Association between the Risk of Preterm Birth and Low Birth Weight with Periodontal Disease in Pregnant Women: An Umbrella Review

Background: The purpose of this review is to determine the association between the risk of preterm birth and low birth weight in newborns and periodontal disease in pregnant women. Methods: A bibliographic search was carried out until November 2021 in the following biomedical databases: PubMed/Medline, Cochrane Library, Scopus, EMBASE, Web of Science, Scielo, LILACS and Google Scholar. Studies reporting the association between the risk of preterm birth and low birth weight in newborns with periodontal disease in pregnant women, which were systematic reviews, in English and without time limits were included. AMSTAR-2 was used to assess the risk of the included studies, and the GRADEPro GDT tool was used to assess the quality of the evidence and the strength of the recommendation of the results. Results: The preliminary search yielded a total of 161 articles, discarding those that did not meet the selection criteria, leaving only 15 articles. Seven articles were entered into a meta-analysis, and it was found that there is an association between the risk of preterm birth and low birth weight in newborns with periodontal disease in pregnant women. Conclusions: There is an association between the risk of preterm birth and low birth weight in newborns with periodontal disease in pregnant women.


Introduction
Periodontal disease (PD) is caused by bacteria affecting the supporting structures of the tooth, causing inflammatory processes and the destruction of the periodontium, which can Dent. J. 2023, 11, 74 2 of 13 lead to tooth loss [1,2]. This disease is initiated and propagated by an interaction between an altered oral microflora and the host's vulnerable immune system [3,4]. Gingivitis is the beginning of the disease and is generally due to the accumulation of dental biofilm due to poor oral hygiene. It is characterized by localized inflammation of the gum, which appears red and sometimes bleeding. If gingival disease is not treated, there is a risk that it will progress to chronic periodontitis [5].
This progression of bacterial infection leads to the severe destruction of the periodontium, causing tooth loss, which compromises chewing, aesthetics, self-confidence and quality of life [6]; it also contributes to systemic inflammation, with bacterial substances and inflammatory mediators capable of initiating and promoting systemic diseases [2,7]. The prevalence of PD has been reported to range from 20% to 50% worldwide [8]. There is evidence that PD is associated with heart disease, diabetes mellitus, chronic obstructive pulmonary disease, rheumatoid arthritis and adverse pregnancy outcomes [9].
The prevalence of PD is approximately 40% in pregnant mothers [10]. During pregnancy, due to hormonal factors (high levels of estrogen and progesterone), 50 to 70% of women develop gingivitis, being more vulnerable to PD than their nonpregnant peers [11].
Approximately 15 million premature babies are born each year in the world; these children, in addition, are usually born weighing less than 2500 g [12]. Premature babies or premature birth (PB) with low birth weight (LBW) are one of the leading causes of infant morbidity and mortality. Some risk factors that influence these adverse pregnancy outcomes are multiparity, low socioeconomic status, mother's age, race, history of PB, maternal infectious processes and alcohol and drug abuse [13,14]. Although more than 60% of PBs occur in Africa and South Asia, preterm birth is a global problem [15].
PBs are a primary public health problem in both developed and developing countries. Despite improvements in obstetric care, preterm birth rates have not decreased in the last ten years [16][17][18].
Some studies have related the presence of PD during pregnancy with PB and/or LBW [19][20][21][22][23][24][25], and the evidence refers to an association of PD with adverse effects in pregnancy. Two pathogenic mechanisms are mentioned to explain the effect of PD on adverse pregnancy outcomes. Firstly, the periodontopathogenic bacteria that are found in the bacterial plaque of the gingiva due to a translocation phenomenon directly affect the fetus by bacteremia [15,26].
Likewise, the inflammatory mediators secreted in the subgingival inflammation zone (IL-1, L-6, IL-8, TNF-alpha, prostaglandin E2) come from the fetoplacental unit and produce an inflammatory reaction [27]. Mothers with PD have a high possibility of giving birth to a baby with LBW, prematurely or both in comparison with a pregnant woman with a healthy periodontium; therefore, they may have seven times the risk of having a PB or LBW baby [22,28]. Therefore, the early detection of PDs in pregnant women will help to prioritize the development of preventive and therapeutic interventions to decrease the occurrence of PBs and LBW newborns [29,30].
Given the relevance of this topic for public health, it is important that, through the analysis of systematic reviews with or without meta-analysis, results are produced that allow for more consistent conclusions to be reached. The main objective of this systematic review is to critically appraise the literature on the association between the risk of PB and LBW in newborns with PD in pregnant women.

