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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 Eur-egio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, out-comes, 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 6 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 Microbi-ology (SEIMC) score, moderate calibration.Conclusion: Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimi-nation and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision -mak-ing.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/). Covid Data Platform (CoDaP); [Interreg-EMR 187]

Preeclampsia is often preceded by abnormal hemodynamic changes with heterogeneous patterns in the first half of pregnancy. We assessed the effect of timely tailored correction of nonphysiological hemodynamic changes on preventing preeclampsia in a high-risk population. Primiparous women with a history of preeclampsia were invited to participate in a longitudinal program in their next pregnancy, including repeated hemodynamic assessments at 12-, 16-, 20- and 30-week gestation additional to regular pregnancy checkups. When at least 2 of the hemodynamic variables were not within physiological reference values, the hemodynamic imbalance between cardiac output and peripheral vascular resistance was counteracted with either labetalol, methyldopa, or nifedipine using a simple treatment algorithm. Normogram-guided women (n=157) were matched to 157 women receiving care as usual (power, 80%; α=0.05). Risk of recurrent preeclampsia was analyzed with logistic regression adjusted for daily low-dose aspirin or calcium supplementation. Hemodynamic changes were considered nonphysiological in 90% of women in the normogram-guided group. Twelve percent of these women developed recurrent preeclampsia compared with 22% in the care-as-usual group (adjusted odds ratio, 0.47 [95% CI, 0.25–0.88]). There were no differences between groups in gestational age at delivery (38 1 and 38 2 weeks in the normogram-guided and care-as-usual groups, respectively) and neonatal birth weight (3148 and 3180 g in the normogram-guided and care-as-usual groups, respectively). Tailored circulatory normalization of nonphysiological hemodynamic changes during pregnancy halves the risk of recurrent preeclampsia, without disadvantageous effects on offspring outcome. This simple and innovative treatment strategy may also be beneficial to other women at increased risk for preeclampsia in pregnancy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04216706.

Objectives Discussing the individual probability of a successful vaginal birth after caesarean (VBAC) can support decision making. The aim of this study is to externally validate a prediction model for the probability of a VBAC in a Dutch population. Methods In this prospective cohort study in 12 Dutch hospitals, 586 women intending VBAC were included. Inclusion criteria were singleton pregnancies with a cephalic foetal presentation, delivery after 37 weeks and one previous caesarean section (CS) and preference for intending VBAC. The studied prediction model included six predictors: pre-pregnancy body mass index, previous vaginal delivery, previous CS because of non-progressive labour, Caucasian ethnicity, induction of current labour, and estimated foetal weight ≥90th percentile. The discriminative and predictive performance of the model was assessed using receiver operating characteristic curve analysis and calibration plots. Results The area under the curve was 0.73 (CI 0.69–0.78). The average predicted probability of a VBAC according to the prediction model was 70.3% (range 33–92%). The actual VBAC rate was 71.7%. The calibration plot shows some overestimation for low probabilities of VBAC and an underestimation of high probabilities. Conclusions The prediction model showed good performance and was externally validated in a Dutch population. Hence it can be implemented as part of counselling for mode of delivery in women choosing between intended VBAC or planned CS after previous CS.

Purpose Adequate calcium intake during pregnancy is of major importance for the health of both mother and fetus. Up to date, evidence on the prevalence of inadequate calcium intake among pregnant women is sparse for Western countries, and it is unknown to what extent inadequate dietary calcium intake is adequately balanced by supplement use. The objective of this study was to estimate calcium intake from diet and supplement use during the early pregnancy in The Netherlands. Methods As part of the Expect cohort study, 2477 pregnant women (8-16 weeks of gestation) completed an online questionnaire including questions on baseline characteristics, the use of calcium containing supplements, and a short food-frequency questionnaire (FFQ). Intake data were used to calculate median calcium intakes from diet, from supplements, and combined, and to compare these values with currently accepted requirement levels. Results Forty-two percent of the pregnant women had a total calcium intake below the estimated average requirement of 800 mg/day. Median (interquartile range) calcium intake was 886 (611-1213) mg/day. Calcium or multivitamin supplements were used by 64.8% of the women at 8 weeks of gestation, with a median calcium content of 120.0 (60.0-200.0) mg/day. Prenatal vitamins were the most often used supplements (60.6%). Conclusions Forty-two percent of Dutch pregnant women have an inadequate calcium intake. Supplements are frequently used, but most do not contain sufficient amounts to correct this inadequate intake.

