Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2018) 1e10

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

The biological basis and prevention of preterm

birth
Gian Carlo Di Renzo*, Valentina Tosto, Irene Giardina
Department of Obstetrics and Gynecology, Centre for Perinatal and Reproductive Medicine, University of
Perugia, Perugia, Italy

a b s t r a c t
Keywords:
Preterm labor The time of birth is a critical determinant of perinatal and long-
Inflammation term outcomes.
Genetic predisposition Preterm birth is still the first cause of infant mortality and
Decidual activation morbidity; unfortunately, rates of preterm birth remain high in both
Microbiome high- and low-resource countries, ranging from 5% to 18%.
Cell-free fetal DNA
Preterm parturition is a syndrome, which can be induced by
various factors such as infection, cervical pathology, uterine over-
distension, progesterone deficiency, vascular alterations (utero-
placental ischemia, decidual hemorrhage), maternal and fetal
stress, allograft reaction, allergic phenomena, and probably other
several unknown factors.
These various etiologies can lead to the pathological activation of a
common pathway of decidua/fetal membranes, which causes
uterine contractility, cervical ripening, and rupture of membranes.
Moreover, the mechanisms responsible for these processes
have been identified, which involve receptors, chemokines, and
inflammatory cytokines. It is very important to understand the
cellular and biochemical pathways responsible for preterm labor to
identify, treat, and prevent negative outcome in a timely manner.
Clinicians and researchers play a key role in improving biochem-
ical knowledge on preterm delivery, identifying risk factors, and
shaping interventions that can address this complex syndrome.
© 2018 Published by Elsevier Ltd.

* Corresponding author. Department of Obstetrics and Gynecology, Centre for Perinatal and Reproductive Medicine, Uni-
versity of Perugia, Santa Maria della Misericordia University Hospital, 06132, San Sisto, Perugia, Italy.
E-mail address: giancarlo.direnzo@unipg.it (G.C. Di Renzo).

https://doi.org/10.1016/j.bpobgyn.2018.01.022
1521-6934/© 2018 Published by Elsevier Ltd.

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Biological basis of preterm birth

Preterm birth (birth occurring before 37 weeks of gestation) is still the first cause of infant mortality
and morbidity; unfortunately, rates of preterm birth remain high in both high- and low-resource
countries, ranging from 5% to 18% [1].
Preterm parturition is a complex syndrome [2] that can be induced by various factors that might
trigger myometrial contractions, premature rupture of membranes, and cervical maturation, thus
resulting in preterm delivery.
Although the global rates are increasing, large differences exist in preterm birth rates worldwide [3].
Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term
and especially preterm remain unclear. It is likely that a “parturition complex cascade” triggers labor at
term; preterm labor (PTL) results from mechanisms that either prematurely stimulate or short-circuit
this cascade, and these mechanisms involve the activation of pro-inflammatory pathways within the
uterus triggered by events like intrauterine infection, hemorrhage, excessive uterine stretch (multiple
pregnancy, polyhydramnios), and/or maternal or fetal stress [4e10].
It is suggested that a “decidual clock” could be involved in the time of birth: the endometrium/
decidua is identified as the organ primarily involved [11].
There are several risk factors known to be associated with preterm birth, including multiple medical
and genetic causes and environmental and socioeconomic factors, which are not always considered
in combination. Previously observed risk factors also include certain infections, maternal or fetal
conditions (e.g., preeclampsia and fetal malformations), previous preterm delivery (a strong risk factor
for recurrence), multifetal gestation, young or advanced maternal age, assisted reproductive technol-
ogy (ART) (especially with multifetal gestation), cervical anomalies, certain ethnicities, smoking,
extreme body mass index (BMI), and low socioeconomic status. Other less well-validated risk factors
include stress, excessive physical work, alcohol and drug consumption, and periodontal disease.
Despite much accumulated knowledge on individual etiological factors, the interactions among risk
factors and the pathophysiology of preterm birth remain unexplained [12].
The switch of the myometrium from a quiescent to a contractile state is accompanied by a shift in
signaling between anti-inflammatory and pro-inflammatory pathways, including chemokine (inter-
leukin-8), cytokine (interleukin-1 and -6), and contraction-associated protein (expression of oxytocin
receptors, connexin 43, prostaglandin receptors) production. Progesterone maintains uterine quies-
cence by repressing the expression of these genes. Increased expression of the miR-200 family near
term can derepress contractile genes and therefore promote progesterone catabolism and thus the
activation of labor. Cervical ripening in preparation for dilatation is mediated by changes in extracel-
lular matrix proteins, which include a loss in collagen cross-linking and an increase in glycosamino-
glycans, as well as changes in epithelial barrier and immune surveillance properties. This decreases the
tensile strength of the cervix, key for cervical dilatation. Decidual/membrane activation refers to the
anatomical and biochemical events involved in the withdrawal of decidual support for pregnancy,
separation of the chorioamniotic membranes from the decidua, and, eventually, membrane rupture.
Increased expression of inflammatory cytokines (TNF-a and IL-1) and chemokines, increased activity of
proteases (MMP-8 and MMP-9), dissolution of cellular cements such as fibronectin (this event explains
the positivity for the Fetal Fibronectin test), and apoptosis have been implicated in this process.

