children

Review
Maternal Infection and Preterm Birth: From Molecular Basis to
Clinical Implications
George Daskalakis 1 , Alexandros Psarris 1 , Antonios Koutras 1 , Zacharias Fasoulakis 1 ,
Ioannis Prokopakis 1 , Antonia Varthaliti 1 , Christina Karasmani 1 , Thomas Ntounis 1 , Ekaterini Domali 1 ,
Marianna Theodora 1 , Panos Antsaklis 1 , Kalliopi I. Pappa 1 and Angeliki Papapanagiotou 2, *

1 First Department of Obstetrics and Gynecology, ‘Alexandra’ Hospital, Medical School, National and
Kapodistrian University of Athens, 157 72 Athens, Greece; [email protected] (G.D.);
[email protected] (A.P.); [email protected] (A.K.); [email protected] (Z.F.);
[email protected] (I.P.); [email protected] (A.V.); [email protected] (C.K.);
[email protected] (T.N.); [email protected] (E.D.); [email protected] (M.T.);
[email protected] (P.A.); [email protected] (K.I.P.)
2 Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens,
157 72 Athens, Greece
* Correspondence: [email protected]

Abstract: As the leading cause of neonatal morbidity and mortality, preterm birth is recognized
as a major public health concern around the world. The purpose of this review is to analyze the
connection between infections and premature birth. Spontaneous preterm birth is commonly associ-
ated with intrauterine infection/inflammation. The overproduction of prostaglandins caused by the
inflammation associated with an infection could lead to uterine contractions, contributing to preterm
delivery. Many pathogens, particularly Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas
vaginalis, Gardnerella vaginalis, Ureaplasma urealyticum, Mycoplasma hominis, Actinomyces, Candida spp.,
and Streptococcus spp. have been related with premature delivery, chorioamnionitis, and sepsis of
the neonate. Further research regarding the prevention of preterm delivery is required in order to
develop effective preventive methods with the aim of reducing neonatal morbidity.
Citation: Daskalakis, G.; Psarris, A.;
Koutras, A.; Fasoulakis, Z.;
Keywords: preterm birth; prematurity; infection; inflammation
Prokopakis, I.; Varthaliti, A.;
Karasmani, C.; Ntounis, T.; Domali,
E.; Theodora, M.; et al. Maternal
Infection and Preterm Birth: From
Molecular Basis to Clinical 1. Introduction
Implications. Children 2023, 10, 907. Preterm birth (PTB), defined as birth prior to 37 weeks’ gestation, is the main cause
https://doi.org/10.3390/ of neonatal death, as 27% of neonatal mortality is related to complications of PTB [1].
children10050907 According to the World Health Organization, the global annual burden of PTB is estimated
Academic Editor: Shmuel Arnon to be 15 million [2]. The incidence of PTB has been calculated at 12.7 % in the United States
of America, while other developed countries such as Sweden, Japan, Australia, and New
Received: 7 April 2023 Zealand have PTB rates between 4.4 and 8.2% [3–5]. Regional variations are similarly clear
Revised: 13 May 2023
in the European Union, where preterm birth rates range between 5 and 10% [6]. According
Accepted: 16 May 2023
to the most recent data from the Hellenic Statistical Authority (ELSTAT), the number of
Published: 22 May 2023
preterm births in Greece increased to 12,831 (11.18%) in 2010 [7]. At the same time, data
suggest that prematurity is higher in the non-Hispanic Black population (16.75% compared
with 10.49% for the non-Hispanic White population) [8]. Prematurity is a major cause of
Copyright: © 2023 by the authors.
infant mortality, while sequelae due to preterm birth are usual in the neonatal period and
Licensee MDPI, Basel, Switzerland. may remain into adulthood [9].
This article is an open access article Preeclampsia or intrauterine growth restriction are common reasons for iatrogenic
distributed under the terms and PTB [10,11], while multiple causes such as immunological disorders, infection/inflammation,
conditions of the Creative Commons uterine overdistension, and vascular disease are considered responsible for spontaneous
Attribution (CC BY) license (https:// preterm births [12]. In addition, periodontal disease, uteroplacental ischemia and hemorrhage,
creativecommons.org/licenses/by/ shortened cervical length, polyhydramnios, multiple gestation, poor maternal nutritional
4.0/). status, and racial disparity are other risk factors for PTB [12–18].

Children 2023, 10, 907. https://doi.org/10.3390/children10050907 https://www.mdpi.com/journal/children

Children 2023, 10, 907 2 of 17

A significant percentage of PTB, ranging between 25 and 40%, has been attributed to
infections, both overt and subclinical [12]. Sometimes, it is unclear whether the infections
are a cause of PTB or part of the processes resulting in PTB. However, both microbiological
and biochemical data suggest that an important percentage of preterm deliveries can be
attributed to both infections and the inflammation caused by infections. Firstly, the higher
levels of inflammatory cytokines found in the amniotic fluid of patients with preterm
labor are a clear indicator [19]. Secondly, the microbial colonization of women with PTB
has been shown to differ between women not in labor and women laboring at term [19].
According to in vitro studies, prostaglandin E2 levels are raised after amnion cells are
exposed to bacterial products [20]. Furthermore, the administration of microbes or microbial
products to pregnant animals has resulted in preterm labor [21,22]. Concurrently, subclinical
uterine infections have also been related to PTB [23]. In other studies, the presence of an
intra-amniotic infection or intrauterine inflammation during the second trimester has
been shown to increase the risk for PTB [24]. Lastly, premature parturition has been
associated with extrauterine maternal infections such as periodontal disease, pneumonia,
and pyelonephritis [25–27].
In many cases, spontaneous preterm labor is a syndrome attributable to multifactorial
inflammatory mechanisms. These inflammatory processes may lead to preterm prema-
ture rupture of membranes (PPROM). Positive amniotic fluid cultures and histological
chorioamnionitis are more common in PPROM patients than in normal controls [28,29].
The purpose of this article is to review what is currently known about maternal
infections and their impact on pregnancy outcomes.

