Early Spontaneous Preterm Birth Research Articles

Associations between maternal blood metal concentrations during the first trimester and spontaneous preterm birth: a nested case-control study

BackgroundFew studies have utilized whole blood samples to investigate the association between metal mixture exposure during early pregnancy and spontaneous preterm birth (SPB). We conduct this nested case–control study to investigate both the independent and joint effect of each metal, and identify critical metals in the metal mixture.ResultsA total of 120 pregnant women with SPB and 120 pregnant women with full-term delivery were selected from the prospective birth cohort. We measured 14 metal concentrations in maternal blood collected during 10–13 weeks gestation. Conditional logistic regression showed that high concentrations of vanadium (V), magnesium, and copper were positively associated with SPB (Adjusted OR = 5.76 (95% CI 2.46–13.53), 3.64 (95% CI 1.64–8.09), 2.88 (95% CI 1.29–6.41), respectively). Moderate manganese (Mn) concentration (50th–75th percentile) group had the lowest estimated OR (Adjusted OR = 0.32 (95% CI 0.13–0.76)). The high level of strontium (Sr) was negatively associated with SPB (Adjusted OR = 0.39 (95% CI 0.17–0.91)). The BKMR model showed a significant positive joint effect of metal mixture exposure on SPB, while V was the most important metal. The non-linear effects of V and lead (Pb) on SPB, and the interaction effects between V–Pb, Sr–Mn were also revealed.ConclusionsMaternal blood metal mixtures in the first trimester were found to be positively associated with SPB, with V exhibiting the strongest independent association. Mn had a potential U-shaped association with SPB. Elimination of metal contamination in the environment has a positive impact on maternal and child health.

Risk factors of early spontaneous preterm birth despite carrying a cervical pessary in singleton pregnancies with a short cervix: Development of a risk prediction model

We aimed to identify the incidence and risk factors of spontaneous preterm birth in pessary carriers with singleton pregnancies and a short cervix in the mid-trimester of pregnancy. Patient data were obtained from the PECEP Trial. We analyzed singleton pregnancies in pessary carriers with a short cervix (≤25mm) between 18 and 22 gestational weeks. Demographics and obstetric history were compared to identify risk factors for spontaneous preterm birth <34 gestational weeks. Each demographic and obstetric variable was compared between spontaneous preterm birth <34 and ≥34 weeks of gestation.Regression analysis was used to identify risk factors. A risk score model was generated using the odds ratio for significant factors. The risk score model and spontaneous preterm birth risk were assessed using the receiver operating characteristic curve. Perinatal outcomes were compared by risk score. Among 190 pregnant individuals, 12 (6.3%) had spontaneous preterm birth <34 gestational weeks. In the bivariate analysis, statistically significant differences between those with and without spontaneous preterm birth were only observed for mean cervical length at diagnosis and mean cervical length after pessary placement. By multiple logistic regression analysis, maternal age (OR 0.818; 95% CI 0.69-0.97; P 0.020), cervical length at diagnosis (OR 0.560; 95% CI 0.43-0.73; P<0.001) and smoking status (OR 7.276; 95% CI 1.02-51.80; P 0.048) remained significantly associated with spontaneous preterm birth.The ROC curve from the multiple logistic regression analysis, including cervical length, maternal age and smoking status, had an area under the curve (AUC) of 0.952 (P< 0.001). The ROC curve for the risk score model incorporating all three variables had an AUC of 0.864 (95% CI 0.77-0.96; P<0.001). A high-risk score was predictive of spontaneous preterm birth with a sensitivity of 75%, specificity of 84%, positive predictive value of 24%, and negative predictive value of 98%.Women with a high-risk score had a significantly reduced latency to delivery and poorer neonatal outcomes than those with a low-risk score. Patients at a high risk for spontaneous preterm birth despite pessary therapy may be identified using cervical length at diagnosis added to maternal age and smoking status.

Umbilical cord thrombosis is more increased according to the progression of outside-in neutrophils migration in extra-placental membranes among early spontaneous preterm birth.

Umbilical cord thrombosis is more increased according to the progression of outside-in neutrophils migration in extra-placental membranes among early spontaneous preterm birth.

