Search

Objective. Reduced calciferol (vitamin D) levels in pregnant women have been associated with an increased risk to infant health. Progesterone sustains pregnancy and reduces the risk of premature birth through its metabolites affecting myometrial contractility. Sex hormone-binding globulin protein (SHBG) is a biomarker of premature birth. The present study aimed to find out if early pregnancy levels of vitamin D, SHBG, and progesterone metabolites may predict preterm birth risk. Methods. Five hundred pregnant women aged 18-43 years during their 2nd and 3rd trimesters from multiple civilian regional medical centers in Lahore participated in the study. Blood samples taken from participants were used to determine vitamin D, SHBG, 11-deoxycorticosterone (DOC), and 16α-hydroxyprogesterone (16α-OHP) levels using specific ELISA kits. Statistical analysis was performed by one-way ANOVA using the latest GraphPad Prism software. Results. A significant decrease in vitamin D, DOC, and SHBG levels (p<0.001, p<0.001, and p<0.05, respectively) in the preterm birth cohorts in the 2nd and 3rd trimester was found compared to the corresponding control groups. Furthermore, 16α-OHP levels in the preterm birth cohorts in the 2nd and 3rd trimesters were significantly increased (p<0.001 and p=0.0062, respectively) compared to their control cohorts. Conclusion. The results of our study confirm that calciferol deficiency in pregnant women is associated with an increased risk of premature birth and indicate that SHBG and progesterone metabolites may be useful biomarkers for the early identification and prediction of preterm birth., (© 2024 Sundas Akram et al., published by Sciendo.)

Background: Mosaicism, characterized by the presence of two or more chromosomally distinct cell lines, is detected in 2% to 4% of chorionic villus samples (CVSs). In these cases, the aberration may be confined to the placenta or additionally present in the fetus. Fetal involvement may manifest as fetal malformations, while confined placental mosaicism (CPM) poses risks such as preterm birth and low birth weight. Differentiating between true fetal mosaicism and CPM at the time of the chorionic villus sampling is challenging and requires follow-up by an amniocentesis and ultrasonography., Objective: To estimate the risk of fetal involvement or adverse pregnancy outcomes for specific chromosomes after detecting mosaicism for an autosomal trisomy in a CVS and identify high (red), intermediate (yellow), and low (green) risk chromosomes. Further, to explore possible associations with level of mosaicism and screening parameters., Study Design: A retrospective descriptive study of all singleton pregnancies with mosaicism detected in CVSs from 1983 to 2021 identified in the Danish Cytogenetic Central Registry and the Danish Fetal Medicine Database., Results: Of 90,973 CVSs, 528 cases had mosaicism involving an autosomal trisomy and where genetic follow-up had been performed. The overall risk of fetal involvement was 13% (69/528) with extensive variations depending on which chromosome was involved (eg, trisomy 7: 0% [0/55] or trisomy 21: 46% [19/41]). Higher levels of mosaicism in the CVS suggested fetal involvement as mean mosaic level was 55% in true fetal mosaics vs 28% in cases confined to the placenta (P=.0002). In cases with CPM (459/528), the risk of delivering small-for-gestational-age neonates was 14% (48/341). The risk of preterm birth (before 37 weeks) was 15% (51/343). The collective risk of adverse outcome was 22% (76/343) in pregnancies that continued and where information on birth weight and gestational age at birth was available. Adverse outcomes varied substantially between chromosomes. Also, multiple-of-the-median (MoM) values of pregnancy-associated plasma protein A was predictive of these issues as it was significantly lower in cases with adverse outcome compared to cases with a normal outcome (small for gestational age: 0.23 MoM vs 0.47 MoM, P<.0001) or preterm birth: 0.25 MoM vs 0.47 MoM, P<.0001). After the introduction of combined first-trimester screening (cFTS) in 2004, the detection of cases with fetal involvement seemed to increase as the risk before 2004 was 9% (16/174) compared to 15% (53/354) after 2004 (risk ratio: 1.7 [95% CI: 1.0; 2.8]). The risk of adverse outcome in CPM pregnancies increased from 16% (22/139) before 2004 to 27% (55/204) after 2004 (risk ratio 1.7 [95% CI: 1.1; 2.7])., Conclusion: Introducing cFTS increased the detection of placental mosaicism with fetal involvement and CPM with adverse outcome. In cases of mosaicism in CVSs, the risk of fetal involvement and adverse outcomes varied considerably between chromosomes. Importantly, adverse outcomes were seen in CPM for many trisomies besides trisomy 16., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Preterm birth, affecting about 10% of pregnancies, significantly contributes to perinatal morbidity and mortality. Recent research indicates that metabolomics could enhance pregnancy outcomes and reduce costs by identifying biomarkers related to common pregnancy complications. Our team focused on analyzing amniotic fluid collected during the second trimester to identify potential biomarkers for preterm birth using 1H-NMR metabolomic analysis. We compared amniotic fluid samples from women who delivered prematurely with those who delivered at term. Multivariate principal component analysis revealed dimethylglycine, glucose, myo-inositol, and succinic acid as potential biomarkers for preterm birth prognosis and early diagnosis. Further analysis demonstrated distinct regulation patterns of these metabolites in relation to fetal growth centiles. For instance, dimethylglycine and glucose were upregulated in fetuses above the 20th centile, while citrate and succinate were upregulated in those below it. With Area Under the Curve (AUROC) values over 0.75 and p-values less than 0.05, these metabolites show promise as reliable biomarkers for predicting fetal growth restriction. This approach could significantly impact maternal-fetal medicine by facilitating early diagnosis and personalized interventions. Future research should focus on validating these findings in larger populations and exploring the underlying mechanisms of metabolite regulation., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Medical outcomes of interest to clinicians may have multiple categories. Researchers face several options for risk prediction of such outcomes, including dichotomized logistic regression and multinomial logit regression modeling. We aimed to compare these methods and provide guidance needed for practice., Methods: We described dichotomized logistic regression, multinomial continuation-ratio logit regression, which is an alternative to standard multinomial logit regression for ordinal outcomes, and logistic competing risks regression. We then applied these methods to develop prediction models of survival and neurodevelopmental outcomes based on the NICHD Extremely Preterm Birth Outcome Tool model. The statistical and practical advantages and flaws of these methods were examined. Both discrimination and calibration of the estimated logistic models of dichotomized outcomes and continuation-ratio logit model were assessed., Results: The dichotomized logistic models and multinomial continuation-ratio logit model had similar discrimination and calibration in predicting death and survival without neurodevelopmental impairment. But the continuation-ratio logit model had better discrimination and calibration in predicting neurodevelopmental impairment. The sum of predicted probabilities of outcome categories from the dichotomized logistic models could deviate from 100% substantially, ranging from 87.7 to 124.0%, and the dichotomized logistic model of neurodevelopmental impairment greatly overpredicted low risks and underpredicted high risks., Conclusions: Estimating multiple logistic regression models of dichotomized outcomes may result in poorly calibrated predictions for an outcome with multiple ordinal categories. Multinomial continuation-ratio logit regression produces better calibrated predictions, constrains the sum of predicted probabilities to 100%, and has the advantages of simplicity in model interpretation, flexibility to include outcome category-specific predictors and random-effect terms for patient heterogeneity by hospital. It also accounts for mutual dependence among multiple categories and accommodates competing risks., (© 2024. The Author(s).)

