Oral Microbiome and Adverse Pregnancy Outcomes: An Update

Ali S

ISSN 0972-5997

Published Quarterly

Mangalore, India

editor.ojhas@gmail.com

Custom Search

OJHAS Vol. 21, Issue 2: (April-June 2022)

Original Article
Oral Microbiome and Adverse Pregnancy Outcomes: An Update

Authors:
Sheeba Ali, Assistant Professor,
Deepak Bhargava, Professor & Head,
Puja Bansal, Professor,
Anurag Hasti, Professor,
Ashish Choudhary, Professor & Head,
Shafali Singh, Assistant Professor,
School of Dental Sciences, Sharda University.

Address for Correspondence
Dr. Sheeba Ali,
Oral Pathology and Microbiology,
School of Dental Sciences,
Sharda University,
Greater Noida, India - 201310.
E-mail: dr.sheebaali@gmail.com.

Citation
Ali S, Bhargava D, Bansal P, Hasti A, Choudhary A, Singh S. Oral Microbiome and Adverse Pregnancy Outcomes: An Update. Online J Health Allied Scs. 2022;21(2):6. Available at URL: https://www.ojhas.org/issue82/2022-2-6.html

Submitted: Mar 11, 2022; Suggested Revision: April 12, 2022; Revised: April 19, 2022; Accepted: Jul 3, 2022; Published: Jul 30, 2022

PDF

This work is licensed under a Creative Commons Attribution-No Derivative Works 2.5 India License

Abstract: From last decade of the 20th century, numerous epidemiological studies and intervention trials have attempted to prove the relationships between maternal oral diseases and adverse pregnancy outcomes (APO). Several physiological, immunological and hormonal changes occurring during pregnancy ensures the woman’s body maintenance throughout the gestational period and the development of foetus. Studies have reported changes in the maternal microbiome in the gut, vagina, and oral cavity during pregnancy. Infections at the foetomaternal interface are known to upregulate the production of local proinflammatory cytokines, metalloproteinases and prostaglandins leading to membrane weakening, early rupture of membranes and uterine contractions. A clear understanding of the association between oral microorganisms and adverse birth outcomes conveys significant health implications. In this paper we reviewed the current literature regarding the link between oral microbiome and adverse pregnancy outcomes including preterm birth, chorioamnionitis, neonatal sepsis, stillbirth, and preeclampsia.
Key Words: Microbiome, Oral pathogens, Pregnancy, Periodontal disease, Premature, Pre-eclampsia

Introduction:

Pregnancy is a unique state that leads to many vascular, metabolic, and physiological adaptations in the mother, these changes support foetal growth and development and prepare the mother for the increased and nutritional demands of lactation to support the new-born’s postnatal growth [1]. However, some physiological, hormonal and dietary changes, in turn, alter the risk for oral diseases, such as periodontal disease and dental caries. These complex changes also affect the microbial composition of various body sites of the expectant mothers, including the oral cavity [2]. Natural release of high levels of steroid sex hormones, such as oestrogen and progesterone cause gingival inflammation linked to biofilms especially in the second and third trimesters [3].

The oral cavity has the second largest and diverse microbiota after the gut. Recently expanded Human Oral Microbiome Database (eHOMD) contains information of approximately 772 prokaryotic species, where only 70% are cultivable. Out of this 70% species, 57% have already been assigned to their names. The 16S rDNA profiling of the healthy oral cavity categorized the inhabitant bacteria into six broad phyla, namely, Firmicutes, Actinobacteria, Proteobacteria, Fusobacteria, Bacteroidetes and Spirochaetes constituting 96% of the total oral bacteria [4] [5]. In a healthy body, the oral microbiota maintains a symbiotic relationship with the host. However, an imbalance or maladaptation within the oral microbial community (dysbiosis) evokes not only a local inflammation but also a significant systemic inflammatory reaction [3].

Current evidence suggests an association between a dysbiotic oral microbiome and several systemic diseases, such as bacterial endocarditis, aspiration pneumonia, osteomyelitis in children, adverse pregnancy outcomes (APO), and cardiovascular disease [6]. The common denominator for this mixture of disease associations appears to be the host inflammatory response and specific microbial pathogens [7]. High hormone levels during pregnancy are associated with impaired connective tissue turnover in the periodontium, which may result in an increased inflammatory response in periodontal tissues and, consequently, in an increase in aerobic and anaerobic bacteria and in the prevalence of pregnancy induced periodontal diseases [8].

The development of proinflammatory maternal status has recently been addressed for its key role in the physio-pathological pathway of obstetrical complications [9]. Data from recent research shows that most preterm births are due to infection result from bacterial pathogens that rise from the vaginal microbiome to infect the clinically sterile intrauterine cavity consisting of the placenta, amniotic fluid, and foetus [7]. However, possibility of hematogenous spread (bacteraemia) due to untreated periodontal diseases (PD), contributing to an adverse pregnancy outcome, such as preterm birth, low-birth weight, chorioamnionitis, stillbirths, miscarriage, intrauterine growth restriction (IUGR) and preeclampsia cannot be precluded [10].

Understanding changes of oral flora during pregnancy, its association to maternal health, and its implications to birth outcomes is essential. In terms of oral microorganisms, researchers reported a higher level of periodontal anaerobes in the subgingival plaque among women with preterm deliveries. Present article aims to comprehensively review the literature on oral microorganisms and pregnancy. We focused on analysing the evidence on oral microbial community changes during pregnancy, including changes of key oral pathogens and summarized the current literature on the relationship between oral diseases and adverse pregnancy outcomes, including preterm birth, chorioamnionitis, neonatal sepsis, stillbirth, and preeclampsia from epidemiological studies, animal models studies and in vitro studies.

Oral Microbiome

Commensal oral microbiome

The microorganisms found in the human oral cavity have been referred to as the oral microflora, oral microbiota, or more recently as the oral microbiome, term coined by Joshua Lederberg [11]. For millions of years, our resident microbes have coevolved and coexisted with us in a mostly harmonious symbiotic relationship. We are not distinct entities from our microbiome, but together we form a 'superorganism' or holobiont, with the microbiome playing a significant role in our physiology and health [12]. It has been estimated that the human body is made up of over 1014 cells, of which around 10% are mammalian. The remainder are the microorganisms that comprise the resident microflora of the host [13]. The resident microbial species in the oral cavity primarily belong to 12 phyla: Actinobacteria, Bacteroidetes, Chlamydiae, Chloroflexi, Firmicutes, Fusobacteria, Gracilibacteria (GN02), Proteobacteria, Spirochaetes, SRI, Synergistetes, and Sacchariabacteria (TM7) [14]. Based on mutual benefits there is a symbiotic relationship between the microorganisms in our oral cavity. The commensal populations do not cause harm and maintain a check on the pathogenic species by not allowing them to adhere to the mucosa. The bacteria become pathogenic only after they breach the barrier of the commensals, causing infection and disease [4]. The principal bacterial genera found in the healthy oral cavity are enumerated in Table 1.

Table 1: Principal bacterial genera found in the healthy oral cavity [4].
Gram positive
Cocci – Abiotrophia, Peptostreptococcus, Streptococcus, Stomatococcus Rods – Actinomyces, Bifidobacterium, Corynebacterium, Eubacterium, Lactobacillus, Propionibacterium, Pseudoramibacter, Rothia.
Gram negative
Cocci – Moraxella, Neisseria, Veillonella Rods – Campylobacter, Capnocytophaga, Desulfobacter, Desulfovibrio, Eikenella, Fusobacterium, Hemophilus, Leptotrichia, Prevotella, Selemonas, Simonsiella, Treponema, Wolinella.

