 3), 12 stud36,37,39-41,43,46-48,50-52 ies were judged at moderate risk of bias and 10 studies32-35,38,42,44,45,49,53 at low risk of bias. The clinical aspect of one pregnant woman affected by periodontal diseases is presented in Fig 2.
The funnel plot in Table 4 shows that there is homogeneity among most of the included studies. Computed RR for periodontal disease is 1.61 (95% CI, 1.33– 1.95). Heterogeneity was found among the included studies (I2 = 79%).
Low birthweight Data reporting newborns’ weights were extracted from 10 studies.32,35,36,42,44,45,47,49,50,53 A total of 1,349 low birthweight cases and 4,344 normal birthweight controls were considered. The prevalence of low birthweight varied from 0.04% to 40.2%. Table 5 shows the data analysis of pooled data. Computed RR for periodontal disease is 1.65 (95% CI, 1.27–2.14). A substantial heterogeneity was found among the included studies (I2 = 79%).
Preterm low birthweight Preterm birth Sixteen studies reported data about preterm birth cases.32-35,37-42,45,47,48,50,52,53 A total of 1,853 preterm birth cases and 6,741 term birth controls were considered. The prevalence of preterm birth varied from 0.03% to 57.3%. Table 4 shows the data analysis of pooled data.
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Four studies reported the number of subjects with both preterm birth and low birthweight.32,45,46,50 One hundred thirty-six cases were described with a prevalence varying from 0.01% to 5.7%. Table 6 shows the data analysis of pooled data. Computed RR for periodontal disease is 3.44 (95% CI: 1.34–8.80). Heterogene-
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Table 3
ID 1
Risk of bias evaluation
Author Rakoto-Alson et al32 33
Was selection of exposed and non-exposed cohorts drawn from the same population?
Can we be confident in the assessment of exposure?
Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these prognostic variables?*
Can we be confident in the assessment of the presence or absence of prognostic factors?
Can we be confident in the assessment of outcome?
Overall risk of bias
Y
Y
Y
Y
Y
Low
2
Ryu et al
Y
Y
Y
Y
Y
Low
3
Guimaraes et al34
Y
Y
Y
Y
Y
Low
35
Y
Y
Y
Y
Y
Low
36
4
Vogt et al
5
Cruz et al
Y
Y
N
Y
Y
Moderate
6
Nabet et al37
Y
Y
N
Y
Y
Moderate
38
7
Goepfert et al
Y
Y
Y
Y
Y
Low
8
Jarjoura et al39
Y
Y
N
Y
Y
Moderate
40
Radnai et al
Y
Y
N
Y
Y
Moderate
Radnai et al41
Y
Y
N
Y
Y
Moderate
9 10
42
11
Siqueira et al
Y
Y
Y
Y
Y
Low
12
Wood et al43
Y
Y
N
Y
Y
Moderate
44
13
Mumghamba and Manji
Y
Y
Y
Y
Y
Low
14
Agueda et al45
Y
Y
Y
Y
Y
Low
15
46
Lopez et al
Y
Y
N
Y
Y
Moderate
16
Marin et al47
Y
Y
N
Y
Y
Moderate
48
17
Offenbacher et al
Y
Y
N
Y
Y
Moderate
18
Guimaraes et al49
Y
Y
Y
Y
Y
Low
19
50
Santa Cruz et al
Y
Y
N
Y
Y
Moderate
20
Ali et al53
Y
Y
N
Y
Y
Moderate
Y
Y
N
Y
Y
Moderate
Y
Y
Y
Y
Y
Low
21 22
51
Abati et al
52
Macedo et al
*, This item was evaluated on the basis of controlled confounders evaluation presented in Table 3.
ity was found among studies included in this comparison (I2 = 90%).
DISCUSSION The present systematic review of the literature, on 17,053 subjects reported by 22 studies, confirms that periodontitis could be considered as a risk factor for preterm birth, low birthweight, and preterm low birthweight. However, the latter correlation was supported by a lower number of subjects if compared to the single outcomes (preterm birth and low birthweight).
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Fig 2 Clinical features of one pregnant woman with periodontal disease.
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Table 4
Forest plot of preterm birth cases Cases
Study or subgroup
Events
Controls
Total
Events
Total
Weight
Risk ratio [M-H, random (95% CI)]
Risk ratio [M-H, random (95% CI)]
1.1.1 Low risk Agueda et al45
31
85
307
1,211
7.8%
1.44 (1.07–1.94)
Goepfert et al38
29
59
15
44
5.9%
1.44 (0.89–2.34)
Guimaraes et al34
90
161
408
1,046
9.0%
1.43 (1.23–1.68)
Macedo et al52
16
46
58
250
6.2%
1.50 (0.95–2.36)
42
131
238
406
1,024
9.1%
1.39 (1.21–1.59)
Rakoto-Alson et al32
33
42
14
162
5.5%
9.09 (5.38–15.37)
Ryu et al33
24
59
37
113
6.7%
1.24 (0.83–1.86)
30
137
297
7.7%
1.37 (1.02–1.85)
4,147
57.8%
1.68 (1.30–2.18)
3.3%
0.51 (0.22–1.21)
Siqueira et al
35
19
Vogt et al
Subtotal (95% CI) Total events
720 373
1,382
Heterogeneity: Tau2 = 0.11; Chi2 = 48.29, df = 7 (P < .00001); I2 = 86% Test for overal effect: Z = 3.92 (P < .0001) 1.1.2 Moderate risk Ali and Abadin53
4
14
Jarjoura et al
25
83
21
120
5.7%
1.72 (1.04–2.86)
Marin et al47
3
8
40
144
2.9%
1.35 (0.53–3.43)
142
620
236
1,094
8.8%
1.06 (0.88–1.28)
Offenbacher et al
42
186
105
834
7.5%
1.79 (1.30–2.47)
Radnai et al40
19
41
5
44
3.1%
4.08 (1.68–9.92)
Radnai et al41
39
Nabet et al37 48
33
59
39
77
18
84
6.1%
2.36 (1.48–3.76)
Santa Cruz et al50
2
54
3
114
1.0%
1.41 (0.24–8.18)
Wood et al43
9
50
14
101
3.8%
1.30 (0.60–2.79)
2,594
42.2%
1.52 (1.10–2.12)
100.0%
1.61 (1.33–1.95)
Subtotal (95% CI) Total events
1,133 285
475
Heterogeneity: Tau2 = 0.14; Chi2 = 26.89, df = 8 (P = .0007); I2 = 70% Test for overal effect: Z = 2.50 (P = .01) Total (95% CI) Total events
1,853 658
6,741 1,857
Heterogeneity: Tau2 = 0.10; Chi2 = 76.44, df = 16 (P < .00001); I2 = 79% Test for overal effect: Z = 4.87 (P < .00001) Test for subgroup differences: Chi2 = 0.21, df = 1 (P = .65); I2 = 0%
These results should be considered carefully due to heterogeneity among studies that also stands in the choice of different definitions of periodontal diseases in the included papers. Moreover, interestingly, these obstetric risks associated with the presence of periodontitis (preterm birth and low birthweight) proved to be substantially higher in the studies with both moderate and low risk of bias. This was probably due to the control of confound-
200
0.01 0.1 1 Favors experimental
10 100 Favors control
ers that could have highlighted the effect of periodontitis. One other issue that could have caused an underestimation of the outcome was the fact that the lower age limit (13 years old36) might have modified the impact of periodontal diseases on the adverse pregnancy outcomes. To the best of our knowledge these positive associations are the result of the largest meta-analysis so far available. However, these results come with a degree of
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Table 5
Forest plot of low birthweight cases Cases
Study or subgroup
Controls
Risk ratio [M-H, random (95% CI)]
Year
15.4%
1.31 (1.13–1.51)
2007
6.1%
1.64 (0.71–3.75)
2007
Events
Total
Events
Total
Weight
122
235
406
1,024
11
150
10
223
Agueda et al
28
78
310
1,218
13.1%
1.41 (1.03–1.93)