Inflammation and infection: a well-documented cause of labor and delivery

Labor is first and foremost a pro-inflammatory event. It is suggested that advanced gestational age is
associated with a withdrawal of active suppression and/or an enhanced sensitivity of the decidua to
signals capable of inducing inflammation cascade. This promotes the release of various biologically
active inflammatory mediators (primarily PGs) leading to the onset of labor. If dysregulation of
decidual inflammatory signaling occurs early, spontaneous PTL will ensue. PTL may also result from
the active induction of decidual inflammation in the midtrimester of pregnancy due, for example, to
intrauterine infection or placental abruption.
Numerous risk factors for spontaneous preterm birth in humans have been identified, including
AfricaneAmerican ethnicity, cervical shortening, lower genital tract infection, under nutrition/over

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nutrition (extreme BMI), anemia, and cigarette smoking. Rather than being causally related to preterm
birth, there is mounting evidence suggesting that these risk factors are simply a marker of dysfunc-
tional immunological defense within the tissues of the uterus.
The decidual clock hypothesis can explain all these adverse pregnancy events depending on when
in gestation the decidual clock is dialed down [11].
Labor and delivery at term and preterm have an underlying pathophysiology marked by inflam-
matory mediators. PTL is hypothesized to be driven by overwhelming inflammation that eclipses fetal
uterotonic signals of organ maturity. Approximately 50% of Preterm Births (PTBs) and 70% of preterm
prelabor rupture of membranes (pPROMs) are associated with intra-amniotic infection (IAI) and
inflammation. Histological and microbiological findings indicate that focal infection and inflammation
may play a significant role in the pathogenesis of PTB and pPROM. Inflammatory changes that precede
PTB are leukocyte activation, increased inflammatory cytokines and chemokines, and collagenolysis of
the extracellular matrix metalloproteinases (MMPs), resulting in a loss of membrane structural
integrity, myometrial activation, and cervical ripening [13e15]. Recent studies have reported that the
heterogeneity in the inflammatory response (cytokines, chemokines, and toll-like receptors) is asso-
ciated with the IAI and PTB risk factors [16e19]. The biomolecular markers that trigger labor-associated
changes are different, and the difference is attributed to both epidemiologic and clinical risk factors.
In fact, the main hypothesis of the etiology of spontaneous preterm delivery is ascending infection
from the lower genital tract up in the sterile uterus invading the decidua, chorioamniotic membranes,
amniotic fluid (AF), and the fetus. Recently, a “sterile intrauterine inflammation” is also described as a
possible trigger for preterm birth and pPROM [20].
The dogma of “sterile womb” has recently been challenged in a study published in Science in 2014,
which suggested that the placenta is not sterile and has a bacterial flora more similar to the oral cavity
than to the vagina [21]. In recent years, it has been documented that women who used oral probiotic
products had reduced risk of preterm delivery [22] and pre-eclampsia [23].
Interestingly, the supernatant of the probiotic organism Lactobacillus rhamnosus has been found to
reduce the lipopolysaccharide (LPS) inflammatory response in placenta trophoblast cells [24].
The decidualized endometrium (decidua) can be seen as a specialized stromal tissue that encap-
sulates and protects the fetoplacental unit throughout pregnancy with intrinsic and specific immu-
nological and endocrine functions. It comprises endogenous decidual stromal cells and various
maternal immune cells, many of which track in from the bone marrow and are present in concen-
trations that vary in a predictable pattern throughout gestation [25]. The endometrial macrophages,
dendritic cells, T regulatory cells (Tregs), and NK cells increase in numbers during the proliferative
phase in preparation for implantation of the blastocyst [25].
The mechanism by which a subclinical (bacterial or viral) infection may prime the immune system
leading to an exaggerated immunological response to a subsequent inflammatory insult is not well un-
derstood but likely involves innate immune pattern recognition receptors and their regulators [28]. Cells
of the maternalefetal interface (trophoblast, decidual, endothelial, and fetal membranes) recognize and
respond to microorganisms through TLRs and Nod-like receptors (NLRs) [29]. In recent years, much
attention has been focused on the role of TLRs in infection-associated preterm labor. TLR4 has gained
particular attention, as it is the receptor responsible for recognizing the major Gram-negative bacterial
component, LPS. However, the activation of TLR2 (which recognizes bacterial peptidoglycan, lipoteichoic
acid, lipoproteins, and fungal zymosan), TLR3 (which senses viral dsRNA), TLR9 (which responds to
bacterial CpG DNA), and Nod1 (which senses bacterial g-d-glutamyl-meso-diaminopimelic acid [iE-DAP])
seems to be involved in these complex mechanisms that lead to labor activation [29,30]. A number
of studies have documented an important role of maternal genetic factors in the time of birth, which the
clinician could consider, especially in the case of history of recurrent preterm birth [26,27].

