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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.
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REVIEW ARTICLE
published: 16 October 2013
doi: 10.3389/fcimb.2013.00058
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
Edited by:
Paul De Figueiredo, Texas A&M
University, USA
Reviewed by:
Qing-Ming Qin, Jilin University,
China
Neetu Singh, Texas A&M University,
USA
*Correspondence:
George L. Mendz, School of
Medicine, Sydney, The University of
Notre Dame Australia, 160 Oxford
St., Darlinghurst, NSW 2010,
Australia
e-mail: george.mendz@nd.edu.au
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
INTRODUCTION
“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
Y
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.,
2004).
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,
2013).
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
in BIAC.
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
DATABASE SEARCHES
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
found.
PHYLOGENETIC ORGANIZATION
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
ANALYSES
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
publications.
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
during pregnancy.
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
morbidities.
Table 1 | Bacteria found in the intra-uterine microbiota of the 349
pregnant women with intra-amniotic infection.
Phylum Order Species Frequency
(n)
Actinobacteria Actinomycetales Actinomyces spp. 1
Brachybacterium spp. 1
Corynebacterium
ammoniagenes
1
Corynebacterium
amycolatum
1
Corynebacterium
tuberculostearicum
1
Mobiluncus mulieris 1
Propionibacterium acnes 1
Propionibacterium spp. 2
Rothia dentocariosa 1
Coriobacteriales Atopobium vaginae 2
Bifidobacteriales Bifidobacterium longum 1
Bifidobacterium
pseudolongum
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
assacharolyticus
4
Peptoniphilus lacrimalis 1
Peptostreptococcus
oralis
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
epidermis
1
Staphylococcus equorum 2
Staphylococcus
pettenkoferi
2
Staphylococcus spp. 6
Lactobacillales Enterococcus faecalis 1
Enterococcus spp. 10
Lactobacillus crispatus 3
Lactobacillus delbrueckii 1
Lactobacillus gasseri 1
(Continued)
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Mendz et al. Intra-amniotic microbiome of pregnant women
Table 1 | Continued
Phylum Order Species Frequency
(n)
Lactobacillus iners 1
Lactobacillus spp. 3
Streptococcus agalactiae 37
Streptococcus anginosus 11
Streptococcus mitis 10
Streptococcus oralis 4
Streptococcus
pneumoniae
3
Streptococcus salivarius 1
Streptococcus spp. 1
Fusobacteria Fusobacteriales Fusobacterium
gonidoformans
1
Fusobacterium
nucleatum
31
Fusobacterium spp. 4
Leptotrichia amnionii 5
Leptotrichia spp. 17
Sneathia sanguinegens 13
Bacteroidetes Bacteroidales Bacteroides fragilis 4
Bacteroides
xylanosolvens
1
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
ureolyticus
3
Campylobacter spp. 1
Neisseriales Kingella denitrificans 1
Neisseria cinerea 1
Neisseria subflava 1
Neisseria spp. 1
Burkholderiales Delftia acidovioans 1
Pasteurellales Haemophilus
haemoglobinophilus
1
Haemophilus influenza 10
Haemophilus
parainluenza
2
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
pathway.
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
studies.
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
cavity.
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
parainfluenza,andStreptococcus pneumoniae.
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
FUTURE RESEARCH
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
to BIAC.
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.
ACKNOWLEDGMENTS
ThisstudywassupportedbyagrantfromtheResearch
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
October 2013.
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:
10.3389/fcimb.2013.00058
This article was submitted to the jour-
nal Frontiers in Cellular and Infection
Microbiology.
Copyright © 2013 Mendz, Kaakoush
and Quinlivan. This is an open-access
article distributed under the terms of
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Frontiers in Cellular and Infection Microbiology www.frontiersin.org October 2013 | Volume 3 | Article 58 |7
... Intra amniotic infection classically occurs in the setting of ruptured membranes, which suggests that the bridge of the fetal membrane provides an important barrier to fetal infection. Pathogens endemic to the vaginal microflora such as group B Streptococcus (GBS), E. coli and Bacteroides species have been found in placental and neonatal cultures 97 . Both primate and murine models demonstrate that vaginal microorganisms can traverse the genital tract and cause disseminated disease in the fetal cavity. ...