Addressing a broken drug pipeline for preterm birth: why early preterm birth is an orphan disease

Preterm birth remains one of the most urgent unresolved medical problems in obstetrics, yet only 2 therapeutics for preventing preterm birth have ever been approved by the United States Food and Drug Administration, and neither remains on the market. The recent withdrawal of 17-hydroxyprogesterone caproate (17-OHPC, Makena) marks a new but familiar era for obstetrics with no Food and Drug Administration-approved pharmaceuticals to address preterm birth. The lack of pharmaceuticals reflects a broad and ineffective pipeline hindered by extensive regulatory hurdles, soaring costs of performing drug research, and concerns regarding adverse effects among a particularly vulnerable population. The pharmaceutical industry has historically limited investments in research for diseases with similarly small markets, such as cystic fibrosis, given their rarity and diminished projected financial return. The Orphan Drug Act, however, incentivizes drug development for "orphan diseases", defined as affecting <200,000 people in the United States annually. Although the total number of preterm births in the United States exceeds this threshold annually, the early subset of preterm birth (<34 weeks' gestation) would qualify, which is predominantly caused by inflammation and infection. The scientific rationale for classifying preterm birth into early and late subsets is strong given that their etiologies differ, and therapeutics that may be efficacious for one subset may not work for the other. For example, antiinflammatory therapeutics would be expected to be highly effective for early but not late preterm birth. A robust therapeutic pipeline of antiinflammatory drugs already exists, which could be used to target spontaneous early preterm birth, in combination with antibiotics shown to sterilize the amniotic cavity. New applications for therapeutics targeting spontaneous early preterm birth could categorize as orphan disease drugs, which could revitalize the preterm birth therapeutic pipeline. Herein, we describe why drugs targeting early preterm birth should qualify for orphan status, which may increase pharmaceutical interest for this vitally important obstetrical condition.

Longitudinal change in cervical length following vaginal or abdominal cervical cerclage: a randomized comparison

Cervical cerclage has been shown to reduce the risk of recurrent spontaneous preterm birth in a high-risk patient population; however, the mechanism is not well understood. Transabdominal cerclage is superior to low and high vaginal cerclage in reducing early spontaneous preterm birth and fetal loss in women with previous failed vaginal cerclage. Cervical length measurements are commonly used to monitor high-risk women and may explain the mechanism of success. This study aimed to evaluate the rate of change in longitudinal cervical length after randomized placement of low transvaginal, high transvaginal, or transabdominal cerclage in women with a previous failed vaginal cerclage. This was a planned analysis of longitudinal transvaginal ultrasound cervical length measurements from patients enrolled in the Vaginal Randomised Intervention of Cerclage trial, a randomized controlled trial comparing transabdominal cerclage or high transvaginal cerclage with low transvaginal cerclage. Cervical length measurements at specific gestational ages were compared over time and between groups, using generalized estimating equations fitted using the maximum-likelihood random-effects estimator. In addition, cervical length measurements were compared in women with transabdominal cerclage placed before and during pregnancy. The diagnostic accuracy of cervical length as a predictor of spontaneous preterm birth at <32 weeks of gestation was explored. This study included 78 women who underwent longitudinal cervical length assessment (70% of the analyzed cohort) with a history of failed cerclage, of whom 25 (32%) were randomized to low transvaginal cerclage, 26 (33%) to high transvaginal cerclage, and 27 (35%) to transabdominal cerclage. Abdominal cerclage was superior to low (P=.008) and high (P=.001) vaginal cerclage at maintaining cervical length over the surveillance period (14 to 26 weeks of gestation) (+0.08 mm/week, 95% confidence interval, -0.40 to 0.22; P=.580). On average, the cervical length was 1.8 mm longer by the end of the 12-week surveillance period in women with transabdominal cerclage (+1.8 mm; 95% confidence interval, -7.89 to 4.30; P=.564). High vaginal cerclage was no better than low cervical cerclage in the prevention of cervical shortening; the cervix shortened by 13.2 mm over 12 weeks in those with low vaginal cerclage (95% confidence interval, -21.7 to -4.7; P=.002) and by 20 mm over 12 weeks in those with high vaginal cerclage (95% confidence interval, -33.1 to -7.4; P=.002). Preconception transabdominal cerclage resulted in a longer cervix than those performed during pregnancy; this difference was significant after 22 weeks of gestation (48.5 mm vs 39.6 mm; P=.039). Overall, cervical length was an excellent predictor of spontaneous preterm birth at <32 weeks of gestation (receiver operating characteristic curve, 0.92; 95% confidence interval, 0.82-1.00). In women with a previous failed cervical cerclage, in the next pregnancy, the cervical length in women treated with vaginal cerclage funneled and shortened over time, whereas there was preservation of cervical length in women who receive transabdominal cerclage. Cervical length remained longer in transabdominal procedures performed before pregnancy than in transabdominal procedures performed during pregnancy. Overall, cervical length was an excellent predictor of spontaneous preterm birth in our cohort. Our findings may explain the mechanism of benefit for transabdominal cerclage, with its high placement better maintaining the structural integrity of the cervix at the level of the internal os.