Role of diet

Humans have a long history of co-evolution with our resident bacteria, and evidence suggests that our ancient hominid microbiota was more diverse and stable than that of modern humans. Two dietary shifts, brought about by the development of agriculture and the Industrial Revolution significantly and rapidly increased the consumption of carbohydrates [15]. Sufficient evidence has shown that abundance ratios of core species are significantly correlated with diet pattern. The abundance of Neisseria and Haemophilus is different between hunter-gatherers and westerners, and traditional farmers fall in between. Some oral pathogens have been found in hunter-gatherers, which show that eating too much meat carries a high risk for oral diseases. For vegetarians, the oral microbiota’s composition is altered significantly at all taxonomic levels, including oral pathogens [16]. While diet influences the oral microbiome, recent data indicate that the oral microbiome influences the dietary preferences of its host. Certain bacteria, such as some Clostridia and Prevotella species, have been associated with taste thresholds, such as sweet, sour, salty, and bitter, plausibly representing a mechanism by which the oral microbiota influences dietary preferences to sustain its membership and persistence in the oral cavity [17].

Oral microbiome shift during pregnancy

The composition of the oral microbiome undergoes a pathogenic shift during pregnancy that reverts back to baseline or a “healthy microbiome” during the postpartum period; the shift is believed to be mediated by female sex hormones, such as progesterone and estrogen [18]. Bacterial community of subgingival plaque (SGP) and saliva at different taxonomic levels have been examined by various researchers using recent advances in next generation sequencing technologies 16 S metagenomics approaches that has provided a more comprehensive picture of oral microbiome during pregnancy [10, 19]. Figure 2 depicts the dominating members of different phyla and genera during pregnancy [20].

During pregnancy species such as Streptococcus species, OT 058 and Terrahaemophilus aromaticivorans are abundant in both saliva and subgingival plaque (SGP) samples. Lin et al. in their study found that the Shannon diversity index of the salivary microbiome in pregnant women is significantly higher than in non-pregnant women. Moreover, in the pregnant group, Treponema, Porphyromonas and Neisseria were more abundant, while Streptococcus and Veillonella were more abundant in the non-pregnant group. Balan et al. confirmed that the oral bacterial community showed higher abundance of pathogenic taxa during a healthy pregnancy as compared with nonpregnant women despite similar gingival and plaque index scores [10,19,21].

Oral Diseases During Pregnancy

Distinct microenvironments at oral barriers harbour unique microbial communities, which are regulated through sophisticated signalling systems and by host and environmental factors. The collective function of microbial communities is a major driver of homeostasis or dysbiosis and ultimately health or disease. Despite different aetiologies, periodontitis and dental caries are each driven by a feedforward loop between the microbiota and host factors (inflammation and dietary sugars, respectively) that favours the emergence and persistence of dysbiosis [22]. Physiological changes and hormonal differences in pregnant women increase their susceptibility to oral diseases. Higher levels of oestrogen and progesterone are produced by the placenta that increases women susceptibility to bacterial plaque provoking the apparition of periodontal diseases, gingivitis, tooth sensitivity and tooth loss, that is most frequent during the second to third trimester of pregnancy [10,20,23]. The exact mechanisms responsible for the increased gingival inflammation during pregnancy are not fully understood. It is clear that perturbations in neutrophil function, modifications in cellular and humoral immunity, hormone induced changes in cellular physiology, and local effects on microbial all play crucial roles [24].

Figure 1: Oral microbiota associated with pregnancy. Adapted from ‘Periodontal Conditions and Pathogens Associated with Pre-Eclampsia: A Scoping Review’, by Gare J et al. 2021, Int J Environ Res Public Health, 18(13), p.7194.

Periodontal disease is one of the most common inflammatory diseases in the adult population, with an incidence varying from 5 to 30%. Periodontal disease, initiated by bacterial biofilms, can cause the destruction of soft and hard periodontal tissues, consequently leading to tooth loss [25]. An increase in the proportion of Gram-negative anaerobic bacteria historically described in 1979 as belonging to Socranski’s “red complex”: Treponema denticola (Td), Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), and Fusobacterium nucleatum (Fn) leads to periodontal dysbiosis. Prevotella intermedia (Pi), Dialister spp., and Selenomonas spp. are also found in abundance in periodontitis, and the high number of spirochetes seems to be associated with the severity of periodontal destruction. However, recent advances in metagenomic sequencing have made it possible to highlight new concepts concerning periodontal dysbiosis associated with periodontitis, which is the result of a qualitative and quantitative modification of a polymicrobial community that includes both commensal and pathogenic bacteria. At the periodontal level, dysbiosis comes more from a change in dominant species than from de novo bacterial colonization [26].

Dental caries is an irreversible microbial disease of the calcified tissues of the teeth, characterized by demineralization of the inorganic part and destruction of the organic substance of the tooth, which often leads to cavitation [27]. The ecological plaque hypothesis describes the currently most widely accepted theory of the etiology and pathogenesis of dental caries. This hypothesis combines the specific plaque hypothesis (acknowledging the role of cariogenic bacteria such as Streptococcus mutans and lactobacilli) and the unspecific plaque hypothesis, assuming that a shift in the described equilibrium (dysbiosis) enables the caries process [28]. Saccharolytic bacteria including Streptococcus, Actinomyces, and Lactobacillus species—degrade fermentable carbohydrates and the bacterial-generated carbohydrate reserve in the biofilm into organic acids via the Embden-Meyerhof-Parnas pathway and several of its branch pathways [29,30]. The formation of lactic acid, along with host factors, lowers down the oxygen coefficient locally, which fosters the rate and progression of dental caries [31]. Pregnant women are at higher risk of tooth decay for several reasons, including increased acidity in the oral cavity, frequent sugary dietary cravings, and limited attention to oral health [32, 33]. If left untreated, dental caries may result in further inflammatory complications, which could influence pregnancy outcomes [34].

Oral Diseases and Adverse Pregnancy Outcomes

Adverse pregnancy outcomes is a broad term that includes preterm birth (delivery <37 weeks gestation), low birth weight (<2500g regardless of gestational age), small for gestational age (birth weight <10th percentile of gestational age), stillbirth (pregnancy loss >20 weeks), preeclampsia (new-onset of hypertension around 20 weeks of gestation and proteinuria), preterm premature rupture of membranes, and neonatal sepsis. Together, adverse pregnancy outcomes affect more than 20% of newborns worldwide annually [18].

Gingival inflammation in women examined early in pregnancy and poor oral hygiene behaviours are considered as risk factors for adverse pregnancy outcomes. Kruse et al in their cohort study found an association between gingivitis and high risk of preterm birth among women without periodontitis in a hospital setting in Germany. López et al did a trial study in pregnant women with gingivitis and demonstrated a significantly higher risk of preterm low birth weight among women with gingivitis who received periodontal treatment after delivery compared with those that received treatment during pregnancy (<28 weeks). Erchick DJ et al (2020) in a community-based study too found gingival inflammation as a risk factor for preterm birth among pregnant women examined during their first trimester [35].

Research in the area of periodontal medicine marks a resurgence in the concept of focal infection, which was first introduced by Miller in 1891 [9]. In 1996 study by Offenbacher and colleagues suggested that maternal periodontal disease was associated with a seven-fold increased risk of delivery of a PLBW infant. Later, Dasanayake et al. confirmed this finding by showing that women with healthy periodontal status had a lower risk of having adverse pregnancy outcomes [36]. Recently, Pockpa ZAD et al. studied the clinical studies that have focused on periodontal diseases and adverse pregnancy outcomes since 1996 till April 2020 and concluded that irrespective of geographical location, the majority of the studies found a statistically significant link between periodontal diseases and some complications of pregnancy [37].

