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Spontaneous preterm birth: Pathogenesis

Author: Charles J Lockwood, MD, MHCM
Section Editor: Vincenzo Berghella, MD
Deputy Editor: Vanessa A Barss, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Jan 2022. | This topic last updated: Feb 09, 2021.

INTRODUCTION

Preterm birth (PTB) is a leading cause of infant morbidity and mortality in the
United States and globally [1,2]. For this reason, the pathogenic processes
leading to PTB and the development of preventive interventions are major
targets of obstetric research.

PTB may be "spontaneous" (sPTB) or "indicated" because of concerns about

maternal or fetal status. Compelling clinical and research evidence suggest
that a number of pathogenic processes can lead to a final common pathway
that results in sPTB ( figure 1). The four major pathogenic processes are:

● Premature activation of the fetal hypothalamic-pituitary-adrenal axis in

response to maternal and/or fetal stress
● Exaggerated inflammatory response/infection and/or an altered genital tract
microbiome
● Decidual hemorrhage (placental abruption)
● Pathologic uterine distention

These four processes, and other less common processes, may be initiated
long before preterm labor or preterm prelabor rupture of membranes is
clinically evident, which is a common feature of cascade biologic pathways.

This topic will discuss the pathogenic processes leading to sPTB. Risk factors
for PTB and risk reduction interventions, as well as diagnosis and treatment,
are reviewed separately.
 ● (See "Preterm birth: Risk factors, interventions for risk reduction, and
maternal prognosis".)
● (See "Preterm labor: Clinical findings, diagnostic evaluation, and initial
treatment".)
● (See "Inhibition of acute preterm labor".)

THE FOUR MAJOR PATHOGENIC PATHWAYS TO sPTB

#1 Stress-induced premature activation of the HPA axis

Causes of stress — Fetal stress is caused by uteroplacental vascular

insufficiency, which, if severe, may manifest clinically as preeclampsia or fetal
growth restriction. Pregnancies manifesting these disorders are more likely
to end in sPTB and/or indicated PTB [3,4]. In regression models, pregnancies
that end in sPTB have a four- to sevenfold increase in histologic evidence of
placental vascular damage, bleeding, fetal vascular disruption, or lack of
normal physiologic conversion of maternal spiral arteries [3]. First
pregnancies that end in sPTB are at increased risk of PTB, preeclampsia, and
fetal growth restriction in the subsequent pregnancy compared with women
with uncomplicated first pregnancies, and the earlier the sPTB, the higher the
risk of one of these complications in the next pregnancy [5].

Major maternal psychosocial stress (eg, depression, posttraumatic stress

disorder, anxiety) can activate the maternal hypothalamic-pituitary-adrenal
(HPA) axis and has been associated with a small (generally less than twofold)
increased risk of sPTB, but the association is weaker than that observed with
fetal stress [6-19]. A prospective cohort study of women with depressive
symptoms early in pregnancy found that these women had almost twice the
PTB risk of women without such symptoms, and the risk increased with
increasing severity of depression, suggesting a dose-response effect [17].

Relationship between stress and hormonal changes leading to

sPTB — Fetal or, less commonly, maternal stress can induce premature
activation of the fetal HPA axis resulting in a cascade of hormonal changes
leading to sPTB. A synopsis of these changes follows:

● Stress-induced increases in placental production and release of corticotropin-

releasing hormone (CRH) appear to program a "placental clock" for earlier
labor and delivery [20-22]. PTB occurs when this process is accelerated, which
may be marked by elevated maternal CRH levels.
● In the mother, CRH released by the hypothalamus stimulates secretion of
adrenocorticotropic hormone (ACTH) from the pituitary, promoting adrenal
secretion of cortisol, which inhibits hypothalamic CRH and pituitary ACTH
release via a negative feedback loop. During pregnancy, the trophoblast,
amniochorion, and decidual cells also secrete CRH (called placental CRH). In a
normal pregnancy, it is hypothesized that maturation of the fetal HPA axis
and development of the fetal zone of the fetal adrenal gland beginning at 25
weeks of gestation cause a progressive physiologic increase in fetal cortisol
secretion, which enhances placental CRH release [23] because, in contrast to
the maternal HPA axis, placental CRH production is stimulated by cortisol in a
positive feedback loop [24-27]. Placental CRH secretion stimulates the fetal
pituitary and adrenal to release cortisol but also stimulates the amniochorion
and decidua to release prostaglandins, which further stimulate placental CRH
release [27] via a second positive feedback loop [28].

