Pathophysiology Of Preterm Birth Research Articles

Lack of association between the VEGFA gene polymorphisms and preterm birth in Korean women.

Preterm birth (PTB), a pregnancy-related disease, is defined as a birth before 37 weeks of gestation. It is a major cause of maternal mortality and morbidity worldwide, and its incidence rate is steadily increasing. Various genetic factors can contribute to the etiology of PTB. Vascular endothelial growth factor A (VEGFA) gene is an important angiogenic gene and its polymorphisms have been reported to be associated with PTB development. Therefore, we conducted a case-control study to evaluate the association between VEGFA rs699947, rs2010963, and rs3025039 polymorphisms and PTB in Korean women. A total of 271 subjects (116 patients with PTB and 155 women at ≥38 weeks of gestation) were analyzed in this study. The genotyping of VEGFA gene polymorphisms was performed using polymerase chain reaction- restriction fragment length polymorphism. No significant association between the patients with PTB and the control groups was confirmed. In the combination analysis, we found a significant association between PTB and VEGFA rs699947 CC-rs2010963 GG-rs3025039 CC combination (odds ratio, 3.77; 95% confidence interval, 1.091 to 13.032; p = 0.031). The VEGFA rs699947, rs2010963, and rs3025039 polymorphisms might have no genetic association with the pathogenesis of PTB in Korean women. However, the combination analysis indicates the possibility that VEGFA acts in PTB pathophysiology. Therefore, larger sample sets and replication studies are required to further elucidate our findings.

A Novel Predictive Machine Learning Model Integrating Cytokines in Cervical-Vaginal Mucus Increases the Prediction Rate for Preterm Birth.

Preterm birth (PB) is a leading cause of perinatal morbidity and mortality. PB prediction is performed by measuring cervical length, with a detection rate of around 70%. Although it is known that a cytokine-mediated inflammatory process is involved in the pathophysiology of PB, none screening method implemented in clinical practice includes cytokine levels as a predictor variable. Here, we quantified cytokines in cervical-vaginal mucus of pregnant women (18-23.6 weeks of gestation) with high or low risk for PB determined by cervical length, also collecting relevant obstetric information. IL-2, IL-6, IFN-γ, IL-4, and IL-10 were significantly higher in the high-risk group, while IL-1ra was lower. Two different models for PB prediction were created using the Random Forest machine-learning algorithm: a full model with 12 clinical variables and cytokine values and the adjusted model, including the most relevant variables-maternal age, IL-2, and cervical length- (detection rate 66 vs. 87%, false positive rate 12 vs. 3.33%, false negative rate 28 vs. 6.66%, and area under the curve 0.722 vs. 0.875, respectively). The adjusted model that incorporate cytokines showed a detection rate eight points higher than the gold standard calculator, which may allow us to identify the risk PB risk more accurately and implement strategies for preventive interventions.

Preterm premature rupture of membranes.

The aim of the presented work is to summarize the current knowledge about the pathophysiology of preterm birth in connection with premature amniotic fluid. To analyze current knowledge and our own experiences regarding of preterm prelabour rupture of membranes. The most important factor influencing neonatal morbidity and mortality is gestational age. Early neonatal sepsis occurs with high risk after premature amniotic fluid outflow, associated with inflammatory complications.

Pharmacodynamic characterization of rytvela, a novel allosteric anti-inflammatory therapeutic, to prevent preterm birth and improve fetal and neonatal outcomes

