Development and validation of prediction models for fetal growth restriction and birthweight: an individual participant data meta-analysis.

Background: Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives: To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design: Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants: Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors: Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes: fetal growth restriction defined as birthweight <10th centile adjusted for gestational age and with stillbirth, neonatal death or delivery before 32 weeks' gestation birthweight. Analysis: First, we externally validated existing models using individual participant data meta-analysis. If needed, we developed and validated new International Prediction of Pregnancy Complications models using random-intercept regression models with backward elimination for variable selection and undertook internal-external cross-validation. We estimated the study-specific performance (c-statistic, calibration slope, calibration-in-the-large) for each model and pooled using random-effects meta-analysis. Heterogeneity was quantified using τ2 and 95% prediction intervals. We assessed the clinical utility of the fetal growth restriction model using decision curve analysis, and health economics analysis based on National Institute for Health and Care Excellence 2008 model. Results: Of the 119 published models, one birthweight model (Poon) could be validated. None reported fetal growth restriction using our definition. Across all cohorts, the Poon model had good summary calibration slope of 0.93 (95% confidence interval 0.90 to 0.96) with slight overfitting, and underpredicted birthweight by 90.4 g on average (95% confidence interval 37.9 g to 142.9 g). The newly developed International Prediction of Pregnancy Complications-fetal growth restriction model included maternal age, height, parity, smoking status, ethnicity, and any history of hypertension, pre-eclampsia, previous stillbirth or small for gestational age baby and gestational age at delivery. This allowed predictions conditional on a range of assumed gestational ages at delivery. The pooled apparent c-statistic and calibration were 0.96 (95% confidence interval 0.51 to 1.0), and 0.95 (95% confidence interval 0.67 to 1.23), respectively. The model showed positive net benefit for predicted probability thresholds between 1% and 90%. In addition to the predictors in the International Prediction of Pregnancy Complications-fetal growth restriction model, the International Prediction of Pregnancy Complications-birthweight model included maternal weight, history of diabetes and mode of conception. Average calibration slope across cohorts in the internal-external cross-validation was 1.00 (95% confidence interval 0.78 to 1.23) with no evidence of overfitting. Birthweight was underestimated by 9.7 g on average (95% confidence interval -154.3 g to 173.8 g). Limitations: We could not externally validate most of the published models due to variations in the definitions of outcomes. Internal-external cross-validation of our International Prediction of Pregnancy Complications-fetal growth restriction model was limited by the paucity of events in the included cohorts. The economic evaluation using the published National Institute for Health and Care Excellence 2008 model may not reflect current practice, and full economic evaluation was not possible due to paucity of data. Future work: International Prediction of Pregnancy Complications models' performance needs to be assessed in routine practice, and their impact on decision-making and clinical outcomes needs evaluation. Conclusion: The International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight models accurately predict fetal growth restriction and birthweight for various assumed gestational ages at delivery. These can be used to stratify the risk status at booking, plan monitoring and management. Study registration: This study is registered as PROSPERO CRD42019135045. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/07) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

One in ten babies is born small for their age. A third of such small babies are considered to be 'growth-restricted' as they have complications such as dying in the womb (stillbirth) or after birth (newborn death), cerebral palsy, or needing long stays in hospital. When growth restriction is suspected in fetuses, they are closely monitored and often delivered early to avoid complications. Hence, it is important that we identify growth-restricted babies early to plan care. Our goal was to provide personalised and accurate estimates of the mother's chances of having a growth-restricted baby and predict the baby's weight if delivered at various time points in pregnancy. To do so, first we tested how accurate existing risk calculators ('prediction models') were in predicting growth restriction and birthweight. We then developed new risk-calculators and studied their clinical and economic benefits. We did so by accessing the data from individual pregnant women and their babies in our large database library (International Prediction of Pregnancy Complications). Published risk-calculators had various definitions of growth restriction and none predicted the chances of having a growth-restricted baby using our definition. One predicted baby's birthweight. This risk-calculator performed well, but underpredicted the birthweight by up to 143 g. We developed two new risk-calculators to predict growth-restricted babies (International Prediction of Pregnancy Complications-fetal growth restriction) and birthweight (International Prediction of Pregnancy Complications-birthweight). Both calculators accurately predicted the chances of the baby being born with growth restriction, and its birthweight. The birthweight was underpredicted by <9.7 g. The calculators performed well in both mothers predicted to be low and high risk. Further research is needed to determine the impact of using these calculators in practice, and challenges to implementing them in practice. Both International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight risk calculators will inform healthcare professionals and empower parents make informed decisions on monitoring and timing of delivery.