2. Inflammation in Labor and Preterm Labor

Numerous studies on preterm birth have shown that term and preterm labor share
the same underlying process, with the only distinction being the gestational age at which
labor begins. It is thought that both conditions share a common pathway. The pathological
processes that lead to preterm labor involve the activation of one or more components of
this common pathway, such as the increased production of prostaglandins and proteases in
the genital tract; the functional withdrawal of progesterone due to a decreased expression of
progesterone receptor (PR) isoforms in the cervix, decidua, and myometrium; and changes
in hormone concentrations such as corticotropin-releasing factor (CRF) and cortisol [30–32].
Preterm birth has also been linked to maternal and fetal stress. Corticotropin-releasing
hormone (CRH) seems to be the mediator of preterm births caused by stress. During preg-
nancy, the hypothalamus and placental, chorionic, amniotic, and decidual cells all produce
the peptide hormone CRH, which is composed of 41 amino acids. Both maternal and fetal
stress can elevate CRH levels, resulting in increased cortisol levels in both the mother and
the fetus. By upregulating the expression of cyclooxygenase-2 (COX-2) and inhibiting
prostaglandin dehydrogenase (PGDH), elevated cortisol levels may increase the release
of prostaglandins (PGs) by the fetal membranes. In addition, prostaglandins promote
cervical changes and PPROM by increasing the expression of matrix metalloproteinases
(MMPs) in the genital tract, increasing the gap junction between uterine cells, promoting the
formation of myometrial oxytocin receptors, and suppressing myometrial PR expression.
PGs also increase the cervical expression of interleukin-8 (IL-8), causing neutrophils to
release additional MMPs and elastases [33–36]. MMPs degrade and decompose collagen,
with their activity increasing in the fetal membranes during PPROM and labor.
Inflammation can be considered a regulative mechanism by which the tissues respond
to injurious stimuli in order to control and repair possible damage. Whether arising from
periodontitis, pneumonia, cholecystitis, pyelonephritis, pancreatitis, sepsis, or genital tract
inflammatory states such as bacterial vaginosis, deciduitis, chorioamnionitis, or intra-
amniotic infections, it has been associated with preterm birth (PTB) [37,38]. This is because
inflammation induces an exaggerated immune response that increases the production of
inflammatory cytokines, elastases, and MMPs (matrix metalloproteinases) and induces
the functional withdrawal of progesterone, a vital hormone for maintaining pregnancy. In
Children 2023, 10, 907 3 of 17

pregnancy, the inflammatory response can be deemed a theoretical model in which the
infected cavity evacuates any products that put at risk the health of the mother, so that the
reproductive capacity is preserved for the future.
Genetic predispositions to inflammation, including specific gene polymorphisms
such as the TNF-a gene T2 allele, which increases the risk of preterm premature rupture
of membranes (PPROM) in African American women, or polymorphisms in TLR-4 (a
significant endotoxin-signaling receptor), have also been linked to PTB. Polymorphisms
in drug-metabolizing genes such CYP1A1, HincII RFLP, and GSTT1 have been linked to
PTB in Chinese women who were exposed to benzene and in American women subjected
to cigarette smoke. African American fetuses at risk for PPROM carry mutations in the
MMP-1 and MMP-9 genes [39–42].
Bacteria are found in the fetal circulation in 30% of incidents of intra-amniotic infection,
leading to a systemic inflammatory response in the fetus. Due to the immaturity of
multiple organ systems, these fetuses are at risk for long-term complications, inversely
correlated with the gestation age, such as cerebral palsy and respiratory and gastrointestinal
complications, underlining that it is not only the immaturity that is responsible for the
complications of infants born preterm but also the inflammatory process [43,44].
Microorganisms, including those of the lower genital tract, have been isolated from
amniotic fluid, suggesting that the most common route of infection is an ascending one. [45].
Bacteria linked to periodontal disease have been detected in amniotic fluid, suggesting the
possibility of hematogenous dispersion with transplacental passage [46]. Preterm birth has
also been linked to infections, which has been linked to invasive medical operations [47].
Human parturition is an inflammatory process. An alteration from an inactive to a
pro-inflammatory environment signals the initiation of labor, which is characterized by
three steps: uterine contractility, cervical ripening, and membrane activation and rupture. It
is believed that the beginning of term labor is the result of processes like progesterone with-
drawal, oxytocin secretion, decidual triggering, and activation of the fetal immunological
response [12].
Several hypotheses have been developed on the association between spontaneous
preterm labor and infection. Most likely pathways for infection-induced PTB include
decidual stimulation and the fetal immunological response, both of which are triggered by
the innate immune system0 s reaction to infection. [17]. Microorganisms and their products
that reach the amniotic cavity are sensed by transmembrane pattern recognition receptors
(PRR), such as acute phase receptors and toll-like receptors (TLRs), which are bound to
patterns of molecular structures on the surface of the microorganisms. There are 11 distinct
TLRs found in humans, and they all have a role in controlling inflammation. [48]. TLR-4
has a role in the immune response to lipopolysaccharides (LPS) and the byproducts of
Gram-positive bacteria, mycoplasmas, and yeast [49]. It has been established that PTB
is linked to increased expression of TLR-2 and TLR-4 in the chorioamniotic membranes,
both of which have been identified in the amniotic epithelium [50]. TLR ligation induces
the synthesis of cytokines (IL-1b, IL-6, TNF-a, granulo-cyte colony-stimulating factor, or
tumor necrosis factor-a) and chemokines (IL-8, MCP-1) by activating nuclear factor kappa
B and other kinases inside the cell [48,51]. These substances promote both the stimulation
of neutrophils and the production of prostaglandins, trigger the uterine contractions,
and induce the metalloproteinase-induced membrane damage in PPROM and PTB [14].
Experimental evidence suggests that TLRs play a vital role in the genesis of spontaneous
preterm labor (SPTL), and defective signaling through TLRs weakens defenses against PTB
caused by bacteria [52].
Moreover, a fetal response takes place as the infection promotes the release of
corticotropin-releasing hormone and subsequently the release of fetal corticotropin
and fetal cortisol from both the placenta and the fetal hypothalamus, resulting in
prostaglandin production [18]. In inflammation- or infection-induced preterm delivery,
both pro- and anti-inflammatory cytokines play critical roles [16]. When an infection
causes premature labor, IL-1 is the first cytokine to be involved. By increasing the syn-
Children 2023, 10, 907 4 of 17

