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48. S. F. Ng et al., Nature 467, 963966 (2010).
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51. B. G. Dias, K. J. Ressler, Nat. Neurosci. 17, 8996 death below the age of 5 years (1). About 15 events: increased uterine contractility, cervical
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52. K. Gapp et al., Nat. Neurosci. 17, 667669 (2014).
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53. S. S. Hammoud et al., Hum. Reprod. 26, 25582569 and the highest rates occur in Africa and North membranes (7). These events represent the com-
(2011). America (2). Neonates born preterm are at an mon pathway of labor. The current understanding
54. A. Noblanc et al., Free Radic. Biol. Med. 65, 719723 increased risk of short-term complications attri- of this process is that the switch of the myo-
(2013).
55. A. Kong et al., Nature 488, 471475 (2012).
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56. R. J. Aitken, T. B. Smith, M. S. Jobling, M. A. Baker, as well as neurodevelopmental disorders, such as is accompanied by a shift in signaling from anti-
G. N. De Iuliis, Asian J. Androl. 16, 3138 (2014). cerebral palsy, intellectual disabilities, and vision inflammatory to pro-inflammatory pathways,
57. W. S. Ward, Mol. Hum. Reprod. 16, 3036 (2010). and hearing impairments (3). Preterm birth is a which include chemokines [interleukin-8 (IL-8)],
58. N. O. Palmer, T. Fullston, M. Mitchell, B. P. Setchell, M. Lane,
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60. T. Fullston et al., FASEB J. 27, 42264243 (2013). the United States is at least $26.2 billion per year ine quiescence by repressing the expression of these
61. E. J. Radford et al., Science 1255903 (2014).
62. M. Manikkam, C. Guerrero-Bosagna, R. Tracey, M. M. Haque,
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M. K. Skinner, PLOS ONE 7, e31901 (2012). Two-thirds of preterm births occur after the 200 (miR-200) family near term can derepress
63. M. Miao et al., Andrology 2, 138144 (2014). spontaneous onset of labor, whereas the remain- contractile genes and promote progesterone ca-
64. R. P. Yadav, N. Kotaja, Mol. Cell. Endocrinol. 382, 498508 der is medically indicated because of maternal or tabolism (8). Cervical ripening in preparation for
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66. G. C. Ostermeier, D. Miller, J. D. Huntriss, M. P. Diamond, intrauterine growth restriction (6). Herein, we matrix proteins, which include a loss in collagen
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67. V. Grandjean et al., Development 136, 36473655 by multiple pathologic processes, summarize im- as well as changes in the epithelial barrier and
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68. A. Soubry, C. Hoyo, R. L. Jirtle, S. K. Murphy, BioEssays 36,
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69. N. Suh et al., Curr. Biol. 20, 271277 (2010). areas for investigation. for cervical dilatation. Decidual or membrane
70. W. M. Liu et al., Proc. Natl. Acad. Sci. U.S.A. 109, 490494 activation refers to the anatomical and bio-
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71. C. P. Concepcion et al., PLOS Genet. 8, e1002797
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72. S. A. Robertson, Cell Tissue Res. 322, 4352 (2005). turition is that preterm labor is merely labor chorioamniotic membranes from the decidua,
73. C. L. Wong et al., Theriogenology 68, 654662 (2007). and eventually membrane rupture. Increased ex-
74. J. J. Bromfield et al., Proc. Natl. Acad. Sci. U.S.A. 111,
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pression of inflammatory cytokines [tumor ne-
1
Perinatology Research Branch, Program for Perinatal Research crosis factora (TNF-a) and IL-1] and chemokines,
75. H. K. Poon, K. H. Lee, C. L. Wong, W. S. O, P. H. Chow,
and Obstetrics, Division of Intramural Research, Eunice Kennedy
Theriogenology 71, 1367 (2009).