Several studies have reported a positive association between dental caries and adverse pregnancy outcomes, including preterm birth and preeclampsia. Dasanayake et al (2005) concluded that oral bacterial species like Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinus, Lactobacillus acidophilus, Lactobacillus casei, Actinomyces naeslundii genospecies (gsp) 1 and 2 can be related to pregnancy outcomes in addition to previously reported periodontal pathogens. These organism levels may not only predict poor pregnancy outcomes, but also be used as modifiable risk factors in reducing prematurity and low birth weight [38]. Durand et al (2009) in their pilot study found that low levels of lactobacilli are associated with preterm birth [39]. Recently, Cho et al (2020) reported that women with dental caries had a slightly but significantly increased risk of delivering large for gestational age (LGA) infants compared with women without dental caries. Although the mechanism underlying the increased risk of delivering LGA infants in mothers with dental caries is not understood, it is hypothesized that sedentary lifestyle and eating and drinking habits are closely associated with being overweight and oral conditions (34,40). Untreated dental caries can lead to oral abscess and facial cellulitis. Children of mothers who have high caries levels are more likely to get caries [32].

Pathogenic Oral Microbes Associated With Adverse Pregnancy Outcomes

Although the exact mechanisms by which oral disease could adversely affect pregnancy are still unclear, the presence of DNA of oral pathogens has been found in amniotic fluid, placental tissues, and the genital tract. Table 2 enumerates clinical studies (2006-2022) in which oral microbes have been extensively detected in placental fetal units resulting in adverse pregnancy outcome. The most prevalent anaerobic bacteria Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) are the most important periodontal pathogens that could induce placental inflammation and subsequent damage.

Table 2: Clinical studies in which oral microbes have been detected in placental fetal units resulting in adverse pregnancy outcome.
S. No	Researcher	Year	Oral microbes detected	Adverse pregnancy outcome	Result
1.	DasanayakeAP et al³⁸	2005	Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinus, Lactobacillus acidophilus, Lactobacillus casei, Actinomyces naeslundii genospecies (gsp) 1 and 2	Preterm delivery and low birth weight.	Concluded that these organism levels may not only predict poor pregnancy outcomes, but also be used as modifiable risk factors in reducing prematurity and low birth weight.
2.	Han YW et al⁴⁹	2006	Bergeyella strain	Preterm birth	Observations suggested that the Bergeyella strain identified in the patient's intrauterine infection originated from the oral cavity
3.	Lin D et al ²¹	2007	P. gingivalis, Tannerella forsythia, Prevotella intermedia, and Prevotella nigrescens	Preterm birth	High levels of periodontal pathogens and low maternal IgG antibody response to periodontal bacteria during pregnancy are associated with an increased risk for preterm delivery.
4.	Barak S et al⁶⁵	2007	Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum sp., Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis, and Treponema denticola.	Pre-eclampsia	Eight of the 16 (50%) placenta specimens were positive for one or more periopathogenic bacteria in the preeclampsia group, compared to only two of the 14 samples (14.3%) from controls. The significant presence of periopathogenic microorganisms or their products in human placentas of women with preeclampsia may suggest a possible contribution of periopathogenic bacteria in its pathogenesis
5.	Katz J et al⁶⁶	2009	Porphyromonas gingivalis	Chorioamnionitis, Preterm birth.	The antigens P. gingivalis were detected in the placental syncytiotrophoblasts, chorionic trophoblasts, decidual cells, and amniotic epithelial cells, as well as vascular cells. P. gingivalis may commonly colonize placental tissue, and that the presence of the organism may contribute to preterm delivery
6.	Han YW et al ⁵⁰	2009	Fusobacterium nucleatum, Leptotrichia (Sneathia) spp., a Bergeyella sp., a Peptostreptococcus sp., Bacteroides spp., and a species of the order Clostridiales	Preterm birth	Demonstrated the involvement of several taxa (F. nucleatum and Bergeyella spp.) providing evidence that, in addition to the vaginal species, bacteria from oral sources may also play a significant role in intra-amniotic infection.
7.	Durand R et al³⁹	2009	Streptococci mutans, Lactobacilli.	Preterm delivery and Low birth weight.	Low levels of Lactobacilli in saliva were found to be associated with preterm birth.
8.	Han YW et al⁶⁷	2010	F. nucleatum	Stillbirth	F. nucleatum may have translocated from the mother’s mouth to the uterus.
9.	Gauthier S et al⁶⁸	2011	F. nucleatum	Chorioamnionitis, Pretermbirth	Three women, all in preterm labor with intact membranes, were included. Intra-amniotic sludge was observed in all of them. A strain of F. nucleatum with 100% sequence identity with the strain detected in the amniotic fluid was found in the oral samples of one of them and of two partners.
10.	Bohrer JC et al⁶⁹	2012	Fusobacterium nucleatum	Acute Chorioamnionitis	Intrauterine infection with Fusobacterium nucleatum can result in severe disease at term.
11.	Hirano E⁷⁰	2012	Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia	Pre-eclampsia	In systemically healthy pregnant women, their findings suggested that the levels of maternal subgingival A. actinomycetemcomitans DNA were elevated in preeclamptic women.
12.	Swati P et al⁷¹	2012	Porphyromonas gingivalis, Fusobacterium nucleatum, T reponema denticola, P revotella intermedia and Aggregatibacter actinomycetemcomitans	Hypertension	In cases with hypertension, periodontal pathogens are present in higher proportion in subgingival plaque and placenta as compared to control group.
13.	Chaparro A et al⁷²	2013	T. denticola and P. gingivalis	Hypertensive disorders	Pregnant women with periodontal disease presented an association in the placental tissue between the presence of T. denticola and P. gingivalis and hypertensive disorders. Additionally, increased expression of TLR-2 was also observed.
14.	Ercan E et al⁷³	2013	Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum, Prevotella intermedia, Campylobacter rectus and Eikenella corrodens.	Pre-term birth and low birth weight	Campylobacter rectus, T. forsythia, P. gingivalis and F. nucleatum were detected in the amniotic fluid and subgingival plaque samples of three patients who gave birth to PTLBW neonates. These findings suggest that the transmission of some periodontal pathogens from the oral cavity of the mother may cause adverse pregnancy outcomes.
15.	Gonzales-Marin C et al⁷⁴	2013	Fusobacterium nucleatum	Preterm birth	Strongly indicate that F. nucleatum subsp. polymorphum of oral origin could be involved with pregnancy complications.
16.	Wang X et al⁷⁵	2013	18 species (7 non-redundant) identified, of which only 2 (Escherichia coli, Streptococcus agalactiae) were cultivated. of those, Bergeyella, Fusobacterium nucleatum, and Sneathia sanguinegens	intra-amniotic infection (IAI) and early-onset neonatal sepsis (EONS).	The majority (72%) of CB species were also detected in the matching AF, with E. coli and F. nucleatum as the most prevalent.
17.	Andonova I et al⁷⁶	2015	Porphyromonas gingivalis, Fuscobacterium nucleatum, Actinomyces actinomycetecomitans	Preterm birth	The study showed a significant association between high levels of periodontal pathogens during pregnancy with an increased risk for preterm delivery.
18.	Amarasekara R et al⁷⁷	2015	Variovorax, Prevotella, Porphyromonas, and Dialister	Pre-eclampsia	This study confirms the presence of bacteria in the placental tissues of a subset of women with pre-eclampsia and supports the role of bacteria in the multifactorial cause of pre-eclampsia.
19.	Vanterpool SF et al⁴⁸	2016	Porphyromonas gingivalis	Preterm delivery, chorioamnionitis, chorioamnionitis with funisitis, preeclampsia, small for gestational age (SGA)	Suggested that the presence of Pg within the villous stroma or umbilical cord may be an important determinant in Pg-associated adverse pregnancy outcomes.
20.	Usin MM⁷⁸	2016	Porphyromonas gingivalis (Pg), Treponema denticola (Td), Tannerella forsythia (Tf) Prevotella intermedia (Pi) and Agreggatibacter actinomycemcomitans (Aa).	Preterm delivery, low weight at birth (PTLBW).	The presences of periodontal pathogens in periodontal pockets from pregnant with different periodontal status would associate with PTLBW infants when the mothers are young, and the normal term and normal birth weight infant are associated with the absence of periodonto bacteria like Pi and Aa.
21.	Parthiban PS⁷⁹	2018	Porphyromonas gingivalis (P. gingivalis), Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia (P. intermedia)	Pre-eclampsia	An association exists between P. gingivalis and P. intermedia with increased TLR-4 and NF-κB expression in the placenta of pre-eclamptic women with periodontitis.
22.	Radochova V et al ⁸⁰	2018	Streptococcus intermedius Fusobacterium nucleatum	Preterm prelabor rupture of membranes (PPROM)	Periopathogenic bacteria (2 × Streptococcus intermedius and 1 × Fusobacterium nucleatum) was found in the amniotic fluid of 4% (3/78) of women.
23.	Ye C et al⁸¹	2020	Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum, and Prevotella intermedia	Threatened preterm labor (TPL) and preterm low birth weight (PLBW)	Their findings suggested that all 6 bacteria may access the placenta. The increased presence of F. nucleatum in placenta might be related to TPL, while advanced maternal age might be associated with PLBW in TPL.
24.	Ye C et al⁸²	2020	Uncluturable bacteria- Eubacterium saphenum, Fretibacterium sp. human oral taxon (HOT) 360, TM7 sp. HOT 356, and Rothia dentocariosa Ccultivable bacteria- Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum and Prevotella intermedia.	Preterm low birth weight	Unculturable periodontitis-associated bacteria may play an important role both in the presence of periodontal inflammation during pregnancy and subsequent PLBW
25.	Ye C et al⁸³	2020	Porphyromonas gingivalis	Small for Gestational Age (SGA), Threatened preterm labour (TPL)	Lower anti-P. gingivalis IgG-1 amounts are related to TPL, while higher anti-P. gingivalis IgG and IgG-4 are related with SGA in TPL. Further, greater colonisation of P. gingivalis in plaque might increase the risk of SGA and can be useful in prediction of SGA in TPL.
26.	Ye C et al⁸⁴	2021	Neisseria	Preterm low birth weight (PLBW)	The low levels of oral commensal Neisseria have potential in the prediction of PLBW