Genetic predisposition

A substantial body of evidence has been accumulated that demonstrates the contribution of genetic
factors in gestational length and preterm birth risk [31e36]. For example, twin and family studies
suggest that 30e40% of the variation in birth timing, or risk for preterm birth, largely arises from
genetic factors but not exclusively from the maternal genome [31e36].

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Zhang et al. recently identified maternal genetic variants that are robustly associated with gesta-
tional duration: four loci (EBF1, EEFSEC, AGTR2, and WNT4) achieved genomewide significance [37].
WNT4 (wingless-type MMTV integration site family member 4) is critical for decidualization of the
endometrium and subsequent implantation and establishment of pregnancy. A functional analysis
showed that an implicated variant in WTN4 alters the binding of the estrogen receptor. Moreover,
common variants in EBF1 (early B-cell factor 1), EEFSEC (eukaryotic elongation factor, selenocysteine
tRNA-specific), and AGTR2 (angiotensin II receptor, type 2) showed association with preterm birth with
genomewide significance.
Recently, researchers studied the associations between spontaneous preterm birth and single or
combined polymorphisms associated with the apoptotic pathways triggered by oxidative stress.
Maternal lifestyle and health factors, which are potentially involved in sPTB, were also studied [38].
Data suggest that independent of all other maternal factors, pregnant women carrying the TT/GA
genotype of the JNK/CASP3 had a higher susceptibility to sPTB than those carrying the GT/GA genotype.
All these studies suggest that the integration of genomic information on women, and likely their
offspring, with birth timing, may allow the development of new options for preventive and therapeutic
measures.
Therefore, it is desirable that scientific research continues to deepen even in this field.

Vascular disease and hemorrhage

Approximately 30% of patients with PTL have placental lesions consistent with maternal vascular
underperfusion, and a similar number has failure of physiologic transformation of the myometrial
segment of the spiral arteries [39]. A subset of patients with PTL with intact membranes and pPROMs
had vaginal bleeding, attributed to defective decidual hemostasis. Thrombin generated during decidual
hemorrhage can stimulate myometrial contractility and degrade extracellular matrix in the
chorioamniotic membranes, predisposing to rupture. Therefore, even in this case, there is a shift to a
pro-inflammatory response. Mothers with evidence of increased thrombin generation are at greater
risk of spontaneous preterm labor.