Shriver National Institute of Child Health and Human
increased activity of proteases [matrix metal-
76. J. K. Kafka et al., AIDS 26, 2736 (2012). loprotease 8 (MMP-8) and MMP-9], dissolution of
Development (NICHD), National Institutes of Health, Bethesda,
ACKN OW LEDG MEN TS
MD, Wayne State University/the Detroit Medical Center, Detroit, extracellular matrix components such as fibro-
MI, USA. 2Department of Obstetrics and Gynecology, University nectin, and apoptosis have been implicated in
M.L., R.L.R., and S.A.R. are funded by the National Health and of Michigan, Ann Arbor, MI, USA. 3Department of Epidemiology
Medical Research Council (Australia). We thank L. Wu for the and Biostatistics, Michigan State University, East Lansing, MI,
this process (10, 11) (Fig. 1).
oocyte image in Fig. 2, and R. Richards and J. Thompson for USA. 4Division of Reproductive Sciences, Perinatal Institute, In our view, the common pathway is activated
critical comments. M.L. is an employee of Repromed Ltd. Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, physiologically in the case of labor at term, whereas
(Australia), and S.A.R. receives royalties on a patent describing use USA. 5Department of Obstetrics, Gynecology and Reproductive
of granulocyte-macrophage colony-stimulating factor in IVF,
several disease processes activate one or more of
Sciences, Department of Anatomy, and Center for Reproductive
licensed to Origio A/S (Denmark). Sciences, University of California San Francisco, San Francisco,
the components of the common pathway in the
CA, USA. case of preterm labor. This conceptual frame-
10.1126/science.1254400 *Corresponding author. E-mail: romeror@mail.nih.gov work has implications for the diagnosis, treatment,
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and prevention of spontaneous preterm labor. nisms of disease implicated in spontaneous In 30% of cases of intra-amniotic infection,
For example, interest in myometrial contrac- preterm labor. Of these, only intra-amniotic bacteria are identified in the fetal circulation
tility, the most recognizable sign of preterm infection has been causally linked to spontane- (16), resulting in a fetal systemic inflammatory
labor, has led clinical and translational research ous preterm delivery (12). The others largely have response (17). Such fetuses have multiorgan
to focus on the use of pharmacologic agents to their bases in associations reported by clinical, involvement and are at risk for long-term com-
arrest or decrease uterine contractility (i.e., epidemiologic, placental pathologic, or experi- plications, such as cerebral palsy and chronic
tocolytics) with the goal of preventing preterm mental studies. lung disease, underscoring that complications
delivery. Yet, after decades of investigation, there of infants born preterm are not only due to
is no persuasive evidence that inhibiting or ar- Microbial-induced inflammation immaturity but also to the inflammatory pro-
resting uterine contractility per se decreases the One of every four preterm infants is born to cess responsible for preterm labor. This has im-
rate of preterm delivery or improves neonatal mothers with an intra-amniotic infection that portant implications because recent evidence
outcome, although these agents can achieve is largely subclinical (12). Microorganisms iso- suggests that down-regulation of congenital sys-
short-term prolongation of pregnancy for steroid lated from the amniotic fluid are similar to temic inflammation in the neonatal period using
administration and maternal transfer to tertiary those found in the lower genital tract, and, nanodevices coupled with anti-inflammatory agents
care centers. We consider that, in most cases, therefore, an ascending pathway is considered can reverse a cerebral palsylike phenotype in an
tocolytic agents address a symptom and not the the most frequent route of infection. Bacteria animal model (18).
underlying cause(s) that activate the parturi- involved in periodontal disease have been From an evolutionary perspective, the onset
tional process. The extent to which the physio- found in the amniotic fluid, suggesting that of preterm labor in the context of infection can
logic signals that mediate labor at term can be hematogenous dissemination with transplacental be considered to have survival value, because it
co-opted in the context of pathologic processes passage can also occur (13). Microbial-induced allows the mother to expel infected tissue and
in preterm labor remains to be elucidated. preterm labor is mediated by an inflammatory maintain reproductive fitness. In a remarkable
process. Microorganisms and their products example of evolutionary co-option, the molecular
Preterm labor as a syndrome associated are sensed by pattern recognition receptors, such mechanisms developed for host defense against
with multiple mechanisms of disease as toll-like receptors (TLRs), which induce the infection in primitive multicellular organisms
Spontaneous preterm labor is often treated im- production of chemokines [e.g., IL-8 and C-C (e.g., pattern-recognition receptors in sponges)
plicitly or explicitly as if it were a single condi- motif ligand 2 (CCL2)], cytokines (e.g., IL-1b and have been deployed in viviparous species to ini-
tion. Accumulating evidence suggests that it is TNF-a), prostaglandins, and proteases leading to tiate parturition. This unique mechanism of ma-
a syndrome attributable to multiple pathologic activation of the common pathway of parturition ternal host defense comes at a price: prematurity.
processes (7). Figure 2 illustrates the mecha- (12, 14, 15) (Fig. 3A). In terms of the fetus, inflammation may also
have survival value near term, contributing to
Myometrium Low High
infant host defense against infection and accel-
connectivity Labor connectivity erating lung maturation (19).
