The Potential Association Between Periodontal Diseases and Adverse Pregnancy Outcomes in Pregnant Women: A Systematic Review of Randomized Clinical Trials

Preceding studies have demonstrated that periodontitis might increase the liability of adverse pregnancy outcomes such as preterm birth, preeclampsia, low birth weight, and perinatal fatality in pregnant women. Nonetheless, there is no convincing testimony that periodontitis is related directly to adverse pregnancy outcomes in pregnant women. This systematic review intended to assess and review all the available randomized clinical trials that concentrated on the association between periodontal diseases and adverse pregnancy outcomes, and the impact of periodontal disease therapy on adverse pregnancy outcomes. The databases like Scopus, PubMed, Google Scholar, and Web of Science were consumed to explore relevant and suitable studies after adopting the inclusion and exclusion criteria. The search included articles with no time restrictions and certain keywords were utilized in the databases. The investigation was done through four independent reviewers employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twenty-three studies fulfilled the exclusion and inclusion criteria and were used and included in this systematic review. The above-mentioned studies assessed the association between periodontal diseases and adverse pregnancy outcomes and the effect of periodontal disease treatment in reducing the influence of adverse pregnancy outcomes. This systematic review revealed that there is a relationship between periodontitis and adverse pregnancy outcomes, and periodontal treatment has a reducing impact on adverse pregnancy outcomes in pregnant women with periodontitis. Prospect studies are warranted to investigate the relationship between periodontitis and different adverse pregnancy outcomes and to decide the best type and the most effective therapy to treat periodontitis in pregnant women.


Introduction And Background
Periodontitis and consecutive immunological reactions are hypothesized to cause adverse pregnancy outcomes such as low birth weight, preeclampsia, preterm birth, gestational diabetes, and perinatal fatality [1]. Periodontal disease, such as periodontitis and gingivitis, is an infection-caused ailment and is an immuno-inflammatory reaction disturbing the tissues promoting the teeth (gingiva, periodontal ligaments, alveolar bone, and cementum) [2]. Periodontitis is a comparatively prevalent ailment, which appears in more than 30% of humans in several communities [3]; the prevalence is between 5% and 20% in pregnant women [4]. A study presumed that the change in progesterone and estrogen levels through pregnancy applies the impact on inflammatory responses and subgingival microbiota in gingival tissues through the changes of chemotaxis, enzymes, cytokines, and antioxidants from gingival fibroblasts (GFs), polymorphonuclear leukocytes (PMNs), and periodontal ligament cells (PDLCs). These changes indirectly commit to increased gingival inflammation. Although, the mechanisms responsible for these changes are not fully known [5]. Moreover, investigators have proposed that periodontal disease leads to the release of inflammatory mediators such as cytokines or pathogens, which then impact amniotic fluid or embryonic tissue through hematogenous transport [4].
In 1996, Offenbacher was the first researcher who chronicled and proposed that pregnant women diagnosed to have periodontitis have a greater risk to deliver preterm and low birth weight infants in comparison with healthy periodontal tissue by 7.5 times [2]. Subsequently, many studies conducted and documented a rapport between periodontitis and adverse pregnancy outcomes, such as Meqa et al. [6], an investigator who reported a significant correlation between periodontitis and low birth weight as well as preterm birth. The adjusted odds were 3.2 times greater for women diagnosed to have periodontitis to have a low-weighted generation in comparison to women without periodontitis. Also, it is 3.4 times greater for women diagnosed to have periodontitis to give premature birth in comparison to women without periodontitis. On the other hand, a prospective study done by Farrell et al. documented no association between periodontal condition and either preterm birth or low birth weight in non-smoker pregnant women in the first three months of the

Methodological Quality and Risk of Bias Assessment of Included Studies
The methodological quality of each article was accomplished utilizing the risk of bias assessment tool outlined in the Cochrane risk-of-bias visualization (robvis) [17]. The Cochrane Collaboration advocates a specific tool to assess the risk of bias in each selected article. The four authors investigated the risk of bias in the included articles based on the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. Each domain was investigated as "low," "unclear," or "high." These assessments were stated for each included article in the "risk of bias" figures. The overall risk of bias associated with each article was graded as follows: low risk of bias: all domains were assessed as "low risk"; unclear risk of bias: at least one domain was assessed as "unclear risk"; and high risk of bias: at least one domain was assessed as "high risk." The risk of bias was investigated during the course of data extraction, which could impress the outcome of each included article.

