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Abstract
Studies have begun to show the presence of bacteria in not only preterm placental tissues,
but in placental tissues from healthy pregnancies that went to term. This has lead researchers to
rethink the idea of the uterine environment, disputing the idea that embryos develop in sterility.
Using culture-based methods, bacteria were recovered from the non-pregnant uterus, indicating
that infection may occur prior to pregnancy, however, even women positive for bacteria within
the endometrium were found to have full, healthy pregnancies (Andrews et al. 2005). Other
studies were able to detect bacterial DNA among placental tissue from preterm and term
pregnancies in the absence of chorioamnionitis, or inflammation of the fetal membranes. It has
been observed that preterm pregnancies tend to have a greater diversity of bacterial species.
Some have begun to believe that the bacteria initiate the microbiome of the developing
fetus, and tried to characterize the species present in healthy term placentas by comparison of the
bacteria found in term placentas. These bacteria may also play a role in pregnancy. For instance,
one bacteria may alter the tissue structure in such a way as to allow other bacteria to colonize
tissue. Unfortunately, it is still unclear what species are necessary to the microbiome and which
are pathogenic, or whether there are other factors that induce pathogenicity of certain bacteria.
The microbiome of a healthy pregnancy appears to be most similar to that of the oral
microbiome. Much more research will be necessary to determine more about the microbiome,
the factors that influence it, and whether it is beneficial, harmless, or harmful.
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Introduction
Little thought is given to the abilities provided to human physiology by microscopic
organisms. It is well-known that bacteria live in our bodies, but what is not often known are the
important functions these bacteria perform for our benefit. Bacteria have the ability to form
colonies that thrive any place, such as on our skin, nose, mouth, guts, and more recently
discovered, the placenta. These communities throughout the human body are referred to as
microbiomes. Though microscopic, these tiny, one-celled organisms overt a great power over us
to which we tend to forget. They can have positive and negative effects on function of the human
body.
One of the most well-known microbiomes is the intestines, which aids in the ability
digest foods and obtain certain vitamins and minerals. Every person has a unique constitution of
the amount and types of bacteria that inhabit their intestines (Hattori and Taylor 2009). The
consequence of this variation can cause some conditions such as irritable bowel syndrome (Iwase
et al. 2010). It has also been observed that alterations to the gut microbiome can have effects in
other areas of the body such as the central nervous system, and is believed to have an influence
on autism, depression, and eating disorders among other psychiatric disorders (Konkel 2013).
Generally, though, the presence and diversity of bacteria is necessary for optimal health
as it provides functions that our body is unable to perform on its own. The human body has a
high degree of complexity, which makes it surprising that each cell within the human body
contains a similar number of genes to that found in the cells of a less complex species such as the
fruit fly. That is to say, the cells within the human body carry only 20,000 genes, which is distant
from what was expected prior to this discovery. When taking into consideration the additional
genes provided by commensal bacteria, this number is likely greater than 100,000, as these
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bacteria outnumber our own cells 10:1 (Belkaid and Hand 2014). These additional genes provide
functions that our body evolved without, such as the ability to produce necessary vitamins and
breakdown complex food material (Turnbaugh et al. 2007). They also act as a boost for the
immune system through initiation and training it to recognize bacterial antigens (Belkaid and
Hand 2014).
The role of these bacteria is so important that scientists have developed the Human
Microbiome Project (HMP). The goal of HMP is to determine the specific bacteria that constitute
the complete microbiome, as well as how they function to improve or compromise human health
(Turnbaugh et al. 2007). Using an advancement in DNA analysis called metagenomics, scientists
are now able to study bacterial genomes within communities from their natural habitat.
Metagenomics has opened doors to ways of studying bacteria that are unable to be cultured. For
instance, many resident species of the gut were not identified previously due to strict
environmental conditions that are not reproducible in a lab setting. Now these species can be
identified from samples taken from the environment. Furthermore, bacteria have been discovered
in places previously thought sterile, such as the placental membranes of infants in utero. Using
advanced DNA Techniques, analysis of the characteristics of the communities have been
performed. (Aagard et al. 2014).