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Background: Existing evidence on the effects of race and ethnicity on pregnancy outcomes is restricted to individual studies done within specific countries and health systems. We aimed to assess the impact of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries, and to ascertain whether the magnitude of disparities, if any, varied across geographical regions. Methods: For this individual participant data (IPD) meta-analysis we used data from the International Prediction of Pregnancy Complications (IPPIC) Network of studies on pregnancy complications; the full dataset comprised 94 studies, 53 countries, and 4 539 640 pregnancies. We included studies that reported perinatal outcomes (neonatal death, stillbirth, preterm birth, and small-for-gestational-age babies) in at least two racial or ethnic groups (White, Black, south Asian, Hispanic, or other). For our two-step random-effects IPD meta-analysis, we did multiple imputations for confounder variables (maternal age, BMI, parity, and level of maternal education) selected with a directed acyclic graph. The primary outcomes were neonatal mortality and stillbirth. Secondary outcomes were preterm birth and a small-for-gestational-age baby. We estimated the association of race and ethnicity with perinatal outcomes using a multivariate logistic regression model and reported this association with odds ratios (ORs) and 95% CIs. We also did a subgroup analysis of studies by geographical region. Findings: 51 studies from 20 high-income and upper-middle-income countries, comprising 2 198 655 pregnancies, were eligible for inclusion in this IPD meta-analysis. Neonatal death was twice as likely in babies born to Black women than in babies born to White women (OR 2·00, 95% CI 1·44–2·78), as was stillbirth (2·16, 1·46–3·19), and babies born to Black women were at increased risk of preterm birth (1·65, 1·46–1·88) and being small for gestational age (1·39, 1·13–1·72). Babies of women categorised as Hispanic had a three-times increased risk of neonatal death (OR 3·34, 95% CI 2·77–4·02) than did those born to White women, and those born to south Asian women were at increased risk of preterm birth (OR 1·26, 95% CI 1·07–1·48) and being small for gestational age (1·61, 1·32–1·95). The effects of race and ethnicity on preterm birth and small-for-gestational-age babies did not vary across regions. Interpretation: Globally, among underserved groups, babies born to Black women had consistently poorer perinatal outcomes than White women after adjusting for maternal characteristics, although the risks varied for other groups. The effects of race and ethnicity on adverse perinatal outcomes did not vary by region. Funding: National Institute for Health and Care Research, Wellbeing of Women.

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 mu g day(-1) combined with B12 < 5.5 mu g day(-1)) are not associated with birthweight [beta 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 [beta 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 [beta adj = -7.10 (-97.90, 83.71) g]. Maternal dietary B12 intake [beta adj = -9.5 (-15.6, -3.3)] and plasma methylmalonic acid [beta 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.

Contains fulltext : 229268.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Low-dose aspirin (LDA) prophylaxis has been shown to reduce women's preeclampsia risk. Evidence regarding LDA adherence rates of pregnant women is based almost exclusively on clinical trials, giving a potentially biased picture. Moreover, these studies do not report on determinants of adherence. Since 2017, obstetric healthcare professionals in a Dutch region have assessed women's preeclampsia risk by means of a prediction tool and counseled those with an above-population average risk on LDA as a prophylactic measure. MATERIAL AND METHODS: From 2017 to 2018, 865 women were recruited in multiple centers and prospectively followed using web-based surveys (Expect Study II). Rates and determinants of LDA usage among women with an increased preeclampsia risk in daily practice were assessed. Results were compared with findings in a similar cohort from a care-as-usual setting lacking risk-based counseling (Expect Study I, n = 2614). Netherlands Trial Register NTR4143. RESULTS: In total, 306 women had a predicted increased preeclampsia risk. LDA usage was higher for women receiving risk-based care than care-as-usual (29.4% vs 1.5%, odds ratio 19.1, 95% confidence interval 11.2-32.5). Daily LDA usage was positively correlated with both predicted risk and women's concerns regarding preeclampsia. Most reported reasons for non- or incomplete use were unawareness of LDA as a preventive intervention, concerns about potential adverse effects and doubts regarding the benefits. CONCLUSIONS: Risk-based counseling was associated with a higher prevalence of LDA usage, but general usage rates were low. Future research regarding potential factors improving the usage of LDA during pregnancy is necessary.