Individualized MRI-based stroke PRediction scOre using plaque Vulnerability for symptomatic carotid artEry disease patients (IMPROVE).

Objective: In TIA and stroke patients with carotid stenosis, estimations of future ipsilateral ischemic stroke risk and treatment decisions are currently primarily based on the degree of stenosis. Intraplaque hemorrhage (IPH), which can be readily visualized on carotid MRI, is increasingly established as an easy to assess and a very strong and independent predictor for ipsilateral stroke risk, stronger than any clinical risk factor. We developed a clinical prediction model (IMPROVE) incorporating IPH, degree of stenosis, and clinical risk factors to select patients with symptomatic carotid stenosis at high risk for stroke. Methods: IMPROVE was developed on pooled clinical and MRI data from five cohort studies of 760 recent TIA or minor stroke patients with carotid plaque who received optimal medical treatment. We used Cox proportional hazards models to determine the coefficients of IMPROVE. IMPROVE was internally validated using bootstrapping and converted to one- and three-year ipsilateral ischemic stroke risk. Results: The development dataset contained 65 ipsilateral incident ischemic strokes that occurred during a median follow-up of 1.2 years (IQR: 0.5-4.1). The IMPROVE model includes five predictors, which are in order of importance: degree of stenosis, presence of IPH on MRI, classification of last event (cerebral vs ocular), sex, and age. Internal validation revealed a good accuracy (C-statistic: 0.82; 95% CI: 0.77-0.87) and no evidence for miscalibration (calibration slope: 0.93). Interpretation: Using presence of IPH on MRI and only four conventional parameters, the IMPROVE model provides accurate individual stroke risk estimates, which may facilitate stratification for revascularization.

Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis.

Objective: To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit. Design: Individual participant data meta-analysis. Data sources: Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset. Eligibility criteria for selecting studies: Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model. Results: The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, -18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of -22.3 g (Allen cohort), -33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (-154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making. Conclusions: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required. Trial registration: PROSPERO CRD42019135045.

Exposure to second-hand smoke and breast cancer risk in non-smoking women: a comprehensive systematic review and meta-analysis.

Through the use of an innovative method to identify original publications, we conducted a meta-analysis of all epidemiological studies evaluating the association between second-hand smoke (SHS) exposure and breast cancer risk among female non-smokers published in English up to October 2022. Pooled relative risks (RR) were obtained through the use of random-effects models. Dose-response relationships were derived using log-linear functions. Out of 73 identified eligible studies, 63 original articles were included in the meta-analysis. The pooled RR for breast cancer for overall exposure to SHS was 1.24 (95% confidence interval, CI, 1.15-1.34, number of articles, n = 52). Regarding the setting of exposure, RRs were 1.17 (95% CI 1.08-1.27, n = 37) for SHS exposure at home, 1.03 (95% CI 0.98-1.08, n = 15) at the workplace, 1.24 (95% CI 1.11-1.37, n = 16) at home or workplace, and 1.45 (95% CI 1.16-1.80, n = 13) for non-specified settings. The risk of breast cancer increased linearly with higher duration (RR 1.29; 95% CI 1.04-1.59 for 40 years of SHS exposure, n = 12), intensity (RR 1.38; 95% CI 1.14-1.67 for 20 cigarettes of SHS exposure per day, n = 6), and pack-years (RR 1.50; 95% CI 0.92-2.45 for 40 SHS pack-years, n = 6) of SHS exposure. This meta-analysis shows a statistically significant excess risk of breast cancer in women exposed to SHS.