2008
Rakoto-Alson et al32
17
22
30
182
11.7%
4.69 (3.15–6.98)
2010
Vogt et al35
18
30
138
297
13.0%
1.29 (0.94–1.77)
2010
Guimaraes et al34
94
604
51
687
12.9%
2.10 (1.52–2.90)
2012
3,631
72.1%
1.82 (1.26–2.61)
Risk ratio [M-H, random (95% CI)]
1.2.1 Low risk Siqueira et al42 Mumghamba and Manji44 45
Subtotal (95% CI)
1,119
Total events
290
945
Heterogeneity: Tau2 = 0.17; Chi2 = 39.96, df = 5 (P < .00001); I2 = 87% Test for overal effect: Z = 3.22 (P = .001) 1.2.2 Moderate risk Marin et al47 36
Cruz et al
Santa Cruz et al50 53
3
7
41
145
5.5%
1.52 (0.62–3.70)
2005
70
164
115
384
14.2%
1.43 (1.13–1.80)
2009
1
54
5
116
1.4%
0.43 (0.05–3.59)
2012
5
34
68
6.8%
1.20 (0.56–2.55)
2012
713
27.9%
1.39 (1.12–1.73)
100.0%
1.65 (1.27–2.14)
3
Ali and Abadin
Subtotal (95% CI)
230
Total events
77 2
195
2
Heterogeneity: Tau = 0.00; Chi = 1.41, df = 3 (P = .70); I2 = 0% Test for overal effect: Z = 3.01 (P = .003) Total (95% CI) Total events
1,349 367
4,344 1,140
Heterogeneity: Tau2 = 0.11; Chi2 = 41.95, df = 9 (P < .00001); I2 = 79% Test for overal effect: Z = 3.78 (P = .0002) Test for subgroup differences: Chi2 = 1.52, df = 1 (P = .22); I2 = 34.2%
downscaling of the estimated risk attributed to periodontitis that appears to be lower than those reported for other major risk factors of preterm birth (for instance previous preterm birth and low socioeconomic status).20 In 2005, Khader and Ta’ani55 included five studies in their meta-analysis. For the 2,076 participants in medium- to high-quality studies (studies with low or moderate risk of bias), the odds ratio for preterm birth was 4.32 (2.50–7.44). On year later, in 2006, Xiong and coworkers, after a careful analysis of case control studies, randomized studies, and controlled trials, warned that such a possible association between periodontitis and abnormal pregnancy outcome needed “more methodologically rigorous studies”.56
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0.01 0.1 1 Favors experimental
10 100 Favors control
As regards preterm birth, Xiong reported a huge range of ORs and RRs from 2.12 to 20.0 depending on the size and quality of the study.56 The findings reported by the present group in 201257 reviewed only case-control studies in order to meet these warnings on either poor quality or small numbers. The exclusion of low-quality and cohort studies allowed proving of the hypothesized association, yet on a risk scale that is comparable to our present findings. As a matter of fact, regarding the main outcome (preterm birth, all classes) the results of the present review are comparable to those presented in the article published in 2012 (OR = 1.75 in the present article and OR = 1.78 reported in 2012). However, it is of
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Table 6
Forest plot of preterm low birthweight cases Cases
Study or subgroup
Events
Controls
Total
Events
Total
Weight
Risk ratio [M-H, random (95% CI)]
Year
Risk ratio [M-H, random (95% CI)]
1.3.1 Low risk Agueda et al45 Rakoto-Alson et al32
16
43
322
1,253
32.8%
1.45 (0.97–2.16)
2008
7
9
4
149
24.6%
28.97 (10.37–80.98)
2010
1,402
57.4%
6.23 (0.33–117.87)
Subtotal (95% CI) Total events
52 23
326
Heterogeneity: Tau2 = 4.35; Chi2 = 28.45, df = 1 (P < .00001); I2 = 96% Test for overal effect: Z = 1.22 (P = .22) 1.3.2 Moderate risk Lopez et al46 Santa Cruz et al50
20
30
213
609
33.9%
1.91 (1.45–2.51)
2002
1
54
1
116
8.7%
2.15 (0.14–33.70)
2012
725
42.6%
1.91 (1.45–2.51)
Subtotal (95% CI) Total events
84 21
214
Heterogeneity: Tau2 = 0.00; Chi2 = 0.01, df = 1 (P = .93); I2 = 0% Test for overal effect: Z = 4.62 (P < .00001) Total (95% CI) Total events
136 44
2,127
100%
540
Heterogeneity: Tau2 = 0.66; Chi2 = 28.62, df = 3 (P < .00001); I2 = 90% Test for overal effect: Z = 2.57 (P = .01) Test for subgroup differences: Chi2 = 0.62, df = 1 (P = .43); I2 = 0%
major clinical interest to highlight that sensitivity analysis and the inclusion of more articles (five more) proved that studies with lower risk of bias reported a significantly higher OR if compared to studies with higher risk. It might be hypothesized that a more adequate study design may have allowed a clearer detection of periodontal disease as a risk factor. One other recent systematic review of the literature reported data about the epidemiology of the association between maternal periodontal disease and adverse pregnancy outcomes.58 The authors found a significant variability in study population, recruitment, and outcome assessment that could have weakened the strength of the association. Similar considerations could be derived from the results of the present study. The present updated systematic review, due to the increased number of studies included, and mostly due to the analytical methodology adopted, provided more
202
3.44 (1.34–8.80)
0.01 0.1 1 Favors experimental
10 100 Favors control
information if compared to the previous one, allowing better understanding of the effects of periodontitis in pregnancy. The evidence that some correlation could exist between maternal periodontitis and adverse pregnancy outcomes should justify the prevention of such complications by periodontal preventive treatment in women willing to conceive. However, a recent systematic review of the literature showed that no significant effect was found for nonsurgical periodontal treatment in improving birth outcomes.59 Unfortunately only one RCT was included in the quantitative analysis due to the strict inclusion criteria. Indeed, contradictory results had been reported by other systematic reviews. Some supported the lack of evidence of nonsurgical periodontal therapy as valid preventive measure,25,60,61 while other authors, by the
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inclusion of a large number of articles (both randomized and non-randomized controlled trials in a recent systematic review), were able to prove a significant effect of nonsurgical periodontal treatment in reducing the occurrence of preterm birth or low birthweight.62
CONCLUSION The present systematic review confirmed the originally postulated association between periodontal disease and preterm delivery, once biased methodologies and heterogeneity of studies were properly considered and corrected. A final, evidence-based step is still required in order to prove beyond doubt that preventive nonsurgical prophylaxis reduces the risk of preterm birth. In the meantime, since no adverse effects can be attributed to periodontal care, we believe that periodontal history and periodontal care should be included in basic obstetrical counseling to women willing to conceive.