... Both primate and murine models demonstrate that vaginal microorganisms can traverse the genital tract and cause disseminated disease in the fetal cavity. Typically, infections arise from genitourinary microbiota and can be polymicrobial 97,98 . To cause dis ease in the uterine cavity, these bacteria would have to ascend the vaginal microbial biofilm and the antimicro bial cervical mucous plug to contact the fetal membranes and cause an inflammatory response locally. ...
... Screening for colonization and intrapartum prophylaxis with anti biotics decreases the incidence of early onset neonatal sepsis 99 . GBS biofilms on fetal membranes have been observed 100 and it is one of the most commonly cultured bacteria in the setting of intra amniotic infections 97 . GBS colonizes the genital tract in ~10-30% of women 101 . ...
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Infections are a major threat to human reproductive health, and infections in pregnancy can cause prematurity or stillbirth, or can be vertically transmitted to the fetus leading to congenital infection and severe disease. The acronym ‘TORCH’ (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) refers to pathogens directly associated with the development of congenital disease and includes diverse bacteria, viruses and parasites. The placenta restricts vertical transmission during pregnancy and has evolved robust mechanisms of microbial defence. However, microorganisms that cause congenital disease have likely evolved diverse mechanisms to bypass these defences. In this Review, we discuss how TORCH pathogens access the intra-amniotic space and overcome the placental defences that protect against microbial vertical transmission.
... Similar to the placenta, the uterus was considered a sterile body site, but recent studies and their collective systematic review have started to shift this idea (Mendz et al., 2013). The consideration that the uterus can be colonized by bacteria opens a much more likely possibility of the same bacteria being transferred to the placenta (Mendz et al., 2013;Lisa F Stinson et al., 2019). ...
... Similar to the placenta, the uterus was considered a sterile body site, but recent studies and their collective systematic review have started to shift this idea (Mendz et al., 2013). The consideration that the uterus can be colonized by bacteria opens a much more likely possibility of the same bacteria being transferred to the placenta (Mendz et al., 2013;Lisa F Stinson et al., 2019). ...
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Objective To assess the available scientific evidence regarding placental microbial composition of a healthy pregnancy, the quality of this evidence, and the potential relation between placental and oral microbiome. Materials and methods Data sources: MEDLINE and EMBASE up to August 1, 2019. Study eligibility criteria: Human subjects; healthy women; term deliveries; healthy normal birth weight; assessment of microorganisms (bacteria) in placental tissue; full research papers in English. The quality of the included studies was assessed by a modified Joanna Briggs Institute checklist for analytical cross-sectional studies. Results 57 studies passed the inclusion criteria. Of these, 33 had a high risk of quality bias (e.g., insufficient infection control, lack of negative controls, poor description of the healthy cases). The remaining 24 studies had a low (N = 12) to moderate (N = 12) risk of bias and were selected for in-depth analysis. Of these 24 studies, 22 reported microorganisms in placental tissues withLactobacillus (11 studies), Ureaplasma (7), Fusobacterium (7), Staphylococcus (7), Prevotella (6) and Streptococcus (6) among the most frequently identified genera. Methylobacterium (4), Propionibacterium (3), Pseudomonas (3) and Escherichia (2), among others, although frequently reported in placental samples, were often reported as contaminants in studies that used negative controls. Conclusions The results support the existence of a low biomass placental microbiota in healthy pregnancies. Some of the microbial taxa found in the placenta might have an oral origin. The high risk of quality bias for the majority of the included studies indicates that the results of individual papers should be interpreted with caution.
