Review
Cervical remodeling during pregnancy and parturition

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Appropriate and timely cervical remodeling is key for successful birth. Premature cervical opening can result in preterm birth which occurs in 12.5% of pregnancies. Research focused on the mechanisms of term and preterm cervical remodeling is essential to prevent prematurity. This review highlights recent findings that better define molecular processes driving progressive disorganization of the cervical extracellular matrix. This includes studies that redefine the role of immune cells and identify diverse functions of the cervical epithelia and hyaluronan in remodeling. New investigations proposing that infection-induced premature cervical remodeling is distinct from the normal process are presented. Recent advances in our understanding of term and preterm cervical remodeling provide new directions for investigation and compel investigators to reevaluate currently accepted models.

Section snippets

Overview

The transformation of the cervix from a closed rigid structure to one that opens sufficiently for birth is an active dynamic process that begins long before the onset of labor. Better understanding of the molecular process of cervical remodeling is critical for the development of therapies to treat preterm birth and postterm pregnancies due to cervical malfunction. In this review, recent insights gained from studies in rodent models will be presented and contrasted with human studies. Although

Distinct phases of remodeling

Cervical remodeling can be loosely divided into four distinct but overlapping phases termed softening, ripening, dilation and postpartum repair (Table 1) 1, 2. Softening can be defined as the first measurable decline in the tensile strength or tissue compliance compared with nonpregnancy. Biomechanical studies in mice or digital examination in women indicate softening begins by day 12 of a 19-day gestation in mice and in the first trimester of pregnancy in women 1, 3. This phase is unique from

Normal cervical remodeling

In 1981, Mont Liggins first proposed a model in which inflammatory cells mediate changes in the cervical ECM leading to cervical ripening [4]. This was an attractive model leading to the hypothesis that infection-mediated preterm birth was simply an acceleration of the inflammatory response that occurred during normal physiological cervical ripening. Leukocytes infiltrating the cervix at birth were proposed to secrete proteases that contribute to the destruction, loss and disorganization of the

Cervical epithelia: barrier properties, immune surveillance and more

The cervical epithelia and mucus have important protective roles during pregnancy and parturition that include prevention of infection and protection against mechanical insult during delivery. To fulfill these roles, epithelia undergo marked proliferation during pregnancy (Figure 1) [35]. In recent years, the observation that the expression of specific proteins are induced and regulated during cervical ripening and dilation in mice further highlight additional roles of epithelia in regulation

Collagen and tissue biomechanics

Characteristic changes of the female cervix in early pregnancy was described by Hegar in 1895 as “softening” [46]. These studies were the first indication that changes in the structural organization of the tissue occur in the first trimester of pregnancy resulting in increased tissue compliance (the physical yielding of tissue to a mechanical force). Biomechanical measurements confirm the progressive increase in tissue compliance that begins in early pregnancy and ends with maximal loss of

Hyaluronan and proteoglycans

Alterations in collagen structure and packing are influenced by the composition of glycosaminoglycans (GAGs) in the ECM (Figure 1, Figure 2). Cervical total GAG content increases with progression of pregnancy and is accompanied by a dramatic change in composition [49]. GAGs include the unsulfated GAG, hyaluronan (HA), as well as proteins containing sulfated GAG chains (proteoglycans). Proteoglycans have diverse functions in signal factor binding and modulate collagen fibril size, spacing and

Other extracellular matrix components

Additional ECM components influence the biomechanical properties of the cervix. Elastin fibers provide recoil to tissues that undergo repeated stretch; in the human cervix, elastin fibers are located in defined regions of the stromal matrix and comprise 0.9–2.4% of the total amount of connective tissue without significant change in content over the course of pregnancy [59]. The importance of elastin fibers in mediating reversible extensibility or elasticity is suggested by the decline in

Working model based on animal studies

Recent advances highlighted in this review allow the development of a working model in mice which distinguish processes important during softening versus those occurring during latter phases of ripening and dilation. Softening is characterized by increased collagen turnover and reduced collagen crosslinking. As mature, crosslinked collagen is depleted from the matrix, it is replaced with the less mature collagen resulting in a progressive decline in tissue stiffness. Concomitant with changes in

Acknowledgements

We thank Roxane Holt for critical reading of the manuscript. This work was supported by National Institutes of Health grants (R01 HD043154 and P01 11149) to M.M.

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