Protocol and Registration
This systematic review followed a protocol defined by the authors according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [31]. This protocol has the registration number CRD42021290027 of the International Prospective Registry of Systematic Reviews (PROSPERO).
To prepare and structure this review, the focused question was formulated using the PICO format (population, intervention, outcomes and results) as detailed below: Outcomes: association between PD and PB (<37 weeks) and LBW (<2500 gm) of the newborn.

Focused Question (PICO)
Is there an association between the risk of PB and LBW with PD in pregnant women?

Search and Selection of Studies
For the present systematic review, 8 electronic databases were reviewed (PubMed/ Medline, Cochrane Library, Scopus, EMBASE, Web of Science, Scielo, LILACS and Google Scholar) until November 2021, combining keywords and subject titles according to the thesaurus of each database: "periodontal disease", "periodontitis", "gingivitis", "preterm birth", "low birth weight", "perinatal outcomes", "premature labor" and "adverse pregnancy outcomes". The search strategies of each of the databases are presented in Table 1.

Data Extraction
For the extraction of data from the eligible studies, a predefined format was used that included the author(s), year of publication, type of study, type of studies included, number of studies included in the qualitative analysis, number of studies included in quantitative analysis, type of periodontal disease, main results, OR/RR and conclusions. Information was extracted independently by three investigators (V.M., S.C. and E.M.) and any disagreement was resolved by consulting the opinion of a fourth investigator.

Risk of Bias (RoB) Assessment
The RoB of the included studies was independently assessed by two calibrated authors (V.M. and T.P.) (k = 0.98) using AMSTAR-2, which is a critical appraisal tool for systematic reviews of health research studies [32], and all disagreements were resolved by discussion with a fourth reviewer (H.V.). According to this tool, a systematic review is evaluated in 16 domains with simple answer options: "yes" when the result is positive; "no" when the standard was not met or there is insufficient information to answer; and "if partial" in cases where there was partial adherence to the standard. They are then classified into four confidence levels: high, moderate, low and critically low.

Analysis of Results
Extracted data were analyzed in RevMan 5.3 (Cochrane Group, Londres, UK) by OR measurement in a fixed effects model with a 95% confidence interval. Additionally, a GRADE analysis was performed using the guideline development tool (GRADEPro GDT) (McMaster University and Evidence Prime Inc., Canada).

Selection of Studies
The strategy used was orientated through electronic and manual search with a total of 161 articles and 69 duplicates ( Figure 1). After the selection of titles and abstracts, we chose 20 full-text articles. Then, five studies were excluded, resulting in 15 systematic reviews meeting the eligibility criteria for qualitative synthesis and seven for the quantitative analysis (meta-analysis). The reasons for the exclusion of the studies are found in Table 2.  [37] Studies not referring to PB or LBW

Risk of Bias in the Analysis of the Studies
Eight studies [19,20,22,23,[38][39][40][41] had a high overall confidence, five [21,24,25,43,44] had a moderate overall confidence and two [42,45] had a low overall confidence (Table 4).   AMSTAR = Measurement tool that evaluates systematic reviews. AMSTAR-2 items: (i) Do the research questions and inclusion criteria for the review include PICO components? (ii) Does the review report include an explicit statement that the review methods were established prior to the execution and justify any significant deviations from the protocol? (iii) Did the reviewers state their decision on the study designs to include in the review? (iv) Did the reviewers apply a comprehensive literature search strategy? (v) Did the reviewers run the study selection in duplicate? (vi) Did the study authors perform data extraction in duplicate? (vii) Did the reviewers provide and justify a list of excluded studies? (viii) Did the reviewers describe the included studies in sufficient detail? (ix) Did the review authors use a satisfactory technique to assess the risk of bias in the individual studies included in the review? (x) Did the review authors report the sources of funding for the studies included in the review? (xi) If a meta-analysis was performed, did the review authors use appropriate methods for the statistical combination of results? (xii) If a meta-analysis was performed, did the review authors assess the potential impact of risk of bias in individual studies on the results of the meta-analysis or other evidence synthesis? (xiii) Did the review authors consider the risk of bias of individual studies when interpreting/discussing the results of the review? (xiv) Did the review authors provide a satisfactory explanation and discuss any observed heterogeneity in the review results? (xv) Quantitative synthesis completed, did reviewers adequately investigate publication bias (small study bias) and discuss its likely impact on review results? (xvi) Did the review authors report any potential sources of conflict of interest, including any funding received to carry out the review? * = critical domain.