F. nucleatum, a filamentous gram-negative anaerobe, however, is an oropulmonary pathogen that is infrequently found in the vaginal tract. Although associated with bacterial vaginosis, the organism is relatively uncommon compared to the frequencies of other species linked with the disease [41]. Strains of F. nucleatum identified in amniotic fluid, fetal membranes, cord blood, neonatal gastric aspirates, fetal lung and stomach suggests appear to match those from the maternal or the partner subgingival sites rather than lower genital tract [42][43]. During periodontal infections, the cell mass of F. nucleatum increases more than 10,000-fold. The frequency of F. nucleatum infection in amniotic fluid is approximately 10 to 30% in women in preterm labor with intact membranes and 10% in women with preterm premature rupture of membranes, in considerable excess compared to most other single species. The species of Fusobacterium most frequently isolated from the lower genital tract, F. naviforme and F. gonidiaformans, are rarely isolated from amniotic fluid cultures. These data suggest that F. nucleatum in the oral cavity may spread hematogenously to infect the pregnant uterus [41].

The reason why F. nucleatum is potentially capable of translocation to the feto-placental unit is in part due to its metabolic diversity and ability to invade endothelial and epithelial cells [42]. The causative role of F. nucleatum in pregnancy complications has been demonstrated in a mouse model. Injection of F. nucleatum into the tail vein (mimicking dental bacteremia) of pregnant mice led to preterm and term fetal loss within 72 hours. Rather than spreading systemically, F. nucleatum was found to be confined to the murine fetal-placental units, originating in the decidua basalis, followed by colonization in the placenta, fetal membranes, amniotic fluid and fetuses. This pattern parallels the pathophysiology of chorioamnionitis in humans, and demonstrates a clear hematogenous route of infection. The kinetics of this acute infection model corroborates with the afore-mentioned human stillbirth case. Control experiments of infection of pregnant mice with E. coli DH5a did not cause fetal loss, indicating the effect on pregnancy is species-specific [43].

It has been shown that F. nucleatum colonizes specifically in the placenta, causing Toll-like receptor 4-mediated localized inflammatory responses leading to preterm or term stillbirth without causing systemic infections. The pattern of infection and inflammation mimics that in humans. It was unclear, however, which virulence factors allowed the bacteria to colonize the placenta [44]. Researchers concluded that certain adhesion complexes like FadA and Fap2 may be critical to fusobacterium invasion of placental tissues [45]. FadA is uniquely encoded in F. nucleatum, absent in most other species of Fusobacterium. The strains detected in the vaginal tract mostly do not belong to the species of F. nucleatum, thus they do not possess FadA, which may be why the vaginal species such as F. gonadiaformans do not invade host cells [43].

Periodontitis in mice elevated fetal weight and the fetal weight/placental weight ratio. This study found that subsp. nucleatum migrated haematogenously to the placenta, leading to APO in mice. The study supports the potential role of Fn in the association between periodontitis and APO [42]

Porphyromonas gingivalis is a pathogenic bacterium associated with increased risk to periodontal breakdown, disease recurrence. There is emerging evidence that Pg may contribute to adverse pregnancy outcomes by directly invading maternal-fetal tissues. In this regard Leon R et al (2007) were the first to report the presence of P. gingivalis in the amniotic fluid of women with diagnosis of threatened premature labor [46]. Michelin MC et al (2014) evaluated the effects of Porphyromonas gingivalis infection before and at different gestation periods in infected wistar rats and concluded that the infection by P. gingivalis resulted in alterations in the gestational pattern and in fetal development. The consequences of infection at mid-gestation were more severe than at the beginning, possibly due to the induction of pro-inflammatory cytokines in the fetal compartment [47]. Vanterpool SF et al (2016) reviewed the research done on women with preeclampsia, they found that Pg detection rates within the uterine compartment ranges between 30 to 92%; with prevalence being highest in studies that sampled the decidua/placental basal plate. In rodents, monotypic infection of the utero-placental tissues produces fetal growth restriction, mild chorioamnionitis, endometrial arteritis, utero-placental thrombosis/hemorrhage with disruption of placental architecture, and increased production of pro-TH1 cytokines such as TNF-α, IFN-γ, IL-1, IL-12, and IL-17 in placental tissues [48]. Consistent with this hypothesis, Lin et al. recently reported that when the oral bacterium Porphyromonas gingivalis was disseminated systemically in pregnant mice, bacterial DNA was detected in the murine placentas associated with intrauterine growth restriction [41].