Racial Disparities in Cervical Length Surveillance in Patients With a History of Spontaneous Preterm Birth [ID: 1378309

INTRODUCTION: Racial disparities in preterm birth are well established. We sought to identify racial disparities in cervical length surveillance in patients with a history of spontaneous preterm birth. METHODS: This was a subgroup analysis performed on data collected from a multi-institutional retrospective cohort study of pregnant patients with a history of early (&lt;34 weeks) and late (≥34 weeks) spontaneous preterm birth (PTB) that underwent transvaginal cervical length surveillance between November 2016 and March 2022. MedStar Health Research Institute IRB approval was obtained. Twin pregnancies were excluded. Data was compared between Black patients and non-Black patients using χ2 tests, t tests, and ANOVA analyses, as appropriate (α=0.05). RESULTS: Of 324 patients, 231 (71.3%) were Black and 93 (28.7%) were non-Black. When comparing patients who had early PTB to late PTB, Black patients were more likely than non-Black patients to have early PTB (76.3 versus 61.3%, P=.005). Average gestational age at time of last spontaneous PTB was significantly earlier in Black patients compared to non-Black patients (28 weeks 3 days versus 30 weeks 4 days, P=.008). Black patients were further along in current gestation at the time of cerclage placement than non-Black patients (16 weeks 6 days versus 14 weeks 1 day, P=.041). CONCLUSION: Black patients are more likely to have later cerclage placement compared to non-Black patients despite a predisposition to earlier gestational age at time of prior preterm birth.

Frequency of cerclage in consecutive pregnancies of women with history of preterm birth.

Serial cervical length screening is performed in women with a history of preterm birth to determine indication for cerclage placement. Our aim is to evaluate the frequency of cerclage placement in consecutive pregnancies with preterm birth history to determine whether performing serial cervical length screening for women with a history of late (34-36 6/7 weeks) spontaneous preterm birth (SPTB) should be reconsidered. Retrospective evaluation of cerclage frequency and gestational age of delivery for consecutive singleton births for 69,671 women whose first birth was a SPTB. History of late SPTB was associated with a lower frequency of cerclage than history of early SPTB (0.83% vs 4.88%, OR 0.16, 95% CI 0.14-0.18). Rates of recurrent SPTB were lower for women with history of late SPTB than those with history of early SPTB (13.45%, 3.74% early, 9.71% late vs 20.69%, 9.12% early, 11.57% late). Women with a history of late PTB have a lower risk of recurrent PTB than those with a history of early PTB but constitute most of those undergoing serial cervical length screening for potential cerclage placement. Practice guidelines for screening women with a history of late PTB should be re-evaluated.