* * * * A central question is why some women de-
*
velop an ascending intra-amniotic infection,
* * *
Connexin 43 whereas most do not. The relationship between
* * * **
* ** the mucosa of the lower genital tract (vagina
* * and cervix) and the microbial ecosystem ap-
pears key. Bacterial vaginosis, a change in the
Smooth
muscle cell miR-200 microbial ecosystem in which there is prolif-
Progesterone action eration of anaerobic bacteria, confers risk for
intra-amniotic infection and spontaneous pre-
Contraction-associated
proteins* term delivery. However, antibiotic treatment of
asymptomatic women with bacterial vaginosis
Prostaglandins F2/E2
Membranes/ signaling has not reduced the rate of preterm delivery. A
decidua comprehensive understanding of microbial ecol-
ogy and genetic factors that control susceptibility
A to infection and the inflammatory response is
C required, particularly in light of evidence that
D Labor
Cervix gene-environment interactions may predispose
some women to preterm labor (20). Viral infec-
tion has recently been shown to alter mucosal
immunity in the lower genital tract and to pre-
Labor E E
dispose one to ascending bacterial infection (21).
A Early studies of the vaginal microbiota in
normal pregnancy using sequence-based tech-
C niques suggested that this ecosystem, which is
D different from that of the nonpregnant state, is
more stable (22). Whether the vaginal micro-
Fig. 1. Labor (term and preterm) is characterized by increased myometrial contractility, cervical biota and the local immune response of the
dilatation, and rupture of the chorioamniotic membranes. Collectively, these events have been vagina are different between women who sub-
referred to as the common pathway of parturition. The switch of the myometrium from a quiescent to a sequently deliver preterm and those who deliv-
contractile state is associated with a change in nuclear progesterone receptor isoforms and an increase er at term are important unanswered questions
in the expression of the miR-200 family, as well as an increase in estrogen receptor a signaling. Cervical (23, 24). The factors responsible for changes in
ripening is mediated by changes in extracellular matrix proteins, as well as alterations in epithelial barrier the vaginal microbiota during pregnancy remain
and immune surveillance properties. Decidual or membrane activation, in close proximity to the cervix, to be established. Sex steroid hormones are at-
occurs in preparation for membrane rupture and to facilitate separation of the chorioamniotic mem- tractive candidates, given that estrogens can in-
branes and placenta from the uterus. E denotes extracellular matrix; M, mucus; Os, cervical os. duce the accumulation of glycogen in the vaginal
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of progesterone receptor antagonists, such as tiple gestations and polyhydramnios (an exces- the midtrimester are at increased risk for spontane-
mifepristone (RU-486), induces cervical ripening, sive amount of amniotic fluid). In nonhuman ous preterm delivery later in gestation (58), and those
spontaneous abortion, and labor in both animals primates, inflation of intra-amniotic balloons can with an episode of preterm labor and high plasma
and humanshence the concept that a decline in stimulate uterine contractility, preterm labor, and concentrations of cff DNA are also at increased risk
progesterone may be responsible for some cases an inflammatory pulse, which is characterized for preterm delivery (59, 60). The concept that cff
of preterm labor. Indeed, progesterone has effects by increased maternal plasma concentrations of DNA can mediate a fetal/placental/maternal dialogue
on each component of the common pathway of IL-1b, TNF-a, IL-8, and IL-6 (53). This finding is to signal the onset of labor in normal pregnancy,
parturition. Throughout gestation, progesterone consistent with the observation that stretching as well as preterm labor after insult, is a fascinat-
promotes myometrial quiescence by reducing the human myometrium results in the overexpression ing hypothesis worthy of investigation.
expression of contraction-associated proteins (51) of inflammatory cytokines.
and inflammatory cytokines/chemokines (e.g., IL-1, Maternal stress is also a risk factor for preterm Progress in the prevention of
IL-8, and CCL2) (50). Near term, increased myo- birth. Stressful stimuli range from a heavy work- spontaneous preterm birth
metrial expression of miR-200 family members After decades of clinical and basic investigation,
load to anxiety and depression, occurring at any
counteracts many actions of progesterone, increas- major progress has been made toward the predic-
time during the preconceptional period and/or
ing its catabolism and inducing expression of tion and prevention of spontaneous preterm birth.
