Introduction

Periodontitis is an inflammatory process that degrades periodontal supporting tissues which eventually lead to the loss of the tooth. Bacteria in the dental biofilm cause an inflammatory reaction in the marginal gingiva that becomes chronic over time and when it advances to the supporting tissues (alveolar bone, periodontal ligament) produces its irreversible destruction. The formation of the periodontal pocket creates a dysbiotic environment for the thriving of microorganisms (e.g. Porphyromonas gingivalis, Tannerella forsythia, Campylobacter spp.) with pathogenic potential that could eventually have an impact on the systemic health [1, 2].

Low birth weight (LBW) and preterm birth (PTB) are two important complications during pregnancy that can impact the health and survival of newborns. A birth weight of less than 2,500 g, regardless of gestational age, is defined as LBW. PTB is characterized by a birth before 37 weeks of gestation. Both LBW and PTB are associated with increased risk of neonatal morbidity and mortality, as well as long-term developmental problems [3, 4•, 5•].

Several investigations have revealed a link between periodontitis and LBW and PTB, however, the evidence is still uncertain. Two likely explanations have been put forward for this relationship. The direct pathway involves the transfer of bacteria from the dental biofilm or its bacterial products into the bloodstream, traveling to and invading the placenta and, as a result, causing inflammation. The indirect pathway involves the systemic production of proinflammatory cytokines from inflamed periodontal tissues, which can interfere with the feto-placental unit and cause intrauterine growth restriction and preterm birth [4•, 5•, 6].

Given the great importance of oral health and pregnancy complications and to inform clinical practice and public health policy, this systematic review is necessary to update the current knowledge on the subject. Additionally, it can also help in the identification of potential risk factors, prevention methods, and treatment options for pregnant women suffering from periodontitis. Consequently, the objective of this systematic review was to determine the association between periodontitis and LBW/PTB.

Methods

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) and registered in the Open Science Framework (OSF; https://doi.org/10.17605/OSF.IO/GCYPN).

PECO Question

Population: pregnant women without restrictions of age, ethnicity, race with and without low birth weight/preterm delivery.

  • Exposure: periodontitis

  • Comparator: without periodontitis

  • Outcome: frequency of women with periodontitis in each group

What is the association between periodontitis and low birth weight/preterm delivery in pregnant women?

Population, Exposure and Comparator

The population of interest included pregnant women regardless of age, ethnicity, or race with and without pregnancy complications such as low birth weight or preterm delivery. The exposure of interest was the presence of periodontitis, determined by clearly established periodontal clinical parameters or by means of periodontal indices. The comparator group exhibited no clinical signs of periodontitis, determined by clearly established periodontal clinical parameters or by means of periodontal indices.

Outcomes

The primary outcome of interest was the prevalence of periodontitis associated with the presence of low birth weight or preterm delivery. As a measure of effect size, the odds ratio (Odds Ratio; 95% confidence interval) was calculated. As secondary outcomes, the means of probing depth (PD) and periodontal attachment level (AL) were evaluated.

Search Strategy

A comprehensive search was performed from inception to May 2023 in the following electronic databases: PubMed/MEDLINE and Scopus. The search strategy included appropriate combinations of free keywords and relevant controlled vocabulary (e.g. Medical Subject Headings-MeSH) terms related to 'low birth weight', 'preterm birth' and 'periodontitis'. Keywords were searched in English, Spanish and Portuguese. In addition to the electronic database search and to identify any potentially eligible studies, snowballing and screening of relevant reference lists of included studies, as well as gray literature search, was performed through Google Scholar and SciELO.

Study Selection Process

Only human, case–control, cohort, and cross-sectional studies that focused on evaluating the presence of periodontitis in women with pregnancy complications were included. Intervention studies, animal studies, previous systematic reviews, conference proceedings, and case reports were excluded.

The inclusion language was limited to English, Spanish and Portuguese.

Initial screening of titles and abstracts was performed by two independent reviewers based on pre-determined eligibility criteria. Full text articles were retrieved for potentially eligible studies. Two independent reviewers then assessed the full-text articles for final eligibility based on the inclusion and exclusion criteria. Any discrepancies were resolved by discussion or consultation with a third reviewer.

Data Extraction

A standardized data extraction form was developed to collect relevant data from the included studies. The following data elements were extracted: study characteristics (author, year, study design), participant characteristics, sample size, exposure details, comparison details, outcome measures, and statistical results. Two independent reviewers performed data extraction. Extracted data were checked for accuracy and any discrepancies were resolved by discussion or consultation with a third reviewer.

Risk of Bias (RoB)

The methodological quality and risk of bias of the included studies were assessed using appropriate tools, such as the Newcastle–Ottawa scale for cohort and case–control studies. The quality result was rated as (7–9) Low risk, (4–6) Moderate risk and (0–3) High risk.

