published: 16 October 2013
Bacterial aetiological agents of intra-amniotic infections
and preterm birth in pregnant women
George L. Mendz1*, Nadeem O. Kaakoush2and Julie A. Quinlivan3
1School of Medicine, Sydney, The University of Notre Dame Australia, Darlinghurst, NSW, Australia
2School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Kensington, NSW, Australia
3School of Medicine, Fremantle, The University of Notre Dame Australia, Fremantle, WA, Australia
Paul De Figueiredo, Texas A&M
Qing-Ming Qin, Jilin University,
Neetu Singh, Texas A&M University,
George L. Mendz, School of
Medicine, Sydney, The University of
Notre Dame Australia, 160 Oxford
St., Darlinghurst, NSW 2010,
Infection-related preterm birth is a leading cause of infant mortality and morbidity;
knowledge of bacterial populations invading the amniotic cavity and the routes of invasion
is required to make progress in the prevention of preterm birth. Signiﬁcant advances
have been made in understanding bacterial communities in the vagina, but much less
studied are intra-uterine bacterial populations during pregnancy. A systematic review of
data published on the intra-uterine microbiome was performed; molecular information and
summaries of species found in healthy individuals and in women with diagnosed infections
served to construct a database and to analyse results to date. Thirteen studies fulﬁlled the
review’s inclusion criteria. The data of various investigations were collated, organized, and
re-analyzed to achieve a more comprehensive understanding of microbial populations in
the intra-amniotic space. The most common intra-amniotic bacterial taxa were species
that can colonies the vagina in health and disease; there were others associated with the
habitats of the mouth, gastrointestinal tract, and respiratory tract. The results suggest
a central role for the ascending route of infections during pregnancy, and point to a
possible secondary contribution via haematogenous invasion of the intra-amniotic space.
The complete census of the intra-uterine microbiome awaits completion.
Keywords: microbiome, intra-uterine infection, preterm birth
“Infections of mothers and their babies (both in utero and
ex utero) are a major global challenge” (Hussein et al., 2011).
Preterm birth (PTB) is the second largest direct cause of deaths
in children younger than 5 years (Blencowe et al., 2012); it is a
major cause of perinatal mortality and serious neonatal morbid-
ity, and moderate to severe childhood disability in developed and
developing countries (Lawn et al., 2005; Hemminki et al., 2007;
Jacobsson, 2007). The burden of PTB is substantial and increased
between 1990 and 2010 in developing and developed countries
with reliable data (Blencowe et al., 2012). Length of gestation
is considered to be a key indicator of infant health, and PTB is
associated with poorer health outcomes in babies.
Premature deliveries can be classiﬁed into two broad groups:
spontaneous and iatrogenic. The majority of PTB occur sponta-
neously as a result of preterm labor or preterm premature rupture
of membranes. Spontaneous preterm delivery occurs in ∼12% of
births in developed countries (Pretorius et al., 2007) and 14%
worldwide (Pararas et al., 2006). Iatrogenic PTB may be sec-
ondary to other complications of pregnancy such as preeclampsia,
intrauterine growth restriction, abruptio placenta, or placenta
praevia (Muglia and Katz, 2010).
“For much of the 20th century, PTB, deﬁned as birth at less
than 37 completed weeks of gestation, was viewed as an unpre-
dictable and inevitable fact of life. Medical efforts thus focused
on ameliorating the consequences of prematurity rather than
preventing its occurrence. This approach resulted in improved
neonatal outcomes, but it remains costly in terms of both the
suffering of infants and their families and the economic bur-
den on society.” (Muglia and Katz, 2010). The burden of PTB
increased during the last 30 years owing to signiﬁcant improve-
ments in neonatal care that made possible the survival of very
preterm infants and resulted in a lowering of the threshold for
preterm Caesarean delivery. Other factors that have contributed
to higher rates of PTB are the multiple gestations arising from
the use of assisted reproductive technologies, advanced mater-
nal age, and improvements in obstetrics outcomes of surgical
interventions to manage invasive lesions (Muglia and Katz, 2010).