Progesterone role

Progesterone is a key component of pregnancy maintenance, and a decline in progesterone action

precedes labor in most species, which can be mediated by a reduction in serum levels of progesterone,
local changes in metabolism, and/or alterations in receptor isoforms/co-activators [40]. Throughout
gestation, progesterone promotes myometrial quiescence by reducing the expression of contraction-
associated proteins and inflammatory cytokines/chemokines (e.g., IL-1, IL-8, CCL2). Near term, the
increased myometrial expression of miR-200 family members counteracts many actions of proges-
terone, increasing its catabolism and inducing expression of pro-inflammatory cytokines/chemokines
and prostaglandin synthase 2 [40]. Progesterone's effects and its rationale use on the decidua and
chorioamniotic membranes include the inhibition of basal- and TNFa-induced apoptosis, which
protects the component cells from calcium-induced cell death and attenuates cytokine-induced MMP
expression/activity.
In conclusion, progesterone would play a role as “a controller” of normal pregnancy, and its
deficiency can cause the lack of an inhibitory brake on inflammatory stimulation.

Microbiome

The human indigenous microbial communities (microbiota) play critical roles in health and may be
especially important for the mother and fetus during pregnancy. Microbiome composition is deter-
mined largely by body site, host genetics, environmental exposures, and time.
Growing scientific evidence suggests that the immune regulation of the maternal-fetal interface
is the result of the coordinated interaction among maternal microbiome, trophoblast, and maternal
cellular components. From this view, we understand PTL as a result of dysregulation of this
equilibrium [41].

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In the case of a human host, the microbiome occupies several specific anatomic niches, for example,
the vagina, gastrointestinal tract, urogenital tract, skin, nasal and paranasal sinuses, and oral cavity.
Under the best conditions, each of these microbiome niches represents a species-balanced community,
which is important for the establishment and maintenance of human health [42]. Significant evidence is
available to consider that the majority of preterm births due to infection result from an ascendancy
of bacterial pathogens from the vaginal microbiome to infect the clinically sterile intrauterine cavity
consisting of the placenta, AF, and fetus. This does not preclude the possibility of a hematogenous spread
(bacteremia) of pathogenic microorganisms and inflammatory mediators originating from other sources,
including untreated periodontal disease, and their contributions to an adverse pregnancy outcome, such
as pre-eclampsia, preterm birth and low birth weight, fetal growth restriction, and fetal loss.
Although bacterial species that are present in preterm pregnancies may not be pathogenic neces-
sarily, a relatively altered microbial community structure (dysbiosis) may convey an environment of
localized inflammation that results in preterm birth.

Oral microbiome:

Chronic periodontitis is a highly prevalent, dysbiosis-initiated inflammatory condition that destructs

the supporting tissues of the teeth. This destructive process, a host response to pathogenic bacteria and
their toxins such as cytolytic enzymes and LPSs, is mediated by a pro-inflammatory cellular response
involving neutrophils, lymphocytes, macrophages, and osteoclasts. The host response also generates
various inflammatory mediators such as interleukin (IL)-1b, tumor necrosis factor-a, IL-6, prostaglandin
E2, MMP-8 and MMP-9, which, in turn, can have a downstream effect on other organ systems by
contributing to the overall inflammatory burden. The medical and dental public health communities
should address intervention strategies aimed at controlling oral inflammatory disease, which will lessen
the systemic inflammatory burden and suppress the potential for adverse pregnancy outcomes [43].