Background: Short cervical length in the mid-trimester is a powerful predictor of preterm birth (PTB). However, clinical significance of cervical length in the third trimester for predicting PTB has not been established yet., Objective: To examine the predictive role of a shortened cervix in the third trimester for PTB in women who had a normal cervical length in the second trimester STUDY DESIGN: This retrospective cohort study included women who underwent cervical length measured at least once in both the second trimester (16+0 weeks to 27+6weeks) and the early third trimester (28+0 weeks to 33+6 weeks). Women with short cervical length in the second trimester, those with multiple pregnancies, those who underwent cerclage operation, and those who had iatrogenic PTB were excluded. The study population was divided into two groups based on cervical length in the third trimester: a short cervix (≤25 mm) group and a control group (>25 mm). Rates of PTB (<37 weeks) were compared between two groups. Predictive performances of cervical length in the third trimester for PTB were assessed., Results: Women with a short cervical length at 28+0 to 33+6 weeks accounted for 12.6% (n=717) of the total study population (n=5682). PTB rate was 9.5% in the short cervix group, which was significantly higher than that (3.2%) in the control group (P<.001). The adjusted odds ratio for short cervical length on PTB was 2.73 (95% CI: 1.96-3.79). A short cervix in the third trimester had a sensitivity of 30.1%, a specificity of 88.1%, a positive predictive value of 9.5%, and a negative predictive value (NPV) of 96.8% in predicting PTB. The addition of third-trimester cervical length to the predictive model significantly increased the area under the curve from 0.64 (95% CI: 0.60-0.68) to 0.67 (95% CI: 0.63-0.71) (P=.002), demonstrating improved predictive performance., Conclusion: Approximately 13% of women with normal cervical length in the mid-trimester had a short cervical length after 28 weeks, which increased the risk of PTB. The high specificity and NPV of third-trimester cervical length measurements underscore their critical utility in identifying women at low risk for preterm delivery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: While cell-free DNA (cfDNA) screening has emerged as a screening modality for common aneuploidies, further research and several publications over the past decade suggested some correlation between the low concentrations of cfDNA and a number of pregnancy-related complications. The primary goal of this systematic review and meta-analysis was to assess the potential value of low-ff levels in the prediction of subsequent PE/PIH, GDM, SGA/FGR, and PTB. The meta-analysis results aim at summarizing the currently available literature data and determining the clinical relevance of this biochemical marker and the potential necessity for additional investigation of its utility in complications other than the detection of common aneuploidies., Methods: This systematic review and meta-analysis was designed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. It included all observational studies that reported low -ff levels after the performance of non-invasive prenatal testing (NIPT) as part of the screening for chromosomal abnormalities and their association with adverse pregnancy outcomes, namely the subsequent development of hypertensive disorders of pregnancy, gestational diabetes, preterm birth, and the detection of small for gestational age fetuses or growth-restricted fetuses. The Medline (1966-2041), Scopus (2004-2024), Clinicaltrials.gov (2008-2024), EMBASE (1980-2024), Cochrane Central Register of Controlled Trials CENTRAL (1999-2024) and Google Scholar (2004-2024) databases were used in our primary search along with the reference lists of electronically retrieved full-text papers. The date of our last search was set at February 29, 2024., Results: Our search identified 128 potentially relevant studies and,overall, 8 studies were included in the present systematic review that enrolled a total of 72,507 patients. Low ff of cfDNA cfDNA was positively associated with HDP (OR 1.66, 95% CI 1.34, 2.06, I-square test: 56%). Low ff of cfDNA was positively associated with GDM (OR 1.27, 95% CI 1.03, 1.56, I-square test: 76%). Furthermore, low ff levels were positively associated with SGA/FGR (OR 1.63, 95% CI 1.32, 2.03, I-square test: 0%). Low ff levels were positively correlated with the risk for PTB but the association did not manage to reach a statistical significant level (OR 1.22, 95% CI 0.89, 1.67, I-square test: 66%)., Conclusion: Our study suggests that low ff is associated with increased risk of adverse perinatal outcomes, including PE/PIH, GDM, and SGA/FGR. However, the relationship between ff and PTB remains unclear due to conflicting evidence. It should be emphasized that further research is needed to reveal the underlying mechanisms behind the association of low ff with adverse pregnancy outcomes and explore its potential role in an overall prenatal screening, which could potentially not be limited to detecting aneuploidies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To assess the prognostic value of cervicovaginal phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) to predict preterm birth in asymptomatic women during the second trimester of pregnancy., Study Design: This is a systematic review and meta-analysis of prognostic factor studies. We searched MEDLINE and Embase to identify cohort studies on the prognostic value of mid-trimester phIGFBP-1 on preterm birth in asymptomatic women. We included studies with singleton and twin gestations if they did not receive treatment to reduce the risk of preterm birth. Two reviewers independently screened the titles and abstracts, evaluated full-text articles, extracted the data and performed the risk of bias assessment using the QUIPS tool. The primary outcome was preterm birth < 37 weeks' gestation. We conducted random-effects meta-analyses, with subgroup analyses on populations with different preterm birth risks., Results: We included 17 studies with a total of 7618 participants. PhIGFBP-1 positive was associated with higher odds of preterm birth (12 studies, 7466 participants, OR 3.87, 95 %CI 1.60-9.32, I 2 87 %). When stratifying by population, phIGFBP-1 positive was associated with higher odds of preterm birth in women with no prior history of preterm birth (6 studies, OR 4.43, 95 %CI 2.50-7.84) but not in women with risk factors for preterm birth (6 studies, OR 1.59, 95 %CI 0.57-4.42). Risk of bias due to confounding was high in included studies., Conclusions: While the prognostic value of PhIGFBP-1 in the prediction of preterm birth is a prognostic research question, it has been often treated as a diagnostic research question in the literature. PhIGFBP-1 may be a potential biomarker to predict PTB during mid-trimester in asymptomatic women, especially for women with low risk of PTB. However, the clinical value of phIGFBP-1 remains limited due to bias in confounding. Future research should use the prognostic research framework to address such questions on biomarkers to maximise the clinical implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: TVS (Transvaginal Sonography) guided Cervical strain elastography (CSE) is now available in tertiary referral centers of LMICs (Low- and Middle-Income Countries). TVS cervical length (CL) assessment is being used routinely. Still, elastography is not used in clinical settings, although enough evidence suggests good predictive value towards sPTD (spontaneous Preterm Delivery). The clinical utility of elastography has not been tested among high-risk populations of LMICs for the prediction of sPTD., Aim: To test the performance of TVS-CSE in predicting sPTD among asymptomatic women in the mid-trimester at risk of sPTD either due to clinical factors or due to a short cervix., Method: Prospective observational study performed at a tertiary hospital in South India. Asymptomatic pregnant women between 16 and 24 weeks who had one or more clinical risk factors for sPTD or CL <2.5 cm were included. GE Voluson E-8 ultrasound machine was used. After CL measurement, elastography color coding was noted around the internal-os in the sagittal view. The strain ratio (SR) was calculated using the trace method on three ROIs (Region of Interest): Internal-os in sagittal view (IN), whole cervix in sagittal view (WN), and internal-os in axial view (AN). Reference Tissue (RT) of similar size and depth was chosen in the darkest blue region on elastography (stiffest area) outside the cervix, posterior/lateral to the cervix over the ligament insertion. Lower the SR - softer the cervix. Two trained fetal medicine consultants performed the initial 57 cases until intra/inter-observer correlation was satisfactory. Delivery before 37 weeks (after 26 weeks), in which the process of labor has begun spontaneously, or labor was induced after PPROM-was considered as sPTD. SRs were assessed to determine how well they could predict sPTD independently or combined with cervical length., Results: Out of 221 recruited,17 were lost to follow-up after 32 weeks; 204 were delivered in our hospital. Irrespective of the route of delivery, 71 (34.8%) had sPTD. Of the remaining 133, 106 delivered at term, and 27 underwent medically indicated PTD. Apart from multiple pregnancies, no other preterm-related risk factors (including CL < 2.5 cm) showed significant association with sPTD. Red CSE pattern around internal-os was associated with a significantly higher (54.5%) incidence of sPTD. CLs were similar (3.63 ± 0.67 vs. 3.63 ± 0.80, p  = .981) whereas SRs in all three ROIs were significantly lower among sPTD group versus no sPTD group (IN:0.65 ± 0.29 vs 0.79 ± 0.30 p  = .001, WN:0.34 ± 0.13 vs 0.39 ± 0.15, p  = .013, AN:0.37 ± 0.16 vs 0.48 ± 0.26, p  = .002, respectively). Using ROC curves, while CL was not predictive (AUROC 0.49, p  = .81), SRs showed moderate predictive value toward sPTD with the best AUC of 0.624 ( p  = .003) at IN. Prediction was slightly better for early sPTD <32 weeks (AUC 0.653 p  = 0.03). The best cutoff for SR at IN was 0.72, below which there was a moderate accuracy in predicting sPTD (sensitivity 52.11%, specificity 60.9%, PPV 41.57%, NPV 70.44%, diagnostic OR 1.69 and overall accuracy of 57.84%). A weak positive correlation is seen between IN and CL (Pearson's correlation R  = 0.181). Multi-variable binary logistic regression analysis suggested that SRs at IN (Adjusted OR - 0.259 CI 0.079-0.850), AN (Adjusted OR 0.182 CI 0.034-0.963), Multiple Pregnancy (Adjusted OR 3.5 CI 1.51-8.13) and previous sPTD/PPROM (Adjusted OR 2.72 CI 0.97-7.61) independently predicted sPTD., Conclusions: TVS CSE performed better than CL as an independent predictive tool toward sPTD, although predictive efficacy was modest at best. Since technology is now available in high-end USG machines in tertiary care centers, we propose optimal utilization of CSE in LMICs to triage at-risk populations since low SRs are strongly associated with sPTD.

Objective: To validate a serum biomarker developed in the USA for preterm birth (PTB) risk stratification in Viet Nam., Methods: Women with singleton pregnancies ( n  = 5000) were recruited between 19 +0 -23 +6 weeks' gestation at Tu Du Hospital, Ho Chi Minh City. Maternal serum was collected from 19 +0 -22 +6 weeks' gestation and participants followed to neonatal discharge. Relative insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) abundances were measured by mass spectrometry and their ratio compared between PTB cases and term controls. Discrimination (area under the receiver operating characteristic curve, AUC) and calibration for PTB <37 and <34 weeks' gestation were tested, with model tuning using clinical factors. Measured outcomes included all PTBs (any birth ≤37 weeks' gestation) and spontaneous PTBs (birth ≤37 weeks' gestation with clinical signs of initiation of parturition)., Results: Complete data were available for 4984 (99.7%) individuals. The cohort PTB rate was 6.7% ( n  = 335). We observed an inverse association between the IGFBP4/SHBG ratio and gestational age at birth ( p  = 0.017; AUC 0.60 [95% CI, 0.53-0.68]). Including previous PTB (for multiparous women) or prior miscarriage (for primiparous women) improved performance (AUC 0.65 and 0.70, respectively, for PTB <37 and <34 weeks' gestation). Optimal performance (AUC 0.74) was seen within 19-20 weeks' gestation, for BMI >21 kg/m2 and age 20-35 years., Conclusion: We have validated a novel serum biomarker for PTB risk stratification in a very different setting to the original study. Further research is required to determine appropriate ratio thresholds based on the prevalence of risk factors and the availability of resources and preventative therapies.