Second-stage cesarean delivery and preterm birth in subsequent pregnancy: A large multi-institutional cohort study

Objective: To estimate the risk of preterm birth associated with mode of delivery in a previous pregnancy.Patients and Methods: This was a multicenter retrospective cohort study. Women who had two consecutive deliveries in the participating hospitals between January 2012 and January 2022 were included in this study. They were divided into three groups according to the mode of delivery in a previous pregnancy: vaginal birth (group A), cesarean section before the second stage of labor (group B), and second stage cesarean section (group C). Data were extracted from the medical records. The primary outcome was the risk of spontaneous preterm birth in the subsequent pregnancy. The secondary outcomes were the risk of early spontaneous preterm birth (< 34 weeks) and the medically indicated preterm birth in the subsequent pregnancy. The logistic regression was employed to estimate odds and adjust for confounders.Results: 18,253 women were included. Among them, 10,951 women were in group A, 5111 women in group B, and 2191 women in group C. The rates of spontaneous preterm birth in groups A, B, and C were 5.5%, 7.3%, and 15.1%, respectively. The rates of early spontaneous preterm birth in groups A, B, and C were 2.3%, 3.4%, and 8.2%, respectively. When compared with vaginal birth, second-stage cesarean section significantly increased the risk of spontaneous preterm birth (aOR, 3.23; 95% CI, 2.02–5.17; P = 0.003) and early spontaneous preterm birth (aOR, 3.59; 95% CI, 2.01–5.19; P <0.001) in the subsequent pregnancy. The rates of medically indicated preterm birth in groups A, B, and C were 2.3%, 2.8%, and 2.2%, respectively. There was no statistical difference across the three groups.Conclusion: History of cesarean section at full dilation is independently associated with an increased risk of spontaneous preterm birth in the subsequent pregnancy.

Placental transcriptomic signatures of spontaneous preterm birth

Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Predictive RNA profiles for early and very early spontaneous preterm birth

Spontaneous preterm birth remains the main driver of childhood morbidity and mortality. Because of an incomplete understanding of the molecular pathways that result in spontaneous preterm birth, accurate predictive markers and target therapeutics remain elusive. This study sought to determine if a cell-free RNA profile could reveal a molecular signature in maternal blood months before the onset of spontaneous preterm birth. Maternal samples (n=242) were obtained from a prospective cohort of individuals with a singleton pregnancy across 4 clinical sites at 12-24 weeks (nested case-control; n=46 spontaneous preterm birth <35 weeks and n=194 term controls). Plasma was processed via a next-generation sequencing pipeline for cell-free RNA using the Mirvie RNA platform. Transcripts that were differentially expressed in next-generation sequencing cases and controls were identified. Enriched pathways were identified in the Reactome database using overrepresentation analysis. Twenty five transcripts associated with an increased risk of spontaneous preterm birth were identified. A logistic regression model was developed using these transcripts to predict spontaneous preterm birth with an area under the curve=0.80 (95% confidence interval, 0.72-0.87) (sensitivity=0.76, specificity=0.72). The gene discovery and model were validated through leave-one-out cross-validation. A unique set of 39 genes was identified from cases of very early spontaneous preterm birth (<25 weeks, n=14 cases with time to delivery of 2.5±1.8 weeks); a logistic regression classifier on the basis of these genes yielded an area under the curve=0.76 (95% confidence interval, 0.63-0.87) in leave-one-out cross validation. Pathway analysis for the transcripts associated with spontaneous preterm birth revealed enrichment of genes related to collagen or the extracellular matrix in those who ultimately had a spontaneous preterm birth at <35 weeks. Enrichment for genes in insulin-like growth factor transport and amino acid metabolism pathways were associated with spontaneous preterm birth at <25 weeks. Second trimester cell-free RNA profiles in maternal blood provide a noninvasive window to future occurrence of spontaneous preterm birth. The systemic finding of changes in collagen and extracellular matrix pathways may serve to identify individuals at risk for premature cervical remodeling, with growth factor and metabolic pathways implicated more often in very early spontaneous preterm birth. The use of cell-free RNA profiles has the potential to accurately identify those at risk for spontaneous preterm birth by revealing the underlying pathophysiology, creating an opportunity for more targeted therapeutics and effective interventions.

Cervical ripening with multiple medical or combined induction methods: Risks of subsequent preterm birth in nulliparous women.