Analysis of the direct economic impact of smoking-related hospitalizations in Italy.

INTRODUCTION: Tobacco-related diseases have a substantial economic impact in terms of medical expenses, loss of productivity, and premature death. Tobacco use is estimated to be responsible for more than 90000 deaths each year in Italy. We aimed to evaluate the annual direct economic impact on the National Health System of hospitalizations attributable to tobacco smoking in Italy. METHODS: We analyzed data from all the hospitalizations of patients aged ≥30 years that occurred in Italy for 12 selected tobacco-related diseases, during 2018. These diseases included oropharyngeal cancer, esophageal cancer, gastric cancer, lung cancer, pancreatic cancer, bladder cancer, laryngeal cancer, ischemic heart disease, stroke, diseases of arteries, arterioles, and capillaries, pneumonia and influenza, and chronic obstructive pulmonary disease. We obtained information on 984322 hospital discharge records, including each hospitalization's direct costs. Using relative risk estimates from the scientific literature, we computed the population attributable fraction for various tobacco-related diseases to estimate the economic impact attributable to tobacco smoking. RESULTS: One-third of all hospitalizations occurred in 2018 in Italy among people aged ≥30 years for 12 tobacco-related diseases were found to be attributable to smoking, accounting for a total cost of €1.64 billion. Among the diseases considered, those with the highest expenditures attributable to tobacco smoking were ischemic heart disease, cerebrovascular disease, and lung cancer, accounting for €556 million, €290 million, and €229 million, respectively. CONCLUSIONS: Tobacco has a substantial economic impact in Italy, accounting for around 6% of the total cost of hospitalizations in 2018. This figure is expected to be largely underestimated due to several conservative assumptions adopted in the statistical analyses. It is imperative to prioritize comprehensive tobacco control measures to counteract the huge healthcare costs due to tobacco smoking.

Factors affecting the implementation of calcium supplementation strategies during pregnancy to prevent pre-eclampsia: a mixed-methods systematic review.

OBJECTIVES: Daily calcium supplements are recommended for pregnant women from 20 weeks' gestation to prevent pre-eclampsia in populations with low dietary calcium intake. We aimed to improve understanding of barriers and facilitators for calcium supplement intake during pregnancy to prevent pre-eclampsia. DESIGN: Mixed-method systematic review, with confidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations-Confidence in the Evidence from Reviews of Qualitative research approach. DATA SOURCES: MEDLINE and EMBASE (via Ovid), CINAHL and Global Health (via EBSCO) and grey literature databases were searched up to 17 September 2022. ELIGIBILITY CRITERIA: We included primary qualitative, quantitative and mixed-methods studies reporting implementation or use of calcium supplements during pregnancy, excluding calcium fortification and non-primary studies. No restrictions were imposed on settings, language or publication date. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. We analysed the qualitative data using thematic synthesis, and quantitative findings were thematically mapped to qualitative findings. We then mapped the results to behavioural change frameworks to identify barriers and facilitators. RESULTS: Eighteen reports from nine studies were included in this review. Women reported barriers to consuming calcium supplements included limited knowledge about calcium supplements and pre-eclampsia, fears and experiences of side effects, varying preferences for tablets, dosing, working schedules, being away from home and taking other supplements. Receiving information regarding pre-eclampsia and safety of calcium supplement use from reliable sources, alternative dosing options, supplement reminders, early antenatal care, free supplements and support from families and communities were reported as facilitators. Healthcare providers felt that consistent messaging about benefits and risks of calcium, training, and ensuring adequate staffing and calcium supply is available would be able to help them in promoting calcium. CONCLUSION: Relevant stakeholders should consider the identified barriers and facilitators when formulating interventions and policies on calcium supplement use. These review findings can inform implementation to ensure effective and equitable provision and scale-up of calcium interventions. PROSPERO REGISTRATION NUMBER: CRD42021239143.