Background: Satisfaction of pregnancy and childbirth is an important quality measure of maternity care. Satisfaction questionnaires generally result in high scores. However, it has been argued that dissatisfaction relies on a different construct. In response to a worldwide call for obstetric care that is more woman-centered, we identified and described the contributors to suboptimal satisfaction with pregnancy and childbirth.Methods: A prospective subcohort of 739 women from a larger cohort (Expect Study I, n = 2614) received a pregnancy and childbirth satisfaction questionnaire. Scores were transformed to a binary outcome whereby a score

BackgroundThe prenatal exposure to maternal n-6 and n-3 polyunsaturated fatty acids (PUFAs) might influence the development of social competence and internalizing and externalizing behaviours of the child, because of the numerous functions of PUFAs within the nervous system.MethodsTo analyse the association of selected maternal PUFAs (i.e., AA, EPA, DHA, total n-6, total n-3, and the n-6:n-3 ratio) measured during gestation with childhood social competence and problem behaviours, we examined 311 mother-child pairs from the Maastricht Essential Fatty Acid Birth (MEFAB) cohort. For each woman, PUFA-specific changes in relative concentrations were calculated by identifying the best-fitting curve of PUFA concentration by linear splines of gestational age. The associations of changes in maternal PUFAs in early and late pregnancy with childhood social competence, total problems, internalizing and externalizing behaviours, measured with the Child Behaviour Checklist 4/18 at age 7, were investigated with linear regression analyses adjusted for maternal and children's socio-demographic characteristics.ResultsIn late gestation (i.e., from gestational week 30), an increase in AA was associated with higher social competence, while a decrease in total n-6 was associated with lower externalizing behaviours. No other significant associations were found.DiscussionIn this prospective study, increasing maternal AA and decreasing total n-6 were associated with improved social competence and externalizing behaviours, respectively, in 7-year old children. Nonetheless, the clinical significance of the identified associations is modest and further investigations are warranted to clarify the relationship between maternal AA and total n-6 during pregnancy and childhood social and behavioural development.

Objectives Woman with a history of a previous cesarean section (CS) can choose between an elective repeat CS (ERCS) and a trial of labor (TOL), which can end in a vaginal birth after cesarean (VBAC) or an unplanned CS. Guidelines describe women’s rights to make an informed decision between an ERCS or a TOL. However, the rates of TOL and vaginal birth after CS varies greatly between and within countries. The objective of this study is to asses nation-wide implementation of counselling with a decision aid (DA) including a prediction model, on intended delivery compared to care as usual. We hypothesize that this may result in a reduction in practice variation without an increase in cesarean rates or complications. Methods In a multicenter controlled before and after cohort study we evaluate the effect of nation-wide implementation of a DA. Practice variation was defined as the standard deviation (SD) of TOL percentages. Results A total of 27 hospitals and 1,364 women were included. A significant decrease was found in practice variation (SD TOL rates: 0.17 control group vs. 0.10 intervention group following decision aid implementation, p=0.011). There was no significant difference in the ERCS rate or overall CS rates. A 21% reduction in the combined maternal and perinatal adverse outcomes was seen. Conclusions Nationwide implementation of the DA showed a significant reduction in practice variation without an increase in the rate of cesarean section or complications, suggesting an improvement in equality of care.

Objective The best screening strategy for gestational diabetes mellitus (GDM) remains a topic of debate. Several organizations made a statement in favor of universal screening, but the volume of oral glucose tolerance tests (OGTT) required may burden healthcare systems. As a result, many countries still rely on selective screening using a checklist of risk factors, but reported diagnostic characteristics vary. Moreover, women's discomfort due to an OGTT is often neglected. Since 2017, obstetric healthcare professionals in a Dutch region assessed women's GDM risk with a prediction model and counseled those with an increased risk regarding an OGTT. Methods From 2017 to 2018, 865 women were recruited in a multicenter prospective cohort. Results In total, 385 women (48%) had an increased predicted GDM risk. Of all women, 78% reported that their healthcare professional discussed their GDM risk. Predicted GDM risks were positively correlated with conducting an OGTT. Conclusion Implementation of a GDM prediction model resulted in moderate rates of OGTTs performed in general, but high rates in high‐risk women. As 25% of women experienced discomfort from the OGTT, a selective screening strategy based on a prediction model with a high detection rate may be an interesting alternative to universal screening. Study cohort registration Netherlands Trial Register: NTR4143; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4143., Synopsis Implementing a gestational diabetes mellitus prediction model resulted in a majority of high‐risk women receiving an oral glucose tolerance test within the recommended gestational window.