The aetiology of PTB is multifactorial, and various factors
have been identiﬁed as contributors to spontaneous PTB (Gracie
et al., 2011), e.g., genetic, infection and inﬂammation, decid-
ual haemorrhage, and environmental, behavioral and social stress
(Figure 1). Infections have been long suspected to be the underly-
ing cause of idiopathic PTB, and microbial intra-uterine infection
is a conﬁrmed leading cause of PTB. In particular, bacterial
invasion of the amniotic cavity (BIAC) is the chief cause of
neonatal mortality worldwide (Gonçalves et al., 2002; Lawn et al.,
2005). Currently, there is overwhelming evidence to implicate
infection in up to 40% of PTB cases, including intra-uterine
(Ganu et al., 2013) and vaginal (Hyman et al., 2013)infections.
Intra-amniotic infections are present in ∼50% of all pregnan-
cies that result in PTB, and the earlier the gestational age at
delivery, the higher the frequency of intra-amniotic infection
(Burd et al., 2012).
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CELLULA R AND INFECTION MICROBIOLOG
Mendz et al. Intra-amniotic microbiome of pregnant women
FIGURE 1 | Pathophysiological mechanisms leading to spontaneous
PTB. More than one pathway can lead to the same immediate cause of
premature delivery, for example, the preterm pre-labor rupture of
membranes (PPROM). HPA axis, hypothalamic-pituitary-adrenal axis.
A study early in the twentieth Century supported the view that
under normal circumstances and prior to labor, the amniotic cav-
ity was sterile (Harris and Brown, 1927).Thegoldstandardfor
identiﬁcation of intrauterine infection has been the isolation of
microbes in amniotic ﬂuid sampled by amniocentesis. Owing to
the ﬁnding that the amniotic ﬂuid of less than 1% of women in
labor at term contains culturable bacteria (Romero et al., 2002),
historically the isolation of any microbes from the amniotic ﬂuid
was considered a pathological ﬁnding. However, investigations
of the intra-uterine ﬂora of women giving birth prematurely
based on non-cultivation taxon-speciﬁc PCR analyses, as well as
more recent studies employing non-cultivation broad-range PCR
methods have demonstrated the presence of microﬂora in the
intra-amniotic cavity even in the absence of any signs of infection
(DiGiulio, 2012). The results of standard microbiological stud-
ies suggest that intrauterine infection accounts for as much as
25–45% of spontaneous PTB (Zhou et al., 2010); but employ-
ing molecular techniques, bacterial footprints have been detected
in as many as 60% of women delivering preterm (Gardella et al.,
The sequence of events leading to PTB, progressing from
intrauterine infection to pro-inﬂammatory cytokine activa-
tion, prostaglandin production, premature contractions, cervical
changes, and premature delivery has been comprehensively stud-
ied on non-human primates (Adams Waldorf et al., 2011). In
humans, the colonization of microbes and/or inﬂammation of
the chorio-decidual interface can induce the production of a cas-
cade of cytokines that result in an inﬂammatory response (Muglia
and Katz, 2010). Bacteria also can have a more direct role in
the pathogenesis of PTB by producing enzymes that degrade
fetal membranes, or by inducing the synthesis and release of
uterotonins such as prostaglandins, able to stimulate uterine con-
tractions and cause preterm labor (Keelan et al., 2003; Lockwood,
Notwithstanding the evidence, current knowledge of
BIAC is insufﬁcient to develop effective strategies to prevent
infection-related PTB because the prevalence, methods of
diagnosis, pathogenicity mechanisms, and host susceptibilities to
various bacteria require further investigations (DiGiulio, 2012).
A necessary step to address these knowledge gaps is to obtain a
complete understanding of the diverse microbial taxa involved
Pathogens may gain access to the amniotic cavity and fetus
by ascending migration of the vaginal ﬂora, haematogenous dis-
semination through the placenta, retrograde seeding from the
peritoneal cavity through the Fallopian tubes, or iatrogenic intro-
duction at the time of invasive procedures (Goldenberg et al.,
2000). Evidence obtained from studies culturing bacteria sup-
ports the view that the most common pathway of BIAC is the
ascending route (Romero and Mazor, 1988; DiGiulio, 2012).