Bergeyella has become a “new” species associated with intrauterine infection. Han YW et al in 2006 using 16S rRNA-based culture-independent technology identified uncultivated Bergeyella strain from the oral cavity in the amniotic fluid in a case of preterm birth [49,50]. Unfortunately, the hospital laboratories still use routine culturing methods for bacterial identification. Thus, a significant portion of intrauterine infection may be underestimated. Interestingly, a significant portion of the translocated species are commensal or opportunistic commensal oral species, such as Campylobacter rectus, Capnocytophaga spp, Eikenella coorodens, Erysipelothrix, Peptostreptococcus micros, Leptotrichia, Neisseria, Parvimonas, Rothis dentocariosa, Prevotella intermedia, Prevotella nigrescens, Selenomonas, Streptococcu mutans, Tannerella forsythia, Treponema denticola and Veillonella. The recently identified uncultivated pathogenic group of TM7 was among the translocated species. This accumulating evidence indicates that oral bacteria, both cultivated and uncultivated, play a previously unrecognized role in intrauterine infection associated with adverse pregnancy outcome [51] [52].

Pathophysiological Mechanisms of Adverse Pregnancy Outcomes Related to Oral Pathogens

Several studies have attempted to demonstrate the connection between oral microbiome and the adverse pregnancy outcomes. There are two major pathways (figure 2) in biological mechanisms of APO related to oral pathogens defined by the consensus report from the joint European Federation of Periodontology/American Academy of Periodontology workshop on periodontitis and systematic diseases:

(a) Direct mechanisms—in oral diseases like gingivitis and periodontitis, the sub gingival biofilm is in close proximity with the highly inflamed gingival marginal tissues, where the epithelium is ulcerated and the underlying connective tissue is highly vascularized, what results in an easy portal of entry for bacterial species and their products (for example, lipopolysaccharide (LPS) or proteases) into the blood circulation (bacteraemia) and possible invasion of the placenta and amniotic cavity or they can invade fetal-placental unit in an ascending route via the genitourinary tract [53-57]

(b) Indirect mechanisms- promoted by inflammatory mediators produced in periodontal tissues, in response to the pathogens invasion. These mediators may directly affect the fetal-placental unit or circulate to the liver and increase the systemic inflammatory response, which could later affect the fetal-placental unit [54-56,58,59].
Alternatively, APO may be triggered through initial colonization by bacteria shared between oral and vaginal sites. If the latter is true than personal hygiene and sexual behavioral factors that may aid sharing of bacterial flora between oral and vaginal sites will be strongly associated with risk of PTB [60]. Dixon et al. had reported the isolation of Capnocytophaga sputigena and Fn from the amniotic cavity in a case of preterm birth with clinical chorioamnionitis; a temporal relation was noted between orogenital contact with a male partner with periodontitis and the onset of clinical infection. It has been also confirmed that oral sex is associated with gum disease and ulceration in the oral cavity Reciprocally, infection from the oral cavity can spread to the genital tract [10].

To elucidate these mechanisms, many researchers have been investigating the use of experimental animal models and in vitro models. Clinical and subclinical bacterial infection trigger a cascade of events that can lead to APO either when the bacteria directly ascend into the maternal uterine cavity and invade the fetal unit invoking a massive fetal inflammatory response and/or by triggering a proinflammatory maternal host response in the uterine tissues. These processes up regulate prostaglandin synthesis and culminate in the onset of myometrial contractility [60]. Moreover, infection/inflammation may cause placental structural changes leading to pre-eclampsia and impaired nutrient transport causing low birthweight. Foetal exposure may also result in tissue damage, increasing the risk for perinatal mortality/morbidity. Finally, the elicited systemic inflammatory response may exacerbate local inflammatory responses at the foeto-placental unit and further increase the risk for APOs [61].

Recent evidence suggests that periodontitis might have systemic consequences through the direct translocation of bacteria and/or bacterial substances and/or the local or distant increase of host inflammatory mediators and cytokines like C-reactive protein (CRP), prostaglandin E2(PGE2), matrix metalloproteinases, interleukin 1 (IL-1), IL-6, and tumour necrosis factor a (TNF-α). Toll-like receptors (TLRs) are pattern recognition receptors that play a key role in pregnancy maintenance, placental immune protection, and delivery initiation. Recently, abnormalities in decidual TLRs expression or function have been linked with preterm delivery and particularly to periodontal pathogens placental infection [9]. Experimental infection in various animal models confirms that invasion of the uterine compartment by P. gingivalis produces a diverse array of APO, including utero-placental pathology, enhanced expression of pro-T helper (TH)1 type cytokines (IFN-γ, IL-2, IL-12, and TNF-α), fetal growth restriction (FGR), and spontaneous preterm delivery. TH17 cells and IL-17 are reported to increase in periodontal lesions and exacerbate the P. gingivalis ligand-induced inflammatory process. More recently, it has been demonstrated that P. gingivalis favors T helper cell polarization to a TH17 profile with generation of TH17-related cytokines and that the P. gingivalis induced T cell differentiation shift is highly specific towards a TH17 cell phenotype in an IL-6 dependent manner. Moreover, a periodontitis rat model study showed a variable site-specific TH17/Treg cell ratio in the oral tissues but detected a TH17 cell increase with a relative Treg cell decrease in peripheral blood, which was proposed to potentially impact development of systemic inflammatory diseases [62]. Various studies have shown that an excess of TH17 with a reduced Treg cell profile can lead to APO [63].

A positive association between Gingival crevicular fluid (GCF) inflammatory mediators such as IL-1β, PGE2, TNF-α levels and APO might be present but the results need to be considered with great caution because of the heterogeneity and variability among the studies. Further studies with an adequate number of patients allowing for an appropriate analysis are warranted to definitely confirm this association [58,64].

The absence of the mother’s IgG antibody against organisms of the red complex is associated with an increased risk of premature birth of the baby. Mothers without a protective red complex IgG response coupled with foetal IgM response to orange complex molecules had the highest rate of prematurity. This evidence suggests the concept that prematurity in pregnant women maybe due to systemic dissemination of oral organisms that translocate to the foetus in the absence of protective maternal antibody response and trigger preterm babies [24].

Figure 2: Two major pathways explaining relationship between periodontal diseases and APO (a) direct- in which oral microorganisms and/or their components reach the foetal-placental unit and (b) indirect- in which Inflammatory mediators circulate and impact the foetal-placental unit. Adapted from Oral microbiome and pregnancy: A bidirectional relationship by Saadaoui M et al, 2021, J Reprod Immunol, 145:103293.

Conclusion

Humans, like all complex multicellular eukaryotes, are not autonomous organisms, but biological units that include numerous microbial symbionts and their genomes. The microbes in and on our bodies form a functional organ that is fundamental to our health and physiology. Recent studies also have shown that there are microbiologic and immunological findings that strongly support the association oral microbial diseases that can lead to placental-fetal exposure and can stimulate a foetal immune/inflammatory response characterized by the production of IgM antibodies against the pathogens and the secretion of elevated levels of inflammatory mediators, which in turn might result in adverse pregnancy outcome. Appropriate attention to oral health during pregnancy is found to reduce adverse pregnancy outcomes and its effect on maternal and newborn. Research universally supports the safety of dental treatment during pregnancy and confirms that maintaining good oral health prior to and during pregnancy is an important factor in achieving better overall health and well-being for women and their infants.