thesis and activity of COX-2, which increases myometrial contractions, it is released by

stimulated monocytes and macrophages [52].
IL-6, IL-16, IL-18, colony-stimulating factors, IL-8, and monocyte chemotactic protein-1
are all pro-inflammatory cytokines thought to play a role in the development of PTB. In
addition, Gram-positive bacterial infections trigger death of tropho-blast cells by activating
Toll-like receptors 1 and 2. Apoptosis is induced in neutrophils and T cells after they
have been stimulated to undergo chemotaxis and activation by IL-6 and IL-8 secreted by
trophoblast cells. This could be a fundamental process underlying SPTL. IL-10, an anti-
inflammatory cytokine, is found to be reduced in the placenta in term patients, suggesting
that its downregulation during labor induces the inflammatory process that is necessary
for parturition. Inhibiting IL-12 and IFN-g production, as well as the stimulation of T cells,
monocytes, and macrophages, IL-10 exerts powerful immunosuppressive activity, making
it essential for pregnancy maintenance [52,53]. Moreover, IL-4 downregulation promotes
spontaneous abortion and preterm birth [54]. Nuclear factor-B (NF-B) is regulated by and
activates pro-inflammatory cytokines. It has a crucial role in the processes associated with
labor. Abnormal activation of NF-B contributes to the initiation of PTL, as it is important
for the production of prostaglandins and MMP expression, and subsequently, for the
stimulation of uterine contractions and cervical ripening [55].
Choriodecidual space infections, amnion infections, chorion infections, placenta in-
fections, amniotic fluid infections, umbilical cord infections, and fetal infections are all
possible during pregnancy [14].
Chorioamnionitis is an inflammation of the amniotic sac and placenta caused by an
infection of the fetus. It often takes years for symptoms of many infections to manifest.
Histological chorioamnionitis is frequently linked to preterm births before 30 weeks of
gestation in about 50% of cases [56]. Histopathology is the gold standard for confirming
intrauterine infections, however clinical, biochemical, and microbiological parameters have
also been used. However, not enough research has been done to fully understand how the
immune system reacts to various infections during chorioamnionitis.
PTB risk factors also include vaginal bleeding, placental abruption, decidual hem-
orrhage, and other vasculopathies. Decidua, the uterine lining during pregnancy, is an
abundant source of tissue factor, and decidual hemorrhage results in an increased produc-
tion of thrombin, which binds to its proteinase-activated receptor, resulting in an increased
expression of MMP-1 and mRNA in the decidual cells. Decidual neutrophils, which are
frequently found in regions of thrombin-induced fibrin deposition and thrombin/PAR-1,
promote the expression of IL-8, mRNA, and inflammatory proteins. Neutrophils are also an
abundant source of elastases and MMP-9, which can cause premature membrane rupture
(PROM) and cervical effacement [57–59].
Mechanical extension of the uterus, such as mechanical dilation of the cervix, has also
been linked to an increased risk of PTB because it induces the expression of prostaglandins
and MMP-1. Other factors, such as polyhydramnios (excessive amniotic fluid) and multi-
fetal gestation, can also enhance the expression of the inflammatory enzyme COX-2. The
expression of oxytocin receptor, COX-2, IL-8, and connexin is induced by myometrial
stretch, which is the elongation of the uterine muscle layer [60].
Various modalities have been employed to prevent preterm birth, and these modalities
are frequently incorporated into the biochemical processes implicated in preterm birth.
Antibiotics have been used, for instance, to treat maternal infections, thereby reducing
the inflammatory response and the risk of preterm birth. Tita et al. discovered, through
a systematic review and meta-analysis, that antibiotics given to expectant women with
bacterial vaginosis, asymptomatic bacteriuria, or group B Streptococcus colonization were
associated with a significant reduction in preterm birth [15].
Progesterone supplementation has also been shown to prevent preterm birth, par-
ticularly in women with a history of spontaneous preterm birth or a short cervix [61].
Progesterone has anti-inflammatory properties and can aid in the maintenance of uter-
ine quiescence, thereby preventing cervical maturation and the uterine contractions that
 bacterial vaginosis, asymptomatic bacteriuria, or group B Streptococcus colonization were
associated with a significant reduction in preterm birth [15].
Progesterone supplementation has also been shown to prevent preterm birth, partic-
Children 2023, 10, 907
ularly in women with a history of spontaneous preterm birth or a short cervix [61]. Pro-
5 of 17