... Vaginal infections caused by group B Streptococcus (GBS), Escherichia coli, Bacteroides species, C. trachomatis, and N. gonorrhoeae can ascend to the genital tract and intraamniotic fluid causing chorioamnionitis (Galinsky et al., 2013;Jain et al., 2022). Infections caused by ascending genito-urinary tract pathogens are typically polymicrobial (Mendz et al., 2013) and often associated with microbial biofilm and antimicrobial cervical mucous plug to reach the intra-amniotic fluid or maternal-fetal interface and induce inflammation locally, which then endangers the fetus due to aberrant inflammation at the fetal membrane (Ayala et al., 2019). There is no clear evidence of how dysbiotic flora crosses the maternal barriers to reach the fetus, but GBS and E. coli are the most common pathogens found in the placenta and late-onset sepsis in neonates (Wilkie et al., 2019;Glaser et al., 2021). ...
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Pregnancy causes physiological and immunological adaptations that allow the mother and fetus to communicate with precision in order to promote a healthy pregnancy. At the same time, these adaptations may make pregnant women more susceptible to infections, resulting in a variety of pregnancy complications; those pathogens may also be vertically transmitted to the fetus, resulting in adverse pregnancy outcomes. Even though the placenta has developed a robust microbial defense to restrict vertical microbial transmission, certain microbial pathogens have evolved mechanisms to avoid the placental barrier and cause congenital diseases. Recent mechanistic studies have begun to uncover the striking role of the maternal microbiota in pregnancy outcomes. In this review, we discuss how microbial pathogens overcome the placental barrier to cause congenital diseases. A better understanding of the placental control of fetal infection should provide new insights into future translational research.
... Считается, что роль вагинальной инфекции в генезе самопроизвольного выкидыша и неразвиваю щейся беременности в I триместре относительно невелика [6,7], хотя у 60% пациенток с невынашиванием беременности в полости матки, цервикальном канале и влагалище обнаруживалась смешанная бактериальная инфекция, представленная условно-патогенными микроорганизмами 1 . Однако перенесенные в начале гестации бактериальный вагиноз (БВ) и аэробный вагинит (АВ) являются доказанными факторами риска спонтанного выкидыша во II триместре, преждевременных родов, осложнений послеродового периода, негативных перинатальных исходов [5,6,8]. ...
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Introduction . The causes for adverse pregnancy outcomes are usually complex and, in some cases, can worsen each other. Aim . To assess the role and establish the interplay of hormonal and infectious factors in the pathological course of pregnancy in women with threatened spontaneous miscarriage. Materials and methods . A total 120 pregnant women were enrolled for the observational prospective study, in which they were divided into 4 groups. Group 1 included 32 patients with threatened spontaneous miscarriage and hyperandrogenism (HA), who received glucocorticosteroids (GCS); group 2 included 28 patients with threatened spontaneous miscarriage and HA, who did not receive GCS; group 3 included 30 patients with threatened spontaneous miscarriage without HA; group 4 (control) included 30 women with a physiological course of pregnancy. The following examination methods were used: clinical assessment of the course of pregnancy; measurement of the serum levels of dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP) and total testosterone at weeks 5 to 8, 9 to 12, 13 to 18, 19 to 24 and 25 to 32 of gestation; microbiological tests of vaginal discharge. Results . The evaluation of androgenic status showed that the levels of the tested hormonal parameters in women with HA significantly exceeded those of the control group, while the changes in 17-OHP and testosterone secretion was comparable to that in women without HA, and DHEA-S level decreased to control values by the third trimester. The use of corticosteroids was associated with significant changes in the values and secretion levels of 17-OHP and DHEA-S, but not testosterone; DHEA-S levels decreased to the values that were significantly lower as compared to all groups in the third trimester of pregnancy. Conclusions . Vaginal infections play an important role in the genesis of gestational failures. Hyperandrogenism exacerbates the problem of miscarriage, however, the use of corticosteroids does not result in improved hormonal characteristics and clinical pregnancy outcomes, deteriorating the vaginal biocenosis.