References

Parikh NI, Gonzalez JM, Anderson CAM et al. Adverse Pregnancy Outcomes and Cardiovascular Disease Risk: Unique Opportunities for Cardiovascular Disease Prevention in Women: A Scientific Statement from the American Heart Association. Circulation. 2021 May 4;143(18):e902-e916. doi: 10.1161/CIR.0000000000000961.
Jang H, Patoine A, Wu TT, Castillo DA, Xiao J. Oral microflora and pregnancy: a systematic review and meta-analysis. Sci Rep. 2021 Aug 19;11(1):16870. doi: 10.1038/s41598-021-96495-1
Rapone B, Ferrara E, Montemurro N et al. Oral Microbiome and Preterm Birth: Correlation or Coincidence? A Narrative Review. Open Access Maced J Med Sci [Internet]. 2020 Jul. 14 [cited 2021 Nov. 27];8(F):123-32. Available from: https://oamjms.eu/index.php/mjms/article/view/4444 https://doi.org/10.3889/oamjms.2020.4444e
Deo PN, Deshmukh R. Oral microbiome: Unveiling the fundamentals. J Oral Maxillofac Pathol. 2019 Jan-Apr;23(1):122-128. doi: 10.4103/jomfp.JOMFP_304_18.
Yang I, Hu YJ, Corwin EJ, Dunlop AL. Exploring the Maternal and Infant Oral Microbiomes: A Pilot Study. J Perinat Neonatal Nurs. 2020 Jul/Sep;34(3):211-221. doi: 10.1097/JPN.0000000000000494.
Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 2005 Nov;43(11):5721-32. doi: 10.1128/JCM.43.11.5721-5732.2005.
Cobb CM, Kelly PJ, Williams KB, Babbar S, Angolkar M, Derman RJ. The oral microbiome and adverse pregnancy outcomes. Int J Womens Health. 2017 Aug 8;9:551-559. doi: 10.2147/IJWH.S142730.
Foratori-Junior GA, Pereira PR, Gasparoto IA et al. Is overweight associated with periodontitis in pregnant women? Systematic review and meta-analysis. Japanese Dental Science Review. 2022;58: 41-5. https://doi.org/10.1016/j.jdsr.2022.01.001
Cetin I, Pileri P, Villa A, Calabrese S, Ottolenghi L, Abati S. Pathogenic mechanisms linking periodontal diseases with adverse pregnancy outcomes. Reprod Sci. 2012 Jun;19(6):633-41. doi: 10.1177/1933719111432871.
Saadaoui M, Singh P, Al Khodor S. Oral microbiome and pregnancy: A bidirectional relationship. J Reprod Immunol. 2021 Jun;145:103293. doi: 10.1016/j.jri.2021.103293
Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner AC, Yu WH, Lakshmanan A, Wade WG. The human oral microbiome. J Bacteriol. 2010 Oct;192(19):5002-17. doi: 10.1128/JB.00542-10. Epub 2010 Jul 23. PMID: 20656903; PMCID: PMC2944498.
Kilian M, Chapple IL, Hannig M etal. The oral microbiome - an update for oral healthcare professionals. Br Dent J. 2016 Nov 18;221(10):657-666. doi: 10.1038/sj.bdj.2016.865.
Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiology (Reading). 2003 Feb;149(Pt 2):279-294. doi: 10.1099/mic.0.26082-0.
Amir M, Brown JA, Rager SL, Sanidad KZ, Ananthanarayanan A, Zeng MY. Maternal Microbiome and Infections in Pregnancy. Microorganisms. 2020 Dec 15;8(12):1996. doi: 10.3390/microorganisms8121996.
Ref 82: Baker JL, Edlund A. Exploiting the Oral Microbiome to Prevent Tooth Decay: Has Evolution Already Provided the Best Tools? Front Microbiol. 2019 Jan 11;9:3323. doi: 10.3389/fmicb.2018.03323.
Lu M, Xuan S, Wang Z . Oral microbiota: A new view of body health. Food Science and Human Wellness 2019;8(1):8-15.
Sedghi L, Di-Massa V, Harrington A, Lynch SV, Kapila YL. The oral microbiome: Role of key organisms and complex networks in oral health and disease. Periodontology 2000. 2021;87:107–131.
Ye C, Kapila Y. Oral microbiome shifts during pregnancy and adverse pregnancy outcomes: Hormonal and Immunologic changes at play. Periodontol 2000. 2021 Oct;87(1):276-281. doi: 10.1111/prd.12386.
Balan P, Chong YS, Umashankar S, Swarup S, Loke WM, Lopez V, He HG, Seneviratne CJ. Keystone Species in Pregnancy Gingivitis: A Snapshot of Oral Microbiome During Pregnancy and Postpartum Period. Front Microbiol. 2018 Oct 9;9:2360. doi: 10.3389/fmicb.2018.02360.
Gare J, Kanoute A, Meda N, Viennot S, Bourgeois D, Carrouel F. Periodontal Conditions and Pathogens Associated with Pre-Eclampsia: A Scoping Review. Int J Environ Res Public Health. 2021 Jul 5;18(13):7194. doi: 10.3390/ijerph18137194.
Lin D, Moss K, Beck JD, Hefti A, Offenbacher S. Persistently high levels of periodontal pathogens associated with preterm pregnancy outcome. J Periodontol. 2007 May;78(5):833-41. doi: 10.1902/jop.2007.060201.
Lamont RJ, Koo H, Hajishengallis G. The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol. 2018 Dec;16(12):745-759. doi: 10.1038/s41579-018-0089-x.
Yenen Z, Ataçag T. Oral care in pregnancy. J Turk Ger Gynecol Assoc. 2019 Nov 28;20(4):264-268. doi: 10.4274/jtgga.galenos.2018.2018.0139.
Suragimath G. Periodontal Disease and Pregnancy Outcome. In: Ostwani AEOA., editor. Gingival Disease - A Professional Approach for Treatment and Prevention [Internet]. London: IntechOpen; 2019 [cited 2022 Mar 03]. Available from: https://www.intechopen.com/chapters/66202 doi: 10.5772/intechopen.84949.
Ferrillo M, Migliario M, Roccuzzo A et al. Periodontal Disease and Vitamin D Deficiency in Pregnant Women: Which Correlation with Preterm and Low-Weight Birth? J Clin Med. 2021 Oct 2;10(19):4578. doi: 10.3390/jcm10194578.
Thomas C, Minty M, Vinel A et al. Oral Microbiota: A Major Player in the Diagnosis of Systemic Diseases. Diagnostics (Basel). 2021 Jul 30;11(8):1376. doi: 10.3390/diagnostics11081376.
Sivapathasundharam B, Raghu AR. Dental Cries. In R Rajendran, Sivapathasundharam B, editors. Shafer's Textbook of Oral Pathology. 7th ed. New Delhi: Elsevier/Reed Elsevier, 2009. p. 419-474.
Sekundo C, Langowski E, Wolff D, Boutin S, Frese C. Maintaining oral health for a hundred years and more? - An analysis of microbial and salivary factors in a cohort of centenarians. J Oral Microbiol. 2022 Apr 4;14(1):2059891. doi: 10.1080/20002297.2022.2059891.
Takahashi N. Oral Microbiome Metabolism: From "Who Are They?" to "What Are They Doing?". J Dent Res. 2015 Dec;94(12):1628-37. doi: 10.1177/0022034515606045.
Usha CRS. Dental caries - A complete changeover (Part I). J Conserv Dent. 2009 Apr;12(2):46-54. doi: 10.4103/0972-0707.55617.
Rathee M, Sapra A. Dental Caries. [Updated 2021 Oct 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551699/