gesterone has anti-inflammatory properties and can aid in the maintenance of uterine qui-
escence, thereby preventing cervical maturation and the uterine contractions that occur
prematurely
occur prematurely[62]. In a meta-analysis,
[62]. RomeroRomero
In a meta-analysis, et al. revealed
et al. that women
revealed who
that already
women whohad
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benefited progesterone supplementa-
from progesterone
tion [63].
supplementation [63].
Cervicalcerclage
Cervical cerclagehas hasbeen
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utilizedasasa apreventive
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women
with cervical insufficiency to reinforce the cervical integrity and prevent premature cervi-
with cervical insufficiency to reinforce the cervical integrity and prevent premature cervical
cal dilation
dilation [64]. Berghella
[64]. Berghella et al. et al. showed
showed in a meta-analysis
in a meta-analysis and comprehensive
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that
that women
women with cervical
with cervical insufficiency
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who receive cervicalcervical
cerclagecerclage have lower
have a much a much lower
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risk ofahaving
having a premature
premature baby [65]. baby [65].preventive
Other Other preventive modalities,
modalities, includingincluding
cervicalcervical
pessariespes-
saries
and and lifestyle
lifestyle interventions,
interventions, have alsohavebeenalso been investigated
investigated as potential as potential interventions
interventions to preventto
prevent preterm birth [66].
preterm birth [66].
InInaddition,
addition,recent
recentdevelopments
developmentsininmolecular
molecularbiology
biologyandandgenetics
geneticshave
haveilluminated
illuminated
potential
potential preterm birth prevention targets. The inhibition of specific inflammatorypath-
preterm birth prevention targets. The inhibition of specific inflammatory path-
ways,
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theNF-B
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shownpromise
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potential
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reducepreterm
pretermbirthbirthassociated
associatedwith withinflammation
inflammation[67]. [67].Similarly,
Similarly,
targeting specific hormonal pathways, such as the progesterone receptor
targeting specific hormonal pathways, such as the progesterone receptor signaling path- signaling pathway,
may
way,provide new therapeutic
may provide approaches
new therapeutic for the for
approaches prevention of preterm
the prevention birth [68].
of preterm birth [68].
Recent as Fettweis et al.’s 2019 Nature
Recent NGS-based research, such as Fettweis et al.’s 2019 Nature Medicinearticle,
NGS-based research, such Medicine article,has
has
shed light on the links between aberrant vaginal microbiotas and preterm births. These
shed light on the links between aberrant vaginal microbiotas and preterm births. These
studies have demonstrated that an imbalance in the vaginal microbiome, which includes
studies have demonstrated that an imbalance in the vaginal microbiome, which includes
a decrease in Lactobacillus species and an increase in diverse anaerobic bacteria, increases
a decrease in Lactobacillus species and an increase in diverse anaerobic bacteria, increases
the risk of preterm birth, chorioamnionitis, and neonatal sepsis. Gardnerella, Prevotella, and
the risk of preterm birth, chorioamnionitis, and neonatal sepsis. Gardnerella, Prevotella, and
Ureaplasma are associated with adverse outcomes. The timing of microbial colonization
Ureaplasma are associated with adverse outcomes. The timing of microbial colonization in
in pregnancy is important because an aberrant vaginal microbiome in early pregnancy is
pregnancy is important because an aberrant vaginal microbiome in early pregnancy is
linked to a higher risk of unfavorable outcomes than one later in gestation. These NGS-
linked to a higher risk of unfavorable outcomes than one later in gestation. These NGS-
based findings strongly imply that targeted therapies to alter the vaginal microbiome could
based findings strongly imply that targeted therapies to alter the vaginal microbiome
avert unfavorable neonatal outcomes. However, additional investigation is needed to
could avert unfavorable neonatal outcomes. However, additional investigation is needed
identify the best measures and to comprehend the complicated connections between the
to identify the best measures and to comprehend the complicated connections between
microbiome of the vagina and perinatal outcomes [69] (Figure 1).
the microbiome of the vagina and perinatal outcomes [69] (Figure 1).