... Chow et al. found that statins could improve the ability of macrophages to kill Staphylococcus aureus by inducing the production of METs through inhibiting the sterol pathway in vitro and in vivo [6]. Streptococcus agalactiae, another Gram-positive bacteria, is associated with adverse pregnancy outcomes in pregnant women [33]. Doster et al. demonstrated that placental macrophages exposed to Streptococcus agalactiae in vitro could release METs and kill the organism, which depended on the production of ROS, and they found METs in human fetal membrane tissues infected in vitro. ...
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Macrophages are an important component of the human immune system and play a key role in the immune response, which can protect the body against infection and regulate the development of tissue inflammation. Some studies found that macrophages can produce extracellular traps (ETs) under various conditions of stimulation. ETs are web-like structures that consist of proteins and DNA. ETs are thought to immobilize and kill microorganisms, as well as play an important role in tissue damage, inflammatory progression, and autoimmune diseases. In this review, the structure, identification, mechanism, and research progress of macrophage extracellular traps (METs) in related diseases are reviewed.
... In adults, although it is considered a low virulence pathogen, it has been isolated in cases of endocarditis, pneumonia, endophthalmitis and peritonitis [2]. Vaginal colonization or isolation in intrauterine bacterial infections is exceptional [3]. However, periodontal disease in pregnant women due to this and other bacteria has been related to premature labor and low birth weight [1], although infections in the fetus and newborn have been scarcely reported. ...
Article
Objectives To describe an infrequent case of bacteremia by Rothia dentocariosa in a newborn and to discuss its potential pathogenicity. Case presentation R. dentocariosa is an aerobic or facultative anaerobic gram-positive bacillus, common in the human oral cavity that has been isolated in cases of endocarditis, pneumonia, endophthalmitis and peritonitis in adults. Infections in the fetus and newborn have been scarcely reported. We present a full-term newborn with prolonged rupture of membranes, acute elevation of C-reactive protein, and isolation of R. dentocariosa in the blood culture. Endocarditis was ruled out and the patient did well with five days of intravenous broad spectrum antibiotics. To date, only a previous case of sepsis by R. dentocariosa in a neonate with meconium aspiration syndrome and an antenatal death of a full-term fetus with hemorrhagic brain lesions probably related to R. dentocariosa have been reported. Conclusions Until more information about the pathogenicity of this germ in the newborn is available, an individualized approach and a close clinical control of the patient with infectious risk factors and bacteremia by R. dentocariosa seem to be prudent.
... Further research revealed that there are uncultivated microbes that may induce inflammatory response in the amniotic fluid of PTD women. In addition, culture-independent techniques showed 46% of women with PTD have intrauterine infections (34). The development of detection technology has increased the detection rate of microbes in amniotic fluid, which promotes the understanding of the relationship between the uterine microbiota and APOs. ...
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From early life to adulthood, the microbiota play a crucial role in the health of the infant. The microbiota in early life are not only a key regulator of infant health but also associated with long-term health. Pregnancy to early life is the golden time for the establishment of the infant microbiota, which is affected by both environmental and genetic factors. Recently, there is an explosion of the studies on the role of microbiota in human diseases, but the application to disease or health is relatively limited because many aspects of human microbiota remain controversial, especially about the infant microbiota. Therefore, a critical and conclusive review is necessary to understand fully the relationship between the microbiota and the health of infant. In this article, we introduce in detail the role of microbiota in the infant from pregnancy to early life to long-term health. The main contents of this article include the relationship between the maternal microbiota and adverse pregnancy outcomes, the establishment of the neonatal microbiota during perinatal period and early life, the composition of the infant gut microbiota, the prediction of the microbiota for long-term health, and the future study directions of microbiota.
... Causality between histopathological changes in the placental tissue, PTB and infection can only be established if the causative pathogen is identified. The development of more sensitive, non-selective diagnostic tools over the last few years, provides researchers with additional options to unravel the link between the triad of PTB, infection and placental histopathological abnormalities [73]. Diagnostic tools reported in the reviewed studies included bacteriological culture, nucleic amplification techniques, immunohistochemical staining of placental tissue, with only one study using 16S rRNA sequencing [49]. ...