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12. Zhang W, Daly CG, Mitchell D, Curtis B. Incidence and magnitude of bacteraemia caused by flossing and by scaling and root planning. J Clin Periodontol 2013;40:41–52. 13. Dinsbach NA. Antibiotics in dentistry: Bacteremia, antibiotic prophylaxis, and antibiotic misuse. Gen Dent 2012;60:200–207. 14. Tomas I, Diz P, Tobias A, Scully C, Donos N. Periodontal health status and bacteraemia from daily oral activities: systematic review / meta-analysis. J Clin Periodontol 2012;39:213–228. 15. Lockhart PB, Loven B, Brennan MT, Fox PC. The evidence base for the efficacy of antibiotic prophylaxis in dental practice. J Am Dent Assoc 2007;138: 458–474. 16. Ioannidou E, Malekzadeh T, Dongari-Bagtzoglou A, Effect of periodontal treatment on serum C-reactive protein levels: a systematic review and meta-analysis. J Periodontol 2006;77:1635–1642. 17. Koutouzis T, Haber D, Shaddox L, Aukhil I, Wallet SM. Autoreactivity of serum immunoglobulin to periodontal tissue components: a pilot study. J Periodontol 2009;80:625–633. 18. D’Aiuto F, Parkar M, Nibali L, Suvan J, Lessem J, Tonetti MS. Periodontal infections cause changes in traditional and novel cardiovascular risk factors: results from a randomized controlled clinical trial. Am Heart J 2006;151:977–984. 19. Hasan A, Sadoh D, Palmer R, Foo M, Marber M, Lehner T. The immune responses to human and microbial heat shock proteins in periodontal disease with and without coronary heart disease. Clin Exp Immunol 2005;142: 585–594. 20. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75–84. 21. Offenbacher S, Katz V, Fertik G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67:1103–1113. 22. Sfyroeras GS, Roussas N, Saleptis VG, Argyriou C, Giannoukas AD. Association between periodontal disease and stroke. J Vasc Surg 2012;55:1178–1184. 23. Cotti E, Dessì C, Piras A, Mercuro G. Can a chronic dental infection be considered a cause of cardiovascular disease? A review of the literature. Int J Cardiol 2011;148:4–10. 24. Polyzos NP, Polyzos IP, Mauri D, et al. Effect of periodontal disease treatment during pregnancy on preterm birth incidence: a metaanalysis of randomized trials. Am J Obstet Gynecol 2009;200:225–232. 25. Polyzos NP, Polyzos IP, Zavos A, et al. Obstetric outcomes after treatment of periodontal disease during pregnancy: systematic review and meta-analysis. Br Med J 2010;341:c7017. 26. Corbella S, Francetti L, Taschieri S, De Siena F, Del Fabbro M. Effect of periodontal treatment on glycemic control of patients with diabetes: A systematic review and meta-analysis. J Diabetes Investig 2013;4:502–509. 27. Linden GJ, Lyons A, Scannapieco FA. Periodontal systemic associations: review of the evidence. J Clin Periodontol 2013;40:S8–S19. 28. Cochrane Bias Methods Group [Internet]. The Cochrane Collaboration; 2014. Available at: http://bmg.cochrane.org/research-projectscochrane-risk-biastool. Accessed 25 May 2014. 29. Khader Y, Al-shishani L, Obeidat B, et al. Maternal periodontal status and preterm low birth weight delivery: a case-control study. Arch Gynecol Obstet 2009;279:165–169. 30. Toygar HU, Seydaoglu G, Kurklu S, Guzeldemir E, Arpak N. Periodontal health and adverse pregnancy outcome in 3,576 Turkish women. J Periodontol 2007;78:2081–2094. 31. Moore S, Randhawa M, Ide M. A case-control study to investigate an association between adverse pregnancy outcome and periodontal disease. J Clin Periodontol 2005;32:1–5. 32. Rakoto-Alson S, Tenenbaum H, Davideau JL. Periodontal diseases, preterm births, and low birth weight: findings from a homogeneous cohort of women in Madagascar. J Periodontol 2010;81:205–213. 33. Ryu JI, Oh K, Yang H, et al. Health behaviors, periodontal conditions, and periodontal pathogens in spontaneous preterm birth: a case-control study in Korea. J Periodontol 2010;81:855–863.
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34. Guimaraes AN, Silva-Mato A, Miranda Cota LO, Siqueira FM, Costa FO. Maternal periodontal disease and preterm or extreme preterm birth: an ordinal logistic regression analysis. J Periodontol 2010;81:350–358. 35. Vogt M, Sallum AW, Cecatti JG, Morais SS. Periodontal disease and some adverse perinatal outcomes in a cohort of low risk pregnant women. Reprod Health 2010;7:29. 36. Cruz SS, Costa Mda C, Gomes-Filho IS, et al. Contribution of periodontal disease in pregnant women as a risk factor for low birth weight. Community Dent Oral Epidemiol 2009;37:527–533. 37. Nabet C, Lelong N, Colombier ML, et al. Maternal periodontitis and the causes of preterm birth: the case-control Epipap study. J Clin Periodontol 2010;37: 37–45. 38. Goepfert AR, Jeffcoat MK, Andrews WW, et al. Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth. Obstet Gynecol 2004;104:777–783. 39. Jarjoura K, Devine PC, Perez-Delboy A, Herrera-Abreu M, D’Alton M, Papapanou PN. Markers of periodontal infection and preterm birth. Am J Obstet Gynecol 2005;192:513–519. 40. Radnai M, Gorzo I, Nagy E, Urban E, Novak T, Pal A. A possible association between preterm birth and early periodontitis. A pilot study. J Clin Periodontol 2004;31:736–741. 41. Radnai M, Gorzo I, Urban E, Eller J, Novak T, Pal A. Possible association between mother’s periodontal status and preterm delivery. J Clin Periodontol 2006;33:791–796. 42. Siqueira FM, Cota LO, Costa JE, Haddad JP, Lana AM, Costa FO. Intrauterine growth restriction, low birth weight, and preterm birth: adverse pregnancy outcomes and their association with maternal periodontitis. J Periodontol 2007;78:2266–2276. 43. Wood S, Frydman A, Cox S, et al. Periodontal disease and spontaneous preterm birth: a case control study. BMC Pregnancy Childbirth 2006;6:24. 44. Mumghamba EG, Manji KP. Maternal oral health status and preterm low birth weight at Muhimbili National Hospital, Tanzania: a case-control study. BMC Oral Health 2007;7:8. 45. Agueda A, Ramon JM, Manau C, Guerrero A, Echeverria JJ. Periodontal disease as a risk factor for adverse pregnancy outcomes: a prospective cohort study. J Clin Periodontol 2008;35:16–22. 46. Lopez NJ, Smith PC, Gutierrez J. Higher risk of preterm birth and low birth weight in women with periodontal disease. J Dent Res 2002;81:58–63. 47. Marin C, Segura-Egea JJ, Martinez-Sahuquillo A, Bullon P. Correlation between infant birth weight and mother’s periodontal status. J Clin Periodontol 2005;32:299–304.