Preterm birth is the leading cause of neonatal morbidity and mortality. Studies have shown that interleukin 1 plays a major role in the pathophysiology of preterm birth by inducing the production of proinflammatory mediators and uterine activation proteins leading to labor. More importantly, uteroplacental inflammation, associated with preterm birth parturition pathways, is detrimental to fetal tissues and leads to long-term sequelae. Our group has developed an allosteric antagonist of the interleukin 1 receptor, rytvela, found to be potent and safe in preventing preterm birth by suppressing inflammation via the inhibition of the mitogen-activated protein kinase pathway while preserving the Nuclear factor kappa B pathway (important in immune vigilance). Rytvela has been shown to inhibit inflammatory up-regulation and uterine activation while preserving fetal development. This study aimed to further the preclinical development of rytvela by evaluating its optimal dose and minimal duration of treatment to inhibit the inflammatory cascade, prolong gestation, and promote neonatal outcomes. Pregnant CD-1 mice were administered with lipopolysaccharide (10 μg, intraperitoneal administration) or interleukin 1 (1 μg/kg, intrauterine administration) on gestational day 16 to induce preterm labor. Rytvela was administered at different doses (0.1, 0.5, 1.0, 2.0, 4.0 mg/kg/d subcutaneously) from gestational days 16 to 18.5. To evaluate the minimal duration of treatment, the mice were administered with rytvela (2 mg/kg/d subcutaneously) for 24, 36, or 48 hours. The rate of prematurity (gestational day <18.5) and neonate survival and weightwere evaluated. Gestational tissues were collected at gestationalday 17.5 to quantify cytokines, proinflammatory mediators, and uterine activating proteins by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The neonatal lungs and intestines were collected from postnatal days 5 to 7 and analyzed by histology. Rytvela exhibited a dose-response profile and achieved maximum efficacy at a dose of 2 mg/kg/d by reducing 70% of lipopolysaccharide-induced preterm births and 60% of interleukin 1β-induced preterm births. In addition, rytvela attained maximum efficacy at a dose of 1 mg/kg/d by increasing neonate survival by up to 65% in both models of preterm birth. Rytvela protected fetuses from inflammatory insult as of 24 hours, preserving lung and intestinal integrity, and prevented preterm birth and fetal mortality by 60% and 50%, respectively, as of 36 hours of treatment. The maximum efficacy of rytvela was achieved at 2 mg/kg/d with improved birth outcomes and prevented inflammatory up-regulation upon 36 hours (only) of treatment. Rytvela exhibited desirable properties for the safe prevention of preterm birth and fetal protection.

Understanding and Reducing Persistent Racial Disparities in Preterm Birth: a Model of Stress-Induced Developmental Plasticity.

Preterm birth is a leading cause of neonatal mortality and is characterized by substantial racial disparities in the US. Despite efforts to reduce preterm birth, rates have risen and racial disparities persist. Maternal stress is a risk factor for preterm birth; however, often, it is treated as a secondary variable rather than a primary target for intervention. Stress is known to affect several biological processes leading to downstream sequelae. Here, we present a model of stress-induced developmental plasticity where maternal stress is a key environmental cue impacting the length of gestation and therefore a primary target for intervention. Black women experience disproportionate and unique maternal stressors related to perceived racism and discrimination. It is therefore not surprising that Black women have disproportionate rates of preterm birth. The downstream effects of racism on preterm birth pathophysiology may reflect an appropriate response to stressors through the highly conserved maternal-fetal-placental neuroendocrine stress axis. This environmentally sensitive system mediates both maternal stress and the timing of birth and is a mechanism by which developmental plasticity occurs. Fortunately, stress does not appear to be an all-or-none variable. Evidence suggests that developmental plasticity is dynamic, functioning on a continuum. Therefore, simple, stress-reducing interventions that support pregnant women may tangibly reduce rates of preterm birth and improve birth outcomes for all women, particularly Black women.

Polymorphisms in vitamin B12 and folate metabolising genes and their association with adverse pregnancy outcome: secondary analysis of a population based case control study