Research
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Four in five neonatal deaths of preterm births occur in low and middle income countries and placental histopathology examination can help clarify the pathogenesis. Infection is known to play a significant role in preterm birth. The aim of this systematic review is to explore the association between placental histopathological abnormality and preterm birth in the presence of confirmed infection. PubMed/Medline, Scopus, Web of Science and Embase were searched using the keywords related to preterm birth, placental histopathology and infection. Titles and abstracts were screened and the full texts of eligible articles were reviewed to extract and summarise data. Of 1529 articles, only 23 studies (13 bacterial, 6 viral and 4 parasitic) were included, and they used 7 different gestational age windows, and 20 different histopathological classification systems, precluding data pooling. Despite this, histopatho-logical chorioamnionitis, and funisitis (when examined) were commonly observed in preterm birth complicated by confirmed bacterial or viral, but not parasitic, infection. The presence of malaria parasites but not pigment in placenta was reported to increase the risk of PTB, but this finding was inconclusive. One in three studies were conducted in low and middle income countries. An array of: definitions of preterm birth subgroups, histological classification systems , histopathologic abnormalities and diagnostic methods to identify infections were reported in this systematic review. Commitment to using standardised terminology and classification of histopathological abnormalities associated with infections is needed to identify causality and potential treatment of preterm birth. Studies on preterm birth needs to occur in high burden countries and control for clinical characteristics (maternal, fetal, labor, and pla-cental) that may have an impact on placental histopathological abnormalities.
Article
Objective: The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. Study design: We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. Results: In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. Conclusion: In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB. Key points: · 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..
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Intra-amniotic infection and inflammation (IAI) affect fetal development and are highly associated with preterm labor and premature rupture of membranes, which often lead to adverse neonatal outcomes. Human amniotic membrane (hAM), the inner part of the amnio-chorionic membrane, protects the embryo/fetus from environmental dangers, including microbial infection. However, weakened amnio-chorionic membrane may be breached or pathogens may enter through a different route, leading to IAI. The hAM and human amniotic fluid (hAF) respond by activation of all components of the innate immune system. This includes changes in 1) hAM structure, 2) presence of immune cells, 3) pattern recognition receptors, 4) cytokines, 5) antimicrobial peptides, 6) lipid derivatives, and 7) complement system. Herein we provide a comprehensive and integrative review of the current understanding of the innate immune response in the hAM and hAF, which will aid in design of novel studies that may lead to breakthroughs in how we perceive the IAI.
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Periodontitis and prematurity are social diseases with common risk factors. In 1996 periodontitis was proven to be a possible significant and independent risk factor of preterm birth of newborns with low body weight. Numerous studies on the influence of periodontitis on the time of birth and/or birth weight of newborns have been conducted throughout the world since, including several ones in Poland, but their results have been inconsistent. Work objective: A meta-analysis of case-control, prospective and cohort studies on the influence of periodontitis on preterm birth and low birth weight. The international and Polish bibliography bases were searched for essays on the relationship between periodontitis and preterm birth and/or low birth weight published between 1996 and 2010. All essays qualified for the meta-analysis were subjected to qualitative evaluation. The calculation of the overall odds ratio used both, fixed-effects and random-effects models (DerSimonian-Liard method). The heterogeneity of the included studies and effect of publication bias were also subjected to evaluation. The meta-analysis included 15 case-control studies, 1 cross-sectional study and 6 cohort studies. The essays came from 4 continents: 8 from Europe (including 2 from Poland), 7 from South America, 4 from North America, and 3 from Asia. The total analysis covered 12047 pregnant women. The overall odds ratio of giving premature birth to a child with low weight for mothers with periodontitis in the model of random effects amounted to 2.35 (1.88-2.93, p < 0.0001). For low birth weight, the overall OR was 1.5 (95% Cl: 1.26-1.79, p = 0.001) for premature births--2.73 (95% CI: 2.06-3.6, p < 0.0001). A significant heterogeneity of the studies included in the meta-analysis was observed, and a significant publication bias was also demonstrated. The hypothesis of periodontitis as an independent risk factor of preterm birth and/or low birth weight needs further verification. In order to achieve that, it is necessary to conduct more methodologically well-planned cohort and intervention studies. The need of dental care for pregnant women as an integral component of the prenatal care program remains to be an important issue.