The net effect of these positive and negative feedback loops is increasing
levels of CRH as gestation progresses, with high concentrations in the
maternal and fetal blood and amniotic fluid by term, and increasing levels of
glucocorticoids and prostaglandins [29]. Prostaglandins are an integral part
of the common final pathway leading to parturition since they promote
cervical maturation and uterine contractility [30]. In a normal pregnancy, the
rise in prostaglandins ultimately results in labor occurring at term. The
effects of CRH are augmented near term by a large reduction in maternal
plasma CRH-binding protein [31], allowing saturation of CRH-binding protein
and making free CRH available to act as a parturition trigger [22], in part
because CRH also has some ability to stimulate uterine contractility directly
[32].

● Stress-induced activation of the fetal HPA axis stimulates increased adrenal

synthesis of dehydroepiandrosterone sulfate (DHEA-S), which is converted to
16-hydroxy-DHEA-S in the fetal liver. Placental CRH directly augments fetal
adrenal DHEA production as well [33]. The placenta converts DHEA and
DHEA-S to estrone (E1), estradiol (E2), and estriol (E3), which, in the presence
of estrogen receptor-alpha (ER-alpha) and reduced progesterone receptor
(PR) action, increases gap junction formation, oxytocin receptors,
prostaglandin activity, and enzymes responsible for coordinated muscle
contraction (myosin light chain kinase, calmodulin) [34-38].

Elevated circulating estrogens are a marker for sPTB. In a prospective study

that obtained serial measurements of salivary E3, mean salivary E3 was
higher from 24 to 34 weeks of gestation in women with singleton
 pregnancies delivering preterm than in those delivering at term, a surge in
salivary E3 occurred three to four weeks before the onset of labor in both
groups, and the predictive value of salivary E3 measurements was greatest
≥
for later PTBs ( 34 weeks) [39]. The precise mechanism for this limitation
remains unknown; however, it likely reflects the requirement for
development of the fetal zone of the fetal adrenal, which is responsible for
the bulk of DHEA production and enlarges rapidly in the last six weeks of
gestation [40].

● Glucocorticoids induce the immunophilin co-chaperone FK506-binding

protein 51 (FKBP51), which binds to the ligand binding site on the PR and
glucocorticoid receptor (GR) to inhibit PR- and GR-mediated transcription.
While this negative feedback circuit prevents pathologic effects accruing from
excess glucocorticoids, it also inhibits PR activity. Consistent with maturation
of the fetal HPA axis and rising maternal cortisol levels at term, human labor
at term is accompanied by increased expression of FKBP51 in decidual cells,
resulting in functional progesterone withdrawal [41]. This is accompanied by
rising concentrations of myometrial ER-alpha, thereby exacerbating
estrogen-induced myometrial activation.

#2 Exaggerated inflammatory response/infection and/or altered genital

tract microbiome — In the setting of infection-induced fetal stress, the fetal
cortisol to DHEA ratio remains low, and there is no direct correlation between
the fetal adrenal gland volume and either cortisol or DHEA levels [42]. This
suggests that infection-mediated sPTB may act via a different pathway than
the premature activation of the HPA axis described above.

Epidemiologic studies using laboratory and clinical data show an association

between sPTB and the presence of systemic and genitourinary tract
pathogens [43-45], as well as an altered microbiome [45-47]:

● In a large retrospective population-based study of 199,093 deliveries, 2.5

percent of patients had asymptomatic bacteriuria, which was independently
associated with PTB (adjusted odds ratio [OR] 1.6, 95% CI 1.5-1.7) [43].
Conversely, the diagnosis and treatment of asymptomatic bacteriuria
appears to reduce the risk of PTB [44].

● Both clinical and subclinical chorioamnionitis are much more common in

preterm than term deliveries and may account for 50 percent of sPTB before
30 weeks of gestation [48]. (See "Preterm birth: Risk factors, interventions for
risk reduction, and maternal prognosis", section on 'Infection'.)
 ● Lactobacillus is the predominant flora of the microbial community in normal
pregnancy, and the prevalence of a Lactobacillus-poor vaginal community
state type 4 (CST 4) is inversely correlated with gestational age at delivery
[49]. In addition, the risk for sPTB is more pronounced for women with CST 4
and elevated Gardnerella or Ureaplasma. However, treatment of bacterial
vaginosis (BV) does not reduce sPTB rates in low-risk patients [46].