To determine the impact of combined medical and medical/mechanical methods for cervical ripening on the risk of preterm birth in subsequent pregnancy, in nulliparous women. A retrospective cohort study of nulliparous women with term singleton gestations induced by single or combined methods at one center who had their subsequent second birth in the same center. Study groups were compared with a control group of nulliparous women not induced. The primary outcome was risk of preterm labor in the second consecutive birth. Secondary outcomes included neonatal and maternal complications. Cohort included 1277 nulliparous women who underwent cervical ripening by single or combined methods. The study group consisted of 942 women induced by one dose of prostaglandin E2 , 248 women induced by combined methods, and 87 women induced by a mechanical method. The control group consisted of 3903 women. Demographic data of the groups were comparable. Rates of spontaneous preterm birth and early spontaneous preterm birth in the subsequent births did not differ between the groups. Cervical ripening with combined methods or multiple medical methods did not increase the rate of subsequent spontaneous preterm births in nulliparous women or change the neonatal and maternal complications rate.

Maternal LINE-1 DNA Methylation in Early Spontaneous Preterm Birth.

Despite considerable effort aimed at decreasing the incidence of spontaneous preterm birth (SPTB), it remains the leading cause of infant mortality and morbidity. The aim of this study was to evaluate maternal LINE-1 DNA methylation (DNAm), along with DNMT polymorphisms and factors proposed to modulate DNAm, in patients who delivered early preterm. This case-control study included women who delivered spontaneously early preterm (23-336/7 weeks of gestation), and control women. DNAm was analyzed in peripheral blood lymphocytes by quantification of LINE-1 DNAm using the MethyLight method. There was no significant difference in LINE-1 DNAm between patients with early PTB and controls. Among the investigated predictors, only the history of previous PTB was significantly associated with LINE-1 DNAm in PTB patients (β = -0.407; R2 = 0.131; p = 0.011). The regression analysis showed the effect of DNMT3B rs1569686 TT+TG genotypes on LINE-1 DNAm in patients with familial PTB (β = -0.524; R2 = 0.275; p = 0.037). Our findings suggest novel associations of maternal LINE-1 DNA hypomethylation with DNMT3B rs1569686 T allele. These results also contribute to the understanding of a complex (epi)genetic and environmental relationship underlying the early PTB.

Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case-control study.

To assess the association between vaginal microbiome (VMB) composition and recurrent early spontaneous preterm birth (sPTB)/preterm prelabour rupture of membranes (PPROM). Nested case-control study. UK tertiary referral hospital. High-risk women with previous sPTB/PPROM <34+0 weeks' gestation who had a recurrence (n = 22) or delivered at ≥37+0 weeks without PPROM (n = 87). Vaginal swabs collected between 15 and 22 weeks' gestation were analysed by 16S rRNA gene sequencing and 16S quantitative PCR. Recurrent early sPTB/PPROM. Of the 109 high-risk women, 28 had anaerobic vaginal dysbiosis, with the remainder dominated by lactobacilli (Lactobacillus iners 36/109, Lactobacillus crispatus 23/109, or other 22/109). VMB type and diversity were not associated with recurrence. Women with a recurrence, compared to those without, had a higher median vaginal bacterial load (8.64 versus 7.89 log10 cells/mcl, adjusted odds ratio [aOR] 1.90, 95% CI 1.01-3.56, P = 0.047) and estimated Lactobacillus concentration (8.59 versus 7.48 log10 cells/mcl, aOR 2.35, (95% CI 1.20-4.61, P = 0.013). A higher recurrence risk was associated with higher median bacterial loads for each VMB type after stratification, although statistical significance was reached only for L. iners domination (aOR 3.44, 95% CI 1.06-11.15, P = 0.040). Women with anaerobic dysbiosis or L. iners domination had a higher median vaginal bacterial load than women with a VMB dominated by L. crispatus or other lactobacilli (8.54, 7.96, 7.63, and 7.53 log10 cells/mcl, respectively). Vaginal bacterial load is associated with early sPTB/PPROM recurrence. Domination by lactobacilli other than L. iners may protect women from developing high bacterial loads. Future PTB studies should quantify vaginal bacteria and yeasts. Increased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth.