Silk H, Douglass AB, Douglass JM and Silk L. Oral Health During Pregnancy. Am Fam Physician. 2008 Apr 15;77(8):1139-1144.
Wagle M, D'Antonio F, Reierth E, Basnet P, Trovik TA, Orsini G, Manzoli L, Acharya G. Dental caries and preterm birth: a systematic review and meta-analysis. BMJ Open. 2018 Mar 2;8(3):e018556. doi: 10.1136/bmjopen-2017-018556.
Cho GJ, Kim Sy, Lee HC. Association between dental caries and adverse pregnancy outcomes. Sci Rep 2020;10(1):5309. https://doi.org/10.1038/s41598-020-62306-2.
Erchick DJ, Khatry SK, Agrawal NK, Katz J, LeClerq SC, Rai B, Reynolds MA, Mullany LC. Risk of preterm birth associated with maternal gingival inflammation and oral hygiene behaviours in rural Nepal: a community-based, prospective cohort study. BMJ Open. 2020 Aug 20;10(8):e036515. doi: 10.1136/bmjopen-2019-036515.
Baskaradoss JK, Geevarghese A, Al Dosari AA. Causes of adverse pregnancy outcomes and the role of maternal periodontal status - a review of the literature. Open Dent J. 2012;6:79-84. doi: 10.2174/1874210601206010079.
Pockpa ZAD, Soueidan A, Koffi-Coulibaly NT, Limam A, Badran Z, Struillou X. Periodontal Diseases and Adverse Pregnancy Outcomes: Review of Two Decades of Clinical Research. Oral Health Prev Dent. 2021;19(1):77-83. doi: 10.3290/j.ohpd.b898969..
Dasanayake AP, Li Y, Wiener H, Ruby JD, Lee MJ. Salivary Actinomyces naeslundii genospecies 2 and Lactobacillus casei levels predict pregnancy outcomes. J Periodontol. 2005 Feb;76(2):171-7. doi: 10.1902/jop.2005.76.2.171.
Durand R, Gunselman EL, Hodges JS, Diangelis AJ, Michalowicz BS. A pilot study of the association between cariogenic oral bacteria and preterm birth. Oral Dis. 2009 Sep;15(6):400-6. doi: 10.1111/j.1601-0825.2009.01559.x.
Orloff NC, Flammer A, Hartnett J, Liqurrman S, Samelson R, Hormes JM. Food cravings in pregnancy: Preliminary evidence for a role in excess gestational weight gain. Appetite October 2016;105(1):259-265
Han YW, Redline RW, Li M, Yin L, Hill GB, McCormick TS. Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice: implication of oral bacteria in preterm birth. Infect Immun. 2004 Apr;72(4):2272-9. doi: 10.1128/IAI.72.4.2272-2279.2004.
Stockham S, Stamford JE, Roberts CT, Fitzsimmons TR, Marchant C, Bartold PM, et al. Abnormal Pregnancy Outcomes in Mice Using an Induced Periodontitis Model and the Haematogenous Migration of Fusobacterium nucleatum Sub-Species to the Murine Placenta. PLoS ONE 2015;10(3): e0120050. https://doi.org/10.1371/journal.pone.0120050
Vander Haar EL, So J, Gyamfi-Bannerman C, Han YW. Fusobacterium nucleatum and adverse pregnancy outcomes: Epidemiological and mechanistic evidence. Anaerobe. 2018 Apr;50:55-59. doi: 10.1016/j.anaerobe.2018.01.008.
Ikegami A, Chung P, and Han YW. Complementation of the fadA Mutation in Fusobacterium nucleatum Demonstrates that the Surface-Exposed Adhesin Promotes Cellular Invasion and Placental Colonization. Infection and Immunity. 2009;77(7):3075-3079. https://doi.org/10.1128/IAI.00209-09
Fischer LA, Demerath E, Bittner-Eddy P, Costalonga M. Placental colonization with periodontal pathogens: the potential missing link. Am J Obstet Gynecol. 2019 Nov;221(5):383-392.e3. doi: 10.1016/j.ajog.2019.04.029.
León R, Silva N, Ovalle A, Chaparro A, Ahumada A, Gajardo M, Martinez M, Gamonal J. Detection of Porphyromonas gingivalis in the amniotic fluid in pregnant women with a diagnosis of threatened premature labor. J Periodontol. 2007 Jul;78(7):1249-55. doi: 10.1902/jop.2007.060368.
Michelin MC, Teixeira SR, Ando-Suguimoto ES, Lucas SR, Mayer MP. Porphyromonas gingivalis infection at different gestation periods on fetus development and cytokines profile. Oral Dis. 2012 Oct;18(7):648-54. doi: 10.1111/j.1601-0825.2012.01917.x
Vanterpool SF, Been JV, Houben ML et al. Porphyromonas gingivalis within Placental Villous Mesenchyme and Umbilical Cord Stroma Is Associated with Adverse Pregnancy Outcome. PLoS One. 2016 Jan 5;11(1):e0146157. doi: 10.1371/journal.pone.0146157
Han YW, Ikegami A, Bissada NF, Herbst M, Redline RW, Ashmead GG. Transmission of an Uncultivated Bergeyella Strain from the Oral Cavity to Amniotic Fluid in a Case of Preterm Birth. J Clin Microbiol. 2006 Apr; 44(4): 1475–1483. doi: 10.1128/JCM.44.4.1475-1483.2006.
Han YW, Shen T, Chung P, Buhimschi IA, Buhimschi CS. Uncultivated Bacteria as Etiologic Agents of Intra-Amniotic Inflammation Leading to Preterm Birth. J Clin Microbiol. 2009 Jan; 47(1): 38–47. doi: 10.1128/JCM.01206-08.
Han YW, Wang X. Mobile microbiome: oral bacteria in extra-oral infections and inflammation. J Dent Res. 2013 Jun;92(6):485-91. doi: 10.1177/0022034513487559.
Han YW. Oral health and adverse pregnancy outcomes - what's next? J Dent Res. 2011 Mar;90(3):289-93. doi: 10.1177/0022034510381905.
Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 2021;21:426–440 https://doi.org/10.1038/s41577-020-00488-6
Marín MJ, Figuero E, González I, O'Connor A, Diz P, Álvarez M, Herrera D, Sanz M. Comparison of the detection of periodontal pathogens in bacteraemia after tooth brushing by culture and molecular techniques. Med Oral Patol Oral Cir Bucal. 2016 May 1;21(3):e276-84. doi: 10.4317/medoral.20842.
Sanz M, Kornman K; working group 3 of the joint EFP/AAP workshop. Periodontitis and adverse pregnancy outcomes: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Periodontol. 2013 Apr;84(4 Suppl):S164-9. doi: 10.1902/jop.2013.1340016.
Terzic M, Aimagambetova G, Terzic S, Radunovic M, Bapayeva G, Laganà AS. Periodontal Pathogens and Preterm Birth: Current Knowledge and Further Interventions. Pathogens. 2021 Jun 9;10(6):730. doi: 10.3390/pathogens10060730.
Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014 May 21;6(237):237ra65. doi: 10.1126/scitranslmed.3008599.
Komine-Aizawa S, Aizawa S, Hayakawa S. Periodontal diseases and adverse pregnancy outcomes. J Obstet Gynaecol Res. 2019 Jan;45(1):5-12. doi: 10.1111/jog.13782.
Mohr S, Amylidi-Mohr SK, Stadelmann P et al. Systemic Inflammation in Pregnant Women With Periodontitis and Preterm Prelabor Rupture of Membranes: A Prospective Case-Control Study. Front. Immunol. 2019 07 November https://doi.org/10.3389/fimmu.2019.02624