The recently discovered presence of bacteria in the tissue that constitutes the placenta has
led researchers to speculate that the placenta may also harbor a unique microbiome,
distinguished from other microbiomes of the body. It will be important to understand how this
integral part of our body comes about, and the factors that influence community structures during
development. A greater understanding of these aspects of the microbiome will allow us to guide
the development of the microbiome into a community optimal for overall health. Some scientists
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believe the development of the human microbiome may begin in utero. If this is true, there are
reasons to believe current practices are outdated and may impair development, including the use
of antibiotics, maternal diet, and delivery methods, among others. The consequences of
impairment so early in development could lead to a cascade of negative consequences relating to
the microbiome later in life, affecting the necessary attributes they provide.
The goal of this review is to combine the observations of current research concerning the
colonization of the placenta, such as the type of bacteria present, the process through which they
colonize, and their possible role in pregnancy or fetal development. It may now be the case that
development of the human microbiome begins in utero and complete at a point in childhood
where the microbiome reaches stability. This point of stability is characterized by similarity in
dynamics of diversity and bacterial counts through adulthood.
Bacterial Colonization in the Placenta: Simple infection?
The presence of bacteria has been observed in the amniotic fluid and chorioamnion for
quite some time and is believed to be the major cause of preterm-birth (Andrews et al. 2005).
Infection begins early in gestation and is derived from ascension from the upper genital tract.
Women who undergo very early preterm delivery typically experience the same results in
following pregnancies. This, in addition to the occurrence of endometritis in nonpregnant women
suggests that colonization occurs prior to pregnancy and may explain why some women
experience repeat preterm labor. This was not supported by one study, as researchers it was
observed that microbial colonization of the endometrium 3 months after delivery was similar in
frequency between women with recent spontaneous preterm delivery, indicated preterm, and
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spontaneous term birth. They found approximately 80% of women were positive for endometrial
bacterial colonization (Andrews et al. 2005).
Previous studies were able to detect bacteria using culture-based methodology, however,
metagenomics have shown the existence of other bacteria in the placental membrane that were
not observed when culture-based methods were used alone. People have begun research into the
bacteria present in the placental tissues and how they might have migrated to this environment
which was previously believed to be sterile. The studies presented here have shown the presence
of bacteria in placental membranes despite the length of gestation and delivery methods. Many
were quick to assume these were simply the result of infection and led to problems such as
preterm birth. Inflammation caused by infection within the amniotic fluid commonly results in
early delivery. Some of the following studies were performed to investigate the types of bacteria
present in placentas of preterm against term pregnancies. Researchers were then able to
determine if the presence of bacteria could only result in preterm birth or if their presence was
not always infective and therefore may serve a purpose.
As early as 2009, researchers believed that bacteria may not have been the major cause of
preterm birth, that they may serve a higher purpose. One study was performed in which
researchers used broad-range 16S rDNA endpoint PCR followed by species-specific real time
PCR in order to detect the presence of bacteria (Jones et al. 2009). Following broad-range 16S
rDNA PCR, 30% of women showed evidence of bacterial DNA within the fetal and placental
membranes. Using species-specific real time PCR, the percent increased to 43%. Of women in
this study, 72% delivered preterm, compared with the 28% control group which delivered to
term. No bacteria were observed in samples obtained by women who went to term and delivered
by cesarean section, whereas all other groups, including 50% of samples from women who went
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to term and delivered vaginally, exhibited bacterial DNA. 90% of samples from women that
experienced spontaneous preterm birth with intact membranes (all were delivered vaginally)
were positive for bacterial DNA. Furthermore, samples were taken from various locations of the
placental tissue to test for the spread of bacteria along the membrane. Figure 1, taken from their
study, shows that bacterial spread was greater in the preterm labor and preterm prolonged rupture
of membranes (PPROM) groups, whereas the term vaginal deliveries were positive, but exhibited
little spread as indicated by a lower number of samples positive for bacteria. They also found a
greater diversity of species among the woman that delivered preterm (preterm labor and
PPROM).