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48. Offenbacher S, Boggess KA, Murtha AP, et al. Progressive periodontal disease and risk of very preterm delivery. Obstet Gynecol 2006;107:29–36. 49. Guimaraes AN, Silva-Mato A, Siqueira FM, Cyrino RM, Cota LOM, Costa FO. Very low and low birth weight associated with maternal periodontitis. J Clin Periodontol 2012;39:1024–1031. 50. Santa Cruz I, Herrera D, Martin C, Herrero A, Sanz M. Association between periodontal status and pre-term and/or low-birth weight in Spain: clinical and microbiological parameters. J Periodontal Res 2013;48:443–451. 51. Abati S, Villa A, Cetin I, et al. Lack of association between maternal periodontal status and adverse pregnancy outcomes: a multicentric epidemiologic study. J Matern Fetal Neonatal Med 2013;26:369–372. 52. Macedo JF, Ribeiro RA, Machado FC, et al. Periodontal disease and oral health-related behaviour as factors associated with preterm birth: a case-control study in south-eastern Brazil. J Periodontal Res 2014;49:458–464. 53. Ali TBT, Abidin KZ. Relationship of periodontal disease to pre-term low birth weight infants in a selected population: a prospective study. Community Dent Health 2012;29:100–105. 54. Armitage GC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol 1999;4:1–6. 55. Khader YS, Ta’ani Q. Periodontal diseases and the risk of preterm birth and low birth weight: a meta-analysis. J Periodontol 2005;76:161–165. 56. Xiong X, Buekens P, Fraser WD, Beck J, Offenbacher S. Periodontal disease and adverse pregnancy outcomes: a systematic review. BJOG 2006;66:135–143. 57. Corbella S, Taschieri S, Francetti L, De Siena F, Del Fabbro M. Periodontal disease as a risk factor for adverse pregnancy outcomes: a systematic review and meta-analysis of case-control studies. Odontology 2012;100:232–240. 58. Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes. J Clin Periodontol 2013;40:S181–S194. 59. Michalowicz BS, Gustafsson A, Thumbigere-Math V, Buhlin K. The effects of periodontal treatment on pregnancy outcomes. J Periodontal Res 2013;40: S195–S208. 60. Fogacci MF, Vettore MV, Leao AT. The effect of periodontal therapy on preterm low birth weight: a meta-analysis. Obstet Gynecol 2011;117:153–165. 61. Chambrone L, Pannuti CM, Guglielmetti MR, Chambrone LA. Evidence grade associating periodontitis with preterm birth and/or low birth weight: II: a systematic review of randomized trials evaluating the effects of periodontal treatment. J Clin Periodontol 2011;38:902–914. 62. Kim AJ, Lo Aj, Pullin DA, Thornton-Johnson DS, Karimbux NY. Scaling and root planning treatment for periodontitis to reduce preterm birth and low birth weight: a systematic review and meta-analysis of randomized controlled trials. J Clin Periodontol 2012;83:1508–1515.
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PERIODONTOLOGY
Stefano Corbella
Adverse pregnancy outcomes and periodontitis: A systematic review and meta-analysis exploring potential association Stefano Corbella, DDS, PhD1/Silvio Taschieri, MD, DDS2/Massimo Del Fabbro, BSc, PhD3/ Luca Francetti, MD, DDS4/Roberto Weinstein, MD, DDS 5/Enrico Ferrazzi, MD, OB/GYN6 Objective: The correlation between periodontal status and systemic conditions, among them pregnancy, is widely described in the scientific literature. The aim of the present systematic review of the literature was to evaluate periodontal diseases as an independent risk factor for adverse pregnancy outcomes. Data: Case-control studies reporting pregnancy outcomes and periodontal status of the subjects were included. Risk of bias evaluation was performed using a tool developed by the Cochrane Bias Methods Group. After risk of bias evaluation of included studies, a meta-analysis was performed computing the Risk Ratio (RR) for each pregnancy outcome. Sources: Electronic databases (MedLine, Embase, Cochrane Central) were searched after preparation of an appropriate
search string. Study selection: The search resulted in 422 entries that were screened. After application of inclusion and exclusion criteria, a total of 22 studies were included in the review accounting for a total of 17,053 subjects. The computed RR for periodontitis was 1.61 for preterm birth evaluated in 16 studies (P < .001), 1.65 for low birthweight evaluated in 10 studies (P < .001), and 3.44 for preterm low birthweight evaluated in four studies. Conclusion: The present systematic review reported a low but existing association between periodontitis and adverse pregnancy outcomes. This assumption is the result of proper corrections of biased methodologies and of heterogeneity of studies. (Quintessence Int 2016;47:193–204; doi: 10.3290/j.qi.a34980)
Key words: adverse pregnancy outcomes, meta-analysis, periodontal diseases, periodontitis, risk factor
Periodontal disease is a group of infectious illnesses with a high prevalence over the global population.1-3 Two main clinical forms are distinguishable: gingivitis, which is a reversible inflammation of marginal gingival tissue, and periodontitis (with its subforms), which is
characterized by a progressive and irreversible loss of alveolar bone and other tissues surrounding the tooth due to an aggressive immune response spreading from gingival connective tissue.4,5
1
Visiting Professor, University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Implantology, Milan, Italy; and IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
5
2
Academic Researcher, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; and University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Health, Milan, Italy.
Full Professor, Head of Department, University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Implantology, Milan, Italy; IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
6
Full Professor, Head of Department, University of Milan, Biomedical and Clinical Sciences School of Medicine, Department of Woman, Mother and Neonate, Buzzi Children’s Hospital, Milan, Italy.
3
Associate Professor, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; and University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Health, Milan, Italy.
4
Associate Professor, University of Milan, Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Research Centre in Oral Implantology, Milan, Italy; and IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
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Correspondence: Dr Stefano Corbella, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi, 4, 20161 – Milan, Italy. Email: [email protected]
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Among the many risk factors and risk indicators that were identified for periodontal diseases, the presence of specific pathogenic bacterial species within the oral microbial biofilm is recognized to be the most important factor initiating and promoting periodontal inflammation, through a complex interaction with the host immune system.6,7 A wide group of bacteria were identified as putative risk factors for periodontitis and most of them were Gram-negative, facultative anaerobic species that colonize the gingival sulcus and determine the activation of the host response.8-10 Even though periodontal diseases symptoms and signs are local, such pathosis may influence the whole systemic environment through mainly three different but concurrent mechanisms. Such biologic pathways could be related to the occurrence of adverse pregnancy outcomes. First, many common daily actions, such as chewing or tooth brushing, can be responsible, and also in periodontal patients with dental plaque there can be an increase in bacteremia.11 Many dental procedures may also induce bacteremia, due to the mechanical communication between blood vessels and the oral cavity.12-14 Among these, tooth extraction is a paradigmatic macro-trauma. This situation may represent an indication for the use of antibiotic prophylaxis in particular cohorts of patients, as widely investigated in the scientific literature.15 The second mechanism of influence to systemic homeostasis is due to the observed increase of systemic inflammatory markers in periodontal patients, both in chronic and acute conditions.16,17 This particular effect of periodontal diseases is hypothesized to bear an important risk factor also into the evolution of cardiovascular disease.18 The third mechanism of influence of periodontal disease on other body systems far from the oral cavity is related to a postulated autoimmune reaction induced by oral bacteria epitopes which are recognized by the host immune system, resulting in an immune reaction against self tissue antigens.19 This extraoral pro-inflammatory condition sustained by periodontal disease is a credible candidate for possible intrusion in the delicate immune balance of pregnancy.