Figure 1. Inflammation leading to preterm labor. Possible mechanisms through which inflamma-
tion can lead to preterm labor (PRR: pattern recognition receptors, TLRs: toll-like receptors, IL-1:
interleukin 1, MMPs: matrix metalloproteinases).
Children 2023, 10, 907 6 of 17

3. Specific Infectious Organisms

Many different types of bacteria have been linked to preterm birth, chorioamnionitis,
and early-onset neonatal sepsis. These include Gardnerella vaginalis, Ureaplasma urealyticum,
Mycoplasma hominis, Chlamydia trachomatis, Trichomonas vaginalis, Neisseria gonorrhoeae, Acti-
nomyces, Candida spp. However, the role of the individual pathogens as the culpable
organisms is less clear.

3.1. Bacterial Vaginosis (BV)

Bacterial vaginosis is the prevailing lower genital tract disorder among women of
reproductive age [70]. This disorder is not caused by a single pathogen, such as in a classical
infection, but is the consequence of a modification in the vaginal flora, where physiological
lactobacilli are replaced by an overgrowth of mixed flora with increased numbers of the
anaerobic bacteria that normally appear in the vagina in smaller amounts, including
Gardnerella vaginalis, Bacteroides spp., Mycoplasma hominis, and Mobiluncus spp. [71,72].
In normal vaginal flora, the H2 O2 that is produced by lactobacilli prevents the over-
growth of anaerobes, acting against the proliferation of other microorganisms by maintain-
ing an acidic vaginal pH. In the presence of BV, there is a shift in the anaerobe-to-aerobe
ratio as the vaginal pH increases due to a decreased amount of the produced H2 O2 . In BV
we found the same kind of bacteria as in the normal flora, but the difference is in the quan-
tity of the present microorganisms [73]. BV is often asymptomatic, although sometimes
results in a gray vaginal discharge with a characteristic “fish odor” [69]. Three out of four
of the Amsel criteria (vaginal pH > 4.7, presence of discharge, amine odor, and presence of
clue cells) or the Nugent score (a Gram-stain grading system) must be met for a classical
diagnosis of BV to be made [74,75].
Abortion, PPROM, chorioamnionitis, amniotic fluid infection, and preterm birth are
among conditions that have been linked to bacterial vaginosis [76,77]. Fifteen percent to
forty-two percent of pregnant women have BV, and it raises the possibility of spontaneous
PTB and PPROM by a factor of two to four [28].
Women with or without symptoms are at higher risk of having a premature baby [78].
An increased risk of spontaneous preterm birth has been linked to the presence of certain
organisms in BV, including Ureaplasma urealyticum and Mycoplasma hominis [79]. New
hypotheses suggest that BV and premature birth may be influenced by both genes and the
environment [69].
However, significant ongoing research is aimed at elucidating the pathophysiologic
processes between BV and premature birth. We still don0 t know why some women0 s BV
clears up on its own and others don0 t [80]. BV is not often an inflammatory disorder,
although many preterm birthing mothers have aberrant vaginal microbiota and an inflam-
matory process. Women with BV often do not have leukocytes in their vaginal discharge.
Pro-inflammatory cytokines like IL-1 are also present, and elevated levels of these cytokines
have a role in the local generation of prostaglandin, which has been linked to premature
birth [81].
The risk of preterm birth in women may be increased by several factors that act
separately or in combination. Firstly, the bacteria of BV ascend to the upper genital tract,
causing chorioamnionitis, premature rupture of membranes, and subsequent preterm
birth [81]. Moreover, bacteria associated with BV produce proteolytic enzymes that change
the permeability of the mucosal epithelium, enabling other, more pathogenic bacteria to
cause ascending infections [56]. In addition, in the presence of BV microorganisms, the
genetically mediated local innate immunity, producing cytokines, chemokines, and growth
factors, has the ability to modulate the response within the vagina and cervix [69,81].
Finally, the degree of difference in the risk of preterm birth may be related either to immune
hypo-responses that allow easier ascending infections or to immune hyper-responses in
which more inflammatory processes are developed, causing preterm birth [82].
Klebanoff et al.’s 2023 systematic review and individual participant data meta-analysis
examined whether BV antibiotics reduce preterm birth risk. The meta-analysis comprised
Children 2023, 10, 907 7 of 17

11 randomized controlled studies with nearly 7000 women. In high-risk populations,

the antibiotic treatment of BV resulted in a significant reduction in preterm birth risk.
Preterm birth and baseline vaginal pH above 4.5 also were shown to increase the effect. The
researchers also warn of antibiotic resistance and the necessity for more research on the best
antibiotic regimen and its long-term effects; however, they support the use of antibiotics
to treat BV to reduce preterm birth and emphasize the need for more investigation and a
thorough examination of the antibiotic treatments’ risks and benefits [83].