Continuous care during labor by maternity care assistants in the Netherlands vs care-as-usual: a randomized controlled trial.

BACKGROUND: Continuous support during labor has many benefits including lower use of obstetrical interventions. However, implementation remains limited. Insights into birth outcomes and peripartum costs are essential to assess whether continuous care by a maternity care assistant is a potentially (cost) effective program to provide for all women. OBJECTIVE: Continuous care during labor, provided by maternity care assistants, will reduce the use of epidural analgesia and peripartum costs owing to a reduction in interventions. STUDY DESIGN: This was a randomized controlled trial comparing continuous support during labor (intervention group) with care-as-usual (control group) with prespecified intention-to-treat and per-protocol analyses. The primary outcome was epidural analgesia use. The secondary outcomes were use of other analgesia, referrals from midwife- to obstetrician-led care, modes of birth, hospital stay, sense of control (evaluated with the Labor Agentry Scale), maternal and neonatal adverse outcomes and peripartum costs. Data were collected using questionnaires. Anticipating incomplete adherence to providing continuous care, both intention-to-treat and per-protocol analyses were planned. Peripartum costs were estimated using a healthcare perspective. Mean costs per woman and cost differences between the intervention and control group were calculated. RESULTS: The population consisted of 1076 women with 54 exclusions and 30 discontinuations, leaving 992 women to be analyzed (515 continuous care and 477 care-as-usual). Intention-to-treat analyses showed statistically nonsignificant differences between the intervention and control group for epidural use (relative risk, 0.88; 95% confidence interval, 0.74-1.04; P=.14) and peripartum costs (mean difference, € 185.83; 95% confidence interval, -€ 204.22 to € 624.54). Per-protocol analyses showed statistically significant decreases in epidural analgesia (relative risk, 0.64; 95% confidence interval, 0.48-0.84; P=.001), other analgesia (relative risk, 0.59; 95% confidence interval, 0.37-0.94; P=.02), cesarean deliveries (relative risk, 0.53; 95% confidence interval, 0.29-0.95; P=.03) and increase in spontaneous vaginal births (relative risk, 1.09; 95% confidence interval, 1.01-1.18; P=.001) in the intervention group, but difference in total peripartum costs remained statistically nonsignificant (mean difference, € 246.55; 95% confidence interval, -€ 539.14 to € 13.50). CONCLUSION: If the provision of continuous care given by maternity care assistants during labor can be secured, continuous care leads to more vaginal births and less epidural use, pain medication, and cesarean deliveries while not leading to a difference in peripartum costs compared with care-as-usual.

Restrictive versus liberal fluid administration strategy (REFILL study) in postpartum hemorrhage and its effects on thromboelastometry (ROTEM®) values: a randomized, controlled trial.

OBJECTIVE: Current obstetric guidelines for postpartum hemorrhage (PPH) vary in fluid resuscitation management. This study aimed to evaluate the effect of fluid management on coagulation parameters in early PPH. METHODS: We performed a multicenter, randomized trial. Women who had 500 mL of blood loss in the third stage of labor were randomized to receive a restrictive fluid administration strategy or a liberal fluid administration strategy. A rotational thromboelastometry panel was performed in 72 patients. We evaluated within-group and between-group differences in the EXTEM clotting time (CT), EXTEM amplitude at 10 minutes (A10), INTEM CT, and FIBTEM A10. We also evaluated the mean fibrinogen concentration, activated partial thromboplastin time, and partial thromboplastin time in the total study population (n = 249). RESULTS: There were no significant differences in hemostatic parameters between the groups after correction for baseline values. CONCLUSIONS: In women with PPH <1500 mL, there is no clinically relevant effect of a restrictive or liberal fluid administration strategy on thromboelastometric hemostatic and regular coagulation parameters.

Calcium supplementation to prevent pre-eclampsia: protocol for an individual participant data meta-analysis, network meta-analysis and health economic evaluation.