Vitamin B12 and folate deficiency leads to accumulation of homocysteine that increases the risk of adverse pregnancy outcomes like preterm birth and low birth weight (LBW) of the neonate. We explored the association of genetic variants of key vitamin B12 and folate metabolising enzymes (MTHFR C677T and A1298C, MTR A2756G, TCN-2 C776G) with preterm birth and LBW in South Indian women. MTHFR A1298C heterozygotes (AC) were at higher risk for preterm delivery, whereas TCN-2 C776G heterozygotes (CG) were at higher risk for both preterm delivery and LBW. MTHFR C677T, A1298C and MTR A2756G haplotype CAG was protective for preterm delivery (p=.036, OR = 0.475; 95% CI: 0.233–0.97), whereas, haplotype CCG increasing the risk of preterm birth by 1.8 folds (p=.018, OR = 1.81; 95% CI: 1.09–2.98). These results underscore the significance of vitamin B12 and folate in the pathophysiology of preterm birth and LBW. Impact Statement What is already known on this subject? Polymorphisms of vitamin B12 and folate metabolising genes have been reported to influence preterm birth and LBW, but the reports are not consistent. What do the results of this study add? We observed a relationship of MTHFR A1298C and TCN-2 C776G with preterm birth, and significant association of TCN-2 C776G with LBW in infants. What are the implications of these findings for clinical practice and/or further research? Identification of women carrying these polymorphic risk alleles may benefit from early nutritional modifications.

Maternal metabolic profiling to assess fetal gestational age and predict preterm delivery: a two-centre retrospective cohort study in the US

ObjectivesThe aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised...

Prospective association of maternal immune pro-inflammatory responsivity and regulation in pregnancy with length of gestation.

The immune system represents a leading pathway of interest in the pathophysiology of preterm birth. The majority of human clinical studies interrogating this pathway have utilized circulating immune biomarkers; however, these concentrations typically reflect only basal production but not key functional properties of the immune system, particularly variation in the pro-inflammatory response to antigen challenge and the regulation of this response. Thus, in this study, we utilized an ex vivo stimulation protocol that quantifies these processes, and we examined their prospective association with the gestation length and risk of preterm birth. Immune responsiveness and regulation were assessed in 128 pregnant women in mid-gestation using an ex vivo stimulation protocol. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β in response to antigen stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of stimulated cytokine response upon co-incubation with increasing dexamethasone concentrations (ie, glucocorticoid receptor resistance; GRR). Higher maternal GRR, indicating impaired regulation of the pro-inflammatory response, was significantly and independently associated with shorter gestational length (β=-0.42, p=.0091) and a 3.0-fold increase in risk for preterm birth (OR=3.01, 95% CI=1.17-7.70, p=.0218). Basal circulating IL-6 and TNF-α were not associated with either outcome. The association of maternal GRR with length of gestation and preterm birth risk suggests that the processes represented by this measure-maternal pro-inflammatory propensity and immune regulation-may provide further mechanistic insight into the pathophysiology of preterm birth.

Serum Decorin and Biglycan as Potential Biomarkers to Predict PPROM in Early Gestation

Preterm birth is a leading cause of neonatal mortality in the US and globally, with preterm premature rupture of fetal membranes (PPROM) accounting for one third of preterm births. Currently no predictive diagnostics are available to precisely assess risk and potentially reduce the incidence of PPROM. Bigycan and decorin, the main proteoglycans present in human fetal membranes, are involved in the physiological maturation of fetal membranes as well as in the pathophysiology of preterm birth. The serum protein sex hormone-binding globulin (SHBG) has recently been identified as a predictor of spontaneous preterm birth. We hypothesize that the balance between serum decorin and biglycan on one hand and SHBG on the other hand may provide insight into the status of the fetal membranes in early pregnancy, thereby predicting PPROM prior to symptoms. Using chart review, 18 patients with confirmed cases of PPROM were identified from 2013-2016. Second trimester residual serum was retreived from freezer storage for these cases along with 5 matched controls for each case. The biomarkers biglycan, decorin and SHBG were analyzed first separately, then in combination to determine their ability to predict PPROM. The predictive score for the combined model displays an AUC = 0.774. The ROC curve of the predicted score has an optimal threshold of 0.238 and a sensitivity and specificity of 0.72 and 0.84 respectively. This prenatal serum panel is a promising serum screening-based biochemical model to predict PPROM in asymptomatic women.

