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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.)

Background: Worldwide, hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR) and preterm birth remain the leading causes of maternal and fetal pregnancy-related mortality and (long-term) morbidity. Fetal cardiac deformation changes can be the first sign of placental dysfunction, which is associated with HDP, FGR and preterm birth. In addition, preterm birth is likely associated with changes in electrical activity across the uterine muscle. Therefore, fetal cardiac function and uterine activity can be used for the early detection of these complications in pregnancy. Fetal cardiac function and uterine activity can be assessed by two-dimensional speckle-tracking echocardiography (2D-STE), non-invasive fetal electrocardiography (NI-fECG), and electrohysterography (EHG). This study aims to generate reference values for 2D-STE, NI-fECG and EHG parameters during the second trimester of pregnancy and to investigate the diagnostic potential of these parameters in the early detection of HDP, FGR and preterm birth., Methods: In this longitudinal prospective cohort study, eligible women will be recruited from a tertiary care hospital and a primary midwifery practice. In total, 594 initially healthy pregnant women with an uncomplicated singleton pregnancy will be included. Recordings of NI-fECG and EHG will be made weekly from 22 until 28 weeks of gestation and 2D-STE measurements will be performed 4-weekly at 16, 20, 24 and 28 weeks gestational age. Retrospectively, pregnancies complicated with pregnancy-related diseases will be excluded from the cohort. Reference values for 2D-STE, NI-fECG and EHG parameters will be assessed in uncomplicated pregnancies. After, 2D-STE, NI-fCG and EHG parameters measured during gestation in complicated pregnancies will be compared with these reference values., Discussion: This will be the a large prospective study investigating new technologies that could potentially have a high impact on antepartum fetal monitoring., Trial Registration: Registered on 26 March 2020 in the Dutch Trial Register (NL8769) via https://www.trialregister.nl/trials and registered on 21 October 2020 to the Central Committee on Research Involving Human Subjects (NL73607.015.20) via https://www.toetsingonline.nl/to/ccmo&#95;search.nsf/Searchform?OpenForm ., (© 2021. The Author(s).)

Background: Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease., Methods and Findings: This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60; P < 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33; P < 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76; P < 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20; P < 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01; P < 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13; P < 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women., Conclusions: In this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy., Competing Interests: All authors have completed the ICMJE uniform disclosure form and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Context: Women with polycystic ovary syndrome (PCOS) are at increased risk for obstetric and perinatal complications. At present, it is unknown how characteristics of PCOS relate to the likelihood of these complications., Objective: To evaluate which preconception features are associated with obstetric and perinatal disease among infertile women with PCOS., Design: Data from two prospective cohort studies completed from January 2004 until January 2014 were linked to Dutch Perinatal national registry outcomes., Setting: Two Dutch university medical centers., Participants: 2768 women diagnosed with PCOS were included. Participants underwent an extensive standardized preconception screening. Exclusion criteria included: age <18 years or >45 years, language barrier, or failure to meet PCOS criteria., Interventions: None., Main Outcome Measures: Outcome measures were obtained from the Dutch Perinatal national registry and included: preeclampsia, preterm delivery, small for gestational age (SGA), low Apgar score, and any adverse outcome., Results: 1715 (62% of participants) women with PCOS were identified as undergoing a pregnancy with live birth after screening. In fully adjusted models, prepregnancy free androgen index was associated with subsequent preeclampsia [OR (95% CI), 1.1 (1.0 to 1.1)]. Fasting glucose [1.4 (1.2 to 1.7)] and testosterone [1.5 (1.2 to 1.7)] predicted preterm delivery. Fasting insulin [1.003 (1.001 to 1.005)], and testosterone [1.2 (1.1 to 1.4)] predicted any adverse outcome. SGA was only predicted by features nonspecific to PCOS., Conclusions: Primary disease characteristics of PCOS, chiefly hyperandrogenism and impaired glucose tolerance, predict suboptimal obstetric and neonatal outcomes. Increased surveillance during pregnancy should focus on women with PCOS and these features to help mitigate disease risk.

