Spontaneous Preterm Birth In Women Research Articles

Diabetes Mellitus as a Risk Factor for Spontaneous Preterm Birth in Women with a Short Cervix after Ultrasound-Indicated Cerclage.

Background: Preterm birth (PTB) is a significant challenge in contemporary obstetrics, affecting over one in ten infants worldwide and accounting for 75% of perinatal mortality. Short cervical length during mid-trimester is well known to be associated with an increased risk of spontaneous preterm birth (sPTB). Ultrasound-indicated cerclage (UIC) is recommended to prevent sPTB in women with a short cervix at mid-trimester and a history of sPTB. Objectives: This retrospective observational study aimed to examine the impact of diabetes and obesity on the occurrence of sPTB in women who underwent UIC due to mid-trimester cervical shortening. Methods/Results: The analysis revealed that cervical length at the time of operation, preoperative erythrocyte sedimentation rate levels, and diabetes were independent risk factors for sPTB. Additionally, the presence of diabetes, particularly when combined with obesity, significantly elevated the risk of sPTB. Women with pregestational diabetes or those requiring insulin treatment had a higher propensity for preterm delivery compared to those with gestational diabetes managed through diet control alone. Conclusions: These findings emphasize the importance of considering maternal metabolic factors, such as diabetes and obesity, in women with a short cervix when planning for UIC and highlight the crucial role of optimizing maternal glucose control and weight management in reducing the risk of sPTB.

Vaginal Progesterone to Prevent Spontaneous Preterm Birth in Women With a Sonographic Short Cervix: The Story of the PREGNANT Trial.

The PREGNANT trial was a randomized, placebo-controlled, multicenter trial designed to determine the efficacy and safety of vaginal progesterone (VP) to reduce the risk of birth < 33 weeks and of neonatal complications in women with a sonographic short cervix (10 to 20 mm) in the mid-trimester (19 to 23 6/7 wk). Patients allocated to receive VP had a 45% lower rate of preterm birth (8.9% vs 16.1%; relative risk = 0.55; 95% CI: 0.33-0.92). Neonates born to mothers allocated to VP had a 60% reduction in the rate of respiratory distress syndrome. This article reviews the background, design, execution, interpretation, and impact of the PREGNANT Trial.

Prediction of spontaneous preterm birth in women with previous full dilatation cesarean delivery

A previous term (≥37 weeks' gestation), full-dilatation cesarean delivery is associated with an increased risk for a subsequent spontaneous preterm birth. The mechanism is unknown. We hypothesized that the cesarean delivery scar characteristics and scar position relative to the internal cervical os may compromise cervical function, thereby leading to shortening of the cervical length and spontaneous preterm birth. This study aimed to determine the relationship of cesarean delivery scar characteristics and position, assessed by transvaginal ultrasound, in pregnant women with previous full-dilatation cesarean delivery with the risk of shortening cervical length and spontaneous preterm birth. This was a single-center, prospective cohort study of singleton pregnant women (14 to 24 weeks' gestation) with a previous term full-dilatation cesarean delivery who attended a high-risk preterm birth surveillance clinic (2017-2021). Women underwent transvaginal ultrasound assessment of cervical length, cesarean delivery scar distance relative to the internal cervical os, and scar niche parameters using a reproducible transvaginal ultrasound technique. Spontaneous preterm birth prophylactic interventions (vaginal cervical cerclage or vaginal progesterone) were offered for short cervical length (≤25 mm) and to women with a history of spontaneous preterm birth or late miscarriage after full-dilatation cesarean delivery. The primary outcome was spontaneous preterm birth; secondary outcomes included short cervical length and a need for prophylactic interventions. A multivariable logistic regression analysis was used to develop multiparameter models that combined cesarean delivery scar parameters, cervical length, history of full-dilatation cesarean delivery, and maternal characteristics. The predictive performance of models was examined using the area under the receiver operating characteristics curve and the detection rate at various fixed false positive rates. The optimal cutoff for cesarean delivery scar distance to best predict a short cervical length and spontaneous preterm birth was analyzed. Cesarean delivery scars were visualized in 90.5% (220/243) of the included women. The spontaneous preterm birth rate was 4.1% (10/243), and 12.8% (31/243) of women developed a short cervical length. A history- (n=4) or ultrasound-indicated (n=19) cervical cerclage was performed in 23 of 243 (9.5%) women; among those, 2 (8.7%) spontaneously delivered prematurely. A multiparameter model based on absolute scar distance from the internal os best predicted spontaneous preterm birth (area under the receiver operating characteristics curve, 0.73; 95% confidence interval, 0.57-0.89; detection rate of 60% for a fixed 25% false positive rate). Models based on the relative anatomic position of the cesarean delivery scar to the internal os and the cesarean delivery scar position with niche parameters (length, depth, and width) best predicted the development of a short cervical length (area under the receiver operating characteristics curve, 0.79 [95% confidence interval, 0.71-0.87]; and 0.81 [95% confidence interval, 0.73-0.89], respectively; detection rate of 73% at a fixed 25% false positive rate). Spontaneous preterm birth was significantly more likely when the cesarean delivery scar was <5.0 mm above or below the internal os (adjusted odds ratio, 6.87; 95% confidence interval, 1.34-58; P =.035). In pregnancies following a full-dilatation cesarean delivery, cesarean delivery scar characteristics and distance from the internal os identified women who were at risk for spontaneous preterm birth and developing short cervical length. Overall, the spontaneous preterm birth rate was low, but it was significantly increased among women with a scar located <5.0 mm above or below the internal cervical os. Shortening of cervical length was strongly associated with a low scar position. Our novel findings indicate that a low cesarean delivery scar can compromise the functional integrity of the internal cervical os, leading to cervical shortening and/or spontaneous preterm birth. Assessment of the cesarean delivery scar characteristics and position seem to have use in preterm birth clinical surveillance among women with a previous, full-dilatation cesarean delivery and could better identify women who would benefit from prophylactic interventions.