INTRODUCTION: Low dietary calcium intake is a risk factor for pre-eclampsia, a major contributor to maternal and perinatal mortality and morbidity worldwide. Calcium supplementation can prevent pre-eclampsia in women with low dietary calcium. However, the optimal dose and timing of calcium supplementation are not known. We plan to undertake an individual participant data (IPD) meta-analysis of randomised trials to determine the effects of various calcium supplementation regimens in preventing pre-eclampsia and its complications and rank these by effectiveness. We also aim to evaluate the cost-effectiveness of calcium supplementation to prevent pre-eclampsia. METHODS AND ANALYSIS: We will identify randomised trials on calcium supplementation before and during pregnancy by searching major electronic databases including Embase, CINAHL, MEDLINE, CENTRAL, PubMed, Scopus, AMED, LILACS, POPLINE, AIM, IMSEAR, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, without language restrictions, from inception to February 2022. Primary researchers of the identified trials will be invited to join the International Calcium in Pregnancy Collaborative Network and share their IPD. We will check each study's IPD for consistency with the original authors before standardising and harmonising the data. We will perform a series of one-stage and two-stage IPD random-effect meta-analyses to obtain the summary intervention effects on pre-eclampsia with 95% CIs and summary treatment-covariate interactions (maternal risk status, dietary intake, timing of intervention, daily dose of calcium prescribed and total intake of calcium). Heterogeneity will be summarised using tau2, I2 and 95% prediction intervals for effect in a new study. Sensitivity analysis to explore robustness of statistical and clinical assumptions will be carried out. Minor study effects (potential publication bias) will be investigated using funnel plots. A decision analytical model for use in low-income and middle-income countries will assess the cost-effectiveness of calcium supplementation to prevent pre-eclampsia. ETHICS AND DISSEMINATION: No ethical approvals are required. We will store the data in a secure repository in an anonymised format. The results will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021231276.

What proportion of clinical prediction models make it to clinical practice? Protocol for a two-track follow-up study of prediction model development publications.

INTRODUCTION: It is known that only a limited proportion of developed clinical prediction models (CPMs) are implemented and/or used in clinical practice. This may result in a large amount of research waste, even when considering that some CPMs may demonstrate poor performance. Cross-sectional estimates of the numbers of CPMs that have been developed, validated, evaluated for impact or utilized in practice, have been made in specific medical fields, but studies across multiple fields and studies following up the fate of CPMs are lacking. METHODS AND ANALYSIS: We have conducted a systematic search for prediction model studies published between January 1995 and December 2020 using the Pubmed and Embase databases, applying a validated search strategy. Taking random samples for every calendar year, abstracts and articles were screened until a target of 100 CPM development studies were identified. Next, we will perform a forward citation search of the resulting CPM development article cohort to identify articles on external validation, impact assessment or implementation of those CPMs. We will also invite the authors of the development studies to complete an online survey to track implementation and clinical utilization of the CPMs.We will conduct a descriptive synthesis of the included studies, using data from the forward citation search and online survey to quantify the proportion of developed models that are validated, assessed for their impact, implemented and/or used in patient care. We will conduct time-to-event analysis using Kaplan-Meier plots. ETHICS AND DISSEMINATION: No patient data are involved in the research. Most information will be extracted from published articles. We request written informed consent from the survey respondents. Results will be disseminated through publication in a peer-reviewed journal and presented at international conferences. OSF REGISTRATION: (https://osf.io/nj8s9).

Which first-trimester risk assessment method for preeclampsia is most suitable? A model-based impact study.