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Preterm delivery represents one of the major obstetric adverse outcomes, affecting from 7% to 17% of pregnancies worldwide. The identification, quantification, and removal of risk factors is still a major aim of clinical and epidemiologic research. Inflammation appears to be a common pathway for risk factors leading to preterm delivery. Periodontal disease represents a paradigm of mucosal bacteria-related inflammation able to activate the release of a cascade of biologic factors that might interfere with myometrium and placental membrane growth and homeostasis. In fact, the role of periodontal disease in abnormal pregnancy outcome has been investigated by systematic reviews20,21 that add to the many studies on other areas of diseases characterized by chronic low-grade inflammation such as diabetes and cardiovascular disease.22-27 However, studies with different designs have been pooled in those papers, which might represent a bias somehow affecting the reliability of the outcomes. Moreover, in recent years, there was a significant increase in the number of studies evaluating the entity of the correlation between periodontal diseases and adverse pregnancy outcomes. Newly published data could add new information about such a hypothetical link. The aim of this systematic review of published case-control and prospective cohort studies was to evaluate the evidence of periodontal diseases as a risk factor for adverse pregnancy outcomes such as preterm birth and low birthweight.
METHOD AND MATERIALS Eligibility criteria This systematic review included all case-control studies and prospective cohort studies according to the following inclusion criteria: • publications in any language dealing with periodontal disease in relation to pregnancy outcomes • retrospective or prospective study designs with the exception of case reports and case series
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•
•
clear definition of periodontal disease, providing the clinical parameters used to define the illness (or health) status prospective studies in which a clear data extrapolation regarding pregnancy outcomes is possible by distinguishing cases (adverse pregnancy outcomes) and control (regular delivery) groups.
When papers from the same group of authors were identified, with very similar databases of patients, materials, methods and outcomes, the authors were contacted to clarify whether the pool of patients was indeed the same. In case of multiple publications relative to consecutive phases of the same study only the most recent data (those with the longer follow-up) were considered.
Search strategy An electronic search was conducted via MEDLINE (Pubmed), Scopus, EMBASE, and the Cochrane Library in the dental literature to select only human studies published from 1965 to January 2015. The search string used with PubMed was: ([“periodontal disease*”] OR [“periodontitis”] OR [“gingivitis”] OR [“periodontal”]) AND ([“preterm birth”] OR [“low birth weight”] OR [“obstetrical complication*”] OR [“preterm low birth weight”] OR [“PTB”] OR [“PTLBW”] OR [“LBW”]) This string was adapted to be used with other electronic databases. A manual forward and backward search was performed of the bibliographies of selected articles and of related articles resulting from the electronic search. In addition a hand search of issues from 1965 to January 2015 was undertaken of the following journals: Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontics, International Journal of Periodontics and Restorative Dentistry, Journal of Dentistry, Community Dentistry and Oral Epidemiology, Journal of the American Dental Association, Obstetrics and Gynecology, American Journal of Obstetrics and Gynecology, Journal of Perinatology, Clinical Perinatology, American Journal of Perinatology. No language restriction was posed.
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Selection of the studies Two reviewers (SC and ST) independently screened the abstracts and, in case of doubts, the full-texts of the retrieved articles for possible inclusion. Any disagreement was resolved by discussion.
Data extraction and risk of bias evaluation An ad hoc designed data extraction form was filled independently by two authors. Demographic data (number of patients, mean age, country) were recorded for each of the studies. Definition of periodontal disease was extrapolated from the study and reported. Number of cases (patients who experienced preterm birth, low birthweight or both) and healthy controls were extracted. For each group the number of patients affected by periodontal disease and the number of periodontally healthy subjects were also recorded. Risk of bias evaluation for included case-control studies was performed by two authors (SC and EF) using the proper tool developed by the Cochrane Bias Methods Group.28 Items from this tool were chosen according to the instructions provided. Five items (in the form of questions) were chosen and the possible answers were only “yes” or “no”. The questions were: 1. Was selection of exposed and non-exposed cohorts drawn from the same population? 2. Can we be confident in the assessment of exposure? 3. Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these prognostic variables? 4. Can we be confident in the assessment of the presence or absence of prognostic factors? 5. Can we be confident in the assessment of outcome? If all the questions could be answered with “yes” the study was judged at low risk of bias. If only one question could be answered with “no” the study was considered at moderate risk. In any other case the study was judged at high risk and not included in the review.
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Q U I N T E S S E N C E I N T E R N AT I O N A L
Main outcome Preterm birth cases, low birthweight cases, and preterm low birthweight cases were extracted from each study and analyzed independently and pooled. Other adverse pregnancy outcomes such as abortions and stillbirths were not considered in this review because of their extremely low prevalence.
18 additional records identified through other sources
Screening
422 records after duplicates removed
422 records screened
397 records excluded
Eligibility
If less than five of the cited parameters were not controlled or the control was not reported the study was judged at low risk of bias as regard as confounding factors; if more than four parameters but less than eight were not controlled or the control was not reported the study was judged at moderate risk; otherwise the study was judged at high risk. Studies with high risk of bias were considered as not adequately responding to the third question in the overall risk of bias evaluation.
415 records identified through electronic searching
25 full-text articles assessed for eligibility
3 full-text articles excluded because of unclear definition of periodontal disease
Included
The control of the following confounding factors served to assess one of the items of risk of bias evaluation: • age • marital status • educational level • socioeconomic status • previous preterm birth • parity • history of abortion • smoking • alcohol • drug abuse • diabetes • Body Mass Index (BMI).
Identification
Corbella et al
Fig 1
22 studies included in qualitative and quantitative synthesis
Flowchart of article selection process.
A subgroup analysis was performed on the basis of the evaluated risk of bias.
Statistical analysis The analysis was performed using the software Review Manager (RevMan) Version 5.0 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). A random-effect meta-analysis using the Mantel-Haenszel method, based on Risk Ratios (RRs) and 95% confidence intervals (CIs), was adopted. The results were graphically presented by means of forest plots and funnel plots.