A nested case-control study of cervicovaginal microbiota among 107 patients

with sPTB and 432 women with term deliveries found Mobiluncus
curtisii/mulieris to be the only bacterial taxa significantly associated with
increased risk of sPTB among all participants. However, among African
American women, five separate taxa were significantly associated with sPTB,
and M. curtisii/mulieris and Mageeibacillus indolicus had the strongest
association with sPTB with rates of over 60 and 55 percent, respectively, at
their highest relative abundance [47]. This association disappeared among
patients with these taxa but who also had abundant Lactobacillus.

● Metagenomic techniques, including surveillance of the 16S rRNA gene, have

increased understanding of the spectrum of cultivated and uncultivated
human microbial agents involved in the pathogenesis of sPTB [50]. By using
metagenomic tools, several groups of investigators reported that, in
pregnancies complicated by sPTB secondary to infection, approximately two-
thirds of the amniotic fluid bacteria detected by culture-independent
methods were not isolated in cultures [51,52]. These included both
uncultivated and difficult-to-cultivate species, such as Fusobacterium
nucleatum, Leptotrichia (Sneathia), Bergeyella, Peptostreptococcus, Bacteroides,
and a species of the order Clostridiales.

In a cohort of approximately 12,000 samples as part of the integrative

Human Microbiome Project, longitudinal analyses of 16S rRNA,
metagenomic, metatranscriptomic, and cytokine profiles from 45 preterm
and 90 term birth controls identified lower vaginal levels of Lactobacillus
crispatus and higher levels of BV-associated bacterium (BVAB) 1 and TM7,
Sneathia amnii, a group of Prevotella species, and nine additional taxa as
harbingers of PTB [53].

Pathophysiology

● Bacterial degradation of membranes and direct uterotonic effects –

Bacteria may have a direct role in the pathogenesis of sPTB.
 • Bacteria produce phospholipase A2 (which leads to prostaglandin synthesis)
and endotoxin, substances that stimulate uterine contractions and can cause
preterm labor [54].

• Some organisms (eg, Pseudomonas, Staphylococcus, Streptococcus, Bacteroides,

and Enterobacter) produce proteases, collagenases, and elastases that can
degrade the fetal membranes, leading to preterm prelabor rupture of
membranes (PPROM), with subsequent spontaneous or indicated PTB
[55,56].

● Bacterial induction of an inflammatory response, leading to uterotonic

effects – Bacterial ligands bind to toll-like receptors (TLRs) expressed on
decidual, amnion, chorion, cervical, placental, and local leukocyte cell
membranes. This induces the transcription factor NF-kappaB, which then
triggers a maternal and/or fetal inflammatory response in susceptible
individuals that is linked to sPTB.

This TLR-mediated response is ultimately characterized by the presence of

activated neutrophils and, to a lesser extent, activated macrophages and
various proinflammatory mediators (eg, interleukin [IL] 1, 6, and 8; tumor
necrosis factor [TNF], granulocyte colony-stimulating factor [G-CSF], colony-
stimulating factor 2 [CSF-2], and matrix metalloproteinases [MMPs]). The key
initial mediators of this response are IL-1beta and TNF, which enhance
prostaglandin production by inducing cyclooxygenase 2 (COX-2) expression in
the amnion and decidua while inhibiting the prostaglandin-metabolizing
enzyme, 15-hydroxyprostaglandin dehydrogenase (PGDH), in the chorion
[57,58]. Moreover, IL-1beta and/or TNF directly enhance the expression of
various MMPs in the amnio-chorion, decidua, and cervix to degrade the
extracellular matrix of the fetal membranes and cervix [59-61].

Immunohistochemical staining of placentas from patients with

chorioamnionitis-associated sPTB demonstrated significantly lower PR levels
in decidual cells [62]. Moreover, treatment of cultured term decidual cells
with IL-1beta decreased PR expression (both PR-B and A isoforms) as well as
PR mRNA levels via ERK1/2 MAP kinase signaling. This reduction in PR
expression may account for studies showing no benefit of progesterone
supplementation [63].

Elevated proinflammatory mediator levels have been demonstrated in the

amniotic fluid of women with preterm labor with intact membranes, and
these levels correlated well with positive results from culture of the amniotic
fluid and fetal membranes [64]. In a review of 17 primary studies including
6270 asymptomatic women, elevated cervicovaginal and amniotic fluid IL-6
levels at midgestation predicted PTB with ORs 3.05 (95% CI 2.00-4.67, number
needed to treat = 7) and 4.52 (95% CI 2.67-7.65, number needed to treat = 7),
respectively [65]. In addition, patients with intraamniotic inflammation
destined to deliver preterm appear to present unique amniotic fluid, vaginal-
cervical secretion, and serum proteomic profiles [66-70].