For cross-sectional studies, the National Heart, Lung, and Blood Institute (NHLBI-NIH) Quality Assessment Tool for Observational Cohort and Cross-sectional Studies was used. The guide is not intended to be a checklist, but rather a tool to identify potential issues that could introduce bias. The quality of each study was rated as low, medium or high (good) as follows:

  • Low quality: High risk of bias for all questions, or any potential bias could seriously affect confidence in the results.

  • Medium quality: risk of bias is unclear for one or more questions, or any plausible bias raises some concerns about the study results.

  • High quality: Low risk of bias for all questions, or any plausible bias is unlikely to seriously affect the study results.

Meta-analysis

Heterogeneity between included studies was assessed using statistical tests, such as Cochran's Q test and the I2 statistic. As substantial heterogeneity (I2 > 50%) was detected, a random effects model was used for meta-analysis. Sensitivity and subgroup analysis were performed to explore potential sources of heterogeneity, including study design, participant characteristics, and methodological quality. All analyses were performed in Review Manager (RevMan) [Computer program]. Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Publication Bias

We visually analyzed funnel plots and statistical tests such as Egger's regression test to assess for publication bias to detect any potential reporting bias.

Quality of Evidence and Strength of Recommendation

The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The GRADE framework assesses the quality of evidence based on factors such as study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. Based on the overall quality of the evidence, the strength of the association between periodontitis and pregnancy complications was determined and graded as high, moderate, low, or very low.

Results

A total of 2,867 potential records were identified in the databases. Of these, 2,582 records were excluded during title and abstract review, while 185 records were duplicated and also deleted. Therefore, 100 records were selected for further review. After this review, 65 records were removed as they did not meet the inclusion criteria (see supplement 1). Finally, 35 full-text studies, including a total of 2,510,556 women, were analyzed in their entirety and included in the qualitative and quantitative analysis (Fig. 1; Table 1). Most studies were from Brazil (6) followed by USA (4), India (5), Spain (4), Colombia (2), England (1), United Kingdom (1), Taiwan (1), Cuba ( 1), Pakistan (1), Italy (1), Argentina (1), Republic of Kosovo (1), Germany (1), Switzerland (1), Romania (1), Malaysia (2) and France (1). The age of the participating women was between 18 and 48 years of age. Eight studies were cohort, 15 case–control, and 12 cross-sectional.

Fig. 1
figure 1

Flow chart of study selection

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Table 1 General characteristics of the included studies
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The quality of the studies (Supplement 2) was rated as low in 4 studies [7,8,9,10], medium in 9 studies [11,12,13,14,15,16,17,18,19] and high in 22 studies [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37, 38••, 39,40,41].

No significant differences were observed in probing depth and periodontal attachment level between women with pregnancy complications and the control group except for the study by Bhavsar et al. [41] who reported a considerably greater probing depth (4.6 mm vs. 2.9 mm) in the case group compared to the control group (Table 2).

Table 2 Periodontal parameters in women with pregnancy complications (LBW or PTB)
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The studies by Noack et al. [19] and Davenport et al. [20] were excluded from the meta-analysis because they did not report the number of women with periodontitis in each group and therefore only 33 studies were included for analysis. According to the meta-analysis, a moderate association (OR 2.48; 95% CI 1.72–3.59) was observed between periodontitis and low birth weight, and the association was much stronger when case–control studies were analyzed independently (OR 3.94; 95% CI 1.95–7.96) (Fig. 2). The heterogeneity of the studies was significantly high. In contrast, cross-sectional studies did not show an association between periodontitis and low birth weight. However, by excluding the 4 studies [17, 36, 40, 41] with the largest effect size and wide confidence interval, the association between periodontitis and low birth weight was weak (OR 1.54; 95% CI 1.26–1.89) and with less heterogeneity (I2 71%). For its part, the association between periodontitis and preterm birth was weak (OR 1.87; 95%CI 1.57–2.22) with highly significant heterogeneity (Fig. 3). When low-quality studies [7,8,9,10] were omitted from the meta-analysis, there was no discernible change in the effect.

Fig. 2
figure 2

Forest-plot of the association between periodontitis and low birth weight (LBW). Cases: mothers with LBW. Controls: mothers without pregnancy complications. Events: the number of mothers with periodontitis

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Fig. 3
figure 3

Forest-plot of the association between periodontitis and preterm birth (PTB). Cases: mothers with PTB. Controls: mothers without pregnancy complications. Events: the number of mothers with periodontitis

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The visual analysis of the funnel plot revealed the presence of publication bias, most likely due to the effect of studies with a small sample (Figs. 4 and 5).