Placental microbiome:

Studies described a possible relationship between placental microbiome and preterm birth, probably
through an inflammation mechanism activation of the chorioamniotic tissue. Doyle et al. in an inter-
esting recent study described the relationship between placental microbiome and birth weight,
newborn length, duration of pregnancy, and head circumference [44]. This study identified a distinct
microbial community in the placenta and fetal membranes of Malawi population, associated with severe
chorioamnionitis and adverse birth outcomes. Bacteria associated with both severe chorioamnionitis
and poor birth outcomes were phylogenetically different and not the most abundant taxa recovered in
the placenta or fetal membranes. Interestingly, the species associated with preterm birth were distinct
from those associated with the three measures of growth restriction. Further studies are needed to
elucidate mechanisms by which bacteria restrict fetal growth without triggering chorioamnionitis or
preterm labor. Strategic control of the microbiome resident in the vagina or oral cavity with proven
efficacy against organisms identified in this study could control potential etiologic agents that spread to
the placenta [44]. Screening of the vaginal flora and/or the presence of cervical inflammation and an
evaluation of oral microbiome during pregnancy could identify the risk groups, which could be targeted
for treatment with selective and limited antibiotics or vaginal probiotics to limit adverse birth outcomes.
Antony et al. [45] suggested the association between preterm placental microbiome and excess
maternal weight gain. By using metagenomic approaches, they observed that the placental micro-
biome profile significantly varied in association with spontaneous preterm birth and that the
taxonomic profiles that are associated with term or preterm pregnancies were accompanied by vari-
ations in bacterial-encoded metabolic pathways [45].

Vaginal microbiome:

Changes in vaginal microbiota, which is associated with preterm birth, leave specific metabolite
fingerprints that can be detected in the cervicovaginal fluid (CVF) by metabolomics techniques.

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Amabebe et al. characterized and validated the CVF metabolite profile of pregnant women presenting
with symptoms of threatened PTL by both H nuclear magnetic resonance spectroscopy (NMR) and
enzyme-based spectrophotometry.
The combination of CVF acetate, FFN, and ultrasound CL in a binary logistic regression model
improved the prediction of PTB compared to the three markers individually, but CVF acetate offered no
predictive improvement over ultrasound CL combined with CVF and FFN. Elevated CVF acetate in
women with symptoms of PTL appears predictive of preterm delivery, as well as delivery within
2 weeks of presentation. An assay of acetate in CVF may prove of clinical utility for predicting PTB [46].
Scientific evidence supports the importance of studying vaginal microbiome and treating vaginosis,
even asymptomatic, in pregnancy due to the acknowledged potential stimulus on preterm labor. The
use of adequate antibiotics in pregnancy is not dangerous for the fetus.

Gut microbiome:

The gastrointestinal tract is populated by a vast and heterogeneous array of microorganisms that
participates in host metabolism, protects from invading microorganisms, and facilitates immune
system function [47]. The gut microbiome is also proposed as a possible source of intrauterine infection
after finding gut-associated taxa in the AF of women with preterm premature rupture of membranes.
Gut-associated microorganisms could colonize the vagina and ascend; hematogenous spread by
translocation from the gut lumen into the bloodstream could also occur.

“Maternal-fetal dialogue”: receptors and ligands

Decidual senescence has been considered a mechanism for spontaneous PTL in the absence of
evident acute inflammation. A recent study described that the AF concentration of soluble CXCR3
and its ligands CXCL9 and CXCL10 changes in patients whose placentas show evidence of chronic
inflammation (chronic chorioamnionitis) or other placental lesions with maternal anti-fetal
rejection [48]. AF concentrations of CXCR3 and its ligands CXCL9 and CXCL10 are higher in
patients with PTL and maternal anti-fetal rejection lesions than in those without these lesions. PTL
with chronic chorioamnionitis is associated with higher expression of CXCL9 and CXCL10 but not
CXCR3. These findings support a role of maternal anti-fetal rejection in a subset of patients with
PTL [48].
Some findings support the role of inflammasomes in preterm labor/birth. Inflammasomes are
cytosolic multiprotein complexes that orchestrate inflammation in response to pathogens and
endogenous danger signals. Women in spontaneous PTL with acute histologic chorioamnionitis
express major inflammasome components; spontaneous PTL with acute histologic chorioamnionitis is
characterized by an upregulation of NLRP3 and the active form of CASP-4, as well as increased
ASC/CASP-1 complex formation, which may participate in the activation of CASP-1 and the maturation
of IL-1b and IL-18 in the chorioamniotic membranes. These findings provide the first evidence that
supports a role of the inflammasome in the pathological inflammation implicated in spontaneous PTL
with acute histologic chorioamnionitis [49].
Another interesting evidence is the relationship between HMGB1 and preterm labor: HMGB1 ini-
tiates an inflammasome-associated inflammatory response in the chorioamniotic membranes. Incu-
bation of the chorioamniotic membranes with HMGB1 (1) induced the release of mature IL-1beta and
IL-6; (2) upregulated the mRNA expression of pro-inflammatory mediators NFKB1, IL6, TNF, IL1A, IFNG,
and HMGB1 receptors RAGE and TLR2; (3) upregulated the mRNA expression of inflammasome
components NLRP3 and AIM2 as well as NOD proteins (NOD1 and NOD2); (4) increased the protein
concentrations of NLRP3 and NOD2; (5) increased caspase-1 concentration and the quantity of its
active form (p20); and (6) upregulated the mRNA expression and active form of MMP-9. In addition,
HMGB1 concentrations in chorioamniotic membrane extracts from women who underwent sponta-
neous PTL were greater than in those from women who underwent spontaneous labor at term. These
findings show that HMGB1 can induce an inflammatory response in the chorioamniotic membranes,
which is partially mediated by inflammasomes [50].