Srinivasan U, Misra D, Marazita ML, Foxman B. Vaginal and oral microbes, host genotype and preterm birth. Med Hypotheses. 2009 Dec;73(6):963-75. doi: 10.1016/j.mehy.2009.06.017.
Madianos PN, Bobetsis YA, Offenbacher S. Adverse pregnancy outcomes (APOs) and periodontal disease: pathogenic mechanisms. J Periodontol. 2013 Apr;84(4 Suppl):S170-80. doi: 10.1902/jop.2013.1340015.
Reyes L, Phillips P, Wolfe B et al. Porphyromonas gingivalis and adverse pregnancy outcome. J Oral Microbiol. 2017 Sep 13;10(1):1374153. doi: 10.1080/20002297.2017.1374153.
Figueiredo AS, Schumacher A. The T helper type 17/regulatory T cell paradigm in pregnancy. Immunology. 2016 May;148(1):13-21. doi: 10.1111/imm.12595. Erratum in: Immunology. 2019 Feb;156(2):213.
Stadelmann P, Alessandri R, Sigrun E, Salvi GE, Surbek D, Sculean A. The potential association between gingival crevicular fluid inflammatory mediators and adverse pregnancy outcomes: a systematic review. Clin Oral Investig. 2013 Jul;17(6):1453-63. doi: 10.1007/s00784-013-0952-0.
Barak S, Oettinger-Barak O, Machtei EE, Sprecher H, Ohel G. Evidence of periopathogenic microorganisms in placentas of women with preeclampsia. J Periodontol. 2007 Apr;78(4):670-6. doi: 10.1902/jop.2007.060362.
Katz J, Chegini N, Shiverick KT, Lamont RJ. Localization of P. gingivalis in preterm delivery placenta. J Dent Res. 2009 Jun;88(6):575-8. doi: 10.1177/0022034509338032.
Han YW, Fardini Y, Chen C et al. Term stillbirth caused by oral Fusobacterium nucleatum. Obstet Gynecol. 2010 Feb;115(2 Pt 2):442-445. doi: 10.1097/AOG.0b013e3181cb9955.
Gauthier S, Tétu A, Himaya E, Morand M, Chandad F, Rallu F, Bujold E. The origin of Fusobacterium nucleatum involved in intra-amniotic infection and preterm birth. J Matern Fetal Neonatal Med. 2011 Nov;24(11):1329-32. doi: 10.3109/14767058.2010.550977.
Bohrer JC, Kamemoto LE, Almeida PG and Ogasawara KK. Acute Chorioamnionitis at Term Caused by the Oral Pathogen Fusobacterium Nucleatum. Hawaii J Med Public Health. 2012 Oct; 71(10): 280–281.
Hirano E, Sugita N, Kikuchi A et al. The association of Aggregatibacter actinomycetemcomitans with preeclampsia in a subset of Japanese pregnant women. J Clin Periodontol. 2012 Mar;39(3):229-38. doi: 10.1111/j.1600-051x.2011.01845.x
Swati P, Ambika Devi K, Thomas B, Vahab SA, Kapaettu S, Kushtagi P. Simultaneous detection of periodontal pathogens in subgingival plaque and placenta of women with hypertension in pregnancy. Arch Gynecol Obstet. 2012 Mar;285(3):613-9. doi: 10.1007/s00404-011-2012-9. Erratum in: Arch Gynecol Obstet. 2018 Jan 22.
Chaparro A, Blanlot C, Ramírez V et al. Porphyromonas gingivalis, Treponema denticola and toll-like receptor 2 are associated with hypertensive disorders in placental tissue: a case-control study. J Periodontal Res. 2013 Dec;48(6):802-9. doi: 10.1111/jre.12074.
Ercan E, Eratalay K, Deren O et al. Evaluation of periodontal pathogens in amniotic fluid and the role of periodontal disease in pre-term birth and low birth weight. Acta Odontol Scand. 2013 May-Jul;71(3-4):553-9. doi: 10.3109/00016357.2012.697576.
Gonzales-Marin C, Spratt DA, Allaker RP. Maternal oral origin of Fusobacterium nucleatum in adverse pregnancy outcomes as determined using the 16S-23S rRNA gene intergenic transcribed spacer region. J Med Microbiol. 2013 Jan;62(Pt 1):133-144. doi: 10.1099/jmm.0.049452-0.
Wang X, Buhimschi CS, Temoin S, Bhandari V, Han YW, Buhimschi IA. Comparative microbial analysis of paired amniotic fluid and cord blood from pregnancies complicated by preterm birth and early-onset neonatal sepsis. PLoS One. 2013;8(2):e56131. doi: 10.1371/journal.pone.0056131
Andonova I, Iliev V, Živkovic N, Sušic E, Bego I, Kotevska V. Can oral anaerobic bacteria cause adverse pregnancy outcomes? Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2015;36(1):137-43.
Amarasekara R, Jayasekara RW, Senanayake H, Dissanayake VH. Microbiome of the placenta in pre-eclampsia supports the role of bacteria in the multifactorial cause of pre-eclampsia. J Obstet Gynaecol Res. 2015 May;41(5):662-9. doi: 10.1111/jog.12619.
Usin MM, Menso J, Rodríguez V et al. Association between maternal periodontitis and preterm and/or low birth weight infants in normal pregnancies, The Journal of Maternal-Fetal & Neonatal Medicine. 2016;29:1:115-119. DOI: 10.3109/14767058.2014.987751
Parthiban PS, Mahendra J, Logaranjani A, Shanmugam S, Balakrishnan A, Junaid M, Namasivayam A. Association between specific periodontal pathogens, Toll-like receptor-4, and nuclear factor-?B expression in placental tissues of pre-eclamptic women with periodontitis. J Investig Clin Dent. 2018 Feb;9(1). doi: 10.1111/jicd.12265.
Radochova V, Kacerovska Musilova I, Stepan M, Vescicik P, Slezak R, Jacobsson B, Kacerovsky M. Periodontal disease and intra-amniotic complications in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2018 Nov;31(21):2852-2861. doi: 10.1080/14767058.2017.1358265.
Ye C, Katagiri S, Miyasaka N, Kobayashi H, Khemwong T, Nagasawa T, Izumi Y. The periodontopathic bacteria in placenta, saliva and subgingival plaque of threatened preterm labor and preterm low birth weight cases: a longitudinal study in Japanese pregnant women. Clin Oral Investig. 2020 Dec;24(12):4261-4270. doi: 10.1007/s00784-020-03287-4.
Ye C, Xia Z, Tang J et al. Unculturable and culturable periodontal-related bacteria are associated with periodontal inflammation during pregnancy and with preterm low birth weight delivery. Sci Rep. 2020 Sep 25;10(1):15807. doi: 10.1038/s41598-020-72807-9.
Ye C, Kobayashi H, Katagiri S, Miyasaka N, Takeuchi Y, Kuraji R, Izumi Y. The relationship between the anti-Porphyromonas gingivalis immunoglobulin G subclass antibody and small for gestational age delivery: a longitudinal study in pregnant Japanese women. Int Dent J. 2020 Aug;70(4):296-302. doi: 10.1111/idj.12548.
Ye C, You M, Huang P, Xia Z, Radaic A, Tang J, Wu W, Wu Y, Kapila Y. Clinical study showing a lower abundance of Neisseria in the oral microbiome aligns with low-birth-weight pregnancy outcomes. Clin Oral Investig. 2021 Oct 8. doi: 10.1007/s00784-021-04214-x