Background Evidence for optimal hemostatic resuscitation in postpartum hemorrhage (PPH) is lacking. Liberal fluid administration may result in acidosis, hypothermia and coagulopathy. Objective We hypothesize that in early PPH a restrictive fluid administration results in less progression to moderate PPH. Study design In four Dutch hospitals we recruited women of 18 years and over, and more than 24 weeks pregnant. Exclusion criteria were: anticoagulant therapy, known coagulation disorders, pre-eclampsia, antenatal diagnosis of abnormally adhesive placenta, and a contraindication for liberal fluid therapy. We blindly randomized participants at 500 mL and ongoing blood loss in the third stage of labor between restrictive fluid administration (clear fluids 0.75–1.0 times the volume of blood lost) and liberal fluid administration (clear fluids 1.5–2.0 times the volume of blood lost). The primary outcome was progression to more than 1000 mL blood loss. Analyses were according to the intention-to-treat principle. Results From August 2014 till September 2019, 5190 women were informed of whom 1622 agreed to participate. A total of 252 women were randomized of which 130 were assigned to the restrictive group and 122 to the liberal group. In the restrictive management group 51 of the 130 patients (39.2%) progressed to more than 1000 mL blood loss versus 61 of the 119 patients (51.3%) in the liberal management group (difference, -12.0% [95%-CI -24.3% to 0.3%], p = 0.057). There was no difference in the need for blood transfusion, coagulation parameters, or in adverse events between the groups. Conclusions Although a restrictive fluid resuscitation in women with mild PPH could not been proven to be superior, it does not increase the need for blood transfusion, alter coagulation parameters, or cause a rise in adverse events. It can be considered as an alternative treatment option to liberal fluid resuscitation. Trial registration NTR3789.

Background In contrast to severe gestational hypertension, it is questioned whether antihypertensive medication for mild to moderate gestational hypertension prevents adverse maternal and offspring outcomes. Hypertensive drugs halve the risk of severe hypertension, but do not seem to prevent progression to preeclampsia or reduce the risk of complications in offspring. In fact, beta-blockers, a first line therapy option, are suspected to impair foetal growth. Disappointing effects of antihypertensive medication can be anticipated when the pharmacological mode of action does not match the underlying haemodynamic imbalance. Hypertension may result from 1) high cardiac output, low vascular resistance state, in which beta blockade is expected to be most effective, or 2) low cardiac output, high vascular resistance state where dihydropyridine calcium channel blockers or central-acting alpha agonists might be the best corrective medication. In the latter, beta-blockade might be maternally ineffective and even contribute to impaired foetal growth by keeping cardiac output low. We propose a randomized controlled trial to determine whether correcting the haemodynamic imbalance in women with mild to moderate hypertension reduces the development of severe hypertension and/or preeclampsia more than non-pharmacological treatment does, without alleged negative effects on foetal growth. Methods Women diagnosed with mild to moderate hypertension without proteinuria or signs of other organ damage before 37 weeks of pregnancy are invited to participate in this randomized controlled trial. Women randomized to the intervention group will be prescribed tailored antihypertensive medication, using a simple diagnostic and treatment algorithm based on the mean arterial pressure/heart rate ratio, which serves as an easy-to-determine proxy for maternal circulatory state. Women randomized to the control group will receive non-pharmacological standard care according to national and international guidelines. In total, 208 women will be randomized in a 1:1 ratio. The primary outcome is progression to severe hypertension and preeclampsia and the secondary outcomes are adverse maternal and neonatal outcomes. Discussion This trial will provide evidence of whether tailoring treatment of mild to moderate gestational hypertension to the individual haemodynamic profile prevents maternal disease progression. Trial registration NCT02531490, registered on 24 August 2015.

Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. Objectives To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. Design This was an individual participant data meta-analysis of cohort studies. Setting Source data from secondary and tertiary care. Predictors We identified predictors from systematic reviews, and prioritised for importance in an international survey. Primary outcomes Early-onset (delivery at Analysis We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I 2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. Results The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. Limitations Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. Conclusion For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. Future work Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. Study registration This study is registered as PROSPERO CRD42015029349. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