Fig. 4
figure 4

Funnel-plot of low birth weight (LBW) studies

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Fig. 5
figure 5

Funnel-plot of preterm birth (PTB) studies

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The quality level of the evidence was rated as low (Table 3). This means that we have limited confidence in the estimate of the effect, and the actual effect may be far from the estimate.

Table 3 Quality of the evidence and strength of the recommendation
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Discussion

Main Findings

The results from our analysis showed an association between periodontitis and adverse pregnancy outcomes but some aspects merit the discussion and interpretation of these findings.

In our study, differences in probing depth and periodontal attachment level between women with pregnancy complications and the control group were evaluated but due to limited data, no meta-analysis of periodontal variables was undertaken. The results did not show significant differences between studies in these variables. Davenport et al. [20] reported in a case–control study that there was no evidence supporting the association between probing depth and the risk of preterm low birth weight after controlling for maternal age, ethnicity, maternal education, smoking, alcohol consumption, infections, and hypertension during pregnancy. Similar findings were reported by Noack et al. [19]. This suggests that the presence of pregnancy complications is not directly related to periodontal disease by itself. In contrast, a recent study [41] found a difference in probing depth of almost 2 mm between groups. Furthermore, research differed in how periodontal condition was evaluated, which could explain the lack of a clear and significant difference between groups. Nevertheless, in the meta-analysis of the prevalence of periodontitis, a moderate association between periodontitis and low birth weight was found and this is in agreement with a previous systematic review [42]. This association was stronger when case–control studies were analyzed independently with high heterogeneity. In contrast, cross-sectional studies did not show a significant association between periodontitis and low birth weight. Furthermore, when studies that carried large effects and confidence intervals were excluded in the sensitivity analysis, the association decreased and was weak. This suggests that the association between periodontitis and low birth weight may vary depending on the study design utilized and the consequent extent of the effect, which should be taken into account when interpreting these findings.

A weak but significant association between periodontitis and preterm birth was detected, which also corresponds with a prior systematic review [42]. However, significant heterogeneity was also observed between the studies. It is important to mention that the sensitivity analysis according to the quality of the studies did not show significant changes in the results, which supports the robustness of the findings. Furthermore, when examining the funnel plots, publication bias was observed probably due to the influence of studies with small samples. Small study effects and publication bias are closely related. Because of publication bias, smaller studies with statistically significant results may be overrepresented in the literature, while larger studies with non-significant results may go unpublished. Hence, publication bias can have major consequences for evidence-based decision-making, leading to overestimation of association or treatment effects.

Methodological and Quality Issues of the Studies

It was observed that most frequently, cross-sectional studies were medium/low quality which indicates that the risk of bias was high as compared to cohort and case–control studies. In terms of bias, cross-sectional studies are more prone to biases such as recall bias and selection bias due to their snapshot nature and lack of temporal sequence. In this systematic review, cross-sectional studies generally failed to offer precise information such as a defined purpose, sample size, group characteristics, and measures to prevent bias and confounding. In contrast, cohort studies are generally considered to have lower risk of bias as they allow for the investigation of temporal relationships, and the exposure is measured before the outcome develops. Case–control studies need careful design and analysis to minimize bias, usually related to the selection of cases and controls and the reliance on participant recall of past exposures. Our examination of cohort and case–control studies found that they were of high quality, implying that researchers utilizing these study designs take additional steps to reduce bias. In general, while cross-sectional studies may have higher risk of bias compared to cohort and case–control studies, each study design serves different purposes and can be valuable in specific research contexts. Researchers should be aware of these considerations when interpreting and generalizing the findings of different study designs and specially in challenging topics such as adverse pregnancy outcomes and periodontitis.

Limitations of this Systematic Review

There are some limitations of this systematic review. Some studies may have had significant bias or problems that impacted reliability. Significant outcomes may be presented, while null/negative findings may be withheld, skewing the review. Small sample sizes restrict statistical power and result in weaker evidence. The heterogeneity of included research (study designs, demographics, exposures, and outcome measures) makes meta-analysis difficult and reduces precision.

Perspective

Although there appears to be an association between periodontitis and adverse pregnancy outcomes, causal inference using the Bradford-Hill criteria does not support such an association [43•]. Given the complexities of this topic and the necessity of making informed healthcare decisions, further high-quality research is required to show a definite causal association between periodontitis and pregnancy outcomes. Until then, healthcare providers should emphasize the importance of oral health during pregnancy and incorporate periodontal examinations and relevant therapies into prenatal care. By doing so, we can help to improve maternal and fetal health outcomes while also pursuing evidence-based approaches in periodontal health management throughout pregnancy.

Conclusion

Low-quality evidence indicates that periodontitis is moderately associated with low birth weight and weakly associated with preterm delivery. This means that we have limited confidence in the estimate of the effect, and the actual effect may be far from the estimate.