Background: Despite extensive research, the identification of effective biomarkers for early prediction of preterm birth (PTB) continues to be a challenging endeavor. This study aims to identify amniotic fluid (AF) protein biomarkers useful for the early diagnosis of PTB., Methods: We initially identified the protein expression profiles in the AF of women with PTB (n = 22) and full-term birth (FTB, n = 22), from the First People's Hospital of Yunnan Province who underwent amniocentesis from November 2019 to February 2020, using mass spectrometry employing the data-independent acquisition (DIA) technique, and then analyzed differentially expressed proteins (DEPs). Subsequently, the least absolute shrinkage and selection operator (LASSO) and random forest analysis were employed to further screen the key proteins for PTB biomarker identification. The receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analyses (DCA) were utilized to assess the discrimination and calibration of the key biomarkers., Results: A total of 25 DEPs were identified between the PTB and FTB groups, comprising 13 up-regulated and 12 down-regulated proteins. Three key protein biomarkers for early PTB diagnosis were identified: IL1RL1 (interleukin-1 receptor-like 1), APOE (apolipoprotein E), and NECTIN4 (nectin cell adhesion molecule 4). The results of the ROC analysis showed that the area under the curve (AUC) of the three proteins combined as a biomarker for early diagnosis of PTB was 0.913 (95% CI: 0.823-1.000), with a sensitivity of 0.864 and a specificity of 0.955, both superior to those of the individual biomarkers. Bootstrap internal validation revealed a concordance index (C-index) of 0.878, with a sensitivity of 0.812 and a specificity of 0.773, indicating the robust predictive performance of these biomarkers., Conclusions: We identified three previously unexplored yet potentially useful protein biomarkers in AF for early PTB diagnosis: IL1RL1, APOE, and NECTIN4., (© 2024. The Author(s).)

Objectives: To assess clinical utility of the urine Congo red dot test (CRDT) in predicting composite adverse maternal and neonatal outcomes in women with suspected preeclampsia (PE)., Methods: CRDT result and pregnancy outcomes were prospectively documented in women with new onset or pre-existing hypertension, new or pre-existing proteinuria, PE symptoms and suspected PE-related fetal growth restriction or abnormal Doppler presenting from 20 weeks' gestation between January 2020 and December 2022. Participants and clinicians were blinded to the CRDT result and managed according to internally agreed protocols. Composite maternal outcome was defined as PE, postpartum hemorrhage, intensive care unit admission, and maternal death. Composite neonatal outcome was defined as small for gestational age, preterm birth, 5-min Apgar score < 7, neonatal intensive care unit admission, and neonatal death., Results: Two hundred and forty-four women out of two hundred and fifty-one (97.2%) had a negative CRDT. All seven women with positive CRDT had both adverse maternal and neonatal outcomes, giving positive predictive values (PPV) of 100%. Rates of composite adverse maternal and neonatal outcomes in CDRT negative women were 103/244 [42.2%, 95% confidence interval (CI) 36.2%-48.5%] and 170/244 (69.7%, 95% CI 63.6%-75.1%), respectively. CRDT negative predictive values (NPV) for adverse maternal and neonatal outcomes were, respectively, 141/244 (57.8%, 95% CI 48.6%-68.2%) and 74/244 (30.3%, 95% CI 23.8%-38.1%)., Conclusion: CRDT had low NPV but high PPV for adverse maternal and neonatal outcomes in women with suspected PE. Its role in clinical management and triage of women with suspected PE is limited as it cannot identify those at low risk of developing adverse outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In order to identify and possibly offer prophylactic treatment to women at risk for preterm birth (PTB), novel prediction models for PTB are needed. Our objective was to utilize high-sensitive plasma protein profiling to investigate whether early prediction of spontaneous PTB (sPTB) before 34 gestational weeks (gw) was possible in a low-risk population., Methods: A case-control study was conducted on 46 women with sPTB before 34 gw and 46 women with normal pregnancies and term deliveries. Prospectively collected plasma sampled at gw 11 (range 7-16) and gw 25 (range 23-30) was analyzed with a high-sensitivity Proximity Extension Assay for levels of 177 inflammation-associated proteins, and statistically processed with multivariate logistic regression analysis., Results: In the first trimester, higher levels of hepatocyte growth factor (HGF) were associated with sPTB <34 gw (OR 1.49 (1.03-2.15)). In the second trimester, higher levels of interleukin (IL)-10 (OR 2.15 (1.18-3.92)), IL-6 (OR 2.59 (1.34-4.99)), and the receptor activator of nuclear factor κB (RANK) (OR 2.18 (1.26-3.77)) were associated with sPTB <34 gw. The area under the curve for the prediction models including these proteins was 0.653 (0.534-0.759) in the first trimester and 0.854 (0.754-0.925) in the second trimester., Conclusion: A combination of inflammation-associated plasma proteins from the second trimester of pregnancy showed a good predictive ability regarding sPTB before 34 gw, suggesting it could be a valuable supplement for the assessment of the clinical risk of sPTB. However, although a high number (n=177) of plasma proteins were analyzed with a high-sensitivity method, the prediction of sPTB in the first trimester remains elusive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Svenvik, Raffetseder, Brudin, Berg, Hellberg, Blomberg, Jenmalm and Ernerudh.)

Background: Biologically active cervical glands provide a mucous barrier while influencing the composition and biomechanical strength of the cervical extracellular matrix. Cervical remodeling during ripening may be reflected as loss of the sonographic cervical gland area. As sonographic cervical length remains suboptimal for universal screening, adjunctive evaluation of other facets of the mid-trimester cervix may impart additional screening benefit., Objective: To sonographically assess the cervical gland area at universal cervical length screening for preterm birth., Study Design: We performed a retrospective cohort study of singletons with transvaginal cervical length screening universally performed during anatomic survey between 18 0/7 and 23 6/7 weeks and subsequent live delivery at a single institution in 2018. Uterine anomalies, cerclage, suboptimal imaging, or medically indicated preterm birth were excluded. Ultrasound images were assessed for cervical length and cervical gland area (with quantitative measurements when present). The primary outcome was spontaneous preterm birth <37 weeks. Absent and present gland groups were compared using χ2, Fisher's exact, T-test, and multivariate logistic regression (adjusting for parity and progesterone use, as well as the gestational age, cervical length, and gland absence at screening ultrasound). Gland measurements were evaluated using the Mann-Whitney-U Test and Spearman's correlation., Results: Among the cohort of 772 patients, absent and present CGA groups were overall similar. Patients were on average 33 years old, ∼20 weeks gestation at screening ultrasound, and overall, 2.5% had history of prior spontaneous preterm birth. The absent gland group was more likely to have been taking progesterone (17% vs 4%, P=.04). Overall rate of preterm birth was 2.6%. However, the 2.3% of patients with absent cervical gland area were significantly more likely to deliver <37 weeks (aOR 23.9, 95% CI 6.4-89, P<.001). Multivariate logistic regression demonstrated better performance of a cervical length screening model for preterm birth prediction with the addition of qualitative gland evaluation (P<.001). Qualitative gland assessment was reproducible (PABAK 0.89), but quantitative gland measurements did not correlate with preterm birth., Conclusion: Qualitative gland absence at mid-gestation cervical length screening was associated with subsequent spontaneous preterm birth, whereas quantitative gland measurements were not. Multifaceted ultrasound screening may be needed to adequately evaluate the multiple biologic functions of the cervix., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aimed to investigate the regulation of amniotic fibroblast (AFC) function by vitamin K-dependent protein Z (PROZ) during preterm birth (PTB) and its potential role in adverse pregnancy outcomes. Proteomic samples were collected from amniotic fluid in the second trimester, and AFC were isolated from the amniotic membrane and cultured in vitro. The expression of extracellular and intracellular PROZ in AFC was modulated, and their biological properties and functions were evaluated. Clinical analysis revealed a significant upregulation of PROZ expression in amniotic fluid from preterm pregnant women. In vitro experiments demonstrated that PROZ stimulated AFC migration, enhanced their proliferative capacity, and reduced collagen secretion. Overexpression of PROZ further enhanced cell migration and proliferation, while knockdown of PROZ had the opposite effect. PROZ plays a crucial role in promoting the proliferation and migration of amniotic membrane fibroblasts. Increased PROZ expression in amniotic fluid is associated with the occurrence of PTB. These findings shed light on the potential involvement of PROZ in adverse pregnancy outcomes and provide a basis for further research on its regulatory mechanisms during PTB., (© 2024. The Author(s).)