3.2. Staphylococcus aureus

Staphylococcus aureus (S. aureus) is a commensal bacterium and a leading source of
invasive infections in humans; it is a well-adapted human pathogen. Nearly 25% of
the human population has become persistently colonized, and 75% is intermittently or
never colonized [84–87]. Chorioamnionitis and preterm premature rupture of membranes
(PPROM), both of which can lead to preterm birth and neonatal illness, have been linked to
S. aureus in recent years. Eleje et al., in a prospective cross-sectional study, found that in
women with PPROM, Streptococcus species, S. aureus and E. coli were significantly increased
in comparison with women without PPROM [88]. In addition, chorioamnionitis associated
with methicillin-resistant S. aureus has also been reported [89].
On the surfaces of soft tissues, a biofilm is formed by S. aureus, contributing to its
resistance to antimicrobials and host immunity [90,91]. S. aureus takes advantage of the
α-hemolysin pro-inflammatory activity to cause the degeneration of vaginal tissue and
improve biofilm generation [92]. Gestational membranes, through receptors that recognize
pathogens, contribute to an active immune control [93]. S. aureus infection of the gestational
membranes produces a biofilm formation that promotes the release of pro-inflammatory
cytokines (IL-1β, IL-2, IL-6, GM-CSF, TNF-α, and IFN-γ) [94]. The produced cytokine cas-
cade results in membrane weakening, leading to preterm premature rupture of membranes
and preterm birth [14].

3.3. Genital Mycoplasmas

Pregnancy is a common time for the isolation of genital mycoplasmas (GMs), which
include Ureaplasma urealyticum and Mycoplasma hominis. Their presence in the amniotic
cavity is associated with adverse pregnancy outcomes such as preterm labor, postpartum
endometritis, PPROM, neonatal systematic inflammatory response, pneumonia, cerebral
palsy, and necrotizing enterocolitis [14,95]. They are the organisms most commonly iso-
lated from the placental membranes and amniotic fluid in both histological and clinical
chorioamnionitis [84].
Mycoplasmas are closely connected to the epithelium, so they are basically restricted to
the mucosal surfaces. The immunogenicity of these attachment molecules permits their
adherence to numerous types of cells such as neutrophils, erythrocytes, and epithelial
cells, triggering the inflammatory response. Moreover, they cause a direct activation of
the complement complex C-1 [96]. In addition, a local cytotoxic outcome is caused by the
secretory substances of the mycoplasmas, ammonia from the mycoplasmas, and urea from the
ureaplasmas, aggravating the inflammatory response [97]. The immune system is believed to
intercede for this response. It is known that M. genitalium, using lipopeptides expressed on
the cell membrane, stimulates toll-like receptors on epithelial cells, which in turn activate
the nuclear factor KB [71]. In a related approach, lipopeptides activate the trophoblasts of
full-term placentas, producing cyclooxygenase-2 and prostaglandin E2. In the presence
of genital mycoplasmas, pro-inflammatory cytokines, such as IL-1b, IL-6, IL-8, and tumor
necrosis factor-a (TNF-a), are increased, promoting the inflammatory response [98].
The frequency of genital mycoplasmas depends on socioeconomic status and geographic
area, while the detection rate of U. urealyticum ranges between 20% and 80% and that of M.
hominis is estimated to be less than 30% in the data [99–103]. Studies have demonstrated that
GMs can fill the amniotic cavity and persist for months, triggering a severe inflammatory
response, while being thought of as commensal organisms in the lower genital canal with
Children 2023, 10, 907 8 of 17

minimal virulence for infection. In 47% and 30% of verified instances of chorioamnionitis,
respectively [100], U. urealyticum and M. hominis were isolated from placental membranes.
The detection of U. parvum in the placental tissue was significantly correlated with acute
chorioamnionitis in the women presenting in extreme preterm labor, according to a case
control study involving 57 women who delivered before 37 weeks of gestation and who
either had (42) or did not have (25) inflammation of the chorioamniotic membranes [97]. In
the Alabama Preterm Birth study, the presence of U. urealyticum and/or M. hominis were
higher in cord blood cultures among women with spontaneous PTB compared with those
with indicated PTB (34.7% vs. 3.2%; p = 0.0001) [84]. In addition, a prospective cohort
research analyzed the microbiota profiles of 70 sam-ples from 36 women with PPROM
between 24 weeks and 33 weeks and 6 days of pregnancy. Women who tested positive
for Mycoplasma and/or Ureaplasma using polymerase chain reaction (PCR) in this study
had babies born at a younger age and weighed less than those born to mothers who
tested negative for these pathogens [104]. In addition, Kataoka et al. found that vaginal
colonization with U. parvum, but not U. urealyticum, is associated with late abortion or early
preterm birth [105].
Although serological testing is unable to distinguish between preceding and current
disease, molecular detection methods are superior to culture-based methods for detection,
allowing an increased specificity and discrimination of species and subtypes [106]. The
pathogenic role of Ureaplasma spp. remains controversial, as the colonization rates of
these organisms are usually also very high in normal pregnancies, and Ureaplasma infec-
tion within placentae is not always associated with inflammation and adverse pregnancy
outcomes. Possible explanations include the timing and duration of colonization, differ-
ences in virulence between species/strains, interactions with other microorganisms and
inflammatory modulators, and lastly, suppression or aggravation via maternal immune
responses [107].
Jonduo et al. published a meta-analysis on the connections between commensal
vaginal mycoplasmas, such as Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma
parvum, and unfavorable pregnancy outcomes. Most intra-amniotic infections involve these
bacteria. Genital mycoplasmas were linked to preterm birth, low birthweight, and fetal
inflammatory response syndrome. Ureaplasma urealyticum and U. parvum were particularly
related to preterm birth. The meta-analysis suggests targeting genital mycoplasmas to de-
crease poor pregnancy outcomes; however, the most effective therapies and the complicated
relationships between these bacteria and unfavorable pregnancy outcomes need additional
research. This meta-analysis also reveals the relevance of commensal genital mycoplasmas in
unfavorable pregnancy outcomes and emphasizes the need for further investigation [108].