#3 Decidual hemorrhage — Decidual hemorrhage (placental abruption)

originates in damaged decidual blood vessels and presents clinically as
vaginal bleeding or retroplacental hematoma formation [71]. It is associated
with a high risk of preterm labor and PPROM [72-74].

The development of PPROM in the setting of abruption may be related to the

high decidual cell expression of tissue factor, the primary cellular mediator of
hemostasis. Following intrauterine hemorrhage from placental abruption,
decidual tissue factor combines with factor VIIa to activate factor Xa, which in
turn complexes with its cofactor, Va, to generate thrombin. Hormonal factors,
such as progesterone, play an important modulator role [75]. Thrombin
activation (measured by serum thrombin-antithrombin [TAT] complex levels)
has been noted in women with preterm labor and in asymptomatic women
who subsequently delivered preterm [76,77].

In addition to its primary hemostatic functions, thrombin binds to protease-

activated receptors (PAR) 1 and 3 to:

● Directly increase the frequency, intensity, and tone of myometrial

contractions, an effect that is suppressed by blood containing thrombin
inhibitors [78,79].

● Upregulate the expression of proteases such as MMPs, which promote

uterine contractility [80-82].

● Initiate functional progesterone withdrawal in the decidua by inhibiting

expression of PRs in decidual cells [83]. As with IL-1beta-mediated inhibition
of decidual cell PR expression, thrombin inhibition of PR protein and mRNA
expression is mediated by ERK1/2 MAP kinase signaling. This may be a
mechanism for contractions in pregnancies complicated by antepartum
bleeding and, again, help account for the failure of progesterone
supplementation to prevent PTB in some studies.

● Induce IL-8 in decidual cells, accounting for the dense neutrophil infiltrate
observed in abruption-associated PPROM in the absence of infection [84].
The interactive effects of thrombin-enhanced MMPs with neutrophil-derived
 proteases promote degradation of the fetal membrane extracellular matrix,
which can result in PPROM and, in turn, preterm labor and spontaneous and
indicated PTB.

#4 Pathologic uterine distention — Multiple gestation, polyhydramnios,

and other causes of excessive uterine distention are well-described risk
factors for sPTB. Enhanced stretching of the myometrium induces formation
of gap junctions, upregulation of oxytocin receptors, and production of
inflammatory cytokines, prostaglandins, and myosin light chain kinase, which
are critical events preceding uterine contractions and cervical dilation [85-87].
Myometrial distention also increases expression of genes with important
roles in collagenolysis and inflammation [88]. (See "Physiology of parturition
at term".)

Distention of the fetal membranes also contributes to myometrial activation,

preterm cervical ripening, and PPROM, likely through the release of
cytokines, prostaglandins, and collagenases [89-91].

OTHER PATHOGENIC PATHWAYS

Cervical insufficiency — Cervical insufficiency refers to pathologic dilation

and/or effacement of the uterine cervix in the absence of uterine
contractions leading to previable pregnancy loss as well as sPTB. Cervical
cerclage may be helpful in select instances [92]. (See "Cervical insufficiency".)

Cervical insufficiency due to intrinsic biochemical factors is probably a rare

event (eg, Ehlers-Danlos syndrome). It is more likely that progressive cervical
shortening and dilation prior to viability results from activation of the
inflammatory and/or hemorrhagic pathways described above at a point in
gestation when myometrial quiescence and amniotic fluid, fetal membrane,
and decidual antiprotease activity are maximal.

Inherited pathogenic variants — sPTB demonstrates familial aggregation.

Women who were themselves born preterm have a higher risk of sPTB, and
the risk of sPTB increases by 80 percent in women whose sisters had sPTB.
There are also significant ethnic differences in risk of sPTB. Taken together,
these findings suggest that genetic factors may be involved. (See "Preterm
birth: Risk factors, interventions for risk reduction, and maternal prognosis",
section on 'Genetic factors'.)