Objective: We aimed to determine whether the semi-quantitative metalloproteinase-8 (MMP-8) bedside test is a worthwhile indicator in reflecting the severity of of intra-amniotic inflammation (IAI) and in predicting adverse pregnancy outcomes., Study Design: This retrospective cohort study comprised 76 singleton-pregnant women admitted to the Seoul National University Bundang Hospital with a diagnosis of preterm premature rupture of membranes (preterm PROM) between 20 weeks 0 days and 33 weeks 6 days of gestation who underwent trans-abdominal amniocentesis to confirm intra-amniotic infection by positive results for aerobic/anaerobic bacteria, fungi, and genital mycoplasma and evaluate lung maturity. The semi-quantitative MMP-8 rapid test kit employs a colourimetric assay to quantify MMP-8 levels in amniotic fluid (AF), expressing results from 0 to 100 percent. Participants were divided into three groups: group 1, including negative MMP-8 test with colour scale of 0 % (negative, n = 17); group 2, including positive MMP-8 test with colour scale < 51 % (weak positive, n = 21); and group 3, including positive MMP-8 test with colour scale of 51 %-100 % (strong positive, n = 38)., Results: Approximately 78 % (59/76) of the participants showed a positive MMP-8 test result; all culture-proven AF samples (33.3 % [25/75]) yielded positive MMP-8 test, categorizing these patients into either group 2 or group 3. A significant trend was observed where the rate of positive culture-proven samples increased with the progression from group 1 (negative) to group 3 (strong positive). Both white blood cell counts in AF and maternal serum C-reactive protein levels were found to escalate with the progression of test results from negative to strong positive. This progression was associated with an increased risk of spontaneous preterm birth within 48 h, 7 days, and 14 days from amniocentesis and within 34 weeks of gestation., Conclusion: The more the test results progress from negative to strong positive, the shorter the interval from amniocentesis to delivery becomes, and the higher the risk of intra-amniotic infection, spontaneous preterm delivery, and other perinatal complications. This relationship highlights the critical value of the semi-quantitative MMP-8 rapid test in predicting adverse pregnancy outcomes in patients with preterm PROM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction., Material and Methods: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth., Results: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68)., Conclusions: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Preterm birth is a serious pregnancy complication that affects neonatal mortality, morbidity, and long-term neurological prognosis. Predicting spontaneous preterm delivery (PTD) is important for its management. While excluding the risk of PTD is important, identifying women at high risk of PTD is imperative for medical intervention. Currently used PTD prediction parameters in clinical practice have shown high negative predictive values, but low positive predictive values. We focused on sulfated and sialylated glycocalyx changes in the uterus and vagina prior to the onset of parturition and explored the potential of electrophysiological detection of these changes as a PTD prediction parameter with a high positive predictive value. In vivo local vaginal bioelectrical impedance (VZ) was measured using two different mouse PTD models. PTD was induced in ICR mice through the subcutaneous injection of mifepristone or local intrauterine injection of lipopolysaccharide (LPS). The PTD rates were 100% and 60% post-administration of mifepristone (16-20 h, n = 4) and LPS (12-24 h, n = 20), respectively. The local VZ values (15 and 10 h after mifepristone or LPS treatment, respectively) were significantly lower in the PTD group than in the non-PTD group. Receiver operator characteristic (ROC) curve analysis of VZ at 125 kHz as a predictor of PTD showed an area under the ROC curve of 1.00 and 0.77 and positive predictive values of 1.00 and 0.86, for the mifepristone and LPS models, respectively, suggesting that local VZ value can predict PTD. Histological examination of the LPS-treated model 6 h post-treatment revealed increased expression of sulfomucins and/or sulfated proteoglycans and sialomucins in the cervical epithelium, cervical stroma and vaginal stroma. In conclusion, local VZ values can determine sulfated and sialylated glycocalyx alterations within the uterus and vagina and might be a useful PTD prediction parameter., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate the differences in vaginal matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMPs) in pregnant patients with a history of prior preterm birth compared with controls., Methods: A prospective cohort pilot study recruited patients during prenatal care with history of prior spontaneous preterm birth (high-risk group) or no history of preterm birth (low-risk/controls). Inclusion criteria were singleton gestation at 11-16 weeks and between 18 and 55 years of age. Exclusion criteria were diabetes mellitus, hypertension, diseases affecting the immune response or acute vaginitis. A vaginal wash was performed at time of enrollment, and patients were followed through delivery. Samples were analyzed using semi-quantitative analysis of MMPS and TIMPS. The study was approved by the IRB and a p-value <0.05 was considered significant., Results: A total of 48 pregnant patients were recruited: 16 with a history of preterm birth (high-risk group) and 32 with no history of preterm birth (low-risk group/controls). Groups were similar in age, race, BMI, and delivery mode. The high-risk group had more multiparous women (100 vs. 68.8 %; p=0.02), a greater preterm birth rate (31.2 vs. 6.3 %; p=0.02), and a lower birth weight (2,885 ± 898 g vs. 3,480 ± 473 g; p=0.02). Levels of vaginal MMP-9 were greater in high-risk patients than low-risk patients (74.9 % ± 27.0 vs. 49.4 % ± 31.1; p=0.01). When dividing the cohort into patients that had a spontaneous preterm birth (7/48, 14.6 %) vs. those with a term delivery (41/48, 85.4 %), the vaginal MMP-9 remained elevated in the cohort that experienced a preterm birth (85.46 %+19.79 vs. 53.20 %+31.47; p=0.01). There were no differences in the other MMPS and in TIMPs between high and low-risk groups., Conclusions: There was an increase in vaginal MMP-9 during early pregnancy in those at high risk for preterm birth and in those who delivered preterm, regardless of prior pregnancy outcome. Vaginal MMP-9 may have potential as a marker of increased risk of preterm birth., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: National second-trimester scanning of cervical length was introduced in Israel in 2010, and in the decade thereafter, a significant systematic reduction in preterm birth and in the delivery of low birthweight babies was found among singletons., Objective: In this study, we sought to estimate the cost-effectiveness of a national policy mandating second-trimester cervical length screening by ultrasound, followed by vaginal progesterone treatment for short cervical length in comparison with no screening strategy., Study Design: We constructed a decision model comparing 2 strategies, namely (1) universal cervical length screening, and (2) no screening strategy. This study used the national delivery registry of Israel's Ministry of Health. All women diagnosed with a second-trimester cervical length <25 mm were treated with vaginal progesterone and were monitored with a bimonthly ultrasound scan for cervical dynamics and threat of early delivery. Preterm birth prevalence associated with short cervical length, the efficacy of progesterone in preterm birth prevention, and the accuracy of cervical length measurements were derived from previous studies. The cost of progesterone and bimonthly sonographic surveillance, low birthweight delivery, newborn admission to intensive care units, the first-year costs of managing preterm birth and low birthweight, and instances of handicaps and the cost of their follow-up were extracted from the publicly posted registry of Israel's Ministry of Health and Israel Social Securities data. Monte Carlo simulations decision tree mode, Tornado diagrams, and 1- and 2-way sensitivity analyses were implemented and the base case and sensitivity to parameters that were predicted to influence cost-effectiveness were calculated., Results: Without cervical length screening, the discounted quality-adjusted life years were 30.179, and with universal cervical length screening, it increased to 30.198 (difference of 0.018 quality-adjusted life years). The average cost of no screening for cervical length strategy was $1047, and for universal cervical length screening, it was reduced to $998. The calculated incremental cost-effectiveness ratio was -$2676 per quality-adjusted life year (dividing the difference in costs by the difference in quality-adjusted life years). Monte Carlo simulation of cervical length screening of 170,000 singleton newborns (rounded large number close to the number of singleton newborns in Israel) showed that 95.17% of all babies were delivered at gestational week ≥37 in comparison with 94.46% of babies with the no screening strategy. Given 170,000 singleton births, the national savings of screening for short cervical length when compared with no cervical length screening amounted to $8.31M annually, equating to $48.84 for a base case, and the incremental cost-effectiveness ratio for each case of low birthweight or very low birthweight avoided was -$14,718. A cervical length <25 mm was measured for 30,090 women, and of those, 24,650 were false positives. The major parameters that affected the incremental cost-effectiveness ratio were the incidence of preterm birth, the specificity of cervical length measurements, and the efficacy of progesterone treatment. At a preterm birth incidence of <3%, universal screening does not lead to a cost saving., Conclusion: National universal cervical length screening should be incorporated into the routine anomaly scan in the second trimester, because it leads to a drop in the incidence of preterm birth and low birthweight babies in singleton pregnancies, thereby saving costs related to the newborn and gaining quality-adjusted life years., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Preterm birth is a major cause of perinatal morbidity and mortality. It is unclear whether the introduction of a universal transvaginal ultrasound cervical length screening program in women at low risk for preterm delivery is associated with a reduction in the frequency of preterm birth., Objective: To test the hypothesis that the introduction of a midtrimester universal transvaginal ultrasound cervical length screening program in asymptomatic singleton pregnancies without prior preterm delivery would reduce the rate of preterm birth at <37 weeks of gestation., Study Design: This study was a multicenter nonblinded randomized trial of screening of asymptomatic singleton pregnancies without prior spontaneous preterm birth, who were randomized to either cervical length screening program (ie, intervention group) or no screening (ie, control group). Participants were randomized at the time of their routine anatomy scan between 18 0/7 and 23 6/7 weeks of gestation. Women randomized in the screening group received cervical length measurement. Those who were found to have cervical length ≤25 mm were offered 200 mg vaginal progesterone daily along with cervical pessary. The primary outcome was preterm birth at <37 weeks. The risk of primary outcome was quantified by the relative risk with 95% confidence interval, and was based on the intention-to-screen principle., Results: A total of 1334 asymptomatic women with singleton pregnancies and without prior preterm birth, were included in the trial. Out of the 675 women randomized in the transvaginal ultrasound cervical length screening group, 13 (1.9%) were found to have transvaginal ultrasound cervical length ≤25 mm during the screening. Preterm birth at <37 weeks of gestation occurred in 48 women in the transvaginal ultrasound cervical length screening group (7.5%), and 54 women in the control group (8.7%) (relative risk, 0.86; 95% confidence interval, 0.59-1.25). Women randomized in the transvaginal ultrasound cervical length screening group had no significant differences in the incidence of preterm birth at less than 34, 32, 30, 28, and 24 weeks of gestation., Conclusion: The introduction of a universal transvaginal ultrasound cervical length screening program at 18 0/6 to 23 6/7 weeks of gestation in singleton pregnancies without prior spontaneous preterm birth, with treatment for those with cervical length ≤25 mm, did not result in significant lower incidence of preterm delivery than the incidence without the screening program., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up., Material and Methods: Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up., Clinicaltrials: gov registration NCT05693285., Results: In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up., Conclusions: Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Preterm birth represents a significant clinical challenge, and the ability to predict it effectively is a priority in obstetrics. The cervix undergoes specific changes during pregnancy, and staging these changes may offer a valuable predictive model for preterm birth, particularly among women with a midtrimester short cervical length., Objective: The study aimed to validate a proposed staging model for asymptomatic women with midtrimester short cervical length and to evaluate its potential for predicting preterm birth. The integration of cervical examination and inspection with cervical length measurement was a novel approach to be assessed., Study Design: This was a multicenter, retrospective cohort study that included 925 pregnant women with a singleton fetus and a midtrimester cervical length measurement of ≤25 mm. Cervical conditions were assessed using ultrasonography, a speculum, and a physical examination and were classified into 1 of 5 cervical stages to correlate with the likelihood of preterm birth. Statistical analyses included Kaplan-Meier survival analysis to illustrate the time-to-event characteristics across the 5 stages and density plot evaluation to visualize the distribution of the gestational ages within the stages., Results: The staging model included 5 stages based on cervical length, appearance, and dilatation. Among the 925 participants, 649 were classified as being stage 1, 245 as stage 2, 18 as stage 3, 10 as stage 4, and 3 as stage 5. The observed rates of preterm birth before 37 weeks for individuals classified in stages 1, 2, 3, 4, and 5 were 22.3%, 26.5%, 44.4%, 60%, and 66.7%, respectively (P=.005). The overall observed rates of preterm birth before 28, 32, 34, and 37 weeks' gestation were 5.5%, 9.9%, 12.2%, and 24.1%, respectively (P=.005)., Conclusion: This study validated the proposed staging criteria as an effective predictor of preterm birth caused by cervical insufficiency. The results demonstrate a significant increase in the preterm birth rate with advancing stage classification, indicating that the staging effectively stratified women based on their risk for preterm birth and highlighting the potential use for targeted interventions. Implementing these staging criteria can potentially improve the counseling and management of pregnant women at risk for preterm birth., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the differences in first-trimester and early-second-trimester transvaginal cervical length between patients with spontaneous preterm birth and those with term birth., Data Sources: PubMed, MEDLINE, Embase, and the Cochrane Library were systematically searched through August 2023., Study Eligibility Criteria: Studies had to include (1) transvaginal cervical length measurement before 16 +0 weeks of gestation and (2) transvaginal cervical length measurement in a population of patients who delivered preterm and at term. Abstracts, studies with duplicated data, and those with cervical length measured by transabdominal ultrasound scan were excluded., Methods: K.W.C. and J.L. searched for, screened, and reviewed the articles independently. The quality of the studies was assessed using the Newcastle-Ottawa scale. Mean differences were calculated using a random-effects model and pooled through a meta-analysis., Results: A total of 5727 published articles were identified. Only 10 studies (which analyzed 22,151 pregnancies) met the inclusion criteria. All studies excluded iatrogenic preterm birth. Transvaginal cervical length was significantly shorter in women with spontaneous preterm birth than in those who delivered at term (mean difference, -0.97; 95% confidence interval, -1.65 to -0.29; P=.005; I 2 =69%). When a linear technique was used to measure transvaginal cervical length, a significantly shorter transvaginal cervical length was associated with spontaneous preterm birth as opposed to term birth (mean difference, -1.09; 95% confidence interval, -1.96 to -0.21; P=.02; I 2 =77%). A shorter transvaginal cervical length measured by other techniques was also associated with spontaneous preterm birth before 34 to 35 weeks (mean difference, -1.87; 95% confidence interval, -3.04 to -0.70; P=.002; I 2 =0%). When studies where interventions were given for a "short" cervix or studies with a mean transvaginal cervical length ≥40 mm were excluded, a significantly shorter transvaginal cervical length was observed among those with spontaneous preterm birth (mean difference, -1.13; 95% confidence interval, -1.89 to -0.37; P=.004; mean difference, -0.86; 95% confidence interval, -1.67 to -0.04; P=.04; respectively). The optimal transvaginal cervical length cutoff was 38 to 39 mm, yielding pooled sensitivity of 0.80, specificity of 0.45, positive likelihood ratio of 1.16, negative likelihood ratio of 0.33, diagnostic odds ratio of 5.12, and an area under the curve of 0.75., Conclusion: Women with spontaneous preterm birth had significantly shorter transvaginal cervical length before 16 weeks of gestation compared with those who delivered at term. The linear method and the 2-line method are acceptable techniques for measuring transvaginal cervical length., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To evaluate associations between serum analytes used for genetic screening and obstetric complications among twin pregnancies., Methods: This cohort included twins delivered at a tertiary care hospital from 2009 to 2017. Abnormal levels of pregnancy associated plasma protein (PAPP-A), first and second trimester human chorionic gonadotropin (hCG), alpha fetoprotein (AFP), estriol, and inhibin, reported as multiples of the median (MoM), were defined as <5 %ile or >95 %ile for our cohort. Associations between abnormal analytes and preterm delivery, small for gestational age, and pregnancy-associated hypertension were calculated using Fisher's exact test., Results: A total of 357 dichorionic/diamniotic and 123 monochorionic/diamniotic twins were included. Among dichorionic/diamniotic twins, elevated AFP (>3.70 MoM) was associated with increased preterm delivery <34 weeks (44.4 vs. 16.5 %, p=0.007), while elevated inhibin (>4.95 MoM) was associated with increased preterm delivery<37 weeks (94.1 vs. 58.8 %, p=0.004). For monochorionic/diamniotic twins, elevated inhibin (>6.34 MoM) was associated increased preterm delivery <34 weeks (66.7 vs. 24.8 %, p=0.04) and hypertension (66.7 vs. 21.4 %, p=0.03)., Conclusions: Selected abnormal analyte levels were associated with increased rates of adverse outcomes in twin pregnancies, which differed by chorionicity. Our findings assist providers in interpreting abnormal analyte levels in twin pregnancies and may help to identify those at increased risk for adverse outcomes., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Preterm birth (PTB) is a leading cause of neonatal mortality, such that the need for a rapid and accurate assessment for PTB risk is critical. Here, we developed a 3D printed microfluidic system that integrated solid-phase extraction (SPE) and microchip electrophoresis (μCE) of PTB biomarkers, enabling the combination of biomarker enrichment and labeling with μCE separation and fluorescence detection., Results: Reversed-phase SPE monoliths were photopolymerized in 3D printed devices. Microvalves in the device directed sample between the SPE monolith and the injection cross-channel in the serpentine μCE channel. Successful on-chip preconcentration, labeling and μCE separation of four PTB-related polypeptides were demonstrated in these integrated microfluidic devices. We further show the ability of these devices to handle complex sample matrices through the successful analysis of labeled PTB biomarkers spiked into maternal blood serum. The detection limit was 7 nM for the PTB biomarker, corticotropin releasing factor, in 3D printed SPE-μCE integrated devices., Significance: This work represents the first successful demonstration of integration of SPE and μCE separation of disease-linked biomarkers in 3D printed microfluidic devices. These studies open up promising possibilities for rapid bioanalysis of medically relevant analytes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GPN and ATW own shares in Acrea3D, a company that is commercializing 3D printers. The other authors have no conflicts to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, the American College of Cardiology and the American Heart Association have reduced the thresholds for a hypertension diagnosis among nonpregnant adults. This change has led to more individuals with reproductive potential to be labeled as being chronically hypertensive, and some were started on antihypertensive medications. When these individuals become pregnant, the obstetrical care provider will have to decide whether to manage them as individuals with chronic hypertensive when only a few years ago they would have been managed as normotensive individuals and when the evidence regarding treatment of these patients during pregnancy is limited. If implemented widely, the management of patients with stage 1 hypertension similar to the traditional chronic hypertension will likely lead to additional maternal and fetal testing, to an increase in hospital admissions, and potentially to unnecessary interventions, such as preterm birth. Our goal was to compile the existing evidence regarding the pregnancy outcomes among patients with stage 1 hypertension to assist providers in their diagnosis and management of this patient group., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: 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., Objective: 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., Study Design: 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., Results: 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)., Conclusion: 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Centrally collected Finnish national health register data on adverse pregnancy outcomes are available for research, but the validity of the data is largely unknown. Our aim was to compare the diagnoses of preeclampsia (PE), gestational diabetes (GDM), and preterm delivery from hospital records with the registry based diagnoses from the Finnish Care Register for Health Care (FCR). Data on gestational age at delivery from the Medical Birth Registry (MBR) was also studied., Methods: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study cohort was used as a data source. Each diagnosis was ascertained from electronic hospital records. The validity of diagnoses obtained by record linkage of FCR and MBR was assessed against the classification previously confirmed independently by a research nurse and a study physician., Results: Sensitivity of PE diagnoses in FCR was 80.3 % (95 % CI 78.3 % to 82.2 %) andspecificity 95.3 % (95 % CI 93.9 % to 96.4 %). Sensitivity for GDM was 64.1 % (95 % CI: 58.7 % - 69.3 %) and specificity 98.5 % (95 % CI: 97.9 % - 98.9 %), whereas sensitivity and specificity for preterm delivery were 32.4 % (95 % CI: 29.0 % - 36.0 %) and 99.7 % (95 % CI: 99.3 % - 99.9 %). Sensitivity of preterm delivery in the MBR was 99.1 % and specificity 99.9 %., Conclusions: FCR registry diagnoses for PE have satisfactory sensitivity and high specificity. Diagnoses for GDM and preterm delivery have lower sensitivity limiting their use in studies, and data from MBR should be preferred when studying preterm deliveries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Preterm birth is one of the most common obstetric complications in low- and middle-income countries, where access to advanced diagnostic tests and imaging is limited. Therefore, we developed and validated a simplified risk prediction tool to predict preterm birth based on easily applicable and routinely collected characteristics of pregnant women in the primary care setting. We used a logistic regression model to develop a model based on the data collected from 481 pregnant women. Model accuracy was evaluated through discrimination (measured by the area under the Receiver Operating Characteristic curve; AUC) and calibration (via calibration graphs and the Hosmer-Lemeshow goodness of fit test). Internal validation was performed using a bootstrapping technique. A simplified risk score was developed, and the cut-off point was determined using the "Youden index" to classify pregnant women into high or low risk for preterm birth. The incidence of preterm birth was 19.5% (95% CI:16.2, 23.3) of pregnancies. The final prediction model incorporated mid-upper arm circumference, gravidity, history of abortion, antenatal care, comorbidity, intimate partner violence, and anemia as predictors of preeclampsia. The AUC of the model was 0.687 (95% CI: 0.62, 0.75). The calibration plot demonstrated a good calibration with a p-value of 0.713 for the Hosmer-Lemeshow goodness of fit test. The model can identify pregnant women at high risk of preterm birth. It is applicable in daily clinical practice and could contribute to the improvement of the health of women and newborns in primary care settings with limited resources. Healthcare providers in rural areas could use this prediction model to improve clinical decision-making and reduce obstetrics complications., (© 2024. The Author(s).)