BACKGROUND: Low-dose aspirin treatment reduces the risk of preeclampsia among high-risk pregnant women. Internationally, several first-trimester risk-calculation methods are applied. OBJECTIVE: This study aimed to assess the costs and benefits of different first-trimester preeclampsia risk estimation algorithms: EXPECT (an algorithmic prediction model based on maternal characteristics), National Institute for Health and Care Excellence (a checklist of risk factors), and the Fetal Medicine Foundation (a prediction model using additional uterine artery Doppler measurement and laboratory testing) models, coupled with low-dose aspirin treatment, in comparison with no risk assessment. STUDY DESIGN: We constructed a decision analytical model estimating the number of cases of preeclampsia with each strategy and the costs of risk assessment for preeclampsia and early aspirin treatment, expressed in euros (€) in a hypothetical population of 100,000 women. We performed 1-way sensitivity analyses to assess the impact of adherence rates on model outcomes. RESULTS: Application of the EXPECT, National Institute for Health and Care Excellence, and Fetal Medicine Foundation models results in respectively 1.98%, 2.55%, and 1.90% of the women developing preeclampsia, as opposed to 3.00% of women in the case of no risk assessment. Overall, the net financial benefits of the EXPECT, National Institute for Health and Care Excellence, and Fetal Medicine Foundation models relative to no risk assessment are €144, €43, and €38 per patient, respectively. The respective percentages of women receiving aspirin treatment are 18.6%, 10.2%, and 6.0% for the 3 risk assessment methods. CONCLUSION: The EXPECT and Fetal Medicine Foundation model are comparable with regard to numbers of prevented preeclampsia cases, and both are superior to the National Institute for Health and Care Excellence model and to no risk assessment. EXPECT is less resource-demanding and results in the highest cost savings, but also requires the highest number of women to be treated with aspirin. When deciding which strategy is preferable, cost savings and easier use have to be weighed against the degree of overtreatment, although low-dose aspirin has no clear disadvantages during pregnancy.

Counseling pregnant women on calcium: effects on calcium intake.

OBJECTIVES: To evaluate the effect of incorporating calcium advice into early pregnancy counseling on calcium intake during pregnancy in the Netherlands. METHODS: A multicenter prospective before-after cohort study was conducted introducing risk-based care including calculating individual pre-eclampsia risk. Part of the intervention was to incorporate calcium advice into routine counseling. We calculated individual daily calcium intake and adequacy of calcium intake (≥1,000 mg/day) at 16, 24 and 34 weeks of pregnancy. We performed a multiple logistic regression adjusting for covariates to identify any differences in the risk of inadequate calcium intake between RC and CAC. RESULTS: In regular care (RC, 2013-2015, n=2,477) 60% had inadequate calcium intake, compared to 49% during calcium advice care (CAC, 2017-2018, n=774) (aOR 0.75, 95% CI 0.64-0.88). Specific calcium supplements were used by 2% and 29% in RC and CAC, respectively (OR 25.1, 95% CI 17.8-36.0). Determinants of an inadequate calcium intake were lower age (aOR per additional year 0.96, 95% CI: 0.94-0.98), nulliparity (aOR 1.22, 95% CI: 1.03-1.45) and non-Caucasian origin (aOR 1.83, 95% CI 1.09-3.09). In CAC, risk of inadequate intake decreased with increasing predicted pre-eclampsia risk, which was a trend reversal compared to RC. CONCLUSIONS: Incorporating calcium advice into early pregnancy counseling was shown to lead to a decrease in the risk of inadequate calcium intake during pregnancy, but still inadequate intake in half of the women suggesting the need for further study on improving implementation. Awareness of individual increased PE risk had positive effect on calcium intake.

Associations Between Late-Onset Preeclampsia and the Use of Calcium-Based Antacids and Proton Pump Inhibitors During Pregnancy: A Prospective Cohort Study.