Types of Outcome Measurements
Primary outcomes: The number of articles reported significant and non-significant associations between periodontal diseases and adverse pregnancy outcomes.
Secondary outcomes: The effect of periodontal diseases on adverse pregnancy outcomes such as low birth weight, preterm birth, preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, intrauterine growth restriction, and gestational diabetes. In addition, several articles reported significant and non-significant associations between periodontal disease treatment and reducing adverse pregnancy outcomes.

Synthesis of Results
Only one table was arranged to gather the included study's characteristics. It also includes the main outcomes of the studies that studied the relationship between periodontal disease and adverse pregnancy outcomes.

Statistician Analysis
Meta-analysis was impossible because of the discrepancy in the included articles. Parametric data relating to the patient's age in the included articles are presented as mean and standard deviation (mean ± SD), in addition to a descriptive evaluation of the findings.

Study Selection
In the beginning, keywords were utilized to have a total of 156 studies from databases. Thirty-four studies were rejected because of their irrelevance or duplicity. Only 122 studies were screened. Forty-one studies were rejected and excluded based on title and abstract. Following assessment for eligibility, after excluding 58 studies due to different reasons, only 23 studies were included in this systematic review. Figure 1 displays the search flow chart summary for this systematic review.

Study Characteristics
This systematic review included 23 human articles that met the inclusion criteria. These studies investigated the relationship between periodontitis and adverse pregnancy outcomes, as well as the effectiveness of periodontal treatment as a factor in reducing adverse pregnancy outcomes in pregnant women with periodontal diseases [3,6,. Only randomized control clinical trials were included in the systematic review, with a total sample size of 9724 participants; the studies were conducted in 12 countries, including the United States, Ireland, Hungary, Spain, Republic of Kosovo, Australia, China, India, Iran, Brazil, Colombia, and Chile ( Table 1). Even though there were no time constraints in this systematic review, all included studies were published from 2002 to 2019. The participants' ages ranged from 16 to 43 years. Eight studies reported the patient's age within a range and a mean age with standard deviation (mean ± SD) [18,26,27,31,[35][36][37][38], three studies reported the patient's age within a range only [6,22,25], three studies reported the minimum patient's age [20,21,32], seven studies reported a minimum age within a range and a mean age with standard deviation (mean ± SD) [19,23,24,[28][29][30]34], and two studies reported the mean age with standard deviation only [3,33]. Caneiro-Queija et al. [18] reported that the ages of subjects ranged from 18 to 40 years old, with a mean age and standard deviation in the control group of 32.25 ± 4.21 and 32.14 ± 4.27 in the test group, whereas Weidlich et al. [25] reported that the ages ranged from 18 to 35 years old. Jiang et al. [21,23] disclosed that the subjects were at least 18 years old, whereas Michalowicz et al. [34] reported that the subjects were at least 16 years old, with a mean age and standard deviation of 25.9 ± 5.5 in the control group and 26.1 ± 5.6 in the treatment group. Furthermore, Novak et al. [33] reported that the control group's mean age was 25.7, while in the treatment group was 27.3. Furthermore, all of the studies included structured their inclusion and exclusion criteria based on the participants' periodontal, medical, and gestational status. To screen and examine the oral cavity for periodontal diseases, various criteria and methods were used. Some studies defined periodontitis as attachment loss of 3 mm on three teeth [3,29]. The gestational age was specified in almost all of the included studies, but it varied from one to the next. Pregnant women in their first trimester were included in some studies [18,19,34], while pregnant women in their third trimester were included in one study [23]. Some articles, on the other hand, included all pregnant women, regardless of gestational age [29,33]. Furthermore, one study limited its population to pregnant women with preeclampsia [30], while another included non-pregnant women planning to conceive within the next year [24]. Only singleton pregnancy was mentioned in 10 articles [19,25,27,[31][32][33][34][35]37,38]. Various adverse pregnancy outcomes were observed and reported in the included studies. Almost all of them mentioned preterm birth and low birth weight as negative pregnancy outcomes. Furthermore, some studies found abortion [19,27], stillbirth [19,20,32], gestational diabetes and hypertension [21], and preeclampsia and HELLP syndrome [30].  HELLP: hemolysis, elevated liver enzymes, and low platelet count.