Spontaneous preterm birth (sPTB) is a major cause of perinatal morbidity and mortality, even in developed countries. Prediction of sPTB is therefore a valuable tool to reduce the associated risks. The current standard for the prediction of sPTB consists, in addition to anamnestic data, of previous sPTB and previous second trimester miscarriage, measurement of cervical length by transvaginal ultrasound (TVU CL) together with assessment of fetal fibronectin levels in cervicovaginal fluid. Other evaluation parameters, such as the level of endocannabinoids in the pregnant woman's blood, could increase the sensitivity of this management. Endocannabinoids (eCBs) are a part of the endocannabinoid system (ECS); out of them anandamide (arachidonoyl-ethanolamide, AEA), in particular, plays an important role in the regulation of pregnancy and childbirth. We present the protocol for an open, non-randomized study to evaluate concentrations of AEA and other endocannabinoids: 2 linoleoylglycerol (2-AG), 2 linoleoylglycerol (2-LG), 2 oleoylglycerol (2-OG), and 2 arachidonoyldopamine (2-ADOPA or also NADA) in the blood of pregnant women as potential predictors of sPTB. In a total of 230 women with a history of sPTB or miscarriage, eCBs levels between 22 and 28 weeks of gestation will be assessed from maternal blood, in addition to the standard procedure. The aim of the study is to determine the relationship between blood concentrations of the endocannabinoids tested and the risk of sPTB. The results of this study will describe the prognostic significance of maternal blood eCBs levels for sPTB, and could subsequently enable improved screening programs for early identification of sPTB.