196
RESULTS The last electronic search was conducted on 30 January 2015. A total of 422 articles were retrieved and screened. Figure 1 is a flowchart that summarizes the article selection process. After title and abstract examination, 397 articles were excluded because of not following the inclusion criteria. Of the 25 full-texts
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Table 1
Characteristics of included studies
ID
Study
Year
Country
Total
Mean age (SD) (cases in age intervals)
Definition of periodontal disease
1
Rakoto-Alson et al32
2010
Madagascar
204
25.6 (5.6)
≥ 3 sites from different teeth with CAL loss ≥ 4 mm
2
Ryu et al33
2010
Korea
172
32.0
> 2 teeth with CAL loss > 3.5 mm
3
Guimaraes et al34
2010
Brazil
1,207
4
Vogt et al35
2010
Brazil
327
123 < 25 y; 204 ≥ 25 y
≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 4 mm ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm, BOP ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm, BOP
Def. 1: ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 4 mm; Def. 2: ≥ 1 site with PD and CAL ≥ 4 mm
5
Cruz et al36
2009
Brazil
548
212 13–20 y; 305 21–35 y; 30 36–48 y
6
Nabet et al37
2010
France
2,202
321 < 25 y; 1,368 25–34 y; 513 ≥ 35 y
7
Goepfert et al38
2004
United States
103
≥ 1 site in any one sextant with CAL loss ≥ 5 mm ≥ 5 sites with CAL loss ≥ 3 mm
39
8
Jarjoura et al
2005
United States
203
9
Radnai et al40
2004
Hungary
85
10
Radnai et al41
2006
Hungary
161
28 (5)
11
Siqueira et al42
2007
Brazil
1,305
779 < 30 y; 263 ≥ 30 y; ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm
12
Wood et al43
2006
Canada
151
13
Mumghamba and Manji44
2007
Tanzania
373
106 ≤ 19 y; 267 > 19 y
14
Agueda et al45
2008
Spain
1,296
29.6
≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm
15
Lopez et al46
2002
Chile
639
24.1 (4.6); 27.1 (4.3)
≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 3 mm
16
Marin et al47
2005
Brazil
152
23.3 (5.7)
≥ 1 sites with PD ≥ 5 mm and ≥ 2 teeth with CAL ≥ 6 mm
17
Offenbacher et al48
2006
United States
1,020
28.2 (6.6)
≥ 4 sites with PD ≥ 5 mm and ≥ 4 sites with CAL loss ≥ 2 mm
18
Guimaraes et al49
2012
Brazil
1,686
19
50
Santa Cruz et al
2012
Spain
170
31.9 (4.0)
≥ 15 sites with CAL ≥ 3 mm
20
Ali et al53
2012
Malaysia
73
29.1
≥ 2 teeth with PD ≥ 5 mm and CAL ≥ 3 mm
51
21
Abati et al
2013
Italy
750
22
Macedo et al52
2013
Brazil
296
≥ 1 site with PD and CAL ≥ 4 mm and BOP ≥ 1 side with PD ≥ 4 mm and BOP 50% teeth
≥ 5% sites with CAL loss ≥ 3 mm ≥ 4 sites with PD ≥ 4 mm and BOP in ≥ 30% sites
≥ 1 tooth with PD and CAL ≥ 4 mm
≥ 1 site with CAL ≥ 4 mm 27.9 (7.2)
Def. 1: ≥ 4 teeth with ≥ 1 sites with PD ≥ 4 mm and CAL ≥ 4 mm; Def. 2: ≥1 site with PD and CAL ≥ 4 mm
BOP, bleeding on probing; CAL, clinical attachment loss; Def., definition; PD, probing depth; SD, standard deviation.
retrieved, three were excluded from the qualitative and quantitative analysis because of the lack of a clear definition of periodontal disease.29-31 A total of 22 studies fulfilled all inclusion criteria and were included in the review.32-53 A total of 17,053 subjects were included in the review. Table 1 shows demographic data of the studies considered in the meta-analysis. All included studies were published between 2002 and 2014. They reported data of women from different countries. The mean age in the included studies ranged from 13 to 48 years.
VOLUME 47 • NUMBER 3 • MARCH 2016
Periodontal criteria used to determine if a subject was exposed to the analyzed risk factor (periodontal disease) or not are shown in Table 1. Most of the used definitions referred to the Armitage classification of periodontal disease published in 1999.54 Control of confounders was evaluated for each study (Table 2). In two studies the confounding factors were controlled between periodontally healthy subjects and periodontally compromised ones.46,47 Only one study reported a significantly different mean age between case and control group.48 A history of previous preterm
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Table 2
Control of possible confounders
Study ID
132
233
334
435
536
637
738
839
940 1041 1142 1243 1344 1445 1546 1647 1748 1849 1950 2051 2152 2253
Age
+
+
+
+
+
+
+
+
+
+
+
+
+
+
/
/
-
-
/
/
+
+
Marital status
+
/
-
+
/
-
/
/
/
/
+
/
-
/
/
/
-
+
/
/
/
+
Educational level
+
/
+
+
+
-
+
/
+
+
-
-
+
+
/
/
/
-
/
/
+
+
Socioeconomic status
/
/
/
/
/
/
/
/
/
/
/
+
/
+
/
/
/
/
/
/
/
+
Previous preterm birth
+
+
+
/
/
/
+
-
/
/
-
/
+
-
-
/
-
+
/
/
/
+
Parity
+
+
+
+
+
+
+
+
/
/
-
+
+
+
/
/
+
-
/
/
/
+
History of abortion
/
+
+
/
/
/
/
/
/
/
-
/
+
/
/
/
/
+
/
/
/
+
Smoking
/
/
+
+
-
-
+
+
-
-
+
-
+
+
/
/
+
-
/
/
+
/
Alcohol
/
+
+
+
-
/
/
/
+
/
+
/
+
/
/
/
+
+
/
/
/
/
Drug abuse
/
/
+
/
/
/
/
/
/
/
+
/
/
/
/
/
+
/
/
/
/
/
Diabetes
/
/
+
/
+*
/
/
/
+*
+*
+
/
+*
+
/
/
/
+
+
/
/
/
BMI
/
/
/
+
/
-
/
+
/
/
/
/
/
-
/
/
/
/
+
/
/
/
Risk of bias
M
M
L
M
H
H
M
H
H
H
M
H
L
M
H
H
H
M
H
H
H
M
+, controlled confounder; -, uncontrolled confounder; /, not reported; *, subjects with diabetes were excluded.
birth was controlled in seven studies,32-34,38,44,49,52 in ten studies it was not reported,35-37,40,41,43,47,50,51,53 while in five studies there was a statistically significant difference of women with previous preterm birth between cases and controls.39,42,45,46,48 Significant differences between study groups were reported considering marital status in four studies,34,37,44,48 educational level in three studies,37,42,43 parity in one study,42 history of abortion in one study,42 smoking status in five studies,36,37,40,41,43 and alcohol misuse in one study.36 In four studies, subjects with diabetes were excluded.36,40,41,44 In two studies, BMI was significantly different between cases and controls.37,45 After risk of bias analysis (Table 3), 12 stud36,37,39-41,43,46-48,50-52 ies were judged at moderate risk of bias and 10 studies32-35,38,42,44,45,49,53 at low risk of bias. The clinical aspect of one pregnant woman affected by periodontal diseases is presented in Fig 2.
The funnel plot in Table 4 shows that there is homogeneity among most of the included studies. Computed RR for periodontal disease is 1.61 (95% CI, 1.33– 1.95). Heterogeneity was found among the included studies (I2 = 79%).
