A non-optimal cervicovaginal microbiota in pregnancy is associated with a distinct metabolomic signature among non-Hispanic Black individuals

Biomechanical and molecular processes of premature cervical remodeling preceding spontaneous preterm birth (sPTB) likely result from interactions between the cervicovaginal microbiota and host immune responses. A non-optimal cervicovaginal microbiota confers increased risk of sPTB. The cervicovaginal space is metabolically active in pregancy; microbiota can produce, modify, and degrade metabolites within this ecosystem. We establish that cervicovaginal metabolomic output clusters by microbial community in pregnancy among Black individuals, revealing increased metabolism within the amino acid and dipeptide pathways as hallmarks of a non-optimal microbiota. Few differences were detected in metabolomic profiles when stratified by birth outcome. The study raises the possibility that metabolites could distinguish women with greater risk of sPTB among those with similar cervicovaginal microbiota, and that metabolites within the amino acid and carbohydrate pathways may play a role in this distinction.

Transcriptome and proteome dynamics of cervical remodeling in the mouse during pregnancy

During gestation, the female reproductive tract must maintain pregnancy while concurrently preparing for parturition. Here, we explore the transitions in gene expression and protein turnover (fractional synthesis rates [FSR]) by which the cervix implements a transition from rigid to compliant. Shifts in gene transcription to achieve immune tolerance and alter epithelial cell programs begin in early pregnancy. Subsequently, in mid-to-late pregnancy transcriptional programs emerge that promote structural reorganization of the extracellular matrix (ECM). Stable isotope labeling revealed a striking slowdown of overall FSRs across the proteome on gestation day 6 that reverses in mid-to-late pregnancy. An exception was soluble fibrillar collagens and proteins of collagen assembly, which exhibit high turnover in non-pregnant cervix compared to other tissues and FSRs that continue throughout pregnancy. This finding provides a mechanism to explain how cross-linked collagen is replaced by newly synthesized, less-cross-linked collagens, which allows increased tissue compliance during parturition. The rapid transition requires a reservoir of newly synthesized, less cross-linked collagens, which is assured by the high FSR of soluble collagens in the cervix. These findings suggest a previously unrecognized form of “metabolic flexibility” for ECM in the cervix that underlies rapid transformation in compliance to allow parturition.

Isthmico-cervical insufficiency associated with cervicovaginal infections: features of the course of pregnancy and perinatal outcomes

Introduction. The formation of isthmic-cervical insufficiency (ICI) in 80% is associated with intraamnial inflammation, this is the subject of discussion of new mechanisms of the pathogenesis of premature cervical remodeling. In this regard, it is of interest to study the relationship of ICS with intrauterine and cervicovaginal infections during pregnancy and their impact on the course and outcomes of pregnancy, which was the purpose of our study.Methods. A prospective cohort study included 100 pregnant women with ICI, taken by a continuous sample. All patients at the time of ICI manifestation underwent a comprehensive clinical and laboratory examination aimed at diagnosing cervicovaginal infections, according to e results of which the pregnant women were divided into 2 groups: the first group consisted of 72 women with ICI and cervicovaginal infections, the second group — 28 women with ICI and normocenosis of the vagina.Results. There were no significant differences between the compared groups in terms of the history of miscarriage, extragenital pathology and the frequency of complications of this pregnancy. Intrauterine infection during pregnancy in patients of group 1 was observed 4 times more often, being 55.6% (40) versus 14.3% (4) in group 2 (RR = 3.9, 95% CI = 1.5-9.9, p <0.001). Preterm birth was significantly more frequent in women of group 1, accounting for 62.5% (45), in group 2 — 28.6% (8). Perinatal mortality cases were observed only in group 1, amounting to 97‰ (7). In children from women in group 1, complications of the early neonatal period were more common, primarily due to prematurity. In addition, IUI in newborns was diagnosed 10 times more often in group 1, reaching 38.8% (26) of cases, compared with group 2 — 3.6% (1) (RR = 10.87, 95% CI = 1.55–76.22, p <0.001).Discussion. Perinatal outcomes in ICI associated with cervicovaginal infections are characterized by the presence of perinatal mortality, a higher incidence of preterm birth and IUI of the newborn than in women with ICI without cervicovaginal infection.

Changes in gene expression of cervical collagens, metalloproteinases, and tissue inhibitors of metalloproteinases after partial cervical excision-induced preterm labor in mice

We investigated changes in gene expression of cervical collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) during pre-gestational uterine cervical excision and/or inflammation-induced preterm labor in mice. Forty sexually mature female mice were uniformly divided into four groups: sham, cervical excision, lipopolysaccharide (LPS) injection, and cervical excision plus LPS injection. Partial cervical tissue excision was performed at five weeks of age before mating. LPS was injected into the lower right uterine horn near the cervix on gestational day 16. Mice were sacrificed immediately postpartum. Uterine cervices were collected and subjected to quantitative real-time PCR. Col4α1 and Col5α1 expression increased significantly in the cervical excision plus LPS injection group compared to the sham group (p < 0.01 and p = 0.024, respectively). MMP-14 expression levels increased in the cervical excision plus LPS injection group compared to the sham group (p < 0.01). TIMP-1 expression was not significantly decreased in this group. Increased expression levels of Col4α1, Col5α1, and MMP-14 were associated with cervical excision plus inflammation-induced preterm labor. Thus, pre-gestational cervical remodeling through specific collagen metabolism and MMP activation may involve the pathogenesis of spontaneous preterm labor.