Objective: Tests capable of accurate prediction of spontaneous preterm birth (sPTB) are crucial to inform clinical decisions to prevent neonatal deaths and reduce the risk of morbidity in surviving infants. A systematic literature review and meta-analysis were performed to assess the utility of the quantitative fetal fibronectin (fFN) test to predict sPTB at different test concentration thresholds., Methods: Literature searches were conducted in MEDLINE, Embase, and the Cochrane Library in May 2022. Observational studies and clinical trials investigating the clinical utility of the quantitative fFN test in asymptomatic pregnancies prior to 37 weeks of gestation were eligible for inclusion. Meta-analysis quantified the risk of sPTB prior to four gestational age milestones (<28, <30, <34 and <37 weeks) based on quantitative fFN levels. No risk of bias assessment was performed however, clinical and methodological heterogeneity was explored to determine the feasibility of performing analyses., Results: 11 studies showed a quantitative assessment of fFN can differentiate between very high and very low risks of sPTB in asymptomatic pregnancies with <10% of women with very low fFN (<10 ng/mL) versus 37-67% of women with very high fFN (>200 ng/mL) delivering before 34 weeks. A meta-analysis of two studies showed, albeit with a low number of events, the odds of sPTB prior to 28 weeks was nine times higher in women testing positive at ≥50 ng/mL, whereas the odds of sPTB was 25 times higher in women with fFN concentrations >200 ng/mL (versus <50 ng/mL reference). Similarly, pooling three studies showed the odds of sPTB prior to 37 weeks was four times higher in women who tested positive at ≥50 ng/ml whereas the odds of delivery before 37 weeks was seven times higher for women with fFN concentrations ≥200 ng/ml (versus <50 ng/mL reference)., Conclusion: Quantitative fFN testing demonstrates increased predictive capabilities and utility of fFN testing in clinical practice, potentially preventing unnecessary intervention for women at very low risk and allowing an opportunity to optimize the management of asymptomatic patients at high risk of preterm delivery.

Objective: The objective of this study is to create a new screening for spontaneous preterm birth (sPTB) based on artificial intelligence (AI)., Methods: This study included 524 singleton pregnancies from 18th to 24th-week gestation after transvaginal ultrasound cervical length (CL) analyzes for screening sPTB < 35 weeks. AI model was created based on the stacking-based ensemble learning method (SBELM) by the neural network, gathering CL < 25 mm, multivariate unadjusted logistic regression (LR), and the best AI algorithm. Receiver Operating Characteristics (ROC) curve to predict sPTB < 35 weeks and area under the curve (AUC), sensitivity, specificity, accuracy, predictive positive and negative values were performed to evaluate CL < 25 mm, LR, the best algorithms of AI and SBELM., Results: The most relevant variables presented by LR were cervical funneling, index straight CL/internal angle inside the cervix (≤ 0.200), previous PTB < 37 weeks, previous curettage, no antibiotic treatment during pregnancy, and weight (≤ 58 kg), no smoking, and CL < 30.9 mm. Fixing 10% of false positive rate, CL < 25 mm and SBELM present, respectively: AUC of 0.318 and 0.808; sensitivity of 33.3% and 47,3%; specificity of 91.8 and 92.8%; positive predictive value of 23.1 and 32.7%; negative predictive value of 94.9 and 96.0%. This machine learning presented high statistical significance when compared to CL < 25 mm after T-test ( p  < .00001)., Conclusion: AI applied to clinical and ultrasonographic variables could be a viable option for screening of sPTB < 35 weeks, improving the performance of short cervix, with a low false-positive rate.

Background: The usefulness of cervical length (CL) measurement in asymptomatic pregnancies in the third trimester of pregnancy is not certain. Therefore, the objective of this study was to assess the performance of CL measurement at 31-34 gestational weeks for the prediction of spontaneous late preterm birth (PTB)., Materials and Methods: This was a prospective study of women with a singleton pregnancy, who had their routine third-trimester scan at 31-34 weeks. The CL was measured transvaginally and was tested, together with maternal demographic and obstetric parameters, for the prediction of late PTB (34 to 36 weeks), using logistic regression and ROC curve analysis., Results: Overall, from a population of 1003 women that consented to participate in the study, 42 (4.2%) delivered at 34-36 gestational weeks. A significant association was identified between gestational age at birth and CL (rho = 0.182, p  < .001), and there were significant differences in the CL between cases of late preterm and term births ( p  < .001). Cervical length alone could predict 17% of late PTB for a 10% false positive rate, corresponding to 22 mm. A model combining CL with parity and method of conception can identify 35% of pregnancies resulting in late PTB, at a false positive rate of 10% (AUC: 0.750; 95% CI: 0.675-0.824)., Conclusions: CL assessment at 31-34 gestational weeks may contribute to the prediction of late PTB when combined with maternal characteristics.