EP19.03: Acute phase response and inflammatory proteins in amniotic fluid associated with spontaneous preterm birth in women with a short cervix (≤25mm)

EP19.03: Acute phase response and inflammatory proteins in amniotic fluid associated with spontaneous preterm birth in women with a short cervix (≤25mm)

Uterocervical angle versus cervical length in the prediction of spontaneous preterm birth in women with history of spontaneous preterm birth: a prospective observational study

BackgroundPreterm delivery is a leading cause of neonatal mortality and morbidity. History of spontaneous preterm birth is the greatest risk factor for another preterm delivery. So, every effort should be made to prevent the recurrence of preterm delivery in this vulnerable group. This study aimed to evaluate the predictive ability of the anterior uterocervical angle and cervical length in preterm birth.Patients and MethodsThis was a prospective cohort study that included 70 patients with a history of spontaneous preterm birth. Ultrasound measurements of cervical length and anterior uterocervical angle were set to be measured for each patient at three visits; first between 16 0/7 and 24 0/7 weeks, second between 24 1/7 and 32 0/7 weeks, and the third was between 32 1/7 and 36 6/7 weeks. The correlation between both measures and the prediction of preterm birth among study participants was the primary outcome of the study. Neonatal outcome among the study patients was a secondary measure of outcome.ResultsThe incidence of preterm birth among study participants was 31.41%. Cervical length and uterocervical angle showed progressive decrease and increase respectively throughout pregnancy. At the 2nd visit, the two measures were significantly different between those who delivered at term and those with preterm delivery with the cervical length being significantly shorter in the preterm arm (3.0 ± 0.49 versus 3.38 ± 0.36, p < 0.001) and uterocervical angle being significantly bigger among the same arm (110.1 ± 18.48 versus 84.42 ± 12.24, p < 0.001). A uterocervical angle > 89.8° at the second visit predicted preterm birth with 81.8% sensitivity and 70.8% specificity while cervical length ≤ 3.22 cm at the second visit predicted preterm birth with 68.1% sensitivity and 62.5% specificity. Multivariant logistic regression analysis showed that uterocervical angle > 89.8° at the second visit increased the odds ratio for preterm birth by 9.ConclusionUterocervical angle can be a useful ultrasound marker for the prediction of preterm birth among high risk patients. A cutoff value of 89.8° can be used as a threshold above which prophylactic measures such as cervical cerclage or progesterone therapy can be provided.Trial registrationNCT05632003 (First posted date: 30/11/2022).

How to screen the cervix and reduce the risk of spontaneous preterm birth in asymptomatic women without a prior preterm birth.

Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality globally. PTB rates have increased in South Korea despite reduction in birth rates. A history of PTB is a strong predictor of subsequent PTB and screening of cervical length between 16 0/7 weeks and 24 0/7 weeks of gestation is recommended in women with a singleton pregnancy and a prior spontaneous PTB. However, the prediction and prevention of spontaneous PTBs in women without a prior PTB remain a matter of debate. The scope of this review article comprises cervical screening and prevention strategies for PTB in asymptomatic women without a prior PTB, based on recent evidence and guidelines.

Genetic variants associated with spontaneous preterm birth in women from India: a prospective cohort study.

Despite having the highest number of preterm births globally, no genomic study on preterm birth was previously published from India or other South-Asian countries. We conducted a genome-wide association (GWA) study of spontaneous preterm birth (sPTB) on 6211 women from India. We used a novel resampling procedure to identify the associated single nucleotide polymorphisms (SNPs) followed by haplotype association analysis and imputation. We found that 512 maternal SNPs were associated with sPTB (p<2.51e-3), of which minor allele at 19 SNPs (after Bonferroni correction) had increased genotype relative risk. Haplotypes containing six of the 19 SNPs (rs13011430, rs8179838, rs2327290, rs4798499, rs7629800, and rs13180906) were associated with sPTB (p<9.9e-4; Bonferroni adjusted p-value <0.05). After imputation in regions around the 19 SNPs, 15 imputed SNPs were found to be associated with sPTB (Bonferroni adjusted p-value <0.05). One of these imputed SNPs, rs35760881, and three other SNPs (rs17307697, rs4308815, and rs10983507) were also reported to be associated with sPTB in women belonging to European ancestry. Moreover, we found that GG genotype at rs1152954, one of the associated SNPs, enhanced risk of sPTB and reduced telomere length. This is the first study from South Asia on the genome-wide identification of maternal SNPs associated with sPTB. These SNPs are known to alter the expression of genes associated with major pathways in sPTB viz. inflammation, apoptosis, cervical ripening, telomere maintenance, selenocysteine biosynthesis, myometrial contraction, and innate immunity. From a public health perspective, the trans-ethnic association of four SNPs identified in our study may help to stratify women with risk of sPTB in most populations. Department of Biotechnology (India), Grand Challenges India - All Children Thriving Program and Biotechnology Industry Research Assistance Council (BIRAC).

Predicting spontaneous preterm birth in asymptomatic high-risk women with cervical cerclage.

To determine the performance of the predictive markers of spontaneous preterm birth, cervicovaginal quantitative fetal fibronectin (fFN) and cervical length, in asymptomatic high-risk women with transabdominal, history-indicated or ultrasound-indicated cervical cerclage. This was a secondary analysis of a prospective cohort of asymptomatic high-risk women with cervical cerclage and no other prophylactic intervention (including progesterone), who attended the preterm birth clinic at a central London teaching hospital between October 2010 and September 2016. Women had either transabdominal cerclage, placed prior to conception, history-indicated cerclage, placed before 14 weeks' gestation, or ultrasound-indicated cerclage for a short cervix (< 25 mm), placed before 24 weeks. All women underwent serial cervical length assessment on transvaginal ultrasound in the second trimester (16-28 weeks), and quantitative fFN testing from 18 weeks onward. Test performance was analyzed for the prediction of spontaneous preterm birth before 30 weeks (cerclage failure), 34 weeks and 37 weeks, using receiver-operating-characteristics (ROC)-curve analysis. Overall, 181 women were included in the analysis. Cervical length and fFN were strong predictors of spontaneous preterm birth before 30 weeks in women with cerclage, with areas under the ROC curve (AUC) of 0.86 (95% CI, 0.79-0.94) and 0.84 (95% CI, 0.75-0.92), respectively. Cervical length was a better predictor of preterm birth before 30 weeks in women with history-indicated compared to those with ultrasound-indicated cerclage, although both showed clinical utility (AUC, 0.96 (95% CI, 0.91-1.00) vs 0.79 (95% CI, 0.66-0.91); P = 0.01). Quantitative fFN was a strong predictor of spontaneous preterm birth before 30 weeks in women with history-indicated cerclage (AUC, 0.91 (95% CI, 0.75-1.00)) and retained clinical utility in those with ultrasound-indicated cerclage (AUC, 0.76 (95% CI, 0.64-0.89)). There were no spontaneous deliveries before 34 weeks in women with a transabdominal cerclage, so AUC was not calculated. Delivery was delayed significantly in this group (P < 0.01). Cervical length and quantitative fFN retain clinical utility for the prediction of spontaneous preterm birth in women with cervical cerclage, and prediction is best in women with a history-indicated stitch. These tests can be relied upon to discriminate risk and have utility when planning clinical management with regard to treatment failure. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A prospective, double-blinded cohort study using quantitative fetal fibronectin testing in symptomatic women for the prediction of spontaneous preterm delivery