A variety of single nucleotide polymorphisms, the majority associated with

inflammation, have been linked to sPTB [93]. In a genome-wide association
study among 43,568 women of European ancestry that used gestational
duration as a continuous variable and either term or sPTB (<37 weeks) as a
dichotomous outcome, four genetic loci (EBF1, EEFSEC, AGTR2, and WNT4)
were significantly associated with gestational duration in both the discovery
and replication datasets [94]. Functional analysis suggested that a variant in
the WNT4 gene altered the binding of the estrogen receptor. Common
variants in EBF1, EEFSEC, and AGTR2 showed association with PTB with
genome-wide significance, and analysis of mother-infant dyads indicated
that they act at the level of the maternal genome.

African Americans have a 50 percent higher rate of sPTB than non-Hispanic

White women [95,96]. This phenomenon may be partially explained by the
observation that multiple maternal and fetal inflammatory pathway genetic
polymorphisms linked to inflammation-associated sPTB are found in greater
prevalence among African American mothers and/or fetuses than among
other racial groups [97,98]. For example, African American mothers
harboring both a polymorphism of the tumor necrosis factor-alpha gene and
bacterial vaginosis are at significantly greater risk of PTB (odds ratio 6.1, 95%
CI 1.9-21.0) [99]. Conversely, higher vaginal levels of the host-derived
antimicrobial peptide, beta-defensin 2, are linked to a lowered risk of sPTB,
while lower levels were linked to spontaneous PTB only among African
American women [47].

SUMMARY AND RECOMMENDATIONS

● There are four discrete mechanisms for the pathogenesis of preterm birth
(PTB):

• Premature activation of the maternal or fetal hypothalamic-pituitary-adrenal

axis related to stress (see '#1 Stress-induced premature activation of the HPA
axis' above)

• Exaggerated inflammatory response/infection and/or an altered genital tract

microbiome (see '#2 Exaggerated inflammatory response/infection and/or
altered genital tract microbiome' above)

• Decidual hemorrhage (placental abruption) (see '#3 Decidual hemorrhage'

above)

• Pathologic uterine distention (see '#4 Pathologic uterine distention' above)

 Although each mechanism has distinct epidemiologic, genetic, and clinical
characteristics, they are not mutually exclusive. They share a final common
pathway involving the formation of uterotonic agents and proteases that
weaken the fetal membranes and cervical stroma, eventually leading to
preterm labor and birth ( figure 1).

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Topic 6785 Version 34.0
GRAPHICS

Pathogenesis of spontaneous preterm birth

Hemorrhage into the decidua (abruption) generates thrombin, which binds to PARs
to activate the ERK1/2 MAP kinase signaling cascade, which directly inhibits PR
expression in decidual cells and activates COX-2 to increase PGF-2alpha production.
The latter contributes to ERK1/2-mediated inhibition of PR expression, which
triggers contractions and directly promotes increased MMP-3 activity, causing a
proteolytic cascade that degrades fetal membranes to promote PROM, and induces
cervical change. Decidual inflammation associated with ascending genital tract
infections with or without chorioamnionitis generates IL-1beta, which binds to its
receptor to also activate the ERK1/2 MAP kinase signaling cascade inhibiting
decidual cell PR expression. In addition, IL-1beta activates COX-2 and releases
MMPs via the NF-kappaB signaling pathway. Premature maturation of the fetal HPA
axis or maternal or fetal stress causes increased circulating cortisol (glucocorticoid),
which binds to its receptor to increase levels of the immunophilin co-chaperone
protein, FKBP51. Increased FKBP51 binds to both the GR and PR to decrease their
transcriptional activity (functional progesterone withdrawal). Thus, ultimately COX-2
is activated and MMP-3 released to promote PTB.
HPA: hypothalamus-pituitary-adrenal; PAR: protease-activated receptors; IL:
interleukin; ERK: extracellular signal-regulated kinase; MAP: mitogen-activated
protein; NF-kappaB: nuclear factor-kappa-light-chain-enhancer of activated B cells;
COX-2: cyclooxygenase 2; FKBP51: FK506-binding protein 51; PGF-2alpha:
prostaglandin F2-alpha; PR: progesterone receptor; MMP: matrix
metalloproteinase; PTB: preterm birth; PROM: premature rupture of membranes;
GR: glucocorticoid receptor.

Courtesy of Charles J Lockwood, MD.

Graphic 59393 Version 6.0

Contributor Disclosures
Charles J Lockwood, MD, MHCM No relevant financial relationship(s) with ineligible
companies to disclose. Vincenzo Berghella, MD Consultant/Advisory Boards:
ProtocolNow [Clinical guidelines].
All of the relevant financial relationships listed have
been mitigated. Vanessa A Barss, MD, FACOG No relevant financial relationship(s)
with ineligible companies to disclose.

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