Sexually Transmitted Infections

PTB has been linked to several STDs that affect the lower genitalia, such as Chlamydia
trachomatis, Trichomonas vaginalis, and Neisseria gonorrhoeae.

3.4. Chlamydia trachomatis

Chlamydia trachomatis is considered the most commonly isolated sexually transmitted
organism. The rate of infection with C. trachomatis in pregnancy ranges from 2 to 26%
but the prevalence varies within each population [109,110]. Untreated maternal cervical
chlamydial infection has been linked to an increased risk of preterm delivery, premature
rup-ture of membranes, and perinatal mortality, however this has been disputed by a
number of research [111,112], conflicting data exist regarding the association between
chlamydia and adverse pregnancy outcome, particularly PTB [113]. A retrospective case
control study reported that genitourinary C. trachomatis infection in the second trimester
increased two- to three-fold the risk of spontaneous PTB, while no association was found
between a third-trimester infection and the risk of spontaneous PTB [114]. Olson-Chen
et al., in a meta-analysis, provided evidence that chlamydia in pregnancy is associated with
a small increase in the odds of multiple adverse pregnancy outcomes [115].
Children 2023, 10, 907 9 of 17

3.5. Trichomonas vaginalis

T. vaginalis is most common in women of childbearing age; it is believed that up to
25 million pregnant women worldwide are infected with the bacterium [116]. Usually,
the protozoan T. vaginalis causes an asymptomatic infection, but sometimes symptomatic
urethritis, vaginitis, or vulvitis can also occur [117]. Research has associated T. vaginalis
with premature rupture of membranes, preterm delivery, and low birthweight [118]. In
a systematic review and meta-analysis of 11 research, Silver et al. found that T. vaginalis
during pregnancy was significantly linked with an elevated risk of preterm birth (RR, 1.42;
95% CI, 1.15–1.75; 9 studies; n = 81,101; I = 62.7%). Small-for-gestational-age infants (RR,
1.51; 95% CI, 1.32–1.73; 2 trials; n = 14,843; I = 0.0%) and PPROM were also observed to
be significantly higher [119]. Although T. vaginalis infection during pregnancy has been
linked to preterm delivery, Klebanoff et al. evaluated the effectiveness of a 2 g dosage of
metronidazole to that of a placebo, administered 48 hours apart. Management of pregnant
women with asymptomatic trichomoniasis did not prevent premature delivery [120,121],
the authors stated. The PTB rate was substantially higher in the antibiotic group (19.0% vs.
10.7%).

3.6. Neisseria gonorrhoeae

Neisseria gonorrhoeae, a sexually transmitted Gram-negative intracellular diplococcal
organism, is often considered a risk factor for PTB, but this association has not been
examined widely. Only a few studies have reported a connection between N. gonorrhoeae
and PTB. A population-based cohort study showed that maternal gonorrhea is associated
with small-for-gestational-age infants [122]. Moreover, Donders et al. reported that N.
gonorrhoeae during pregnancy increased the risk of developing PROM compared with not
having N. gonorrhoeae by six times [123]. However, in another unmatched case control study
among women who were in the third trimester of pregnancy, no association was found
between N. gonorrhoeae and PROM [118]. Co-infection with T. vaginalis and C. trachomatis
increases the risk for PPROM [124–126]. The additive inflammatory response may be a
possible explanation for the increased risk of PROM in multiple infections [126,127].

3.7. Actinomyces
Actinomyces is an opportunistic pathogen that is part of the normal vaginal flora and
can be found in the oral cavity, the uterus, the lungs, and the gastrointestinal tract. It can
result in infection after a break in the normal defenses of the mucosa [128]. Actinomycosis
is found in pregnancy very rarely, but according to a recent review, if it occurs, it is mainly
associated with preterm deliveries [129].

3.8. Candida Species

About 40% of pregnant women have vaginal colonization with Candida spp. This
occurs because of the increased concentration of circulating estrogens and the vaginal accu-
mulation of glycogen and other substrates [130]. Candida species rarely result in chorioam-
nionitis despite the high prevalence of vulvovaginal candidiasis in pregnancy. There is
some evidence that eliminating Candida during pregnancy can reduce the risk of premature
birth and late miscarriage, despite the fact that vaginal colonization with Candida is not
usually linked to an increased probability of preterm delivery [130].
Chorioamnionitis caused by Candida spp. is very rare, less than 0.8%, and few cases
have been reported [131,132]. The predominant species is Candida albicans (71.3% of all
cases), and preterm labor as well as PROM in early preterm pregnancies (<28 weeks) are the
most common clinical manifestations. Most reported cases of Candida chorioamnionitis have
been associated with iatrogenic origins, such as cerclage of amniocentesis and IVF, while
the tendency of Candida to form a biofilm amplifies these correlations [132–134]. Therefore,
candidal chorioamnionitis should be considered when a suspected intra-amniotic infection
develops after these interventions.
Children 2023, 10, 907 10 of 17

Although many case reports of preterm births due to chorioamnionitis caused by

Candida albicans have been reported, only a few studies of small groups are available in
the literature due to the infrequency of the infections [135,136]. Maki et al. reviewed
the medical records of women with candidal chorioamnionitis and found that the most
prevalent predisposing condition was PPROM (25.2%), while pregnancy with a retained
intrauterine contraceptive device was in second place (21.1%), followed by a pregnancy
after in vitro fertilization (20.3%) [137].