This study reviews and organizes systematically data published
on the identity and frequency of detection of bacterial taxa found
in the intra-amniotic space of women who delivered preterm. Its
focus is on the dramatic advance of the knowledge of the bacte-
rial communities present in the genital microbiota of pregnant
women made in the last 18 years by non-cultivation, high-
throughput techniques of analysis, and the potential contribu-
tions systematic investigations of the female genital microbiome
can make to preventing PTB.
SOURCES AND STUDY SELECTION
An initial search of PubMed was conducted employing the broad
concepts: “pregnancy,” “preterm birth,” and “intrauterine infec-
tion” or “chorioamnionitis,” as well as appropriate synonyms
and truncations via the Boolean search method. The searches
returned up to 1242 titles. Adding the term “bacteria” reduced
the number of publications to 328. The titles and abstracts of this
list were examined, and a selection was made following the inclu-
sion criteria for studies that: (1) were published between 1995 and
2013; (2) contained data on bacterial taxa in the uterus of preg-
nant women delivering preterm; and (3) employed cultivation or
molecular methods of identiﬁcation of bacterial species. Excluded
were publications: (a) in a language other than English; and (b)
that did not specify the type of microbes involved in the invasion
of the amniotic space.
Perusal of the selected papers and references therein yielded
13 papers containing information required for this review (Jalava
et al., 1996; Markenson et al., 1997; Gardella et al., 2004;
DiGiulio et al., 2008, 2010a,b,c; Han et al., 2009; Jones et al.,
2009; Srinivasan et al., 2009; Zhou et al., 2010; Marconi et al.,
2011). The data from the selected studies were extracted to
construct a database of intra-uterine bacterial taxa or gen-
era identiﬁed in PTB and the frequencies at which they were
Phylogenetic trees of various bacterial phyla and their respective
orders, families, genera and species, were employed as templates
to classify the identity of intrauterine bacterial genera and species
found in pregnant women who gave birth before term. The pro-
cess served to arrange bacterial taxa into appropriate phyla and
orders according to the NCBI taxonomy database.
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Mendz et al. Intra-amniotic microbiome of pregnant women
The frequency at which a taxon or genus was present was
determined from the data in the 13 publications included
in this study by adding the number of women with intra-
uterine infections who delivered preterm in which the taxon
was found. The number of taxa in different phyla and orders
were calculated in a similar way from the data in these
RESULTS AND CONCLUSIONS
The review includes 761 women delivering before term of which
349 (46%) presented with an intra-uterine infection. The use of
non-culture direct-detection techniques has increased by ∼5-fold
the number of taxa known to be present in intrauterine infections
Meta-analyses of randomized trials evaluating antibiotic treat-
ments report statistically signiﬁcant prolongation of pregnancy
associated with the use of antibiotics in women with preterm
labor and intact membranes (King and Flenady, 2002), and
reduction in the delivered number of babies within 48 h in
preterm premature rupture of the membranes (Kenyon et al.,
2010). Thus, there is a strong association between the presence
of some bacteria in the intra-amniotic cavity and PTB.
Bacteria belonging to a total of 5 phyla and 16 orders were
found in the intra-uterine microbiota of the 349 pregnant women
with intra-amniotic infection (Ta b l e 1,Figure 2). They belonged
to 44 genera and more than 87 different taxa (identiﬁcation of
some bacteria was performed only at the genus level) (Ta b l e 1).
The highest frequencies were determined for genera of the order
Mycoplasmatales (59%) and Lactobacillales (25%) (Tab l e 1 ).
Bacteria of the phylum Firmicutes were the most abundant
and were detected in 343 women with infection included in this
study; the second most common phylum among these women
was Fusobacteria, found in 71 subjects (Figure 2). The phyla with
larger number of different orders and taxa were Firmicutes and
Proteobacteria (Tab le 1 ).