Introduction: Preterm birth (PTB) is among the leading causes of perinatal and childhood morbidity and mortality. Therefore, accurate identification of pregnant women at high risk of PTB is key to enable obstetric healthcare professionals to apply interventions that improve perinatal and childhood outcomes. Serial transvaginal cervical length measurement is used to screen asymptomatic pregnant women with a history of PTB and identify those at high risk for a recurrent PTB. Cervical length measurement, fetal fibronectin test or a combination of both can be used to identify women at high risk of PTB presenting with symptoms of threatened PTB. The predictive capacity of these methods can be improved. Cervical softening is a precursor of cervical shortening, effacement and dilatation and could be a new marker to identify women a high risk of PTB. However, the predictive value of cervical softening to predict spontaneous PTB still needs to be determined., Methods and Analysis: This is a single-centre, prospective cohort study, conducted at the Amsterdam University Medical Centers in the Netherlands. Cervical softening will be investigated with a non-invasive CE-marked device called the Pregnolia System. This device has been developed to evaluate consistency of the cervix based on tissue elasticity. Two different cohorts will be investigated. The first cohort includes women with a history of spontaneous PTB <34 weeks. These women undergo biweekly measurements between 14 and 24 weeks of gestation. The second cohort includes women with symptoms of threatened PTB. These women will receive the measurement once at presentation between 24 and 34 weeks of gestation. The primary outcome is spontaneous PTB before 34 weeks for women with a history of PTB and delivery within 7 days for women with threatened PTB. The minimum sample size required to analyse the primary outcome is 227 women in the cohort of women with a history of PTB and 163 women in the cohort of women with symptoms of threatened PTB. Once this number is achieved, the study will be continued to investigate secondary objectives., Ethics and Dissemination: The study is approved by the Medical Ethics Committee of Amsterdam UMC (METC2022.0226). All patients will give oral and written informed consent prior to study entry. Results will be disseminated via a peer-reviewed journal., Trial Registration Number: NCT05477381., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Primary outcomes were to determine; 1) the desire for more patient information from healthcare professionals on preterm birth (PTB) prevention 2) the desire for PTB screening surveillance or participation in research or 3) the acceptability of transvaginal ultrasound (TVUS) or vaginal examinations to predict spontaneous PTB., Methods: A 19-question, piloted, self-administered survey was completed by unselected pregnant women in a tertiary maternity hospital in Dublin, Ireland. Data was collected to include maternal socio-demographics, past obstetric history, and current pregnancy details, in addition to views and preferences on PTB screening and preventative treatments. Statistical analysis to include binary and multinomial regression was performed by IBM SPSS Statistics for Windows (Version 29.0)., Results: 277 women completed the study survey. 9.4% of women had attended the preterm birth surveillance clinic (PSC). 75.1% of respondents indicated a preference for more information from healthcare professionals about PTB. 65% reported that TVUS and vaginal examinations were acceptable in pregnancy. The acceptability of antenatal examinations was significantly influenced by ethnicity; white European (OR 2.58, CI 1.12-5.95, p = 0.003) and Asian (OR 3.39, CI 1.18-9.67, p = 0.02). Discomfort (25.3%) and vaginal bleeding (11.9%) were the most frequently reported concerns about TVUS. 95.7% of unselected women indicated that they would accept treatment to prevent PTB. Vaginal progesterone (53.8%) was preferred treatment compared to cervical cerclage (15.9%) or cervical pessary (16.6%). 55.6% of respondents stated they attend or wish to attend for additional appointments or research opportunities for PTB screening. Women with a previous PTB or second trimester miscarriage were more likely to attend or wish to attend for PTB screening (OR 3.23, CI 1.34-7.79, p = 0.009)., Conclusion: PTB is an important healthcare priority for pregnant women in Ireland. However, women require more information, counselling and reassurance about the utility and safety of TVUS in PSCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Preterm birth is the leading cause of global neonatal mortality. Amniotic fluid sludge, thought to indicate intra-amniotic infection, may have potential as a clinical biomarker of preterm birth risk., Objective: This study aimed to analyze whether the presence of amniotic fluid sludge in pregnant participants with a known short cervical length can help improve the understanding of the etiology and guide management choice., Study Design: This was a retrospective cohort study analyzing the effects of amniotic fluid sludge presence on the risk of preterm birth in high-risk asymptomatic pregnant participants with a short cervical length (<25 mm) at a large tertiary referral maternity center in London. Amniotic fluid sludge was detected on a routine transvaginal ultrasound scan., Results: Overall, 147 pregnant participants with a short cervical length were identified, 54 of whom had amniotic fluid sludge. Compared with pregnant participants without amniotic fluid sludge, pregnant participants with amniotic fluid sludge were more likely to have a short cervical length (19 vs 14 mm, respectively; P<.0001) and increased cervicovaginal fetal fibronectin concentrations at diagnosis (125 vs 45 ng/mL, respectively; P=.0006). Pregnant participants with amniotic fluid sludge were at increased risk of midtrimester loss and delivery before 24 weeks of gestation (relative risk, 3.4; 95% confidence interval, 1.2-10.3). Furthermore, this study showed that pregnant participants with amniotic fluid sludge have increased cervicovaginal interleukin 8 concentrations, supporting the concept of amniotic fluid sludge as an indicator of an inflammatory response to microbial invasion (P=.03). Neonatal outcomes were similar between the 2 groups., Conclusion: In our cohort of high-risk asymptomatic pregnant participants with a short cervical length, the presence of amniotic fluid sludge is associated with an increased risk of delivery before 24 weeks of gestation. Moreover, pregnant participants with amniotic fluid sludge were more likely to have raised fetal fibronectin levels and inflammatory cytokines, particularly interleukin 8, in the cervicovaginal fluid, supporting the concept that amniotic fluid sludge is associated with an infective or inflammatory process. Future research should aim to further establish the clinical significance of amniotic fluid sludge presence and guide subsequent management., (Copyright © 2023. Published by Elsevier Inc.)