pregnancy. Stress signals increase the production
proinflammatory cytokines/chemokines and pros- The two most important predictors of spontaneous
of maternal and fetal cortisol, which in turn could
taglandin synthase 2 (8). Progesterones effects preterm birth are a sonographic short cervix in the
stimulate placental production of corticotropin-
on the decidua and chorioamniotic membranes midtrimester (61) and spontaneous preterm birth
releasing hormone and its release into the ma-
include inhibition of basal- and TNF-ainduced in a prior pregnancy. As for prevention, vaginal pro-
ternal and fetal circulations (54).
apoptosis, which protects the component cells gesterone administered to asymptomatic women
from calcium-induced cell death and attenuates Cell-free fetal DNA with a short cervix in the midtrimester reduces the
cytokine-induced MMP expression and activity Cell-free fetal (cff) DNA has recently been proposed rate of preterm birth at <33 weeks by 45% and de-
(52). Progesterone has been implicated in the con- as a signal for the onset of labor (55). In pregnant creases the rate of neonatal complications, includ-
women, cffDNA is normally present in the plas-
trol of cervical ripening by regulating extracellular ing neonatal respiratory distress syndrome (62). In
ma, and concentrations increase as a function of
matrix metabolism (9). It is possible that the effi- women with a previous spontaneous preterm birth,
cacy of progesterone in reducing preterm birth gestational agepeaking at the end of pregnancy the administration of 17-alpha hydroxyprogester-
is due to a pharmacological effect rather than just before the onset of labor. cffDNA (in contrast one caproate reduces the rate of preterm birth at
treatment of a progesterone deficiency. with adult cell-free DNA) is hypomethylated, can <37 weeks by 34% and decreases the need for ox-
engage TLR-9 (56, 57), and induce an inflammatory ygen supplementation in singleton gestation (63).
Other mechanisms of disease response. The downstream consequences could in- Cervical cerclage in patients with a previous spon-
Uterine overdistension has been implicated in clude activating the common pathway of labor. Inter- taneous preterm birth and a short cervix reduces
spontaneous preterm birth associated with mul- estingly, patients who have an elevation of cffDNA in the rate of preterm birth at <35 weeks by 30%, as
well as composite perinatal mortality
and morbidity. However, vaginal pro-
A Amnion Chorion B gesterone is as efficacious as cervical
DAPI 16S rRNA FISH Merge
cerclage in these patients and does
Prostaglandins
Proteases not require anesthesia or a surgical
procedure.
Amniotic
fluid The combination of transvaginal
IL-1 IL-8 TNF
ultrasound in the midtrimester to
Myometrium
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ACKN OW LEDG MEN TS female brains irrespective of the normal expres- to mate in a bird population largely determines
The authors regret that, because of page limitations, the sion of parenting displays and are modulated by which parent cares for offspring. For example,
contributions of many investigators to the study of parturition intrinsic and environmental factors. male shorebirds are more likely to care for off-
could not be credited in this article. The authors thank spring in populations where males are more abun-
S. Curtis for editing the manuscript. The work of R.R. is Diversity in parental care
supported by the Division of Intramural Research of the
dant than females (17).
Eunice Kennedy Shriver NICHD, NIH/Department of Health and Parental care has evolved repeatedly across ver- Amphibians display striking diversity in pa-
Human Services. Studies from S.K.D.s lab were supported tebrate and invertebrate taxa (2). The involvement rental care. Many species of anurans and sal-
in part by grants from the NIH (HD068524 and DA06668) and amanders display care for offspring beyond egg
March of Dimes (21-FY12-127 and 22-FY14-470). The work of 1
Howard Hughes Medical Institute, Department of Molecular
S.F. is supported by R37 HD076253 and U54 HD055764.
laying, with roughly 50 independent evolution-
and Cellular Biology, Center for Brain Science, Harvard
We thank M. Gormley for assistance preparing the figures. University, Cambridge, MA 02138, USA. 2FAS Center for
ary transitions to parental care (18). These be-
System Biology, Harvard University, Cambridge, MA 02138, USA. haviors include preparation of foam nests (19),
10.1126/science.1251816 *Corresponding author. E-mail: dulac@fas.harvard.edu egg guarding, transport of offspring piggyback