Primary Outcomes
The primary outcomes demonstrated the number of studies that reported a significant association between periodontal diseases and adverse pregnancy outcomes. Three studies out of 23 focused mainly on the relationship between periodontal disease and adverse pregnancy outcomes [6,33,38]. All three articles showed a significant association between acute/chronic periodontal diseases and adverse pregnancy outcomes [6,33,38]. An informative summary of the article's features and their main outcomes is illustrated in Table 1.

Secondary Outcomes
The secondary outcomes described the impact of periodontal diseases on adverse pregnancy outcomes such as low birth weight, preterm birth, preeclampsia, eclampsia, HELLP syndrome, intrauterine growth restriction, and gestational diabetes. All studies focused on and observed the relationship between periodontitis and both preterm delivery and low birth weight [3,6,. Moreover, six studies observed neonatal mortality such as stillbirth and abortion in addition to preterm delivery and low birth weight [19][20][21]27,29,32]. Table 1 illustrated the types of adverse pregnancy outcomes observed through all included studies. In addition, secondary outcomes demonstrated the number of studies that reported a significant impact of periodontal disease treatment on reducing the risk of adverse pregnancy outcomes. Twenty-three articles focused on and observed the impact of periodontal disease on reducing the risk of adverse pregnancy outcomes [3,6,. Out of 23 studies, 11 showed a significant association and positive impact of periodontitis therapy on decreasing the risk of adverse pregnancy outcomes [6,19,25,27,28,31,33,[35][36][37][38].
In contrast, nine studies showed no impact of periodontal disease therapy on reducing adverse pregnancy outcomes [3,18,22,24,26,29,30,32,34]. One study showed a positive impact of periodontitis treatment on some adverse pregnancy outcomes and no impact on other adverse pregnancy outcomes [20]. In addition, two studies showed limitations in assessing the impact of periodontal disease treatment on reducing adverse pregnancy outcomes because of the small size of the sample in both studies [21,23]. An informative summary of the article's features and their main outcomes is illustrated in Table 1.

Quality and Risk Assessment of the Included Articles
The quality and risk assessment of all included articles were concluded by four authors. All articles that have been included were determined by following the Cochrane risk-of-bias visualization (robvis) [17] to assess the risk of bias. The preponderance of the included articles had a low risk of bias in the following domains: selective reporting (73.9%) and other sources of bias (73.9%). All studies revealed a low risk of bias (100%) in random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcomes assessment, and incomplete outcome data domains ( Figure 2). Thoroughly, among the 23 studies, only six studies (26.1%) had an unclear risk of bias. Seventeen studies (73.9%) had a low risk of bias as demonstrated in Figures 2, 3. The scoring of unclear risk of bias was given to six studies due to inadequacy of sufficient information to make a clear judgment in the following domains: selective reporting and other sources of bias ( Figure 3).