Equine Cervical Remodeling during Placentitis and the Prepartum Period: A Transcriptomic Approach

Cervical remodeling is a critical component in both term and preterm labor in eutherian mammals. However, the molecular mechanisms underlying cervical remodeling remain poorly understood in the mare. The current study compared the transcriptome of the equine cervix (cervical mucosa (CM) and stroma (CS)) during placentitis (placentitis group, n=5) and normal prepartum mares (prepartum group, n=3) to normal pregnant mares (control group, n=4). Transcriptome analysis identified differentially expressed genes (DEGs) during placentitis (5310 in CM and 907 in CS) and during the normal prepartum period (189 in CM and 78 in CS). Our study revealed that cervical remodeling during placentitis was dominated by inflammatory signaling as reflected by the overrepresented toll-like receptor signaling, interleukin signaling, T cell activation, and B cell activation pathways. These pathways were accompanied by upregulation of several proteases, including matrix metalloproteinases (MMP1, MMP2, and MMP9), cathepsins (CTSB, CTSC, and CTSD) and a disintegrin and metalloproteinase with thrombospondin type 1 motifs (ADAMTS1, ADAMTS4, and ADAMTS5), which are crucial for degradation of cervical collagens during remodeling. Cervical remodeling during placentitis was also associated with upregulation of water channel-related transcripts (AQP9 and RLN), angiogenesis-related transcripts (NOS3, ENG1, THBS1, and RAC2), and aggrecan (ACAN), a hydrophilic glucosaminoglycan, with subsequent cervical hydration. The normal prepartum cervix was associated with upregulation of ADAMTS1, ADAMTS4, NOS3 and THBS1, which might reflect an early stage of cervical remodeling taking place in preparation for labor. In conclusion, our findings revealed the possible key regulators and mechanisms underlying equine cervical remodeling during placentitis and the normal prepartum period.

Shear Wave Dispersion as a Potential Biomarker for Cervical Remodeling During Pregnancy: Evidence From a Non-Human Primate Model

Shear wave dispersion (variation of phase velocity with frequency) occurs in tissues with layered and anisotropic microstructure and viscous components, such as the uterine cervix. This phenomenon, mostly overlooked in previous applications of cervical Shear Wave Elasticity Imaging (SWEI) for preterm birth risk assessment, is expected to change drastically during pregnancy due to cervical remodeling. Here we demonstrate the potential of SWEI-based descriptors of dispersion as potential biomarkers for cervical remodeling during pregnancy. First, we performed a simulation-based pre-selection of two SWEI-based dispersion descriptors: the ratio R of group velocities computed with particle-velocity and particle-displacement, and the slope S of the phase velocity vs. frequency. The pre-selection consisted of comparing the contrast-to-noise ratio (CNR) of dispersion descriptors in materials with different degrees of dispersion with respect to a low-dispersive medium. Shear waves induced in these media by SWEI were simulated with a finite-element model of Zener viscoelastic solids. The pre-selection also considered two denoising strategies to improve CNR: a low-pass filter with automatic frequency cutoff determination, and singular value decomposition of shear wave displacements. After pre-selection, the descriptor-denoising combination that produced the largest CNR was applied to SWEI cervix data from 18 pregnant Rhesus macaques acquired at weeks 10 (mid-pregnancy stage) and 23 (late pregnancy stage) of the 24.5-weeks full pregnancy. A maximum likelihood linear mixed-effects model (LME) was used to evaluate the dependence of the dispersion descriptor on pregnancy stage, maternal age, parity and other experimental factors. The pre-selection study showed that descriptor S combined with singular value decomposition produced a CNR 11.6 times larger than the other descriptor and denoising strategy combinations. In the Non-Human Primates (NHP) study, the LME model showed that descriptor S significantly decreased from mid to late pregnancy (−0.37 ± 0.07 m/s-kHz per week, p< 0.00001) with respect to the base value of 15.5 ± 1.9 m/s-kHz. This change was more significant than changes in other SWEI features such as the group velocity previously reported. Also, S varied significantly between the anterior and posterior portions of the cervix (p= 0.02) and with maternal age (p= 0.008). Given the potential of shear wave dispersion to track cervical remodeling, we will extend its application to ongoing longitudinal human studies.

Cervical Assessment for Predicting Preterm Birth—Cervical Length and Beyond

Preterm birth is considered one of the main etiologies of neonatal death, as well as short- and long-term disability worldwide. A number of pathophysiological processes take place in the final unifying factor of cervical modifications that leads to preterm birth. In women at high risk for preterm birth, cervical assessment is commonly used for prediction and further risk stratification. This review outlines the rationale for cervical length screening for preterm birth prediction in different clinical settings within existing and evolving new technologies to assess cervical remodeling.