BackgroundSpontaneous preterm birth (PTB) affects 6.5% of deliveries in Hong Kong. Quantitative fetal fibronectin (fFN) is under-utilised as a test for PTB prediction in Hong Kong. Our objective was to evaluate the effectiveness of quantitative fFN in predicting spontaneous PTB in women with symptoms of threatened preterm labour (TPTL) in our population.MethodsA prospective, double-blinded cohort study of women with a singleton gestation and TPTL symptoms presenting to a tertiary hospital in Hong Kong between 24 + 0 to 33 + 6 weeks was performed from 1st October 2020 and 31st October 2021. Women with vaginal bleeding, ruptured membranes, and cervical dilation > 3 cm were excluded. The primary outcome was to test the characteristics of quantitative fFN in predicting spontaneous PTB < 37 weeks. Secondary outcome was to investigate the relationship between fFN value and time to PTB. Test characteristics of quantitative fFN at different thresholds were evaluated.Results48 women with TPTL were recruited. All had fFN testing at admission with the results being concealed from the obstetrician managing the patient. 10 mothers had PTB (< 37 weeks’ gestation). 7/48 (15%) had a subsequent PTB within 14 days from testing and 5 (10%) delivered within 48 h. The negative predictive value (NPV) of predicting delivery within 14 days was 97.3% and 100% when using a cut-off of < 50ng/ml and < 10ng/ml respectively. Using > 200 ng/ml as cut-off can also reliably predict delivery within 48 h – 7 days with positive predictive value PPV of 100%; as well as PTB before 37 weeks.ConclusionsQuantitative fFN has predictive value for spontaneous PTB prediction in symptomatic women in a Hong Kong population. fFN concentration could help clinicians rule out PTB and avoid unnecessary interventions and hospitalisation.

The risk factors and causes of spontaneous preterm birth in women with previous term delivery

Previous spontaneous preterm delivery is the most important risk factor of preterm birth, whereas term delivery without obstetric complication is a reassuring evidence for the subsequent pregnancy. However, we sometimes experience spontaneous preterm birth after uncomplicated term delivery. This study was performed to evaluate the risk factors and causes of spontaneous preterm birth after previous term delivery(sPAT). Retrospective cohort study was performed. Singleton pregnant women with spontaneous preterm birth whose previous pregnancy outcomes had been uncomplicated term deliveries were enrolled. We analyzed their causes of preterm birth and compared clinical characteristics and perinatal outcomes to controls with two consecutive term deliveries during the same period. The optimal interpregnancy interval(OPI) was defined between 18-59 months. Preterm birth with maternal-fetal indication, stillbirth, or congenital anomaly were excluded. A total 196 pregnant women met the inclusion criteria and 463 women were selected as controls. The mean gestational age at delivery was 33+3 weeks of gestation in sPAT group. Preterm premature rupture of membrane(PPROM) was the most common cause of spontaneous preterm birth, followed by preterm labor with intact membrane, and cervical insufficiency. The cervical lengths at midtrimester in the sPAT group were above 2.5cm in most cases. Women with sPAT had less total weight gain and average weight gain per week during pregnancy compared to controls. The proportion of women with OPI was significantly lower in women with sPAT than in controls. The cesarean delivery(CD) rate of the index term pregnancy was similar between the two groups, but the CD rate of the subsequent pregnancy was significantly higher in sPAT group than controls. Unlike the general spontaneous preterm birth, PPROM is the cause of preterm birth in more than half of the women with sPAT. Lower weight gain during pregnancy and inadequate interpregnancy interval were associated with preterm birth even in women with a previous term delivery.