Figure 1: “The spread of bacteria in placental tissue and fetal membranes from term and very preterm
deliveries. Atotal of 5 samples were taken from each women. DNA was extracted and then subject to broad-
range 16S rDNA endpoint PCR and species-specific realtime PCR. The percentage (and number) of
individuals that had 3–5 samples, 1–2 samples, and 0 samples positive for bacteria are shown for each group.
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(CS) caesarean section, (V) spontaneous vaginal delivery, (PTL) preterm labour with intact membranes,
(PPROM) preterm prolonged rupture of membranes. (Jones et al. 2009)
As for determining the association between bacteria and inflammation, referred to as
chorioamnionitis, these same researchers found a higher prevalence among preterm labor (68%)
and PPROM (88%) groups. Similar to other studies, not all cases were positive for both bacteria
and chorioamnionitis, indicating that bacteria do not always cause inflammation. It can be
inferred then that there are other etiological forces that may have attributed to the resulting
inflammation other than the presence of bacteria. Figure 2, taken from their study, summarizes
the comparison of presence of bacteria, chorioamnionitis, or both among preterm groups.
Figure 2: “The presence of histological chorioamnionitis in fetalmembranes from very preterm
deliveries. Fetal membranes of all deliveries before 32 weeks gestation were assessed routinely for histological
chorioamnionitis. Here we show the association between the presence of bacteria in fetal membranes and
placental tissue and histological chorioamnionitis in preterm labour with intact membranes (PTL), preterm
prolonged rupture of membranes (PPROM), and indicated preterm delivery.” (Jones et al. 2009)
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Their final conclusions were that bacterial presence and diversity is greater among
preterm labor and PPROM groups. Furthermore, they determined that there is a positive
correlation of bacterial presence and chorioamnionitis, and that infection of the membranes is
more common than amniotic fluid in cases of preterm delivery. They suggest that the action of
labor may play a role in bacterial colonization, as intraamniotic infection is higher in active labor
in contrast to those delivered by cesarean section. Ultimately, they also concluded that though
there was a high correlation between chorioamnionitis and bacterial colonization, bacterial
colonization did not necessarily result in an established infection and result in preterm labor.
Similarly, Stout et al. (2013) began research to determine if bacteria were present in the
basal plate of the placenta specifically, and whether these bacteria were associated with preterm
birth. They found both gram positive and gram negative bacteria in all shapes present both as
individuals and as a biofilm in 27% of the placental samples. In all samples, only 17% were
diagnosed with choriamnionitis, or evidence of an intraamniotic infection. This provides further
evidence that the presence of bacteria did not always result in intraamniotic infection. About
35% of the samples were from preterm births, whereas the remaining 65% were from
pregnancies that made it to full-term. They concluded that preterm birth occurred regardless of
the presence of bacteria in the basal plate; though they did note high prevalence of bacteria in the
basal plate of pregnancies delivered at less than 28 weeks.
Satokari et al. (2009) looked specifically for Bifidobacterium and L. rhamnosus in
placentas of healthy term pregnancies and found that most samples were positive for both
regardless the mode of delivery. Neither were able to be cultured, but were discovered by use of
species specific DNA analysis using PCR. They discuss failures of cultivation due to freezing of
samples for storage as well as the possibility that the DNA detected were from dead cell parts
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and not from viable cells. They hypothesize that the bacterial DNA may facilitate development
of the immune system of the fetus while still in utero.
To sum, it has been shown that bacteria invade the endometrium of non-pregnant women,
however this is not believed to be associated with preterm birth. Bacteria have been observed in
placental samples despite gestation length or delivery method, even in the absence of
inflammation of the membranes. Bacteria have been observed in healthy, full-term placental
samples and in the absence of chorioamnionitis supports the hypothesis that bacteria do not
always cause preterm birth, and that their presence may play a physiological role in pregnancy or
infant development.