Bacterial vaginosis as a risk factor for preterm birth

At the moment, the problem of preterm birth is one of the most urgent in the modern world. Preterm birth is of the greatest interest in obstetrics, as they can lead to various conditions that interfere with the further development and vital activity of the baby, which can lead to various disorders in the babys body systems, and in the worst case, can also lead to its death. Nowadays, there is no complete understanding of the mechanisms of development of preterm labor. The pathogenesis and pathophysiology of preterm birth are extremely complex, however, of course, many factors affect the development of this process, including the state of the microflora of the female genital tract. This article provides a review of current literature on the effects of bacterial vaginosis and significant infectious microorganisms (Prevotella sp., Mobiluncus sp., Gardnerella vaginalis, Mycoplasma hominis, etc.) on the development of preterm labor. This work presents a review of the current literature on the available data on the effect of various microorganisms of the female genital tract, as well as the significant cytokines, defensins, prostaglandins, and other biologically active substances secreted by them that are most likely involved in the process of preterm delivery. A probable mechanism for the development of preterm labor is presented under the influence of changes in the vaginal microflora and the predominance of pathogenic and conditionally pathogenic flora with the participation of matrix metalloproteinases, phospholipases and ligands of Toll-like receptors.

Serum Decorin and Biglycan as Potential Biomarkers to Predict PPROM in Early Gestation.

Preterm birth is a leading cause of neonatal mortality in the US and globally, with preterm premature rupture of fetal membranes (PPROM) accounting for one third of preterm births. Currently no predictive diagnostics are available to precisely assess risk and potentially reduce the incidence of PPROM. Bigycan and decorin, the main proteoglycans present in human fetal membranes, are involved in the physiological maturation of fetal membranes as well as in the pathophysiology of preterm birth. The serum protein sex hormone-binding globulin (SHBG) has recently been identified as a predictor of spontaneous preterm birth. We hypothesize that the balance between serum decorin and biglycan on one hand and SHBG on the other hand may provide insight into the status of the fetal membranes in early pregnancy, thereby predicting PPROM prior to symptoms. Using chart review, 18 patients with confirmed cases of PPROM were identified from 2013-2016. Second trimester residual serum was retreived from freezer storage for these cases along with 5 matched controls for each case. The biomarkers biglycan, decorin and SHBG were analyzed first separately, then in combination to determine their ability to predict PPROM. The predictive score for the combined model displays an AUC = 0.774. The ROC curve of the predicted score has an optimal threshold of 0.238 and a sensitivity and specificity of 0.72 and 0.84 respectively. This prenatal serum panel is a promising serum screening-based biochemical model to predict PPROM in asymptomatic women.

Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model.

Preterm birth is the world's leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. Data of all known Dutch patients with Sjögren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. Preterm birth is a hallmark of Sjögren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact "experiments of nature" and as such they shed new lights on the mechanisms causing preterm birth.

Methylation differences reveal heterogeneity in preterm pathophysiology: results from bipartite network analyses.

Recent studies have shown that epigenetic differences can increase the risk of spontaneous preterm birth (PTB). However, little is known about heterogeneity underlying such epigenetic differences, which could lead to hypotheses for biological pathways in specific patient subgroups, and corresponding targeted interventions critical for precision medicine. Using bipartite network analysis of fetal DNA methylation data we demonstrate a novel method for classification of PTB. The data consisted of DNA methylation across the genome (HumanMethylation450 BeadChip) in cord blood from 50 African-American subjects consisting of 22 cases of early spontaneous PTB (24-34 weeks of gestation) and 28 controls (>39 weeks of gestation). These data were analyzed using a combination of (1) a supervised method to select the top 10 significant methylation sites, (2) unsupervised "subject-variable" bipartite networks to visualize and quantitatively analyze how those 10 methylation sites co-occurred across all the subjects, and across only the cases with the goal of analyzing subgroups and their underlying pathways, and (3) a simple linear regression to test whether there was an association between the total methylation in the cases, and gestational age. The bipartite network analysis of all subjects and significant methylation sites revealed statistically significant clustering consisting of an inverse symmetrical relationship in the methylation profiles between a case-enriched subgroup and a control-enriched subgroup: the former was predominantly hypermethylated across seven methylation sites, and hypomethylated across three methylation sites, whereas the latter was predominantly hypomethylated across the above seven methylation sites and hypermethylated across the three methylation sites. Furthermore, the analysis of only cases revealed one subgroup that was predominantly hypomethylated across seven methylation sites, and another subgroup that was hypomethylated across all methylation sites suggesting the presence of heterogeneity in PTB pathophysiology. Finally, the analysis found a strong inverse linear relationship between total methylation and gestational age suggesting that methylation differences could be used as predictive markers for gestational length. The results demonstrate that unsupervised bipartite networks helped to identify a complex but comprehensible data-driven hypotheses related to patient subgroups and inferences about their underlying pathways, and therefore were an effective complement to supervised approaches currently used.