Plasma long-chain omega-3 fatty acid status and risk of recurrent early spontaneous preterm birth: a prospective observational study.

A 2018 Cochrane review found that omega-3 supplementation in pregnancy was associated with a risk reduction of early preterm birth of 0.58; prompting calls for universal supplementation. Recent analysis suggests the benefit may be confined to women with a low baseline omega-3 fatty acid status. However, the contemporary omega-3 fatty acid status of pregnant women in the UK is largely unknown. This is particularly pertinent for women with a previous preterm birth, in whom a small relative risk reduction would have a larger reduction of absolute risk. This study aimed to assess the omega-3 fatty acid status of a UK pregnant population and determine the association between the long-chain omega-3 fatty acids and recurrent spontaneous early preterm birth. A total of 283 high-risk women with previous early preterm birth were recruited to the prospective observational study in Liverpool, UK. Additionally, 96 pregnant women with previous term births and birth ≥39+0 weeks in the index pregnancy provided a low-risk population sample. Within the high-risk group we assessed the odds ratio of recurrent early preterm birth compared with birth at ≥37+0 weeks of gestation according to plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) at 15-22weeks of gestation. Our participants had low EPA+DHA; 62% (143/229) of women with previous preterm birth and 69% (68/96) of the population sample had levels within the lowest two quintiles of a previously published pregnancy cohort. We found no association between long-chain omega-3 status and recurrent early preterm birth (n=51). The crude odds ratio of a recurrent event was 0.91 (95% CI 0.38-2.15, p=0.83) for women in the lowest, compared with the highest three quintiles of EPA+DHA. In the majority of our participants, levels of long-chain omega-3 were low; within the range that may benefit from supplementation. However, levels showed no association with risk of recurrent early spontaneous preterm birth. This could be because our population levels were too low to show benefit in being omega-3 "replete"; or else omega-3 levels may be of lesser importance in recurrent early preterm birth.

Vaginal Microbiome Composition in Early Pregnancy and Risk of Spontaneous Preterm and Early Term Birth Among African American Women.

ObjectiveTo evaluate the association between the early pregnancy vaginal microbiome and spontaneous preterm birth (sPTB) and early term birth (sETB) among African American women.MethodsVaginal samples collected in early pregnancy (8-14 weeks’ gestation) from 436 women enrolled in the Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Study underwent 16S rRNA gene sequencing of the V3-V4 region, taxonomic classification, and community state type (CST) assignment. We compared vaginal CST and abundance of taxa for women whose pregnancy ended in sPTB (N = 44) or sETB (N= 84) to those who delivered full term (N = 231).ResultsNearly half of the women had a vaginal microbiome classified as CST IV (Diverse CST), while one-third had CST III (L. iners dominated) and just 16% had CST I, II, or V (non-iners Lactobacillus dominated). Compared to vaginal CST I, II, or V (non-iners Lactobacillus dominated), both CST III (L. iners dominated) and CST IV (Diverse) were associated with sPTB with an adjusted odds ratio (95% confidence interval) of 4.1 (1.1, infinity) and 7.7 (2.2, infinity), respectively, in multivariate logistic regression. In contrast, no vaginal CST was associated with sETB. The linear decomposition model (LDM) based on amplicon sequence variant (ASV) relative abundance found a significant overall effect of the vaginal microbiome on sPTB (p=0.034) but not sETB (p=0.320), whereas the LDM based on presence/absence of ASV found no overall effect on sPTB (p=0.328) but a significant effect on sETB (p=0.030). In testing for ASV-specific effects, the LDM found that no ASV was significantly associated with sPTB considering either relative abundance or presence/absence data after controlling for multiple comparisons (FDR 10%), although in marginal analysis the relative abundance of Gardnerella vaginalis (p=0.011), non-iners Lactobacillus (p=0.016), and Mobiluncus curtisii (p=0.035) and the presence of Atopobium vaginae (p=0.049), BVAB2 (p=0.024), Dialister microaerophilis (p=0.011), and Prevotella amnii (p=0.044) were associated with sPTB. The LDM identified the higher abundance of 7 ASVs and the presence of 13 ASVs, all commonly residents of the gut, as associated with sETB at FDR < 10%.ConclusionsIn this cohort of African American women, an early pregnancy vaginal CST III or IV was associated with an increased risk of sPTB but not sETB. The relative abundance and presence of distinct taxa within the early pregnancy vaginal microbiome was associated with either sPTB or sETB.