Low birthweight Data reporting newborns’ weights were extracted from 10 studies.32,35,36,42,44,45,47,49,50,53 A total of 1,349 low birthweight cases and 4,344 normal birthweight controls were considered. The prevalence of low birthweight varied from 0.04% to 40.2%. Table 5 shows the data analysis of pooled data. Computed RR for periodontal disease is 1.65 (95% CI, 1.27–2.14). A substantial heterogeneity was found among the included studies (I2 = 79%).
Preterm low birthweight Preterm birth Sixteen studies reported data about preterm birth cases.32-35,37-42,45,47,48,50,52,53 A total of 1,853 preterm birth cases and 6,741 term birth controls were considered. The prevalence of preterm birth varied from 0.03% to 57.3%. Table 4 shows the data analysis of pooled data.
198
Four studies reported the number of subjects with both preterm birth and low birthweight.32,45,46,50 One hundred thirty-six cases were described with a prevalence varying from 0.01% to 5.7%. Table 6 shows the data analysis of pooled data. Computed RR for periodontal disease is 3.44 (95% CI: 1.34–8.80). Heterogene-
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Table 3
ID 1
Risk of bias evaluation
Author Rakoto-Alson et al32 33
Was selection of exposed and non-exposed cohorts drawn from the same population?
Can we be confident in the assessment of exposure?
Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these prognostic variables?*
Can we be confident in the assessment of the presence or absence of prognostic factors?
Can we be confident in the assessment of outcome?
Overall risk of bias
Y
Y
Y
Y
Y
Low
2
Ryu et al
Y
Y
Y
Y
Y
Low
3
Guimaraes et al34
Y
Y
Y
Y
Y
Low
35
Y
Y
Y
Y
Y
Low
36
4
Vogt et al
5
Cruz et al
Y
Y
N
Y
Y
Moderate
6
Nabet et al37
Y
Y
N
Y
Y
Moderate
38
7
Goepfert et al
Y
Y
Y
Y
Y
Low
8
Jarjoura et al39
Y
Y
N
Y
Y
Moderate
40
Radnai et al
Y
Y
N
Y
Y
Moderate
Radnai et al41
Y
Y
N
Y
Y
Moderate
9 10
42
11
Siqueira et al
Y
Y
Y
Y
Y
Low
12
Wood et al43
Y
Y
N
Y
Y
Moderate
44
13
Mumghamba and Manji
Y
Y
Y
Y
Y
Low
14
Agueda et al45
Y
Y
Y
Y
Y
Low
15
46
Lopez et al
Y
Y
N
Y
Y
Moderate
16
Marin et al47
Y
Y
N
Y
Y
Moderate
48
17
Offenbacher et al
Y
Y
N
Y
Y
Moderate
18
Guimaraes et al49
Y
Y
Y
Y
Y
Low
19
50
Santa Cruz et al
Y
Y
N
Y
Y
Moderate
20
Ali et al53
Y
Y
N
Y
Y
Moderate
Y
Y
N
Y
Y
Moderate
Y
Y
Y
Y
Y
Low
21 22
51
Abati et al
52
Macedo et al
*, This item was evaluated on the basis of controlled confounders evaluation presented in Table 3.
ity was found among studies included in this comparison (I2 = 90%).
DISCUSSION The present systematic review of the literature, on 17,053 subjects reported by 22 studies, confirms that periodontitis could be considered as a risk factor for preterm birth, low birthweight, and preterm low birthweight. However, the latter correlation was supported by a lower number of subjects if compared to the single outcomes (preterm birth and low birthweight).
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Fig 2 Clinical features of one pregnant woman with periodontal disease.
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Table 4
Forest plot of preterm birth cases Cases
Study or subgroup
Events
Controls
Total
Events
Total
Weight
Risk ratio [M-H, random (95% CI)]
Risk ratio [M-H, random (95% CI)]
1.1.1 Low risk Agueda et al45
31
85
307
1,211
7.8%
1.44 (1.07–1.94)
Goepfert et al38
29
59
15
44
5.9%
1.44 (0.89–2.34)
Guimaraes et al34
90
161
408
1,046
9.0%
1.43 (1.23–1.68)
Macedo et al52
16
46
58
250
6.2%
1.50 (0.95–2.36)
42
131
238
406
1,024
9.1%
1.39 (1.21–1.59)
Rakoto-Alson et al32
33
42
14
162
5.5%
9.09 (5.38–15.37)
Ryu et al33
24
59
37
113
6.7%
1.24 (0.83–1.86)
30
137
297
7.7%
1.37 (1.02–1.85)
4,147
57.8%
1.68 (1.30–2.18)
3.3%
0.51 (0.22–1.21)
Siqueira et al
35
19
Vogt et al
Subtotal (95% CI) Total events
720 373
1,382
Heterogeneity: Tau2 = 0.11; Chi2 = 48.29, df = 7 (P < .00001); I2 = 86% Test for overal effect: Z = 3.92 (P < .0001) 1.1.2 Moderate risk Ali and Abadin53
4
14
Jarjoura et al
25
83
21
120
5.7%
1.72 (1.04–2.86)
Marin et al47
3
8
40
144
2.9%
1.35 (0.53–3.43)
142
620
236
1,094
8.8%
1.06 (0.88–1.28)
Offenbacher et al
42
186
105
834
7.5%
1.79 (1.30–2.47)
Radnai et al40
19
41
5
44
3.1%
4.08 (1.68–9.92)
Radnai et al41
39
Nabet et al37 48
33
59
39
77
18
84
6.1%
2.36 (1.48–3.76)
Santa Cruz et al50
2
54
3
114
1.0%
1.41 (0.24–8.18)
Wood et al43
9
50
14
101
3.8%
1.30 (0.60–2.79)
2,594
42.2%
1.52 (1.10–2.12)
100.0%
1.61 (1.33–1.95)
Subtotal (95% CI) Total events
1,133 285
475
Heterogeneity: Tau2 = 0.14; Chi2 = 26.89, df = 8 (P = .0007); I2 = 70% Test for overal effect: Z = 2.50 (P = .01) Total (95% CI) Total events
1,853 658
6,741 1,857
Heterogeneity: Tau2 = 0.10; Chi2 = 76.44, df = 16 (P < .00001); I2 = 79% Test for overal effect: Z = 4.87 (P < .00001) Test for subgroup differences: Chi2 = 0.21, df = 1 (P = .65); I2 = 0%
These results should be considered carefully due to heterogeneity among studies that also stands in the choice of different definitions of periodontal diseases in the included papers. Moreover, interestingly, these obstetric risks associated with the presence of periodontitis (preterm birth and low birthweight) proved to be substantially higher in the studies with both moderate and low risk of bias. This was probably due to the control of confound-
200
0.01 0.1 1 Favors experimental
10 100 Favors control
ers that could have highlighted the effect of periodontitis. One other issue that could have caused an underestimation of the outcome was the fact that the lower age limit (13 years old36) might have modified the impact of periodontal diseases on the adverse pregnancy outcomes. To the best of our knowledge these positive associations are the result of the largest meta-analysis so far available. However, these results come with a degree of
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Table 5
Forest plot of low birthweight cases Cases
Study or subgroup
Controls
Risk ratio [M-H, random (95% CI)]
Year
15.4%
1.31 (1.13–1.51)
2007
6.1%
1.64 (0.71–3.75)
2007
Events
Total
Events
Total
Weight
122
235
406
1,024
11
150
10
223
Agueda et al
28
78
310
1,218
13.1%
1.41 (1.03–1.93)
2008
Rakoto-Alson et al32
17
22
30
182
11.7%
4.69 (3.15–6.98)
2010
Vogt et al35
18
30
138
297
13.0%
1.29 (0.94–1.77)
2010
Guimaraes et al34
94
604
51
687
12.9%
2.10 (1.52–2.90)
2012
3,631
72.1%
1.82 (1.26–2.61)
Risk ratio [M-H, random (95% CI)]
1.2.1 Low risk Siqueira et al42 Mumghamba and Manji44 45