Taxa of the order Mycoplasmatales were found in 205 (58.7%)
women, and bacteria of the genus Ureaplasma were detected
in 172 women (49%). Recognized genital pathogenic species
were found at high frequencies, e.g., Ureaplasma uralyticum
(11%), Streptococcus agalactiae (11%), Mycoplasma hominis (9%)
and Fusobacterium nucleatum (9%) (Tabl e 1 ). These results are
in broad agreement with previous more limited knowledge of
BIAC. A review of the pathogens involved in sepsis in neona-
tal intensive care units found that the majority were mixed
genitaltractﬂora(Garland and Bowman, 2003). Meta-analyses
of antibiotic administration to women with bacterial vaginosis
showed an association of the treatment with a signiﬁcant reduc-
tion in the incidence of PTB and low weight babies (Smaill,
2001). This work indicated taxa present at higher frequencies
belonged to bacteria normally found in the urogenital and gas-
trointestinal tracts; a result that supports the view that most
cases of chorioamnionitis arise from pathogens ascending from
the vagina. Thus, it is reasonable to hypothesize that preventing
ascending genital tract infection and the initiation of inﬂam-
matory cascades will reduce PTB, neonatal fever and other
Table 1 | Bacteria found in the intra-uterine microbiota of the 349
pregnant women with intra-amniotic infection.
Phylum Order Species Frequency
Actinobacteria Actinomycetales Actinomyces spp. 1
Brachybacterium spp. 1
Mobiluncus mulieris 1
Propionibacterium acnes 1
Propionibacterium spp. 2
Rothia dentocariosa 1
Coriobacteriales Atopobium vaginae 2
Biﬁdobacteriales Biﬁdobacterium longum 1
Gardnerella vaginalis 11
Firmicutes Clostridiales Clostridium hiranonis 2
Clostridium perfringens 2
Eubacterium halii 1
Eubacteriun spp. 1
Faecalibacterium spp. 1
Filifactor alocis 1
Finegoldia magna 2
Peptoniphilus lacrimalis 1
Peptostreptococcus spp. 14
Oribacterium sinus 1
Erypsipelotricales Coprobacillus spp. 1
Mycoplasmatales Mycoplasma hominis 33
Ureaplasma parvum 22
Ureaplasma urealyticum 38
Ureaplasma spp. 112
Bacillales Listeria monocytogenes 2
Staphylococcus aureus 6
Staphylococcus equorum 2
Staphylococcus spp. 6
Lactobacillales Enterococcus faecalis 1
Enterococcus spp. 10
Lactobacillus crispatus 3
Lactobacillus delbrueckii 1
Lactobacillus gasseri 1
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Mendz et al. Intra-amniotic microbiome of pregnant women
Table 1 | Continued
Phylum Order Species Frequency
Lactobacillus iners 1
Lactobacillus spp. 3
Streptococcus agalactiae 37
Streptococcus anginosus 11
Streptococcus mitis 10
Streptococcus oralis 4
Streptococcus salivarius 1
Streptococcus spp. 1
Fusobacteria Fusobacteriales Fusobacterium
Fusobacterium spp. 4
Leptotrichia amnionii 5
Leptotrichia spp. 17
Sneathia sanguinegens 13
Bacteroidetes Bacteroidales Bacteroides fragilis 4
Bacteroides spp. 3
Prevotella bivia 4
Prevotella copri 2
Prevotella oris 1
Prevotella spp. 3
Flavobacteriales Bergeyella spp. 1
Myroides spp. 1
Proteobacteria Campylobacterales Campylobacter
Campylobacter spp. 1
Neisseriales Kingella denitriﬁcans 1
Neisseria cinerea 1
Neisseria subﬂava 1
Neisseria spp. 1
Burkholderiales Delftia acidovioans 1
Haemophilus inﬂuenza 10
Haemophilus quentini 1
Enterobacteriales Citrobacter koseri 1
Enterobacter aerogenes 1
Enterobacter spp. 2
Escherichia coli 25
Proteus mirabilis 4
Shigella spp. 2
The frequency is given as the number of women (n) carrying a particular species.