Purpose: Preeclampsia is a leading cause of maternal morbidity and mortality. Calcium-based antacids and proton pump inhibitors (PPIs) are commonly used during pregnancy to treat symptoms of gastroesophageal reflux disease. Both have been hypothesized to reduce the risk of preeclampsia. We determined associations of calcium-based antacid and PPI use during pregnancy with late-onset preeclampsia (≥34 weeks of gestation), taking into account dosage and timing of use. Patients and Methods: We included 9058 pregnant women participating in the PRIDE Study (2012-2019) or The Dutch Pregnancy Drug Register (2014-2019), two prospective cohorts in The Netherlands. Data were collected through web-based questionnaires and obstetric records. We estimated risk ratios (RRs) for late-onset preeclampsia for any use and trajectories of calcium-based antacid and PPI use before gestational day 238, and hazard ratios (HRs) for time-varying exposures after gestational day 237. Results: Late-onset preeclampsia was diagnosed in 2.6% of pregnancies. Any use of calcium-based antacids (RR 1.2 [95% CI 0.9-1.6]) or PPIs (RR 1.4 [95% CI 0.8-2.4]) before gestational day 238 was not associated with late-onset preeclampsia. Use of low-dose calcium-based antacids in gestational weeks 0-16 (<1 g/day; RR 1.8 [95% CI 1.1-2.9]) and any use of PPIs in gestational weeks 17-33 (RR 1.6 [95% CI 1.0-2.8]) seemed to increase risks of late-onset preeclampsia. We did not observe associations between late-onset preeclampsia and use of calcium-based antacids (HR 1.0 [95% CI 0.6-1.5]) and PPIs (HR 1.4 [95% CI 0.7-2.9]) after gestational day 237. Conclusion: In this prospective cohort study, use of calcium-based antacids and PPIs during pregnancy was not found to reduce the risk of late-onset preeclampsia.

Predicting COVID-19 prognosis in the ICU remained challenging: external validation in a multinational regional cohort.

OBJECTIVES: Many prediction models for coronavirus disease 2019 (COVID-19) have been developed. External validation is mandatory before implementation in the intensive care unit (ICU). We selected and validated prognostic models in the Euregio Intensive Care COVID (EICC) cohort. STUDY DESIGN AND SETTING: In this multinational cohort study, routine data from COVID-19 patients admitted to ICUs within the Euregio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, outcomes, and reporting. Furthermore, general ICU scores were assessed. Discrimination was assessed by area under the receiver operating characteristic curves (AUCs) and calibration by calibration-in-the-large and calibration plots. A random-effects meta-analysis was used to pool results. RESULTS: 551 patients were admitted. Mean age was 65.4 ± 11.2 years, 29% were female, and ICU mortality was 36%. Nine out of 238 published models were externally validated. Pooled AUCs were between 0.53 and 0.70 and calibration-in-the-large between -9% and 6%. Calibration plots showed generally poor but, for the 4C Mortality score and Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) score, moderate calibration. CONCLUSION: Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimination and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision-making.

External validation and updating of prediction models for estimating the 1-year risk of low health-related quality of life in colorectal cancer survivors.

OBJECTIVES: Timely identification of colorectal cancer (CRC) survivors at risk of experiencing low health-related quality of life (HRQoL) in the near future is important for enabling appropriately tailored preventive actions. We previously developed and internally validated risk prediction models to estimate the 1-year risk of low HRQoL in long-term CRC survivors. In this article, we aim to externally validate and update these models in a population of short-term CRC survivors. STUDY DESIGN AND SETTING: In a pooled cohort of 1,596 CRC survivors, seven HRQoL domains (global QoL, cognitive/emotional/physical/role/social functioning, and fatigue) were measured prospectively at approximately 5 months postdiagnosis (baseline for prediction) and approximately 1 year later by a validated patient-reported outcome measure (European Organization for Research and Treatment of Cancer Quality of life Questionnaire-Core 30). For each HRQoL domain, 1-year scores were dichotomized into low vs. normal/high HRQoL. Performance of the previously developed multivariable logistic prediction models was evaluated (calibration and discrimination). Models were updated to create a more parsimonious predictor set for all HRQoL domains. RESULTS: Updated models showed good calibration and discrimination (AUC ≥0.75), containing a single set of 15 predictors, including nonmodifiable (age, sex, education, time since diagnosis, chemotherapy, radiotherapy, stoma, and comorbidities) and modifiable predictors (body mass index, physical activity, smoking, anxiety/depression, and baseline fatigue and HRQoL domain scores). CONCLUSION: Externally validated and updated prediction models performed well for estimating the 1-year risk of low HRQoL in CRC survivors within 6 months postdiagnosis. The impact of implementing the models in oncology practice to improve HRQoL outcomes in CRC survivors needs to be evaluated.