Background: Preterm delivery (PTD) includes three main presenting subtypes: spontaneous preterm labour (sPTL), preterm premature rupture of membranes (pPROM) and clinician-initiated preterm delivery (ciPTD). PTD subtype data are rarely available from birth registries and are onerous to derive from medical records., Objectives: To develop and test the validity of a questionnaire to classify PTD subtype based on birthing parent recall of labour and delivery events., Methods: The questionnaire was sent in 2022 to 581 patients with PTD history documented in the LIFECODES study, a hospital-based birth cohort in Boston, Massachusetts. Eighty-two respondents reported 94 PTDs that could be linked to medical records. Data on PTD subtype were extracted from medical records as the reference standard., Results: Medical records indicated 47 spontaneous (24 sPTL, 23 pPROM) and 47 ciPTD deliveries occurring a median eight years earlier. The sensitivity and specificity of the recall questionnaire were 88% (95% confidence interval: 68, 97%) and 89% (79, 95%) for sPTL; 96% (78, 100%) and 94% (86, 98%) for pPROM; and 83% (69, 92%) and 100% (92, 100%) for ciPTD, respectively. Greater time since pregnancy did not degrade the sensitivity or specificity of the parental recall questionnaire., Conclusions: Although derived from a modest sample, the moderate-to-high sensitivity and specificity of the parental recall questionnaire to classify sPTL, pPROM and ciPTD demonstrates its potential for large studies of PTD and for correction of misclassification bias. Future studies are required to test the questionnaire in a variety of populations., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Introduction: Cervical length measurement using transvaginal sonography at 18 +0 -24 +0  weeks of gestation is used to identify women at risk of preterm delivery, who may benefit from treatment with progesterone to prevent premature birth. Few and conflicting data exist regarding the predictive value of cervical length measurement performed at later gestational ages. The primary objective of this study was to evaluate the predictive accuracy for spontaneous preterm birth of a single cervical length measurement performed between 24 and 32 weeks of gestation in asymptomatic singleton pregnancies at low risk for spontaneous preterm birth. The secondary objective was to test the predictive accuracy of different cervical length thresholds in the same population., Material and Methods: This was a historical cohort study conducted in a tertiary referral hospital. A total of 2728 asymptomatic women with singleton pregnancy at low risk for spontaneous preterm birth were recruited. Of these women, 1548 had cervical length measured at 24 +0 -27 +6  weeks of gestation and 2191 women at 28 +0 -32 +0  weeks. In all, 1010 women were present in both gestational age windows. Maternal demographics, medical and obstetrical history, and pregnancy outcome were reviewed. The predictive value of cervical length for spontaneous preterm birth was evaluated through logistic regression analysis. Results were adjusted for confounding factors., Results: Overall, spontaneous preterm birth occurred in 53/2728 women (1.9%). In both the 24 +0 -27 +6 and 28 +0 -32 +0  weeks groups, a shorter cervical length was significantly associated with spontaneous preterm birth (p < 0.01), but it had a low predictive value, as shown by the receiver operating characteristics curve analysis (areas under the curve 0.62, 95% CI 0.50-0.74 for the 24 +0 -27 +6  weeks group, and 0.61, 95% CI 0.52-0.70 in the 28 +0 -32 +0  weeks group). When the predictive accuracy for preterm delivery of different cervical length cut-offs was evaluated, the sensitivity and positive predictive value were low in both gestational age windows, irrespective of the threshold used., Conclusions: In asymptomatic women with singleton pregnancy at low risk for spontaneous preterm birth, the predictive value of cervical length after 24 +0  weeks of gestation is low. Therefore, cervical length screening in these women should be discouraged., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Microbiome dysbiosis can have long-lasting effects on our health and induce the development of various diseases. Bronchopulmonary dysplasia (BPD) is a multifactorial disease with pre- and postnatal origins including intra-amniotic infection as main risk factor. Recently, postnatal pathologic lung microbiota colonization was associated with BPD. The objectives of this prospective observational cohort study were to describe differences in bacterial signatures in the amniotic fluid (AF) of intact pregnancies without clinical signs or risk of preterm delivery and AF samples obtained during preterm deliveries and their variations between different BPD disease severity stages., Methods: AF samples were collected under sterile conditions during fetal intervention from intact pregnancies (n = 17) or immediately before preterm delivery < 32 weeks (n = 126). Metabarcoding based approaches were used for the molecular assessment of bacterial 16S rRNA genes to describe bacterial community structure., Results: The absolute amount of 16S rRNA genes was significantly increased in AF of preterm deliveries and detailed profiling revealed a reduced alpha diversity and a significant change in beta diversity with a reduced relative abundance of 16S rRNA genes indicative for Lactobacillus and Acetobacter while Fusobacterium, Pseudomonas, Ureaplasma and Staphylococcus 16S rRNA gene prevailed. Although classification of BPD by disease severity revealed equivalent absolute 16S rRNA gene abundance and alpha and beta diversity in no, mild and moderate/severe BPD groups, for some 16S rRNA genes differences were observed in AF samples. Bacterial signatures of infants with moderate/severe BPD showed predominance of 16S rRNA genes belonging to the Escherichia-Shigella cluster while Ureaplasma and Enterococcus species were enriched in AF samples of infants with mild BPD., Conclusions: Our study identified distinct and diverse intrauterine 16S rRNA gene patterns in preterm infants immediately before birth, differing from the 16S rRNA gene signature of intact pregnancies. The distinct 16S rRNA gene signatures at birth derive from bacteria with varying pathogenicity to the immature lung and are suited to identify preterm infants at risk. Our results emphasize the prenatal impact to the origins of BPD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The timely identification of nulliparas at high risk of adverse fetal and neonatal outcomes during pregnancy is crucial for initiating clinical interventions to prevent perinatal complications. Although machine learning methods have been applied to predict preterm birth and other pregnancy complications, many models do not provide explanations of their predictions, limiting the clinical use of the model., Objective: This study aimed to develop interpretable prediction models for a composite adverse perinatal outcome (stillbirth, neonatal death, estimated Combined Apgar score of <10, or preterm birth) at different points in time during the pregnancy and to evaluate the marginal predictive value of individual predictors in the context of a machine learning model., Study Design: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be data, a prospective cohort study in which 10,038 nulliparous pregnant individuals with singleton pregnancies were enrolled. Here, interpretable prediction models were developed using L1-regularized logistic regression for adverse perinatal outcomes using data available at 3 study visits during the pregnancy (visit 1: 6 0/7 to 13 6/7 weeks of gestation; visit 2: 16 0/7 to 21 6/7 weeks of gestation; visit 3: 22 0/7 to 29 6/7 weeks of gestation). We identified the important predictors for each model using SHapley Additive exPlanations, a model-agnostic method of computing explanations of model predictions, and evaluated the marginal predictive value of each predictor using the DeLong test., Results: Our interpretable machine learning model had an area under the receiver operating characteristic curves of 0.617 (95% confidence interval, 0.595-0.639; all predictor variables at visit 1), 0.652 (95% confidence interval, 0.631-0.673; all predictor variables at visit 2), and 0.673 (95% confidence interval, 0.651-0.694; all predictor variables at visit 3). For all visits, the placental biomarker inhibin A was a valuable predictor, as including inhibin A resulted in better performance in predicting adverse perinatal outcomes (P<.001, all visits). At visit 1, endoglin was also a valuable predictor (P<.001). At visit 2, free beta human chorionic gonadotropin (P=.001) and uterine artery pulsatility index (P=.023) were also valuable predictors. At visit 3, cervical length was also a valuable predictor (P<.001)., Conclusion: Despite various advances in predictive modeling in obstetrics, the accurate prediction of adverse perinatal outcomes remains difficult. Interpretable machine learning can help clinicians understand how predictions are made, but barriers exist to the widespread clinical adoption of machine learning models for adverse perinatal outcomes. A better understanding of the evolution of risk factors for adverse perinatal outcomes throughout pregnancy is necessary for the development of effective interventions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Threatened preterm labor is the major cause of hospital admission during the second half of pregnancy. An early diagnosis is crucial for adopting pharmacologic measures to reduce perinatal mortality and morbidity. Current diagnostic criteria are based on symptoms and short cervical length. However, there is a high false-positive rate when using these criteria, which implies overtreatment, causing unnecessary side effects and an avoidable economic burden., Objective: This study aimed to compare the use of placental alpha microglobulin-1 and interleukin-6 as vaginal biomarkers combined with cervical length and other maternal characteristics to improve the prediction of preterm delivery in symptomatic women., Study Design: A prospective observational study was conducted in women with singleton pregnancies complicated by threatened preterm labor with intact membranes at 24+0 to 34+6 weeks of gestation. A total of 136 women were included in this study. Vaginal fluid was collected with a swab for placental alpha microglobulin-1 determination using the PartoSure test, interleukin-6 was assessed by electrochemiluminescence immunoassay, cervical length was measured by transvaginal ultrasound, and obstetrical variables and newborn details were retrieved from clinical records. These characteristics were used to fit univariate binary logistic regression models to predict time to delivery <7 days, time to delivery <14 days, gestational age at delivery ≤34 weeks, and gestational age at delivery ≤37 weeks, and multivariate binary logistic regression models were fitted with imbalanced and balanced data. Performance of models was assessed by their F2-scores and other metrics, and the association of their variables with a risk or a protective factor was studied., Results: A total of 136 women were recruited, of whom 8 were lost to follow-up and 7 were excluded. Of the remaining 121 patients, 22 had a time to delivery <7 days and 31 had a time to delivery <14 days, and 30 deliveries occurred with a gestational age at delivery ≤34 weeks and 55 with a gestational age at delivery ≤37 weeks. Univariate binary logistic regression models fitted with the log transformation of interleukin-6 showed the greatest F2-scores in most studies, which outperformed those of models fitted with placental alpha microglobulin-1 (log[interleukin-6] vs placental alpha microglobulin-1 in time to delivery <7 days: 0.38 vs 0.30; time to delivery <14 days: 0.58 vs 0.29; gestational age at delivery ≤34 weeks: 0.56 vs 0.29; gestational age at delivery ≤37 weeks: 0.61 vs 0.16). Multivariate logistic regression models fitted with imbalanced data sets outperformed most univariate models (F2-score in time to delivery <7 days: 0.63; time to delivery <14 days: 0.54; gestational age at delivery ≤34 weeks: 0.62; gestational age at delivery ≤37 weeks: 0.73). The performance of prediction of multivariate models was drastically improved when data sets were balanced, and was maximum for time to delivery <7 days (F2-score: 0.88±0.2; positive predictive value: 0.86±0.02; negative predictive value: 0.89±0.03)., Conclusion: A multivariate assessment including interleukin-6 may lead to more targeted treatment, thus reducing unnecessary hospitalization and avoiding unnecessary maternal-fetal treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: CCL2 and CXCL10 are putative biomarkers for the prediction of spontaneous preterm birth. This study evaluates these markers in a cohort of pregnant high-risk women., Material and Methods: In our prospective study, we included 109 women with signs of preterm labor between 20 + 0 and 31 + 6 weeks of gestation. Inclusion criteria were regular (< 3/30 min) or painful contractions, cervical length < 25 mm or a history of previous preterm birth (PTB). Blood samples were obtained upon first admission to our clinic. Biomarker concentrations were measured using pre-coated sandwich immunoassays (ELISA). Primary study outcome was spontaneous preterm birth < 34 weeks, secondary outcome was delivery < 37 weeks or within seven days after study inclusion., Results: Sixteen women (14.7%) delivered < 34 weeks and twenty women between 34 + 0 and 36 + 6 weeks (18.4%). Six patients (5.5%) gave birth within seven days after study admission. CXCL10 showed higher medium serum levels in women with PTB < 34 weeks (115 pg/ml compared to 61 pg/ml ≥ 34 weeks; p < 0.001) and < 37 weeks (103 pg/ml vs. 53 pg/ml; p < 0.001). In contrary, lower CCL2 serum levels were associated with PTB < 34 weeks (46 pg/ml vs. 73 pg/ml; p = 0.032) and birth within 7 days (25 pg/ml vs. 73 pg/ml; p = 0.008). The CXCL10/CCL2-ratio further improved the predictive model with a ROC-AUC of 0.83 (95% CI 0.73-0.93, p < 0.001) for delivery < 34 weeks. These corresponds to a sensitivity, specificity and positive predictive value of 0.67, 0.86 and 0.43 at a cut-off of 2.2., Conclusion: Low maternal serum CCL2 levels are associated with a higher risk of preterm delivery within seven days. High CXCL10 serum levels are more associated with a high risk for preterm birth < 34 weeks. Elevated CXCL10/CCL2-ratio is showing the best predictive performance., Trial Registration Number (drks-Id): DRKS00010763, Registration date: September 02, 2016., (© 2023. The Author(s).)

Background: Preterm birth (PTB) is a complex and significant challenge in obstetrics. Thus, clinicians and researchers have paid a keen interest in the identification of women at a high risk for PTB. This study aimed to develop a PTB risk assessment scale based on the preliminary 32-item Preterm Birth Risk Assessment Scale-Korean version (PBRAS-K)., Methods: We enrolled 298 participants (167 in the exploratory factor analysis group from March 3, 2021 to August 31, 2021 and 131 in the confirmatory factor analysis group from December 3, 2021 to February 14, 2022) who delivered before 37 +0  weeks after experiencing preterm symptoms and were admitted to high-risk pregnancy maternal-fetal intensive care units (MFICUs). After an item-reduction process in the exploratory factor analysis, the psychometric property scales were assessed using SPSS Statistics version 27.0, and the confirmatory factor analysis was conducted using AMOS version 27.0., Results: The Kaiser-Meyer-Olkin (KMO) test and Bartlett's χ 2 test of sphericity confirmed the adequacy of the sample for factor analysis (KMO = .81 (> .80), χ 2  = 1841.38, p < .001). The final version of the PBRAS-K comprised 23 items within seven dimensions. Factor analysis identified items explaining 65.9% of the total variance. The PBRAS-K achieved a mean score of 35.58 (± 10.35) and showed high internal consistency and satisfactory reliability (Cronbach's alpha = .85). Regarding concurrent validity, the PBRAS-K exhibited a low-to-moderate correlation with the PTB risk (r = .45, p < .001). As for criterion validity and convergent validity, the PBRAS-K showed a positive and high correlation with the Somatic Awareness Scale with Spontaneous Preterm Labor (SPL-SAS) (r = .65, p < .001) and pregnancy-related stress (r = .57, p < .001), respectively. Risk scoring for preterm delivery and SPL-SAS were moderately correlated (r = .53, p < .001)., Conclusions: PBRAS-23-K is a valid and reliable instrument for assessing the risk for PTB in pregnant women. Clinical nurses are encouraged to apply and obtain information regarding effective interventions in MFICUs. This scale provides meaningful results and reflects the opinions of women who had experienced PTB. The PBRAS-23-K should be evaluated for standardization and cut-off scores using larger sample sizes in the future., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We employed digital light processing-stereolithography 3D printing to create microfluidic devices with different designs for microchip electrophoresis (µCE). Short or long straight channel, and two- or four-turn serpentine channel microfluidic devices with separation channel lengths of 1.3, 3.1, 3.0, and 4.7 cm, respectively, all with a cross injector design, were fabricated. We measured current as a function of time and voltage to determine a separation time window and conditions for the onset of Joule heating in these designs. Separations in these devices were evaluated by performing µCE and measuring theoretical plate counts for electric field strengths near and above the onset of Joule heating, with fluorescently labeled glycine and phenylalanine as model analytes. We further demonstrated µCE of peptides and proteins related to preterm birth risk, showing increased peak capacity and resolution compared to previous results with 3D printed microdevices. These results mark an important step forward in the use of 3D printed microfluidic devices for rapid bioanalysis by µCE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests GPN and ATW own shares in Acrea3D, a company that is commercializing 3D printers. The other authors have no conflicts to declare, (Copyright © 2023 Elsevier B.V. All rights reserved.)