3.9. Campylobacter, Salmonella, and Yersinia

Campylobacter, Salmonella, and Yersinia are well-known causative agents of bacterial
gastroenteritis in humans. However, the effects of infection with these bacteria during
pregnancy remain largely unknown. Several types of Campylobacter have been linked to
premature births and septic abortions [138–140]. Impaired embryo im-plantation, poor
fetal development, and fetus resorption were observed in mice that were injected with
Campylobacter at several stages of pregnancy [141]. Animal studies also show that Yersinia
enterocolitica can trigger miscarriages [142]. During the first trimester of pregnancy, Kantso
et al. evaluated the serological markers for Campylobacter, Salmonella, and Yersinia in the
serum of 192 women who had contact with domestic animals. Researchers identified an
association between preterm birth and high levels of Salmonella antibodies [143].

3.10. Sneathia
Sneathia spp. may be another pathogen related to undesirable neonatal outcomes,
according to a recent review by Theis et al. Women with bacterial vaginosis and other
vaginal infections are more susceptible to Sneathia spp. in their vaginal microbiome, a
pathogen that has been linked to premature birth, chorioamnionitis, and intra-amniotic
infection in research (Figure 2). Sneathia spp. may cause premature delivery by inflaming
the cervical and vaginal epithelium and allowing pathogenic bacteria to enter. The analysis
suggests incorporating Sneathia spp. in future vaginal microbiota and preterm birth studies,
Children 2023, 10, x FOR PEER REVIEW 11 of 17
as its occurrence in diverse groups and efficient prevention and treatment options requires
further study [144].

Figure 2. The prevalence of specific vaginal microorganisms in pregnant women. (B. vaginosis,
Figure 2. The prevalence of specific vaginal microorganisms in pregnant women. (B. vaginosis, mainly
mainly concerning Gardnerella vaginalis, varies from 15 to 42% in the general population of pregnant
concerning Gardnerella vaginalis, varies from 15 to 42% in the general population of pregnant women,
women, depending on the continent. Similar discrepancies are observed in colonization rates of U.
depending onC.
urealyticum, the continent. and
trachomatis, Similar discrepancies
T. vaginalis, are observed
depending on the in colonization
population rates
under of U. urealyticum,
study.).
C. trachomatis, and T. vaginalis, depending on the population under study.).

4.4.Conclusions
Conclusions
Genitalinfections
Genital infections during
during pregnancy
pregnancy maymay
leadlead to abnormal
to abnormal inflammatory
inflammatory reactions
reactions and
and adverse
adverse pregnancy
pregnancy outcomes.
outcomes. In addition,
In addition, therethere
is anisincreased
an increased
risk risk of adverse
of adverse mater-
maternal
nal outcome,
outcome, prematurity,
prematurity, and neonatal
and neonatal morbidity
morbidity and mortality.
and mortality. The fundamental
The fundamental goal
goal of any
treatment/prevention intervention should be pregnancy prolongation, the improvement im-
of any treatment/prevention intervention should be pregnancy prolongation, the of
provement of maternal–fetal health, and in cases where preterm birth is unavoidable, the
amelioration of possible neonatal jeopardies.
While placental microbiota research is ongoing, ascending vaginal bacteria are re-
sponsible for most preterm birth infections. Thus, preventing infectious preterm birth re-
Children 2023, 10, 907 11 of 17

maternal–fetal health, and in cases where preterm birth is unavoidable, the amelioration of
possible neonatal jeopardies.
While placental microbiota research is ongoing, ascending vaginal bacteria are respon-
sible for most preterm birth infections. Thus, preventing infectious preterm birth requires
identifying the risk factors and developing effective treatments. Targeted microbiome-
based therapies for preterm birth prevention should also be investigated. Probiotics or
other microbiome-modifying agents can establish a healthy vaginal microbiota and avoid
pathogenic bacteria overgrowth. Rapid and accurate vaginal infection diagnostic tests
could reduce the risk of preterm birth through early detection and treatment.
Large studies are necessary for the illumination of the vaginal microbiota function
and the maternal and fetal immune response in both normal pregnancies and in cases of
spontaneous preterm labor. This may involve studying immune system–vaginal microbiota
interactions and how dysregulation may affect prenatal outcomes.
In conclusion, future research should identify risk factors, create effective therapies,
and understand how vaginal microbiome dysbiosis causes unfavorable perinatal outcomes,
including premature birth. An extensive comprehension of microbial ecology and the
genetic factors that regulate the reaction to infection and the inflammatory response is
essential in light of the evidence that gene–environment relations may lead to preterm
labor.

Author Contributions: G.D., A.P., A.K., Z.F. and I.P. contributed to conception and design.; G.D. and
A.P. (Angeliki Papapanagiotou) were responsible for overall supervision. A.V., C.K., T.N. and E.D.
drafted the manuscript, which was revised by A.P. (Alexandros Psarris), M.T., P.A. and K.I.P. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: The authors are grateful to all who provided assistance during the preparation
of this manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

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