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Gomez-Lopez et al. recently described how the direct activation of invariant natural killer T (iNKT)
cells via alfa-galactosylceramide induces preterm labor/birth largely by initiating systemic and local
(decidual and myometrial) innate immune responses [51]. Another example of the mother-fetus
dialogue complexity is given by evidence that umbilical cord CD71 þ erythroid cells are reduced in
preterm newborns, and this can influence the immune regulation of the newborns [52]. In conclusion,
literature has been enriched with evidence to support the involvement of numerous molecules, whose
upregulation or downregulation can influence the trigger of preterm labor. However, further studies
are necessary to consolidate these early findings and to explain aspects that are still unknown.

Cell-free fetal DNA: a new hypothesis

A role of cell-free fetal (cff) DNA as a signal for the onset of labor has recently been proposed [53]. In
pregnant women, cff DNA is normally present in the plasma, and concentrations increase as a function
of gestational age, peaking at the end of pregnancy just before the onset of labor. Interestingly, patients
who have an elevated cff DNA in the midtrimester are at increased risk for spontaneous preterm
delivery [54]. This evidence, along with the established pro-inflammatory effects of cff DNA, underpins
the theory that cff DNA may represent a common trigger to parturition in mammals [55]. Furthermore,
elevated cff DNA in the maternal circulation has been observed in pathological pregnancies, in asso-
ciation with placental dysfunction and inflammation. For these reasons and others, cff DNA is
increasingly used for diagnostic purposes to decrease the use of invasive amniocentesis. Mechanisti-
cally, cff DNA can bind to TLR9 to induce a conformational change in the homodimers of the receptor
resulting in the close apposition of the TIR signaling domains and downstream activation of NF-kB and
transcription of inflammatory cytokine genes [56].
Herrera CA et al. recently studied the relationship among cell-free DNA, inflammation, and the
initiation of spontaneous labor: spontaneous labor at term is associated with greater cell-free DNA
methylation ration and IL-6 than nonlabored controls. Women in labor had a greater total cell-free DNA
concentration and thus could theoretically have more hypomethylated DNA available for interaction
with the inflammatory cascade. All these issues could be a starting point to widen the study to women
facing the threat of preterm birth [57]. Larger studies are needed to investigate this theory. The concept
that cff DNA can mediate a fetal/placental/maternal dialogue to signal the onset of labor in normal
pregnancy as well as in PTL after insult is a fascinating hypothesis worthy of investigation.