Background In 2009, the Steering Committee for Pregnancy and Childbirth in the Netherlands recommended the implementation of continuous care during labor in order to improve perinatal outcomes. However, in current care, routine maternity caregivers are unable to provide this type of care, resulting in an implementation rate of less than 30%. Maternity care assistants (MCAs), who already play a nursing role in low risk births in the second stage of labor and in homecare during the postnatal period, might be able to fill this gap. In this study, we aim to explore the (cost) effectiveness of adding MCAs to routine first- and second-line maternity care, with the idea that these MCAs would offer continuous care to women during labor. Methods A randomized controlled trial (RCT) will be performed comparing continuous care (CC) with care-as-usual (CAU). All women intending to have a vaginal birth, who have an understanding of the Dutch language and are > 18 years of age, will be eligible for inclusion. The intervention consists of the provision of continuous care by a trained MCA from the moment the supervising maternity caregiver establishes that labor has started. The primary outcome will be use of epidural analgesia (EA). Our secondary outcomes will be referrals from primary care to secondary care, caesarean delivery, instrumental delivery, adverse outcomes associated with epidural (fever, augmentation of labor, prolonged labor, postpartum hemorrhage, duration of postpartum stay in hospital for mother and/or newborn), women’s satisfaction with the birth experience, cost-effectiveness, and a budget impact analysis. Cost effectiveness will be calculated by QALY per prevented EA based on the utility index from the EQ-5D and the usage of healthcare services. A standardized sensitivity analysis will be carried out to quantify the outcome in addition to a budget impact analysis. In order to show a reduction from 25 to 17% in the primary outcome (alpha 0.05 and bèta 0.20), taking into account an extra 10% sample size for multi-level analysis and an attrition rate of 10%, 2 × 496 women will be needed (n = 992). Discussion We expect that adding MCAs to the routine maternity care team will result in a decrease in the use of epidural analgesia and subsequent costs without a reduction in patient satisfaction. It will therefore be a cost-effective intervention. Trial registration Trial Registration: Netherlands Trial Register, NL8065. Registered 3 October 2019 - Retrospectively registered.

Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. Methods IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. Results Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model’s calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. Conclusions The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Contains fulltext : 229440.pdf (Publisher’s version ) (Open Access) BACKGROUND: Obstetric health care relies on an adequate antepartum risk selection. Most guidelines used for risk stratification, however, do not assess absolute risks. In 2017, a prediction tool was implemented in a Dutch region. This tool combines first trimester prediction models with obstetric care paths tailored to the individual risk profile, enabling risk-based care. OBJECTIVE: To assess impact and cost-effectiveness of risk-based care compared to care-as-usual in a general population. METHODS: A before-after study was conducted using 2 multicenter prospective cohorts. The first cohort (2013-2015) received care-as-usual; the second cohort (2017-2018) received risk-based care. Health outcomes were (1) a composite of adverse perinatal outcomes and (2) maternal quality-adjusted life-years. Costs were estimated using a health care perspective from conception to 6 weeks after the due date. Mean costs per woman, cost differences between the 2 groups, and incremental cost effectiveness ratios were calculated. Sensitivity analyses were performed to evaluate the robustness of the findings. RESULTS: In total 3425 women were included. In nulliparous women there was a significant reduction of perinatal adverse outcomes among the risk-based care group (adjusted odds ratio, 0.56; 95% confidence interval, 0.32-0.94), but not in multiparous women. Mean costs per pregnant woman were significantly lower for risk-based care (mean difference, -€2766; 95% confidence interval, -€3700 to -€1825). No differences in maternal quality of life, adjusted for baseline health, were observed. CONCLUSION: In the Netherlands, risk-based care in nulliparous women was associated with improved perinatal outcomes as compared to care-as-usual. Furthermore, risk-based care was cost-effective compared to care-as-usual and resulted in lower health care costs.

Background: The effect of vitamin B-12 from different animal foods on vitamin B-12 biomarker status has not previously been evaluated in pregnant women.Objective: We examined the association of vitamin B-12 intake from dairy, meat, fish (including shellfish), and eggs with circulating concentrations of vitamin B-12 biomarkers and with the presence of vitamin B-12 deficiency in 1266 pregnant women participating in the KOALA Birth Cohort Study.Methods: Blood samples were collected in weeks 34-36 of pregnancy, and vitamin B-12 intake from foods and supplements was estimated with a semiquantitative food-frequency questionnaire (FFQ). Total vitamin B-12, holotranscobalamin (holoTC), and methylmalonic acid (MMA) were determined in plasma. Vitamin B-12 deficiency was defined as holoTC 0.45 mu mol/L. Associations were evaluated with linear and logistic regression analyses, adjusting for potential confounders.Results: Significant dose-response relations were observed between vitamin B-12 intake from dairy, meat, and fish and plasma vitamin B-12, holoTC, and MMA [P-trend for (shell) fish with MMA = 0.002; P-trend for dairy, meat, and fish with all other markers Conclusions: In pregnant Dutch women, higher intakes of vitamin B-12 from dairy, meat, and fish were positively associated with vitamin B-12 status, suggesting that dairy, meat, and fish are good sources of bioactive vitamin B-12 in pregnancy. Nevertheless, for (lacto-) vegetarians, vitamin B-12 supplementation is recommended.