The pathophysiology of preterm birth from the view point of intestinal and vaginal microbiota

The pathophysiology of preterm birth from the view point of intestinal and vaginal microbiota

Polymorphisms in NR5A2, gene encoding liver receptor homolog-1 are associated with preterm birth.

Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. There is strong evidence of genetic susceptibility. Objective of this study was to identify genetic variants contributing to PTB. Genotyping was performed for 24 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NR5A2, FSHR, FOXP3, and SERPINH1). Genotyping was completed on 728 maternal triads (mother and maternal grandparents of a preterm infant). Data were analyzed with Family Based Association Test. For all maternal triads rs2737667 of NR5A2 showed significant association at P = 0.02. When stratifying by gestational age three SNPs in NR5A2 had P values <0.05 in the <32-wk gestational age group (rs12131233, P = 0.007; rs2737667, P = 0.04; rs2816949, P = 0.02). When preterm premature rupture of membranes cases were excluded rs2737667 of NR5A2 showed the strongest association with a P value <0.0002. This association remained significant after correction for multiple testing. This study suggests a potential association between intronic SNPs in the NR5A2 gene and PTB. NR5A2 gene encodes for the liver receptor homolog-1 protein, which plays a critical role in regulation of cholesterol metabolism, steroidogenesis, and progesterone synthesis. These findings suggest that NR5A2 may be important in the pathophysiology of PTB and exploring noncoding regulators of NR5A2 is warranted.

14: Methylation differences reveal heterogeneity in spontaneous preterm birth pathophysiology: a visual analytical approach

14: Methylation differences reveal heterogeneity in spontaneous preterm birth pathophysiology: a visual analytical approach

Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth

Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother-daughter pairs. We identified novel variants shared between the two mother-daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother-daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p value=6.91e-5, OR=1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.

466: Relationship of placental inflammation and progesterone in the setting or preterm birth

Progesterone (P4) provides protection from preterm birth in at risk individuals. The role of placental progesterone in response to inflammation, a key factor in the pathophysiology of preterm birth, is not completely understood. Our objective was to examine the relationship of placental progesterone in the setting of inflammation in a preterm birth cohort.

15: Bioinformatics analysis of biomarkers reveal differential maternal-fetal contributions to spontaneous preterm birth pathophysiology

15: Bioinformatics analysis of biomarkers reveal differential maternal-fetal contributions to spontaneous preterm birth pathophysiology

The prevalence of preterm birth and season of conception

Preterm birth is a major obstetric problem. An exploration of the season of conception in relation to preterm birth may provide direction in the search for risk factors. We conducted a retrospective cohort study of 82 213 singleton livebirths (20-45 weeks' gestation) to 61,630 women at Magee-Womens Hospital, Pittsburgh, PA, from 1995 to 2005. Conception was estimated based on gestational age determined by best obstetric estimate. Fourier series analysis was used to model seasonal trends. Spontaneous preterm birth at <37 weeks was associated with conception season (P < 0.05). The peak prevalence occurred among conceptions in winter and spring (peaking February 23 at 6.9%), with an average trough among late summer/early autumn conceptions (August 25 at 6.2%). The pattern for spontaneous preterm birth <32 weeks was similar (P < 0.05), with the peak on March 13 (1.7%), and nadir on September 12 (1.4%). Results were similar when indicated preterm births were included. These seasonal changes may increase our insight into the role of exposures with seasonal periodicity in the pathophysiology of preterm birth.