Spatial variation in tobacco smoking among pregnant women in South Limburg, the Netherlands, 2016-2018: Small area estimations using a Bayesian approach.

The aim of this study was to provide small area estimations (SAE) of smoking prevalence during pregnancy in South Limburg, the Netherlands. To illustrate improvements in accuracy and precision of estimates compared to traditional frequentist analyses, we used Bayesian inference with the Integrated nested Laplace approximation to account for spatial structures and area-level proxies. Results revealed a heterogenous prevalence of smoking with a range between 6.7% (95% credible interval 4.7,8.7) and 16.7% (14.3,19.2) among municipalities; and an even more heterogenous prevalence among neighbourhoods a range from 0 (-14.9,6.5) to 32.1 (20.3,46.8). Clusters with significant lower- and higher-than-average risk were identified (RR between 0.6-1.4 and 0.0-2.4 for municipality- and neighbourhood-level, respectively). Higher proportion of non-western migrants and lower average income were associated with higher prevalence of tobacco smoking. The obtained estimates should inform local prevention policies, as well as provide methodological example for public health researchers on application of Bayesian methods for SAE.

The effects of COVID-19 restrictions and other perinatal factors on women's sense of control during childbirth: a prospective cohort study.

BACKGROUND: Restrictions around childbirth, introduced during the COVID-19 pandemic in 2020, could decrease maternal feelings of control during birth. The aim of this study was to compare the sense of control of women who gave birth during the COVID-19 pandemic with women who gave birth before COVID-19. The secondary objective was to identify other factors independently associated with women's sense of control during birth. METHODS: A prospective cohort study, in a sub-cohort of 504 women from a larger cohort (Continuous Care Trial (CCT), n = 992), was conducted. Sense of control was measured by the Labor Agentry Scale (LAS). Perinatal factors independently associated with women's sense of control during birth were identified using multiple linear regression. RESULTS: Giving birth during the COVID-19 pandemic did not influence women's sense of control during birth. Factors statistically significantly related to women's sense of control were Dutch ethnic background (ß 4.787, 95%-CI 1.319 to 8.254), antenatal worry (ß - 4.049, 95%-CI -7.516 to -.581), antenatal anxiety (ß - 4.677, 95%-CI -7.751 to 1.603) and analgesics during birth (ß - 3.672, 95%-CI -6.269 to -1.075). CONCLUSIONS: Despite the introduction of restrictions, birth during the COVID-19 pandemic was not associated with a decrease of women's sense of control.

Imbalanced Folate and Vitamin B12 in the Third Trimester of Pregnancy and its Association with Birthweight and Child Growth up to 2 Years.

SCOPE: Folic acid supplementation during pregnancy may lead to an imbalance when vitamin B12 intake is low (folate trap) and may affect child's growth. METHODS: The authors study the association between third trimester maternal intakes of folate and B12 and birthweight and postnatal growth of 2632 infants from the KOALA Birth Cohort Study. Plasma vitamin biomarkers are measured in 1219 women. RESULTS: Imbalanced total intakes (folate > 430 µg day-1 combined with B12 < 5.5 µg day-1 ) are not associated with birthweight [ß adj (95% CI) = -14.87 (-68.87, 39.13)] compared with high intakes of both. Imbalanced intake is associated with a lower z score of weight at 1-2 years [ß adj = -0.14 (-0.25, -0.03)]. Having red blood cell folate > 745 nmol L-1 and plasma B12 < 172 pmol L-1 is not associated with birthweight [ß adj = -7.10 (-97.90, 83.71) g]. Maternal dietary B12 intake [ß adj = -9.5 (-15.6, -3.3)] and plasma methylmalonic acid [ß adj = 234 (43, 426)] are associated with birthweight. CONCLUSION: Low maternal dietary B12 intake and elevated methylmalonic acid rather than imbalanced vitamins are associated with higher birthweight, suggesting that low maternal B12 can predispose the infants for later obesity.