ObjectiveTo review and critically appraise published and preprint reports of models that aim to predict either (i) presence of existing COVID-19 infection, (ii) future complications in individuals already diagnosed with COVID-19, or (iii) models to identify individuals at high risk for COVID-19 in the general population.DesignRapid systematic review and critical appraisal of prediction models for diagnosis or prognosis of COVID-19 infection.Data sourcesPubMed, EMBASE via Ovid, Arxiv, medRxiv and bioRxiv until 24thMarch 2020.Study selectionStudies that developed or validated a multivariable COVID-19 related prediction model. Two authors independently screened titles, abstracts and full text.Data extractionData from included studies were extracted independently by at least two authors based on the CHARMS checklist, and risk of bias was assessed using PROBAST. Data were extracted on various domains including the participants, predictors, outcomes, data analysis, and prediction model performance.Results2696 titles were screened. Of these, 27 studies describing 31 prediction models were included for data extraction and critical appraisal. We identified three models to predict hospital admission from pneumonia and other events (as a proxy for covid-19 pneumonia) in the general population; 18 diagnostic models to detect COVID-19 infection in symptomatic individuals (13 of which were machine learning utilising computed tomography (CT) results); and ten prognostic models for predicting mortality risk, progression to a severe state, or length of hospital stay. Only one of these studies used data on COVID-19 cases outside of China. Most reported predictors of presence of COVID-19 in suspected patients included age, body temperature, and signs and symptoms. Most reported predictors of severe prognosis in infected patients included age, sex, features derived from CT, C-reactive protein, lactic dehydrogenase, and lymphocyte count.Estimated C-index estimates for the prediction models ranged from 0.73 to 0.81 in those for the general population (reported for all 3 general population models), from 0.81 to > 0.99 in those for diagnosis (reported for 13 of the 18 diagnostic models), and from 0.85 to 0.98 in those for prognosis (reported for 6 of the 10 prognostic models). All studies were rated at high risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, and poor statistical analysis, including high risk of model overfitting. Reporting quality varied substantially between studies. A description of the study population and intended use of the models was absent in almost all reports, and calibration of predictions was rarely assessed.ConclusionCOVID-19 related prediction models are quickly entering the academic literature, to support medical decision making at a time where this is urgently needed. Our review indicates proposed models are poorly reported and at high risk of bias. Thus, their reported performance is likely optimistic and using them to support medical decision making is not advised. We call for immediate sharing of the individual participant data from COVID-19 studies to support collaborative efforts in building more rigorously developed prediction models and validating (evaluating) existing models. The aforementioned predictors identified in multiple included studies could be considered as candidate predictors for new models. We also stress the need to follow methodological guidance when developing and validating prediction models, as unreliable predictions may cause more harm than benefit when used to guide clinical decisions. Finally, studies should adhere to the TRIPOD statement to facilitate validating, appraising, advocating and clinically using the reported models.Systematic review registration protocolosf.io/ehc47/,registration: osf.io/wy245Summary boxesWhat is already known on this topic-The sharp recent increase in COVID-19 infections has put a strain on healthcare systems worldwide, necessitating efficient early detection, diagnosis of patients suspected of the infection and prognostication of COVID-19 confirmed cases.-Viral nucleic acid testing and chest CT are standard methods for diagnosing COVID-19, but are time-consuming.-Earlier reports suggest that the elderly, patients with comorbidity (COPD, cardiovascular disease, hypertension), and patients presenting with dyspnoea are vulnerable to more severe morbidity and mortality after COVID-19 infection.What this study adds-We identified three models to predict hospital admission from pneumonia and other events (as a proxy for COVID-19 pneumonia) in the general population.-We identified 18 diagnostic models for COVID-19 detection in symptomatic patients.-13 of these were machine learning models based on CT images.-We identified ten prognostic models for COVID-19 infected patients, of which six aimed to predict mortality risk in confirmed or suspected COVID-19 patients, two aimed to predict progression to a severe or critical state, and two aimed to predict a hospital stay of more than 10 days from admission.-Included studies were poorly reported compromising their subsequent appraisal, and recommendation for use in daily practice. All studies were appraised at high risk of bias, raising concern that the models may be flawed and perform poorly when applied in practice, such that their predictions may be unreliable.