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Problem: The role played by microbial invasion of the amniotic cavity (MIAC) in preterm pre-labor rupture of membranes (pPROM) is inadequately characterized, in part because of reliance on cultivation-based methods. Method of study: Amniotic fluid from 204 subjects with pPROM was analyzed with both cultivation and molecular methods in a retrospective cohort study. Broad-range and group-specific polymerase chain reaction (PCR) assays targeted small subunit ribosomal DNA (rDNA), or other gene sequences, from bacteria, fungi, and archaea. Results were correlated with measurements of host inflammation, as well as pregnancy and perinatal outcomes. Results: The prevalence of MIAC was 34% (70/204) by culture, 45% (92/204) by PCR, and 50% (101/204) by both methods combined. The number of bacterial species revealed by PCR (44 species-level phylotypes) was greater than that by culture (14 species) and included as-yet uncultivated taxa. Some taxa detected by PCR have been previously associated with the gastrointestinal tract (e.g., Coprobacillus sp.), the mouth (e.g., Rothia dentocariosa), or the vagina in the setting of bacterial vaginosis (e.g., Atopobium vaginae). The relative risk for histologic chorioamnionitis was 2.1 for a positive PCR [95% confidence interval (CI), 1.4-3.0] and 2.0 for a positive culture (95% CI, 1.4-2.7). Bacterial rDNA abundance exhibited a dose relationship with gestational age at delivery (R(2) = 0.26; P < 0.01). A positive PCR was associated with lower mean birthweight, and with higher rates of respiratory distress syndrome and necrotizing enterocolitis (P < 0.05 for each outcome). Conclusion: MIAC in pPROM is more common than previously recognized and is associated in some cases with uncultivated taxa, some of which are typically associated with the gastrointestinal tract. The detection of MIAC by molecular methods has clinical significance.
Article
Reproductive tract infection is a major initiator of preterm birth (PTB). The objective of this prospective cohort study of 88 participants was to determine whether PTB correlates with the vaginal microbiome during pregnancy. Total DNA was purified from posterior vaginal fornix swabs during gestation. The 16S ribosomal RNA gene was amplified using polymerase chain reaction primers, followed by chain-termination sequencing. Bacteria were identified by comparing contig consensus sequences with the Ribosomal Database Project. Dichotomous responses were summarized via proportions and continuous variables via means ± standard deviation. Mean Shannon Diversity index differed by Welch t test (P = .00016) between caucasians with PTB and term gestation. Species diversity was greatest among African Americans (P = .0045). Change in microbiome/Lactobacillus content and presence of putative novel/noxious bacteria did not correlate with PTB. We conclude that uncultured vaginal bacteria play an important role in PTB and race/ethnicity and sampling location are important determinants of the vaginal microbiome.
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Haemophilus influenzae rarely causes acute endometritis and the few published cases have always been associated with intrauterine devices (IUD). A 48-year-old female presented to the emergency department with a 3-day history of lower abdominal pain and fever. On physical examination she was tachycardic, hypotensive and had fundic tenderness to palpation. Imaging showed uterine leiomyomas and no IUD. Blood cultures grew a non-typable H. influenzae. Endometrial biopsy demonstrated acute endometritis. Tissue Gram stains and cervico-vaginal cultures were negative; however, polymerase chain reaction (PCR) determined presence of H. influenzae on the formalin-fixed, paraffin-embedded tissue biopsy. Evidence of H. influenzae in the endometrium demonstrates that the uterus can be the nidus for sepsis when invasive H. influenzae is found with no distinct usual primary focus. This case underscores the importance pathologic diagnosis and molecular testing.