FIGURE 2 | Chart of the ﬁve phyla of the intra-uterine bacteria of 349
women with intra-amniotic infection who gave birth preterm. Each
segment is proportional to the number of women in which bacteria of a
given phylum are found: Actinobacteria (25), Firmicutes (343), Fusobacteria
(71), Bacteroidetes (20), and Proteobacteria (58). The data indicate that taxa
from more than one phylum were present in most of these women.
Pathogens that are ordinarily found in the gastrointestinal
tract and may reach the vagina, also can cause haematoge-
nous invasion of the uterus. Listeria monocytogenes crosses the
mucosal barrier of the intestine to disseminate haematogenously
to any site, with a unique tendency to infect the fetoplacental
unit (Baud and Greub, 2011). Generally, the bacteremia mani-
fests clinically as non-speciﬁc inﬂuenza-like symptoms, and may
remain asymptomatic. A review of 36 cases of maternofetal lis-
teriosis showed that the mothers generally were affected mildly
by the infection. Twelve pregnancies ended with abortion or
stillbirth; among the children born alive, 15 were diagnosed
with bacteremia/septicemia, 3 with pneumonia, 3 with neonatal
meningitis, 1 died, and 3 were unaffected (Smith et al., 2009).
There is evidence to support the hypothesis that bacterial
infections at sites distant from the urogenital tract, in particular
the oronasal cavity and the respiratory tract, may be important
causes of preterm labor probably through the activation of abnor-
mal inﬂammatory responses within the uterus and intrauterine
tissues. Data from clinical and animal studies on maternal peri-
odontal status combined with a biologically plausible mechanism
provide strong evidence for a negative impact of periodontal
infection on pregnancy outcome (Baskaradoss et al., 2012).
BIAC BY ORONASAL MICROFLORA
This review showed that a number of taxa found in periodon-
tal disease were associated with PTB; they had a frequency
of ca. 13% in women delivering before term. Identiﬁed taxa
of the oronasal habitat included Bergeyella spp., Dialister spp.,
Fusobacterium nucleatum,Oribacterium sinus,Peptostreptococcus
oralis, Prevotella oris, Rothia dentocariosa, Streptococcus oralis,
Streptococcus salivarius,Veillonella parvula, and Veillonella spp. It
should be noted that many of these taxa are frequently detected in
faces, e.g., S. salivarius and F. nuc l eat u m; and in the vagina, e.g.,
P. ora l i s ,P. o r i s,S. salivarius,Veillonella spp., and Dialister spp.
Using 16S and 23S rDNA molecular methods, a Bergeyella spp.
strain detected in the amniotic ﬂuid of a pregnant woman with
clinical intrauterine infection and histologic necrotizing acute
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Mendz et al. Intra-amniotic microbiome of pregnant women
and chronic chorioamnionitis was detected also in the subgin-
gival plaque of the patient but not in her vaginal tract. The
results suggested that the woman’s intrauterine infection with this
Bergeyella strain originated from the oral cavity (Han et al., 2006).
Capnocytophaga spp. are part of the normal human oral bacte-
rial ﬂora, but as opportunistic pathogens can produce extra-oral
infections including septicaemia and, less commonly, chorioam-
nionitis and neonatal infections. Evidence suggests that a number
of cases of intra-amniotic infection with this bacterium occurred
by the ascending route, but several cases that involved early-onset
of sepsis due to Capnocytophaga spp. infection yielded no vaginal
cultures of this bacterium suggesting haematogenous spread from
the oral cavity (Lopez et al., 2010).
Evidence that the oral pathogen F. nu clea tum may be transmit-
ted haematogenously to the placenta and cause adverse pregnancy
outcomes was obtained in pregnant mice injected intravenously
with the bacterium. F. nu c leat um colonizes the placenta and pro-
liferates rapidly, inducing fetal death by localized infection inside
the uterus; the bacterial infection was restricted inside the uterus,
without spreading systemically (Han et al., 2004).