Background: Promotion of healthy pregnancies has gained high priority in the Netherlands because of relatively unfavorable perinatal outcomes. In response, a nationwide study, 'Healthy Pregnancy 4 All' (HP4ALL), has been initiated. Part of this study involves systematic and broadened antenatal risk assessment (the Risk Assessment substudy). Risk selection in current clinical practice is mainly based on medical risk factors. Despite the increasing evidence for the influence of nonmedical risk factors (social status, lifestyle or ethnicity) on perinatal outcomes, these risk factors remain highly unexposed. Systematic risk selection, combined with customized care pathways to reduce or treat detected risks, and regular and structured consultation between community midwives, gynecologists and other care providers such as social workers, is part of this study., Methods/design: Neighborhoods in 14 municipalities with adverse perinatal outcomes above national and municipal averages are selected for participation. The study concerns a cluster randomized controlled trial. Municipalities are randomly allocated to intervention (n = 3,500 pregnant women) and control groups (n = 3,500 pregnant women). The intervention consists of systematic risk selection with the Rotterdam Reproductive Risk Reduction (R4U) score card in pregnant women at the booking visit, and referral to corresponding care pathways. A risk score, based on weighed risk factors derived from the R4U, above a predefined threshold determines structured multidisciplinary consultation. Primary outcomes of this trial are dysmaturity (birth weight < p10), prematurity (birth <37 weeks), and efficacy of implementation., Discussion: The 'HP4ALL' study introduces a systematic approach in antenatal health care that may improve perinatal outcomes and, thereby, affect future health status of a new generation in the Netherlands., Trial Registration: Dutch Trial Registry ( NTR-3367) on 20 March 2012.

Objectives: To determine if fetal volume (FV) measurements with three-dimensional ultrasound in the first trimester of pregnancy can detect the fetus at risk for preterm birth and/or low birth weight., Methods: In this prospective cohort study, 538 participants were included during the routine first trimester ultrasound examination. Volume measurements were performed with VOCAL (9°). Firstly, the relation between FV and gestational age for a set of participants with normal pregnancies (training set), was assessed using multiple linear regression analysis, which was then used to determine the expected normal values. Secondly, for a new set of participants with normal pregnancies and a set of participants with complicated pregnancies (preterm birth and/or low birth weight), i.e. the validation set, the observed fetal volumes (FVobserved) were compared with their expected normal values (FVexpected) and expressed as a percentage of the expected normal value. The difference in mean percentage was then assessed with independent-samples t-test. Finally, logistic regression analysis was applied to the validation set to analyze the ability to predict the pregnancy outcome with FV calculation., Results: Linear regression analysis of FV as a predictor of preterm birth and/or low birth weight did not result in significant (p=0.630 and 0.290, respectively) or clinical relevant results (standardized effect sizes of 0.061 and 0.179, respectively). The predicting quality was also very low (AUC=0.508 and 0.545 respectively)., Conclusions: Fetal volume measurements in the first trimester of pregnancy are not useful as a prognostic tool for predicting pregnancies of high risk for preterm birth or a low birth weight., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To develop and validate a prognostic model for prediction of spontaneous preterm birth., Study Design: Prospective cohort study using data of the nationwide perinatal registry in The Netherlands. We studied 1,524,058 singleton pregnancies between 1999 and 2007. We developed a multiple logistic regression model to estimate the risk of spontaneous preterm birth based on maternal and pregnancy characteristics. We used bootstrapping techniques to internally validate our model. Discrimination (AUC), accuracy (Brier score) and calibration (calibration graphs and Hosmer-Lemeshow C-statistic) were used to assess the model's predictive performance. Our primary outcome measure was spontaneous preterm birth at <37 completed weeks., Results: Spontaneous preterm birth occurred in 57,796 (3.8%) pregnancies. The final model included 13 variables for predicting preterm birth. The predicted probabilities ranged from 0.01 to 0.71 (IQR 0.02-0.04). The model had an area under the receiver operator characteristic curve (AUC) of 0.63 (95% CI 0.63-0.63), the Brier score was 0.04 (95% CI 0.04-0.04) and the Hosmer Lemeshow C-statistic was significant (p<0.0001). The calibration graph showed overprediction at higher values of predicted probability. The positive predictive value was 26% (95% CI 20-33%) for the 0.4 probability cut-off point., Conclusions: The model's discrimination was fair and it had modest calibration. Previous preterm birth, drug abuse and vaginal bleeding in the first half of pregnancy were the most important predictors for spontaneous preterm birth. Although not applicable in clinical practice yet, this model is a next step towards early prediction of spontaneous preterm birth that enables caregivers to start preventive therapy in women at higher risk., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)