Conclusions

Scientific literature has been enriched by many studies in recent years, which seek to explain the
basics of premature labor activation and preterm birth. What emerges is that the etiologies are
certainly many, but they are to be attributed to an early mechanism of activation of the inflammatory
pathway. All possible causes of preterm delivery can lead to the same basic biochemical mechanism:
the inflammatory activation. In this regard, a very recent study has extensively analyzed the maternal
leukocyte immunophenotype during the various periods of pregnancy [55]. The onset of labor in
rodents and humans is associated with physiological inflammation, which is manifested by the infil-
tration of activated maternal peripheral leukocytes (mPLs) into uterine tissues. Flow cytometry is used
to immunophenotype mPLs throughout gestation and labor, both term and preterm. Peripheral blood
was collected from nonpregnant women and pregnant women in the 1st, 2nd, and 3rd trimesters.
Samples were also collected from women in active labor at term (TL) or preterm (PTL) and compared
with those of women in term not in labor (TNIL) and preterm not in labor (PTNIL). Different leukocyte
populations were identified by surface markers such as CD45, CD14, CD15, CD3, CD4, CD8, CD19, and
CD56. Their activation status was measured by the expression levels of CD11b, CD44, CD55, CD181, and
CD192 proteins [55]. Of all circulating CD45 þ leukocytes, a significant increase was detected in
CD15 þ granulocytes in pregnant women versus nonpregnant women; in TL women versus TNIL
women and versus pregnant women in the 1st/2nd/3rd trimester; and in PTL women versus PTNIL
women. In conclusion, Zhang et al. identified subpopulations of mPLs that are specifically activated in
association with gestation (granulocytes) or with the onset of labor (granulocytes, monocytes, and
lymphocytes).

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It is very important to understand the cellular and biochemical pathways responsible for PTL in
order to identify, treat, and prevent negative outcome in a timely manner. Clinicians and researchers
play a key role in improving biochemical knowledge on preterm delivery, identifying risk factors, and
shaping interventions that address this complex syndrome.

Preterm birth: pathogenesis

Pathways of preterm delivery

Activation of maternal-fetal
Inflammation
Decidual
Pathological uterine

hpa axis hemorrhage distension
(Abruption)

Maternal-fetal stress
Infection

Premature onset of physiologic (Chorion-decidual (Multifetal pregnancy,
initiators and systemic) polyhydramnios, uterine abnormality)
Role of microbiome
(maternal and fetal)
CRH IL-1, IL-6, IL-3, TNF, CSF, FasL Thrombin Mechanical stretch, GAP JCT,
E1 e E3 Thrombin Rc OXYTOCIN RECEPTOR, IL-8

Summary

Despite great medical advances in preventing maternal and infant mortality in the past century, one
issue remains unresolved: why do so many women give birth prematurely? In this manuscript, we
have discussed the possible pathways leading to a premature interruption of pregnancy and their
biochemical basis. Scientific literature has been enriched by many studies in recent years, which seek to
explain the basics of premature labor activation and preterm birth.
This manuscript briefly presents the main assumptions about the biological bases of preterm birth,
identifying its possible causes as some “triggers” that are able to activate premature labor through early
activation of the inflammatory response, normally involved at term of gestation. Knowing the
biological bases that lead to this condition is essential to try to improve, as far as possible, the diag-
nostic and therapeutic approaches and therefore to try to limit the serious negative outcomes that
might result (severe morbidity in short and long term, high psychological costs for families, and
economic consequences on the healthcare system).

Conflict of interest

No conflict of interest to be reported.

Practice points

Preterm birth: one syndrome with many etiologies.

The various etiologies of preterm birth relate to the same basic biological mechanism: early
inflammatory activation pathway.

There is scientific evidence of shift in signaling between anti-inflammatory and pro-
inflammatory response in preterm labor activation (increased/decreased expression of
specific chemokines, cytokines, and contraction-associated proteins).

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Research agenda

Knowledge on the biological bases of preterm delivery is probably not yet completely known.

More complete studies are needed to know more and bring clinical/practical improvements
to the diagnostic and therapeutic approach of preterm labor.

Other signaling pathways could be deeply studied.

Future directions in preterm birth research? Possible focuses of future investigations could
be on the role of microbiome niches, molecular and epigenetic-based research …

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Best Practice & Research Clinical Obstetrics and Gynaecology (2018), https://doi.org/10.1016/
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Please cite this article in press as: Di Renzo GC, et al., The biological basis and prevention of preterm birth,
Best Practice & Research Clinical Obstetrics and Gynaecology (2018), https://doi.org/10.1016/
j.bpobgyn.2018.01.022