Article
The study focuses on the macroscopic and microscopic aspects of the placentae resulting from abortions or febrile births and their correlation with acute disorders of the upper or lower respiratory apparatus in pregnant women in various stages of pregnancy. The viral, bacterial or mycotic disorders were considered responsible for triggering septic abortion, premature or full-term deliveries, followed by septic complications of the child÷fetus or of the mother. When the mother's acute respiratory infection is induced by highly virulent pathogens, in patients with low immunity or lacking adequate medical treatment, the infection may spread through the mother's bloodstream to the placenta. The study was conducted on 90 placentae. Microscopic analysis of the tissue samples revealed acute inflammatory infiltration. Two of the study cases should be mentioned here: a four-month pregnant woman suffering from septic abortion and a nine-month pregnant woman whose fetus died in the womb because of acute pneumopathy on a non-breathing lung. Both pregnant women had the same type of disorder and neither followed any medical treatment prescribed by a physician. The prevention of placental infection is closely connected to the prevention of acute respiratory diseases or their proper treatment after their onset.
Article
In 2005, the World Health Organization estimated that 9.6% or 12.9 million births worldwide were born preterm at <37 weeks of gestation and were accompanied by a mortality rate as high as 42% (http://www.who.int/bulletin/volumes/88/1/08-062554). Significant data suggesting that intrauterine infection is an important modifier for the risk of preterm birth have emerged over the past four decades. However, causative microbial culprits have yet to be identified, and interventional trials with antimicrobials have uniformly failed to demonstrate a significant benefit. To the contrary, treatment for clinically asymptomatic, commonly associated polymicrobial communities (i.e., bacterial vaginosis) has resulted in an increase in the rate of preterm birth. This article discusses the importance of vaginal microbiome and the variance in its composition during normal pregnancy. We will expand this discussion to include possible mechanisms that might trigger preterm birth in at-risk subjects. Finally, we will review why preterm birth may be an ideal forum with which to apply our rapidly expanding metagenomic sequencing and analytic pipelines to discern the role of host and microbe in the relative continuum of health and disease.
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We conducted a case-control study at three main inner-city hospitals in Birmingham, UK between 2004 and 2006, to determine the risk of adverse perinatal outcomes in pregnant women with tuberculosis (TB) (n = 24), compared with healthy pregnant controls (n = 72). The incidence of TB was 62/100,000 pregnancies, with 54.2% cases having pulmonary TB (41.7% extra-pulmonary; 4.2% both). Infants of mothers with TB had a significantly lower mean birth weight compared with controls (2,735 g vs 3,135 g; p = 0.03). Mean birth weight was lower in pulmonary TB than in the extra-pulmonary TB. Multivariate analysis showed that low birth weight was associated with pre-term delivery (p < 0.001). We conclude that pregnant women with TB are at higher risk of low birth weight due to higher odds of pre-term delivery.
Article
Objective: Bacterial polymerase chain reaction (PCR) was used to detect early subclinical intraamhiotic infection. We used universal primers which amplify a DNA fragment of 16S ribosomal DNA (rDNA) from all known bacteria and sequenced the positive samples to identify the bacterial species. Design: Transabdominally obtained amniotic fluid samples from 20 pregnant women with prelabour rupture of the fetal membranes (PROM), showing no signs of clinical infection, and 16 control samples were analysed with universal bacterial PCR. In addition, routine bacterial culture and amniotic fluid glucose were studied. Results: Out of 20 PROM patients, five were positive in the PCR. PCR detected Ureaplasma urealyticum in two cases, Haemophilus influenzae in one case, Streptococcus oralis in one case and Fusobacterium sp. in one case. Only two of these were positive in a routine bacterial culture. Both were multibacterial infections, which caused discrepancies between the PCR and culture results. Two patients developed infectious complications: both were identified with the PCR assay. Amniotic fluid glucose was lower in PCR positive patients compared with PCR negative patients. Conclusion: Bacterial 16S rDNA PCR, in properly controlled conditions, promises to be a fast and reliable test for early intra-amniotic infection especially concerning Ureaplasma urealyticum.