STUDY QUESTION: Is embryo culture media used during an IVF/ICSI treatment associated with differences in growth, body composition and cardiovascular development as determined in 9-year-old singleton IVF children?SUMMARY ANSWER: The choice of in vitro culture medium for human embryos is associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9, while no significant differences were observed in cardiovascular development.WHAT IS KNOWN ALREADY: Children born after IVF/ICSI have an increased risk of low birthweight, which is correlated with a higher risk of cardiovascular diseases. Some studies show that IVF children exhibit a significantly higher systolic and diastolic blood pressure and higher fasting glucose levels compared to naturally conceived children. After alternating assignment to G1 (TM) Version 3 (Vitrolife) or K-SICM (Cook) embryo culture media, birthweight of the resulting children was significantly higher in the Vitrolife group and they remained heavier during the first 2 years of life.STUDY DESIGN, SIZE, DURATION: In this observational cohort study (MEDIUM-KIDS), parents of singletons from a previous study were approached for further follow-up after the ninth birthday of their child. The singletons were born after fresh embryo transfer of cleavage stage embryos resulting from an IVF/ICSI treatment performed between July 2003 and December 2006 in our clinic, when two different culture media were used alternately: either G1 (TM) Version 3 (Vitrolife) or K-SICM (Cook). Follow-up measurements were performed between March 2014 and December 2016.PARTICIPANT/MATERIALS, SETTINGS, METHODS: Parents were invited to attend our clinic with their child for a single visit lasting similar to 2.5 h. Two experienced clinicians performed all measurements as part of the MEDIUM-KIDS study in a standardized way. Height and weight of the child was measured using calibrated scales, 4-point skinfold thickness measurements were measured in triplicate and waist and hip circumference were measured using a tape measure. The following cardiovascular parameters were measured in a standardized way: blood pressure, heart rate and endothelial function by skin laser-Doppler with iontophoresis using vasodilatory drugs. Cortisol and cortisone concentrations in hair were measured. A blood sample was taken after an overnight fast for insulin, glucose, TSH and lipid analysis. Blood samples of the IVF children were compared with a non-IVF control group. Differences between culture medium groups were analysed by Student's t-test and effects of confounders were analysed using multivariable regression analysis.MAIN RESULTS AND THE ROLE OF CHANCE: Of the 294 eligible children (168 Vitrolife and 126 Cook), 136 children (75 Vitrolife and 61 Cook) participated in the study. Baseline characteristics of the participating children from the Vitrolife and Cook group were similar. Birthweight was higher in the Vitrolife group, in keeping with the full cohort. After correction for confounders, the difference in weight and BMI attributable to culture medium was 1.58 kg (95% CI: 0.01-3.14) and 0.84 kg/m(2) (95% CI: 0.02-1.67), respectively, with the Vitrolife children being heavier. Height and height corrected for age and gender (SDS scores) were similar in both groups. Furthermore, waist circumference was significantly higher in the Vitrolife group with a corrected difference of 3.21 cm (95% CI: 0.60-5.81) leading to a 0.03 increase (95% CI: 0.01-0.05) in waist/hip ratio. Subscapular skinfolds combined with suprailiacal skinfolds (defined as truncal adiposity), was also significantly higher in Vitrolife children (adjusted difference 3.44 cm [95% CI: 0.27-6.62]). Both systolic (adj. beta 0.364 [95% CI: -2.129 to 2.856],) and diastolic (adj. beta 0.275 [95% CI: -2.105 to 2.654]) blood pressures (mmHg) were comparable for the two groups. After an overnight fast, cholesterol, glucose, insulin, low and high-density lipoprotein, triglycerides and TSH were normal and similar in the two groups. Endothelial function in the microcirculation was compared by using maximum perfusion units corrected for the baseline value as a measure for vasodilatory capacity. There were no significant differences between the two groups. Cortisol and cortisone concentration in hair samples were comparable.LIMITATIONS, REASONS FOR CAUTION: A limitation of the original study was its pseudo-randomized design. This and the dwindling enthusiasm of families for participation (47.7% after 9 years) prevent us from drawing robust causal conclusions from the observed association. Nevertheless, to date this is oldest cohort of IVF/ICSI children where culture medium was allocated alternatingly and used in a blinded setting, to be studied. We believe that our participants are representative for the full cohort. The current number of participants was sufficient to rule out differences as little as 3 mmHg in systolic and diastolic blood pressures.WIDER IMPLICATIONS OF THE FINDINGS: This study underlines the importance of structured follow-up of IVF/ICSI children to further elucidate possible long-term health effects. Health professionals and culture medium manufacturers should be aware that small changes in culture conditions and culture medium composition for the early embryo can have long-term health effects. The similar cardiovascular results for the two groups are reassuring but the children may still be too young to detect differences in cardiovascular development. Prolonged follow-up and structured investigations up until adulthood are necessary to gain more insight and reassurance in the cardiovascular development of IVF offspring, although long-term follow-up will become more complicated by confounding life-style and environmental factors possibly influencing development.STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the March of Dimes (Grant number #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.