Synthesis of the Results
The association between the risk of PB and LBW in newborns with PD in pregnant women was determined in seven studies [19,20,23,[38][39][40]42]. It was shown that PD in pregnant women is associated with the risk of PB, LBW and PB with LBW in newborns (Figures 2-4).
appropriate methods for the statistical combination of results? (xii) If a meta-analysis was performed, did the review authors assess the potential impact of risk of bias in individual studies on the results of the meta-analysis or other evidence synthesis? (xiii) Did the review authors consider the risk of bias of individual studies when interpreting/discussing the results of the review? (xiv) Did the review authors provide a satisfactory explanation and discuss any observed heterogeneity in the review results? (xv) Quantitative synthesis completed, did reviewers adequately investigate publication bias (small study bias) and discuss its likely impact on review results? (xvi) Did the review authors report any potential sources of conflict of interest, including any funding received to carry out the review? * = critical domain.

Synthesis of the Results
The association between the risk of PB and LBW in newborns with PD in pregnant women was determined in seven studies [19,20,23,[38][39][40]42]. It was shown that PD in pregnant women is associated with the risk of PB, LBW and PB with LBW in newborns (Figures 2-4).

GRADE Analysis
When evaluating the included studies, it was observed that there is low and moderate certainty in the association of PD in pregnant women with PB and LBW in newborns (Table 5).

GRADE Analysis
When evaluating the included studies, it was observed that there is low and moderate certainty in the association of PD in pregnant women with PB and LBW in newborns (Table 5).

Discussion
Diagnoses, treatments and clinical decisions in dentistry must be based on the best available scientific evidence, which comes from systematic reviews.
One of the objectives is to analyze whether these systematic reviews had an optimal design and execution process. For this, the AMSTAR tool was developed, which was introduced for the first time in 2007 [32,46,47]. To increase the applicability of the AMSTAR tool, a group of experts made reviews and created the AMSTAR-2 tool [32,47], which was used in the present review.
The main problem found was that one of the studies [42] did not use an exhaustive literature search strategy, and another study [45] did not present the list of excluded studies. Several protocols, such as those found in Cochrane systematic reviews, recommend that authors provide lists of included and excluded articles, allowing the reader to easily judge the quality of the selected articles.
Additionally, some studies [21,24,25,43,44] did not meet certain points for high overall confidence; for example, they did not perform duplicate study selection and data extraction. These are important issues that authors of systematic reviews should pay attention to in the future.
In the present study, it was observed that there is an association between the risk of PB and LBW in newborns with PD in pregnant women. This may be due to inflammatory processes occurring at the placenta-fetus junction or elevated systemic inflammation in pregnant women or due to the translocation of periodontopathogenic bacteria to the uteroplacental circulation [48].
The World Health Organization (WHO) established, as one of its goals, the reduction in the incidence of PB and LBW of newborns given the great impact that these problems have on children's morbidity and mortality indicators. In this sense, the efforts that health teams must make to reduce the incidence of PB and LBW of newborns not only aim to reduce maternal-fetal consequences but also the costs of hospitalization, use of units of intensive care, care and prevention in long-term health [49][50][51], as well as the implementation of preventive care protocols during the gestation period to reduce bacterial plaque rates from first care to subsequent visits [52]. Therefore, the authors emphasize the association found in this review so that the necessary public health measures can be taken.
However, this review has some limitations, such as the use of the AMSTAR-2 tool, which only considers the general confidence of the systematic reviews and their elements but does not describe this confidence in the studies included in each systematic review. In addition, the studies included in the systematic reviews that were able to determine the association between PD in pregnant women with PB and LBW had different study designs.
However, it has several important strengths, such as the fact that the present review cannot be compared with other previous studies since an umbrella review has not been previously carried out using the AMSTAR-2 tool. An exhaustive search of the scientific literature was carried out in the main bibliometric search engines, and a result was obtained based on systematic reviews with meta-analyses with high general confidence.

Conclusions
The systematic reviews included in the present study showed, in general, high confidence. In addition, there is an association between the risk of PB and LBW in newborns born and mothers with PD. A pregnant woman with PD is two to three times more likely to have a PB and a LBW.

Conflicts of Interest:
The authors declare no conflict of interest.