Discussion
This systematic review aimed to evaluate and illustrate research findings that fulfilled this research objective. All randomized control clinical trials that studied the relationship between periodontitis and adverse pregnancy outcomes and the impact of periodontal therapy on adverse pregnancy outcomes have been included, with no time restriction. Our review exhibited an exhaustive group of evidence collected from 23 studies that satisfied the inclusion and exclusion criteria.
The primary outcome of this systematic review is to assess the association between periodontitis and adverse pregnancy outcomes. All the studies that are included in this review and focused on this objective reported a significant association between periodontitis and adverse pregnancy outcomes [6,33,38]. In contrast, research failed to catch periodontal bacteria in the amniotic fluid of women with periodontitis who delivered preterm, despite these pathogens being often found in dental plaque. In addition, Fusobacterium nucleatum in vaginal swab samples and dental plaque were not associated and related to the presence of the bacteria in amniotic fluid [36].
The secondary outcomes reported the impact of periodontal disease therapy in reducing the influence of adverse pregnancy outcomes. The effect varied among studies in which several studies reported a significant association between periodontitis therapy and decreasing the risk of adverse pregnancy outcomes in pregnant women with periodontitis. Merchant et al. [19] disclosed that periodontal treatment may prevent preterm births. This therapy was provided to mothers at a gestational age of less than 21 weeks with mild to moderate periodontal disease. The treatment group had 49 preterm births in comparison to the control group, which had 52 preterm births, and five spontaneous abortions or stillbirths in the treatment group in comparison to 14 spontaneous abortions or stillbirths in the control group. This explains the favorability of using periodontal therapy to decrease the risk of adverse pregnancy outcomes such as preterm births and spontaneous abortions or stillbirths. The intention-to-treat hazard ratio for preterm birth comparing the treatment versus control groups was 0.93 (95% CI: 0.63-1.37). On the other hand, Pirie et al. [24] reported that non-surgical periodontal treatment at a gestational age between 20 and 24 weeks in the white population did not reduce adverse pregnancy outcomes including preterm and low birth weight. This was justified by the fact that the differences are insignificant between both the control and test groups in regard to birth length (P = 0.64), Apgar scores, type of delivery, and head circumference (P = 0.29). Moreover, both groups had similar cytokine levels in cord serum. Pirie et al. [24] mentioned that the difference is insignificant between the control and test groups in terms of gestational age (P = 0.23) and birth weight (P = 0.89). Results show that gestational age was slightly lower, and the birth weight was higher in the test group. Another randomized control trial performed by Jiang et al. [20] disclosed that periodontal therapy has a significant impact in decreasing the rate of premature rupture of the membranes but has no effect on gestational age or birth weight. They used alcohol-free antimicrobial cetylpyridinium chloride (CPC) mouth rinse during pregnancy. The women in the treatment group had a significantly lesser rate of premature rupture of the membranes (1.4%) in comparison with the control group (5.7%) (OR = 0.23, 95% CI = 0.07-0.84, P = 0.03).
Up to date, there are six systematic reviews that assessed the relationship between periodontitis and adverse pregnancy outcomes [2,[39][40][41][42][43], and only 10 systematic reviews assessed the impact of periodontal treatment on decreasing the risk of adverse pregnancy outcomes in all the past years [4,[43][44][45][46][47][48][49][50][51]. Of these systematic reviews, five systematic reviews supported the association between periodontal diseases and adverse pregnancy outcomes [2,[39][40][41][42]. In contrast, only one systematic review reported no association between periodontitis and adverse pregnancy outcomes [43]. In addition, four systematic reviews supported periodontal therapy in reducing the influence of adverse pregnancy outcomes [45,48,50,51], and four systematic reviews concluded periodontal disease therapy has no effect on decreasing the risk of adverse pregnancy outcomes [4,46,47,49]. Furthermore, one systematic review reported that periodontal therapy has a positive impact on reducing the risk of low birth weight, but no difference was seen in preterm birth, small for gestational age, preeclampsia, or perinatal mortality [43]. Additionally, one systematic review had insufficient differential findings to assess the impact of periodontal therapy on adverse pregnancy outcomes [43].
Pockpa et al. [2] did a review of clinical studies over two decades and published it in 2021. This review included 232 articles (n = 119,774 participants). Geographical interpretation declared that most of the included studies were conducted in the United States (42 studies, 18.10%), followed by Brazil (33 studies, 14.22%) and then India (25 studies, 10.78%) [2]. The preponderance of the studies reports a statistically significant association between periodontitis and preterm birth (63.96%), low birth weight (71.87%), preterm low birth weight (59.18%), preeclampsia (68.89%), and other pregnancy complications like premature rupture of membrane (65.38%) [2]. Moreover, Iheozor-Ejiofor et al. in 2017 did a review to assess the impact of periodontal disease treatment in pregnant women to decrease perinatal morbidity and fatality [44]. Fifteen randomized control trials were included in this review (n = 7161 participants). Periodontal treatment with the control group during pregnancy has been compared in 11 studies and the meta-analysis reported no difference in regard to preterm birth  [44]. It concluded that it is ambiguous with low-quality evidence if periodontal therapy during pregnancy has an effect on preterm birth, and there is also low-quality evidence that periodontal therapy may reduce low birth weight [44].
Obstetric physicians should take this association into consideration by guiding and advising any pregnant woman complaining of periodontitis symptoms to visit the dentist to treat it. Treatment of periodontitis is very simple and cost-effective in comparison with managing adverse pregnancy outcomes. This approach will help in decreasing the incidence of adverse pregnancy outcomes and in cutting costs. Furthermore, preconception screening for periodontitis to treat it before conception and oral hygiene instruction will play a very important role in eliminating periodontitis as a risk factor. Moreover, periodic dental visits during pregnancy should be part of the antenatal visits and assessments to detect periodontitis in its mild stage and treat it.
In summary, this systematic review illustrated an overview of different articles exhibiting the relationship between periodontal diseases and adverse pregnancy outcomes as well as the effect of periodontal disease therapy on adverse pregnancy outcomes ( Table 1). It can be established that there are deficient data to relieve the relationship between periodontal diseases and adverse pregnancy outcomes, and the effectiveness of periodontal treatment as a reducing factor of adverse pregnancy outcomes to treat pregnant women with periodontal diseases for now. However, the results from the included studies in this review advocate the need for more clinical trials to be capable to acknowledge periodontal therapy as a reducing factor of adverse pregnancy outcomes in pregnant women with periodontitis to be an approach in these types of patients. Obstetric physicians should take this association into consideration to decrease the incidence of adverse pregnancy outcomes by guiding these kinds of patients to the dentist to treat periodontitis. Moreover, medical and dental clinical assessment in pregnant women is essential before utilizing this form of therapy in pregnant women with periodontal diseases. The strength of this current review is that it included 23 articles that have been peer-reviewed and published from 2002 to 2019.