CRAFT (Cerclage after full dilatation caesarean section): protocol of a mixed methods study investigating the role of previous in-labour caesarean section in preterm birth risk

BackgroundFull dilatation caesarean sections are associated with recurrent early spontaneous preterm birth and late miscarriage. The risk following first stage caesarean sections, are less well defined, but appears to be increased in late-first stage of labour. The mechanism for this increased risk of late miscarriage and early spontaneous preterm birth in these women is unknown and there are uncertainties with regards to clinical management. Current predictive models of preterm birth (based on transvaginal ultrasound and quantitative fetal fibronectin) have not been validated in these women and it is unknown whether the threshold to define a short cervix (≤25 mm) is reliable in predicting the risk of preterm birth. In addition the efficacy of standard treatments or whether benefit may be derived from prophylactic interventions such as a cervical cerclage is unknown.MethodsThere are three distinct components to the CRAFT project (CRAFT-OBS, CRAFT-RCT and CRAFT-IMG).CRAFT-OBS: Observational Study; To evaluate subsequent pregnancy risk of preterm birth in women with a prior caesarean section in established labour. This prospective study of cervical length and quantitative fetal fibronectin data will establish a predictive model of preterm birth.CRAFT-RCT: Randomised controlled trial arm; To assess treatment for short cervix in women at high risk of preterm birth following a fully dilated caesarean section.CRAFT-IMG: Imaging sub-study; To evaluate the use of MRI and transvaginal ultrasound imaging of micro and macrostructural cervical features which may predispose to preterm birth in women with a previous fully dilated caesarean section, such as scar position and niche.DiscussionThe CRAFT project will quantify the risk of preterm birth or late miscarriage in women with previous in-labour caesarean section, define the best management and shed light on pathological mechanisms so as to improve the care we offer to women and their babies.Trial registrationCRAFT was prospectively registered on 25th November 2019 with the ISRCTN registry (https://doi.org/10.1186/ISRCTN15068651).

Obstetric History and Risk of Short Cervix in Women with a Prior Preterm Birth.

We aimed to assess the relationship between obstetric history and incidence of short cervical length (CL) at <24 weeks gestational age (GA) in women with a prior spontaneous preterm birth (PTB). Women with a singleton gestation and a history of spontaneous PTB on progesterone who received prenatal care at a single center from 2011 to 2016 were included. Those who did not undergo screening or had a history-indicated cerclage were excluded. The associations between short CL (<25 mm) before 24 weeks and obstetrical factors including: number of prior PTBs, history of term birth, and GA of earliest spontaneous PTB were estimated through modified Poisson regression, adjusting for confounding factors. Multiple pregnancies for the same woman were accounted for through robust sandwich standard error estimation. Among 773 pregnancies, 29% (n = 224) had a CL <25 mm before 24 weeks. The number of prior PTBs was not associated with short CL, but a prior full-term delivery conferred a lower risk of short CL (absolute risk reduction or aRR 0.79, 95% CI 0.63-1.00). Earliest GA of prior spontaneous PTB was associated with short CL. The strongest association was observed in women with a prior PTB at 160/7 to 236/7weeks (aRR 1.98, 95% CI: 1.46-2.70), compared with those with deliveries at 340/7 to 366/7 weeks. Yet, even women whose earliest PTB was 340/7 to 366/7 weeks remained at risk for a short CL, as 21% had a CL <25 mm. The number of prior PTBs did not modify the effect of GA of the earliest prior PTB (interaction test: p = 0.70). GA of earliest spontaneous PTB, but not the number of prior PTBs, is associated with short CL. Nevertheless, women with a history of later PTBs remain at sufficiently high risk of having a short CL at <24 weeks gestation that we cannot recommend modifications to existing CL screening guidelines in this group of women. · Prior 16 to 236/7 weeks birth is a key risk factor for CL <25 mm.. · One in five women with prior late PTB had a short CL.. · Number of PTBs is a less important risk factor..

Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial

In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy. The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks. The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69). In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.

The role of maternal infection in preterm birth: evidence from the Brazilian Multicentre Study on Preterm Birth (EMIP)

OBJECTIVES:Evidence suggests that infection or inflammation is a major contributor to early spontaneous preterm birth (sPTB). Therefore, this study aimed to investigate the development and causes of maternal infection associated with maternal and neonatal outcomes in women with sPTB.METHODS:This was a secondary analysis of a multicenter cross-sectional study with a nested case–control component, the Brazilian Multicentre Study on Preterm Birth (EMIP), conducted from April 2011 to July 2012 in 20 Brazilian referral obstetric hospitals. Women with preterm birth (PTB) and their neonates were enrolled. In this analysis, 2,682 women undergoing spontaneous preterm labor and premature pre-labor rupture of membranes were included. Two groups were identified based on self-reports or prenatal or hospital records: women with at least one infection factor and women without any maternal infection (vulvovaginitis, urinary tract infection, or dental infection). A bivariate analysis was performed to identify potential individual risk factors for PTB. The odds ratios (ORs) with their respective 95% confidence intervals were calculated.RESULTS:The majority of women with sPTB fulfilled at least one criterion for the identification of maternal infection (65.9%), and more than half reported having urinary tract infection during pregnancy. Approximately 9.6% of women with PTB and maternal infection were classified as having periodontal infection only. Apart from the presence of a partner, which was more common among women with infectious diseases (p=0.026; OR, 1.28 [1.03-1.59]), other variables did not show any significant difference between groups.CONCLUSION:Maternal infection was highly prevalent in all cases of sPTBs, although it was not clearly associated with the type of PTB, gestational age, or any adverse neonatal outcomes.

15: Markers of placental dysfunction and spontaneous preterm birth

Placental dysfunction is an understudied potential cause of spontaneous preterm birth (SPTB). Levels of pregnancy-associated plasma protein-A1 (PAPP-A1, a growth-promoting enzyme that cleaves insulin-like growth factor binding protein-1 and -4 [IGFBP1 and IGFBP4]) are decreased, and levels of PAPP-A2 (which downregulates trophoblast differentiation) are increased in maternal serum samples from other pregnancy complications associated with placental dysfunction, including preeclampsia and fetal growth restriction. We sought to compare maternal plasma and placental levels of PAPP-A1, PAPP-A2, IGFBP1, and IGFBP4 across birth outcomes. We performed a case-control study comparing levels of PAPP-A1, PAPP-A2, IGFBP1, and IGFBP4 in maternal plasma and placenta biopsy samples obtained from 20 early SPTB cases (< 32 weeks), 20 term deliveries (38-40 weeks), and 20 medically-indicated preterm births (MPTB, < 32 weeks). Protein levels were measured by enzyme-linked immunosorbent assay. Protein levels were stratified by neonatal sex. Demographics of the study groups are presented in Table 1. Maternal plasma and placental levels of PAPP-A1, PAPP-A2, IGFBP1, and IGFBP4 are presented in Table 2. Among the 60 women in the cohort, placental levels of PAPP-A1 and PAPP-A2 differed by birth outcome (P< .001). Maternal plasma levels of PAPP-A1 and PAPP-A2 were lower in SPTB compared to MPTB and term deliveries (P=0.003 and < 0.001). Placental levels of IGFBP4 were significantly greater in MPTB compared to SPTB and term deliveries (P< 0.001). Mothers of male fetuses had significantly lower plasma levels of IGFBP1 and IGFBP4 compared to females. Plasma levels of PAPP-A1 and PAPP-A2 did not differ by sex. This study demonstrates differential expression of placental proteins that influence trophoblast invasion and differentiation in SPTB cases. Additional studies investigating functional pathways that involve these proteins, such as the sonic hedgehog pathway and insulin-like growth factor axis, in relation to SPTB are warranted.View Large Image Figure ViewerDownload Hi-res image Download (PPT)