The bacterium Rothia dentocariosa is a common inhabitant of
the human oral cavity where it rarely causes serious infections;
it has been associated with endocarditis, pneumonia, septicemia,
and abscesses in adults. R. dentocariosa caused septicemia in a
neonatal infant with meconium aspiration syndrome (Shin et al.,
2004), and was detected in the blood of a stillborn baby (Karlsson
and Jacobsson, 2005). Its presence in the vagina is rare; only one
woman with no signs of infection was reported in a study com-
prising 394 subjects (Ravel et al., 2011). The infrequent detection
of this bacterium in the vagina makes it plausible that in the
cases of neonatal septicemia and the stillborn infant, the access
to the intra-amniotic cavity occurred via the haematogenous
Streptococcus oralis has been found in the intra-amniotic cav-
ity (Jalava et al., 1996), and was associated with PTB in a study
comparing women delivering preterm or at term (Skuldbøl et al.,
2006), but the routes of invasion were not established in these
A clinical study of 812 deliveries from a cohort study of preg-
nant mothers entitled “Oral Conditions and Pregnancy” demon-
strated that both antepartum maternal periodontal disease and
incidence/progression of periodontal disease are associated with
PTB and growth restriction after adjusting for traditional obstet-
ric risk factors. The results support the concept that maternal
periodontal infection in the absence of a protective maternal anti-
body response is associated with systemic dissemination of oral
organisms that translocate to the fetus resulting in prematurity
(Madianos et al., 2001). Analysis of oral bacteria in the amni-
otic cavity of women delivering preterm agreed with the results
of a meta-analysis of 12,047 pregnant women that found a 2.73
overall odds ratio (95% CI: 2.06–3.6, p<0.0001) of giving pre-
mature birth to a child for mothers with periodontitis (Konopka
and Paradowska-Stolarz, 2012). These ﬁndings provide support
for the hypothesis that haematogenous dissemination of oronasal
bacteria is probably one of their routes of access to the amniotic
BIAC BY RESPIRATORY TRACT MICROFLORA
Haematogenous spreading of infections from the upper or lower
airways to the placenta may occur at any stage of the pregnancy
(Sandu et al., 2013). The data collected in this review indi-
cated that in the intra-amniotic cavity of women giving birth
preterm were found at low frequencies bacteria that colonies
the respiratory tract such as Haemophilus inﬂuenza,Haemophilus
Although these and other respiratory tract pathogens have
been found in the vaginal microbiota (Ravel et al., 2011), in moth-
ers with acute respiratory infection induced by highly virulent
pathogens, the infection may spread haematogenously to the pla-
centa inducing spontaneous and/or septic abortions, premature
births, fetal damage or intra-uterine fetal death (Sandu et al.,
2013). Pregnant women with pulmonary tuberculosis have higher
odds of PTB (Asuquo et al., 2012). In a stillbirth where the mother
had an upper respiratory infection of F. nucl eatum , the bacterium
was isolated from the placenta and the infant, and the same clone
was identiﬁed in her subgingival plaque, but not in the vagina or
rectum (Han et al., 2010).
Haemophilus inﬂuenzae is primarily responsible for neonatal
meningitis and respiratory tract infections in children. It has a
low prevalence rate in genital tract cultures and rarely causes acute
endometritis, but intra-amniotic infection and positive blood cul-
tures have been reported (Shute and Kimber, 1994). A sepsis
secondary to an acute H. inﬂuenzae infection led to placental
abruption and spontaneous abortion (Calner et al., 2012); also
a case has been reported with the uterus as the primary focus
of sepsis with presence of the bacterium in blood but not in the
vagina (Martin et al., 2013). Vertical transmission of H. inﬂuenzae
appears to be the most common route of infection of the fetus,
but ascending infections are less common in H. parainﬂuenzae
infections (Garcia et al., 1997).