Study Strengths and Limitations of This Systematic Review
Our systematic review accumulated and assessed all peer-reviewed studies published in the past years that met the inclusion criteria. We used Scopus, PubMed, Google Scholar, and Web of Science as search instruments. One superiority of utilizing Google Scholar is that it averts researchers from missing any important study that has been published in journals but has not yet been cited in Scopus, Web of Science, or PubMed. To avoid making our question too specific, we used broad and general search terms. Furthermore, studies included were conducted on human subjects only and only randomized controlled trials were included. On the other hand, meta-analysis was impossible because of the discrepancy in the included articles. Moreover, future systematic reviews should include different study designs such as observational studies to evaluate the relationship between periodontal diseases and perinatal morbidity and mortality, malformations, and chromosomal abnormalities.

Conclusions
This systematic review revealed that there is an association between periodontal diseases and adverse pregnancy outcomes, and periodontal therapy has a reducing effect on adverse pregnancy outcomes in pregnant women with periodontitis. Obstetric physicians and dentists should take this association into consideration to treat periodontitis in pregnant women to decrease the incidence of adverse pregnancy outcomes and cut costs. Future studies are warranted to investigate the relationship between periodontitis and different adverse pregnancy outcomes and to decide the best type and the most effective therapy to treat periodontitis in pregnant women.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.