Interventions to Prevent Spontaneous Preterm Birth in Women With Singleton Pregnancy Who Are at High Risk: Systematic Review and Network Meta-Analysis

(BMJ. 2022;376:e064547. doi: https://doi.org/10.1136/bmj-2021-064547) Two-thirds of preterm births (&lt;37 wk gestation) occur spontaneously, while one-third are intentionally induced. Patients at risk of spontaneous preterm birth may or may not exhibit symptoms. Among high-risk patients without symptoms, cervical length &lt;25 mm and history of spontaneous preterm birth are the 2 strongest predictors of a subsequent spontaneous preterm birth. In the United Kingdom, vaginal progesterone or cervical cerclage are the recommended interventions for preventing spontaneous preterm birth in patients with those 2 predictors, though only 16% of preterm birth clinics in the UK routinely administer vaginal progesterone in this setting. This study used network meta-analysis estimates and compares the effectiveness of vaginal progesterone and cervical cerclage in preventing spontaneous preterm birth in at-risk patients.

Interventions to Prevent Spontaneous Preterm Birth in Women With Singleton Pregnancy Who Are at High Risk: Systematic Review and Network Meta-analysis

(Abstracted from BMJ 2022;376:e064547) The leading cause of neonatal mortality are complications due to preterm birth. To manage the risk of preterm birth, the NICE (National Institute for Health and Care Excellence) recommends using vaginal progesterone or cervical cerclage.

The use of fetal fibronectin and cervical length measurements in the prediction of spontaneous preterm birth in women with an Arabin pessary in situ

ObjectivesThe ability to predict spontaneous PTB (sPTB) has improved greatly, allowing women at risk to be managed with prophylactic interventions such as cervical cerclage and the Arabin pessary. Cervicovaginal fetal fibronectin (qfFN) concentration and ultrasound measurement of cervical length (CL) are the two most established tools to predict sPTB. There is however limited data regarding the predictive value of qfFN and CL tests following insertion of an Arabin pessary. Our aim was therefore to determine the clinical use of qfFN and CL measurements to predict sPTB in women fitted with an Arabin pessary. Study designThis study is a secondary analysis on the SUPPORT trial data. Data were prospectively collected from women attending high-risk preterm surveillance clinics in 3 London centres between July 2015 and April 2020. The matched control group was pregnant women attending the same high-risk preterm surveillance clinics who had not received an Arabin pessary. Receiver operating characteristic (ROC) curves for prediction of birth by 34 and by 37 weeks’ gestation were generated for qfFN and CL measurements combined for both study groups. A formal comparison of area under the curve before 34 weeks’ gestation (AUC < 34 weeks) was made between the two study groups. ResultsAt our primary endpoint of sPTB < 34 weeks' gestation, qfFN was a good predictor of sPTB in cases with an Arabin pessary in situ (AUC, 0.79, 95% CI: 0.62–0.90) and no worse than the control group who did not have an Arabin pessary, (AUC 0.74, 95% CI: 0.48–0.96). CL had good prediction for sPTB < 34 weeks’ gestation in the control group (AUC 0.76, 95% CI: 0.63–0.88) but was lower and non-significant in the Arabin pessary case group (AUC 0.60, 95% CI: 0.43–0.76). ConclusionsThis study showed that cervicovaginal qfFN concentration is equally reliable in the prediction of sPTB in pregnant women at increased risk of sPTB with and without an Arabin pessary in situ, and significantly better than CL measurement alone for predicting delivery before 34 weeks. This commonly used test therefore has utility in predicting sPTB in pregnant women fitted with an Arabin pessary.

Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis

ObjectivesTo compare the efficacy of bed rest, cervical cerclage (McDonald, Shirodkar, or unspecified type of cerclage), cervical pessary, fish oils or omega fatty acids, nutritional supplements (zinc), progesterone (intramuscular, oral,...

Lactobacilluscrispatus dominance in the vaginalmicrobiome reduces the occurrence of spontaneouspreterm birth in women with a short cervical length