Subtotal (95% CI)
1,119
Total events
290
945
Heterogeneity: Tau2 = 0.17; Chi2 = 39.96, df = 5 (P < .00001); I2 = 87% Test for overal effect: Z = 3.22 (P = .001) 1.2.2 Moderate risk Marin et al47 36
Cruz et al
Santa Cruz et al50 53
3
7
41
145
5.5%
1.52 (0.62–3.70)
2005
70
164
115
384
14.2%
1.43 (1.13–1.80)
2009
1
54
5
116
1.4%
0.43 (0.05–3.59)
2012
5
34
68
6.8%
1.20 (0.56–2.55)
2012
713
27.9%
1.39 (1.12–1.73)
100.0%
1.65 (1.27–2.14)
3
Ali and Abadin
Subtotal (95% CI)
230
Total events
77 2
195
2
Heterogeneity: Tau = 0.00; Chi = 1.41, df = 3 (P = .70); I2 = 0% Test for overal effect: Z = 3.01 (P = .003) Total (95% CI) Total events
1,349 367
4,344 1,140
Heterogeneity: Tau2 = 0.11; Chi2 = 41.95, df = 9 (P < .00001); I2 = 79% Test for overal effect: Z = 3.78 (P = .0002) Test for subgroup differences: Chi2 = 1.52, df = 1 (P = .22); I2 = 34.2%
downscaling of the estimated risk attributed to periodontitis that appears to be lower than those reported for other major risk factors of preterm birth (for instance previous preterm birth and low socioeconomic status).20 In 2005, Khader and Ta’ani55 included five studies in their meta-analysis. For the 2,076 participants in medium- to high-quality studies (studies with low or moderate risk of bias), the odds ratio for preterm birth was 4.32 (2.50–7.44). On year later, in 2006, Xiong and coworkers, after a careful analysis of case control studies, randomized studies, and controlled trials, warned that such a possible association between periodontitis and abnormal pregnancy outcome needed “more methodologically rigorous studies”.56
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0.01 0.1 1 Favors experimental
10 100 Favors control
As regards preterm birth, Xiong reported a huge range of ORs and RRs from 2.12 to 20.0 depending on the size and quality of the study.56 The findings reported by the present group in 201257 reviewed only case-control studies in order to meet these warnings on either poor quality or small numbers. The exclusion of low-quality and cohort studies allowed proving of the hypothesized association, yet on a risk scale that is comparable to our present findings. As a matter of fact, regarding the main outcome (preterm birth, all classes) the results of the present review are comparable to those presented in the article published in 2012 (OR = 1.75 in the present article and OR = 1.78 reported in 2012). However, it is of
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Table 6
Forest plot of preterm low birthweight cases Cases
Study or subgroup
Events
Controls
Total
Events
Total
Weight
Risk ratio [M-H, random (95% CI)]
Year
Risk ratio [M-H, random (95% CI)]
1.3.1 Low risk Agueda et al45 Rakoto-Alson et al32
16
43
322
1,253
32.8%
1.45 (0.97–2.16)
2008
7
9
4
149
24.6%
28.97 (10.37–80.98)
2010
1,402
57.4%
6.23 (0.33–117.87)
Subtotal (95% CI) Total events
52 23
326
Heterogeneity: Tau2 = 4.35; Chi2 = 28.45, df = 1 (P < .00001); I2 = 96% Test for overal effect: Z = 1.22 (P = .22) 1.3.2 Moderate risk Lopez et al46 Santa Cruz et al50
20
30
213
609
33.9%
1.91 (1.45–2.51)
2002
1
54
1
116
8.7%
2.15 (0.14–33.70)
2012
725
42.6%
1.91 (1.45–2.51)
Subtotal (95% CI) Total events
84 21
214
Heterogeneity: Tau2 = 0.00; Chi2 = 0.01, df = 1 (P = .93); I2 = 0% Test for overal effect: Z = 4.62 (P < .00001) Total (95% CI) Total events
136 44
2,127
100%
540
Heterogeneity: Tau2 = 0.66; Chi2 = 28.62, df = 3 (P < .00001); I2 = 90% Test for overal effect: Z = 2.57 (P = .01) Test for subgroup differences: Chi2 = 0.62, df = 1 (P = .43); I2 = 0%
major clinical interest to highlight that sensitivity analysis and the inclusion of more articles (five more) proved that studies with lower risk of bias reported a significantly higher OR if compared to studies with higher risk. It might be hypothesized that a more adequate study design may have allowed a clearer detection of periodontal disease as a risk factor. One other recent systematic review of the literature reported data about the epidemiology of the association between maternal periodontal disease and adverse pregnancy outcomes.58 The authors found a significant variability in study population, recruitment, and outcome assessment that could have weakened the strength of the association. Similar considerations could be derived from the results of the present study. The present updated systematic review, due to the increased number of studies included, and mostly due to the analytical methodology adopted, provided more
202
3.44 (1.34–8.80)
0.01 0.1 1 Favors experimental
10 100 Favors control
information if compared to the previous one, allowing better understanding of the effects of periodontitis in pregnancy. The evidence that some correlation could exist between maternal periodontitis and adverse pregnancy outcomes should justify the prevention of such complications by periodontal preventive treatment in women willing to conceive. However, a recent systematic review of the literature showed that no significant effect was found for nonsurgical periodontal treatment in improving birth outcomes.59 Unfortunately only one RCT was included in the quantitative analysis due to the strict inclusion criteria. Indeed, contradictory results had been reported by other systematic reviews. Some supported the lack of evidence of nonsurgical periodontal therapy as valid preventive measure,25,60,61 while other authors, by the
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inclusion of a large number of articles (both randomized and non-randomized controlled trials in a recent systematic review), were able to prove a significant effect of nonsurgical periodontal treatment in reducing the occurrence of preterm birth or low birthweight.62
CONCLUSION The present systematic review confirmed the originally postulated association between periodontal disease and preterm delivery, once biased methodologies and heterogeneity of studies were properly considered and corrected. A final, evidence-based step is still required in order to prove beyond doubt that preventive nonsurgical prophylaxis reduces the risk of preterm birth. In the meantime, since no adverse effects can be attributed to periodontal care, we believe that periodontal history and periodontal care should be included in basic obstetrical counseling to women willing to conceive.
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