Reports indicate involvement of oral and, less commonly,
respiratory tract pathogens in intra-uterine infections. The pres-
ence of the same bacterium at the original point of infection
and in the uterus supports a causal relationship and a role for
haematogenous BIAC during pregnancy that could lead to PTB.
Streptococcus pneumoniae is a common pathogen of the gen-
eral population; it is a frequent cause of pneumonias, meningitis,
bacteremia, and sepsis. This bacterium is uncommon in the vagi-
nal ﬂora and is rarely associated with gynecologic infections, but
has been found in intra-amniotic infections causing septic abor-
tions with no evidence of vaginal infection (Liang and Yeh, 2005).
In a study of 29 cases of S. pneumonia infection of neonates, one
mother had bacterial infection at delivery and clinical amnionitis
(Hoffman et al., 2003).
The vast majority of the genera identiﬁed in intra-amniotic
infections belong to bacteria found in the indigenous human
microbiota. Leaving out exogenously acquired bacteria, and con-
sidering that more than a trillion microbes inhabit body surfaces
and cavities, and outnumber human cells by at least a factor of
10, the human body is a rich potential source for opportunis-
tic BIAC. Pathogens residing in body sites that could access the
ascending migration or haematogenous route will inﬂuence the
diversity and abundance of bacteria in the amniotic ﬂuid.
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Mendz et al. Intra-amniotic microbiome of pregnant women
Amongst newborns, low and very low weight infants are at the
highest risk of early death or disability, thus, a major focus of
research in Obstetrics should be a better understanding of the
processes that lead to PTB and the development of preventive
interventions (Lockwood, 2013).
“Future efforts to reduce the rate of PTB depend upon gaining
an improved understanding of the causative mechanism(s), deter-
mining differences in individual susceptibility, and identifying
speciﬁc early-stage biomarkers that will allow the development of
novel and timely intervention strategies.” (Hussein et al., 2011).
In the last 15 years, the signiﬁcant progress made in the knowl-
edge of the diversity of bacterial communities in the female genital
tract and the role of bacterial infections in PTB wrought by
novel sequencing techniques and bioinformatics tools, have made
reduction of PTB a goal achievable by research directed toward
prevention of BIAC by pathogens.
Considering the limitations of studies based on bacterial
cultivation to reveal all the microﬂora present, new comprehen-
sive investigations employing non-culture methods and state-
of-the-art sequencing analyses are required to establish the
intra-uterine microbiome in health and disease. A complete
census of the intra-uterine microbiota during pregnancy con-
ducted concurrently with a census of the vaginal microbiome
will serve to outline the characteristics of the bacterial commu-
nities in the female genital tract; in particular, the elucidation
of the microbial intra-uterine populations in healthy pregnant
women, as well as the contribution of ascending infections
Future investigations that establish with more accuracy the
bacterial taxa found in association with PTB, as well as their
routes of invasion of the intra-amniotic cavity will provide impor-
tant knowledge to support the development of earlier and more
speciﬁc diagnostic methods of maternal genital infections. This
will result in better targeted and more effective treatments,
including many infections that presently are clinically silent and
can cause signiﬁcant morbidity in fetuses and infants. A full
understanding of the female urogenital microbiome will render
these infections amenable to intervention and will have an impact
in the prevention of PTB.
Foundation of the Cerebral Palsy Alliance of Australia. The
authors are grateful for the contribution of E. L. Menendez to
the compilation a large data set of bacteria found in the intra-
amniotic space, their phylogeny, their primary locations in the
human body, and the diseases they cause.
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Conﬂict of Interest Statement: The
authors declare that the research
was conducted in the absence of any
commercial or ﬁnancial relationships
that could be construed as a potential
conﬂict of interest.
Received: 28 July 2013; accepted: 16
September 2013; published online: 16
Citation: Mendz GL, Kaakoush NO and
Quinlivan JA (2013) Bacterial aetiolog-
ical agents of intra-amniotic infections
and preterm birth in pregnant women.
Front. Cell. Infect. Microbiol. 3:58. doi:
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