Microbiome Development Begins in the Placenta
Aagaard et al. (2014) hypothesized these bacteria were the beginning of development of
the infant microbiome, and constitute the placental microbiome. They found a distinct difference
in the gut microbiome of full-term infants in their first week compared to infants weighing less
than 1200g, suggesting that development of the infant microbiome begins in utero through the
placenta. They then performed research to identify the bacterial species and the community
construction found among the placental microbiome. It was observed in their findings that
individuals varied in species composition, however, most exhibited E. coli in the greatest
abundance. Oral species Prevotella tannerae and Neisseria (nonpathogenic) were also common.
They further determined that typical phyla include Proteobacteria and Tenericutes such as
Mycoplasma and Ureaplasma, Firmicutes, Bacteroidetes, and Fusobacteria. The researchers
concluded that altogether these form a placental microbiome consisting of nonpathogenic
bacteria with little diversity.
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Another study was performed to detect bacteria in the placental membranes of preterm
and term pregnancies and characterize the differences between them. The bacteria were also
compared in relation to how each pregnancy was delivered (Doyle et al. 2014). They discovered
a greater abundance as well as a more diverse group of bacteria in placental membranes of
preterm infants compared with term infants. Recall that this increased diversity was also seen in
the previous study by Jones et al. (2009). Term placental membranes did not differ greatly in
genera observed by different delivery methods, and exhibited Streptococcus, Microbacterium,
Rhodococcus, and Corynebacterium. Preterm placental membranes exhibited increased amounts
of Fusobacterium, Streptococcus, Mycoplasma, Aerococcus, Gardnerella, and Ureaplasma
genera as well as the family Enterobacteriaceae compared to term placental membranes.
Sequences found specific to preterm infants delivered vaginally were determined to represent F.
nucleatum, Mycoplasma hominis, Aerococcus christensenii, Streptococcus anginosus,
Streptococcus agalactiae, Gardnerella vaginalis, and Streptococcus itis. Figure 3 shows their
results indicating the abundance of various bacteria detected by sequencing analysis of two 16s
hypervariable regions in placentas of term infants delivered vaginally or through cesarean
section, and preterm infants delivered vaginally. Bacteria that were observed in the study by
Aagard et al. (2014) are marked with a blue star, and bacteria observed in the study by Jones et
al. (2009) are marked with a red star
They have noticed the species detected in this study resemble other studies which
associated bacteria to the placenta or preterm birth, including S. agalactiae, S. mitis group, and
Mycoplasma hominis. For the first time, A. christenensii was observed. They concluded that
bacteria are an important aspect in preterm birth, however there are distinct species composition
associated with preterm birth, differing from those observed in term births. Furthermore there are
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no significant differences observed in relation to different methods of delivery. They also noted
that the genera observed by Aagard et al. (2014) are dissimilar to those observed in this study,
though the same regions were sequence and analyzed. They believe the two 16S hypervariable
regions used do not allow for observation of the diversity present in completeness.
In a previously mentioned study (Jones et al. 2009), other researchers found that that the
most common species detected were U. parvum, Fusobacterium spp. Furthermore, most of the
species observed are associated with the vaginal tract, and have been linked to bacterial
vaginosis and a change in the vaginal microbiome; both of which are already known as important
factors of preterm birth. Some organisms present were associated with the upper respiratory
tract. Most of the species found to make-up the nonpathogenic microbiome of the placenta in the
research by Aagard et al. (2014) closely resembled the oral microbiome
These bacteria are believed to travel to the placenta from their respective microbiomes
via the blood, or hematogenous transmission. There has been a mechanism proposed by Perez et
al. (2007) in which viable bacteria from the intestinal lumen are transported by mononuclear
phagocytes such as dendritic cells to the mammary glands, where they can be secreted in breast
milk. This same mechanism, or perhaps a similar mechanism, may also serve as a transport
system to the placenta.
To sum, multiple phyla have been observed in the healthy term placenta with much
variation between individuals. Two studies found common phyla which include Fusobacterium,
Mycoplasma, Prevotella, Bacteroides, and Ureaplasma. These were also present in placenta
samples from preterm birth however they were observed in larger abundance. So far the
placental biome is most similar to that of the oral microbiome, and bacteria are believed to travel
to the placenta from various locations around the body through the blood.