Introduction: The majority of pregnant women with a short cervix will deliver at term and, thus, may unnecessarily receive advanced monitoring and treatment. It is still necessary to define more accurately which sub-population of women with a short cervix is at elevated risk for early delivery. Objective: To determine if vaginal microbiome composition influenced the rate of spontaneous preterm birth in women with a short cervical length. Methods: In an exploratory, observational prospective study, vaginal secretions were obtained from 591 women at 21–24 week gestation. Vaginal microbiome composition was determined by analyzing the V1–V3 region of the bacterial 16S ribosomal RNA gene. Results: Lactobacillus crispatus was numerically dominant in the vagina in 41.7% of subjects, followed by L. iners in 32% and Gardnerella vaginalis in 12%. In women whose cervix was ≤25mm, the sensitivity to predict an spontaneous preterm birth was 11.8%. However, when L. crispatus was not the dominant vaginal bacterium, this sensitivity increased to 81.8%. Similarly, in women with a cervical length ≤30mm, the sensitivity to predict an spontaneous preterm birth increased from 21.7 to 78.3% when L. crispatus was not the dominant vaginal bacterium.In women with a prior spontaneous preterm birth and a cervix ≤25 or ≤30mm, L. crispatus dominance was also associated with a reduced rate of spontaneous preterm birth in the current pregnancy (p&lt;0.001). Conclusion: In pregnant women with a cervix ≤25mm or ≤30mm, the risk for an spontaneous preterm birth is increased if L. crispatus is not dominant in the vagina.

Protein microarray analysis of amniotic fluid proteins associated with spontaneous preterm birth in women with preterm labor.

To identify proteins present in the amniotic fluid (AF) that could be associated with spontaneous preterm birth (SPTB; delivery<7 days) in women with preterm labor (PTL). First, the AF proteome of 20 women with PTL and SPTB was compared with that of 20 matched women with term deliveries using an antibody microarray. Next, nine identified candidate biomarkers of SPTB were further validated in 267 singleton pregnant women with PTL who underwent amniocentesis at 26-33 weeks of gestation using ELISA, and whether the degree of expression of these proteins was associated with the risk severity for subsequent SPTB was retrospectively assessed. Of the 507 proteins evaluated in the microarray analysis, 27 displayed significant intergroup differences. In particular, ELISA quantification confirmed that the expression of EN-RAGE, IL-6, IL-8, IP-10, lipocalin-2, MMP-8, MMP-9, S100 A8/A9, and TNFR2 were all increased in the AF of women spontaneously delivering within 7days of sampling compared with those delivering after 7 days. Moreover, the odds of SPTB within 7 days, even upon adjusting for confounders, tended to significantly increase with each increasing quartile of baseline AF levels of each protein (P-value for trend<.05). Nine AF proteins were found to be independently associated with higher risk of subsequent SPTB in women with PTL, all of which were immune-, inflammation-, and extracellular matrix-related proteins. Moreover, risk severity for this subsequent SPTB is closely related to the degree of expression of each of these proteins.

Complement Activation Fragments in Cervicovaginal Fluid Are Associated with Intra-Amniotic Infection/Inflammation and Spontaneous Preterm Birth in Women with Preterm Premature Rupture of Membranes.

We sought to determine whether the levels of complement and other inflammatory and angiogenic mediators in cervicovaginal fluid (CVF) are independently associated with intra-amniotic infection and/or inflammation (IAI) and imminent spontaneous preterm birth (SPTB, £48 hours of sampling) in women with preterm premature rupture of membranes (PPROM). This was a retrospective study consisting of 85 singleton pregnant women with PPROM at 200/7 to 336/7 weeks. Amniotic fluid (AF) obtained via amniocentesis was cultured and assayed for interleukin-6. CVF samples collected at the time of amniocentesis were assayed for complement C3a, C4a, and C5a, HSP70 (heat shock protein 70), M-CSF (macrophage colony-stimulating factor), M-CSF-R (macrophage colony-stimulating factor-receptor), S100 A8, S100 A9, thrombospondin-2, VEGF (vascular endothelial growth factor-receptor), and VEGFR-1 (vascular endothelial growth factor-receptor 1) by enzyme-linked immunosorbent assay. Multivariate logistic regression analyses revealed that elevated CVF concentrations of complement C3a, 4a, and 5a were significantly associated with an increased risk of IAI and imminent SPTB, whereas those of M-CSF were associated with IAI, but not imminent SPTB (p = 0.063), after adjustment for baseline covariates (e.g., gestational age at sampling). However, univariate, and multivariate analyses showed that the CVF concentrations of angiogenic (thrombospondin-2, VEGF, and VEGFR-1) and inflammatory (HSP70, M-CSF-R, S100 A8, and S100 A9) proteins were not associated with either IAI or imminent SPTB. In women with PPROM, elevated CVF concentrations of complement C3a, C4a, and C5a are independently related to an increased risk of IAI and imminent SPTB. These findings suggest that complement activation in CVF is significantly involved in mechanisms underlying preterm birth and in the host response to IAI in the context of PPROM. · Elevated CVF levels of C3a, 4a and 5a are associated with IAI and SPTB.. · CVF C3a, 4a and 5a have better predictability for SPTB, compared to AF WBC.. · Elevated CVF levels of M-CSF were associated with IAI, but not SPTB..