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Figure 3 A) Bacteria found through amplification of two variable regions within samples of both term elective
caesarean sections (T CS) and vaginal deliveries (TL V). The bacteria observed were amplified by the two variable
regions shown as either red or blue; with varying shades ofeach to represent the abundance ofthe specific bacteria
observed.B) Bacteria found through amplification of two variable regions within samples of both preterm (PTL V)
vaginal deliveries as well as term vaginal deliveries for a direct comparison. Figures from Doyle et al. 2014. Stars
indicate bacteria in which
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The final Answer: Are these bacteria commensal or pathogenic?
Some studies, such as Onderdonk et al. (2008), found that preterm delivery was
positively correlated with high rates of colonization. In their research, they seen that colonization
of the placental parenchyma decreased as gestational age at birth increased. In that study,
however, culture-based methods were used, and researchers did not observe placentas from
pregnancies that went to term. While it is undoubtedly true that bacteria play a role in preterm
birth, they are not exclusive causes (Payne and Bayatibojakhi 2014), and they may play different
roles in the placenta as well.
Thus far, what is shown is that there is a great diversity among specimens in the bacteria
species present, and a greater diversity within a sample may indicate preterm birth. As many
studies could not detail specific bacterial species that are associated with either the preterm or
term placentas, we see a few genera overlap between the two such as Fusobacterium,
Mycoplasma, Ureaplasma, Streptococcus. This may just simply be that some species within
these genera are non-pathogenic, whereas the others are pathogenic and may result in preterm
birth. Another possible reason could be the genetic variation found within species. Different
bacterial taxa as well as species can vary widely in their DNA content. (Allen-Daniels et al.
2015). Bacteria have the ability to transfer DNA both between and within species, pick it up
from the environment, and evolve quickly due to their quick and constant reproduction. This
results in multiple strains of the same species. It is not unreasonable, nor uncommon, to find that
different strains of the same bacteria then may be pathogenic whereas some may be commensal.
Mycoplasma hominis, a species which has been heavily associated with preterm risks, is
one such species that is not always pathogenic. Harmless in nonpregnant women, it has been
shown to cause intraamniotic infection and result in chorioamnionitis (Allen-Daniels et al. 2015).
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Allen-Daniels et al. (2015) set out to find genes specific to intraamniotic infectious strains of
Mycoplasma hominis compared to a previously genetically sequenced strain, PG21. The three
experimental strains were referred to as AF1, AF3, and PL5. For the most part, all four strains
were genetically similar, however there were three genes found within the infectious strains that
were absent in PG21. These genes encoded alanine racemase (alr), a second gene (designated as
goiB) which may encode a secreted protease, and a third gene (designated as goiC) which is also
unknown in function and dissimilar to any known proteins. Researchers then looked attempted to
determine the association of these genes with preterm outcome. Vaginal flora samples were
obtained (n=58), 17 of which were positive for M. hominis. Of these 17, 4 samples were from
women that delivered preterm. The gene alr was present in 2 of the preterm samples and 5 of the
term samples. 3 and 4 preterm samples were positive for the genes goiB and goiC respectively,
while in term pregnancies, 6 and 4 were positive, respectively. GoiC was associated significantly
with preterm birth samples. Further research showed that the gene may facilitate colonization of
the placenta or in amniotic fluid preferentially than to the vagina.
Another factor that may cause some bacteria to become pathogenic could be bacteria
found within the community. For instance, pregnant woman with bacterial vaginosis are at
higher risk of having a pre-term birth when they are colonized by bacteroides and M. hominis.
(Hillier et al. 1995). The study performed by Allen-Daniels et al. (2015) found that the strain of
M. hominis that carried goiC had greater survival over Ureaplasma, indicated by a negative
correlation between the presence of the two. This is odd in that M. hominis and Ureaplasma are
often observed simultaneously in preterm samples. The sample size (n=4) that provided
evidence of presence of goiC in the absence of Ureaplasma was very small, however, and may
need to be researched further.
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Still, there are other reasons that may explain the overlap in genera observed in preterm
and term placentas. One explanation is that these bacteria serve a role in the development of the
microbiome, such as initiating colonization. It turns out that there may be a bacteria able to
perform such a role; the mechanism for colonization or infection of bacteria has been proposed
by Fardini et al. (2011). Fusobacterium nucleatum is a gram-negative bacteria found in the oral
microbiome that contains a molecule on its cell surface called FadA. Only F. nucleatum oral
species have shown this molecule as well as an increased ability to bind and penetrate host cells.
Furthermore, it was shown in their research that F. nucleatium binding increases the ability of
other bacteria to spread through these tissues. It is proposed that F. nucleatum as well as other
bacteria travel via the blood from the oral microbiome to the placenta using hematogenous
transmission; F. nucleatum bind to the endothelium of placental tissue and indirectly allow
passage to other bacteria which then colonize or infect the placental tissue.
In their review, Prince et al. (2014) describes a mechanism in which bacteria may even
aid in the maintenance of pregnancy. The bacteria described however were located in the vaginal
microbiome and authors expected them to colonize the infant during delivery. It may not be
unreasonable to extend this idea of maintenance to bacteria that inhabit the placenta.
Final Conclusions
At least one author is still skeptical and questions the validity of Aagard et al. (2014)
findings, as well as Stout et al. (2013). Kliman (2014) remarks that the methods used in the study
performed by Aagard et al. (2014) do not distinguish living, dead, ruptured or fragmented
bacteria; all of which would produce positive signals. In addition, these bacteria discovered
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could be from contamination of maternal blood, and a control should have been performed in
order to test for the bacteria present in a remote vein. This would make their findings of live
bacteria invalid. Kliman (2014) also questions whether intact live bacteria are able to be
observed in tissue samples only 5µm (Stout et al. 2013). Aagard (2014) retorted, explaining that
procedures performed in order to prevent contamination were initiated during collection of
samples, and that available evidence made the control for small samples of maternal blood
unnecessary. Furthermore, Aagard (2014) reports the HMP showed that there was a distinct lack
of colonization of other body sites by bacteria in the oral microbiome, and no evidence of oral
bacterial DNA fragments found within the gut or the venous system have been observed by other
researchers that they are aware. He does acknowledge that they made no conclusions as to
whether these bacteria were living or dead in their research (Aagard et al. 2014), however they
are not the first to observe the placenta is non-sterile.
Indeed, they were not the first to observe bacteria of the placental membranes. All studies
discussed here have evidenced the prevalence of bacteria in the placentas of both preterm and
healthy term labors. Whether bacteria are present or not is no longer a question. The question
that remains unanswered is which bacteria are harmful, or what bacterial interactions may result
in infection, inflammation, and finally preterm labor. Knowing this, we then ask ourselves what
can be done to stop this from occurring. There has been a great diversity of bacteria in samples
both within studies and between studies. This may be due to differences in methodology; as
some studies amplified and sequenced general DNA regions whereas others looked for DNA
sequences specific to bacteria identities previously associated with intraamniotic infection and
preterm labor.
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Several studies have observed the colonization of the placenta by a large proportion of
species associated with the oral microbiome. Though many studies do not mention a reason for
this in terms of the development of the microbiome as a starting point, one can be hypothesized
for testing. For instance, if placental colonization does initiate the start of the infant microbiome,
these species could aid in digestion or development of the infant microbiome following birth by
acting as competitive selectors of bacteria that may try to colonize other parts of the infant such
as the gut. To test this, the oral microbiome of the neonate can be compared to that of placenta.
It is clear that multiple, more definitive studies must be performed in order to clarify if
there are specific bacteria that lead to preterm labor, or if it is simply the result of colonization by
a greater diversity and multitude of bacteria. To do this, it may be necessary to try and obtain
samples during pregnancy, although this will be difficult as sampling may be dangerous to the
pregnancy. Sampling may be taken when procedures such as amniocentesis are ordered, however
this is usually done only in cases where there are already risks to the infant or pregnancy, and
thus the results may be biased. Furthermore as many studies have observed the placental
microbiome to resemble that of the oral microbiome, it may be beneficial to obtain parallel
samples of the mother’s oral microbiome in addition to placental specimens for direct
comparison.
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