Proteomic identification of novel plasma biomarkers associated with spontaneous preterm birth in women with preterm labor without infection/inflammation.

ObjectiveWe sought to identify plasma biomarkers associated with spontaneous preterm birth (SPTB, delivery within 21 days of sampling) in women with preterm labor (PTL) without intra-amniotic infection/inflammation (IAI) using label-free quantitative proteomic analysis, as well as to elucidate specific protein pathways involved in these cases.MethodsThis was a retrospective cohort study comprising 104 singleton pregnant women with PTL (24–32 weeks) who underwent amniocentesis and demonstrated no evidence of IAI. Analysis of pooled plasma samples collected from SPTB cases and term birth (TB) controls (n = 10 for each group) was performed using label-free quantitative mass spectrometry for proteome profiling in a nested case-control study design. Eight candidate proteins of interest were validated by ELISA-based assay and a clot-based assay in the total cohort.ResultsNinety-one proteins were differentially expressed (P < 0.05) in plasma samples obtained from SPTB cases, of which 53 (58.2%) were upregulated and 38 (41.8%) were downregulated when compared to TD controls. A validation study confirmed that plasma from women who delivered spontaneously within 21 days of sampling contained significantly higher levels of coagulation factor Ⅴ and lower levels of S100 calcium binding protein A9 (S100A9), especially the former which was independent of baseline variables. The top-ranked pathways related to the 91 differentially expressed proteins were liver-X-receptor/retinoid X receptor (RXR) activation, acute phase response signaling, farnesoid X receptor/RXR activation, coagulation system, and complement system.ConclusionsProteomic analyses in this study identified potential novel biomarkers (i.e., coagulation factor V and S100A9) and potential protein pathways in plasma associated with SPTB in the absence of IAI in women with PTL. The present findings provide novel insights into the molecular pathogenesis and therapeutic targets specific for idiopathic SPTB.

Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth: A Dutch population-based cohort study with 45,259 pregnancy outcomes.

BackgroundExcisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease.Methods and findingsThis Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth.In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women.ConclusionsIn this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.

Maternal gut microbiota reflecting poor diet quality is associated with spontaneous preterm birth in a prospective cohort study

A processed diet, high in fat and low in fiber, is associated with differences in the gut microbiota and adverse health outcomes in humans; however, little is known about the diet-microbiota relation and its impact on pregnancy. Spontaneous preterm birth (SPTB), a pregnancy outcome with serious short- and long-term consequences, occurs more frequently in black and in obese women in the United States. In a prospective, case-control sample matched for race and obesity (cases=16, controls=32), we compared the fecal gut microbiota, fecal and plasma metabolites, and diet in the late second trimester. We hypothesized that a Western diet would be associated with reduced microbiota richness and a metabolic signature predicting incidence of SPTB. The fecal microbiota was characterized by 16S-tagged sequencing and untargeted metabolomics was used to analyze both plasma and fecal metabolites. Wilcoxon's rank-sum test was used for the comparison of microbiota genera, α-diversity, fecal and plasma metabolites, and dietary variables between term and SPTB. β-Diversity was analyzed using permutational multivariate ANOVA, and metabolite associations were assessed by module analysis. A decrease in α-diversity was strongly associated with the development of SPTB, especially in the taxonomic class of Betaproteobacteria. Of 824 fecal metabolites, 22 metabolites (mostly lipids) differed between cases and controls (P<0.01), with greater DHA (22:6n-3) and EPA (20:5n-3) in cases [false discovery rate (FDR)<0.2]. The most significant fecal metabolite module (FDR-adjusted P=0.008) was dominated by DHA and EPA. Dietary saturated fat (primarily palmitate) intake was greater in cases (31.38±7.37 compared with 26.08±8.62 g, P=0.045) and was positively correlated with fecal DHA and EPA (P<0.05). Reduced α-diversity of the gut microbiota and higher excretion of omega-3 (n-3) fatty acids in stool may provide a novel biomarker signature predicting SPTB in women with a low-fiber, high-fat diet. Further investigation of these markers in a larger sample is needed for validation.