BACKGROUND: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers.METHODS: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility.RESULTS: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk.CONCLUSION: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.

Problem behaviors are of increasing public health concern. Twin studies have revealed substantial genetic and environmental influences on children's behavior, and examining birth-weight difference could allow the identification of the specific contribution of multiple non-shared prenatal environmental factors. The Twins and Multiple Births Association Heritability Study, a UK, volunteer-based study, recruited mothers of twins aged 18 months to 5 years; 960 twins (480 pairs) were included in the analysis. Twins’ mothers answered questions relative to their pregnancy and their twins’ characteristics, and completed the Child Behavior Checklist (CBCL) 1½–5. The association between the absolute birth-weight difference and each CBCL scale's score difference was analyzed by means of multiple linear regressions. Expected mean CBCL score differences were calculated. In monozygotic (MZ) twins, statistically and clinically significant associations were found between intrapair birth-weight difference and difference in total problems, internalizing problems, and emotional reactiveness. No significant results were observed neither in dizygotic (DZ) twins when analyzed as a separate group nor in MZ and DZ twins combined. The results of the present study suggest that with increasing the absolute birth-weight difference, the intrapair difference in total problems, internalizing behaviors and emotionality increases, with smaller twins being at major risk for later behavior problems. Moreover, these results suggest a causal association between birth weight and behavior development.

Introduction Prediction models may contribute to personalized risk‐based management of women at high risk of spontaneous preterm delivery. Although prediction models are published frequently, often with promising results, external validation generally is lacking. We performed a systematic review of prediction models for the risk of spontaneous preterm birth based on routine clinical parameters. Additionally, we externally validated and evaluated the clinical potential of the models. Material and methods Prediction models based on routinely collected maternal parameters obtainable during first 16 weeks of gestation were eligible for selection. Risk of bias was assessed according to the CHARMS guidelines. We validated the selected models in a Dutch multicenter prospective cohort study comprising 2614 unselected pregnant women. Information on predictors was obtained by a web‐based questionnaire. Predictive performance of the models was quantified by the area under the receiver operating characteristic curve (AUC) and calibration plots for the outcomes spontaneous preterm birth

Background Postpartum hemorrhage (PPH) is associated with maternal morbidity and mortality and has an increasing incidence in high-resource countries, despite dissemination of guidelines, introduction of skills training, and correction for risk factors. Current guidelines advise the administration, as fluid resuscitation, of almost twice the amount of blood lost. This advice is not evidence-based and could potentially harm patients. Methods All women attending the outpatient clinic who are eligible will be informed of the study; oral and written informed consent will be obtained. Where there is more than 500 ml blood loss and ongoing bleeding, patients will be randomized to care as usual, fluid resuscitation with 1.5–2 times the amount of blood loss or fluid resuscitation with 0.75–1.0 times the blood loss. Blood loss will be assessed by weighing all draping. A blood sample, for determining hemoglobin concentration, hematocrit, thrombocyte concentration, and conventional coagulation parameters will be taken at the start of the study, after 60 min, and 12–18 h after delivery. In a subgroup of women, additional thromboelastometric parameters will be obtained. Discussion Our hypothesis is that massive fluid administration might lead to a progression of bleeding due to secondary coagulation disorders. In non-pregnant individuals with massive blood loss, restrictive fluid management has been shown to prevent a progression to dilution coagulopathy. These data, however, cannot be extrapolated to women in labor. Our objective is to compare both resuscitation protocols in women with early, mild PPH (blood loss 500–750 ml) and ongoing bleeding, taking as primary outcome measure the progression to severe PPH (blood loss > 1000 ml). Trial registration Netherlands Trial Register, NTR 3789. Registered on 11 January 2013. Electronic supplementary material The online version of this article (10.1186/s13063-018-2512-z) contains supplementary material, which is available to authorized users.

Objectives Maternal pre-pregnancy weight is known to affect foetal development. However, it has not yet been clarified if gestational weight gain is associated with childhood behavioural development. Methods We performed a pooled analysis of two prospective birth cohorts to investigate the association between gestational weight gain and childhood problem behaviours, and the effect modification of maternal pre-pregnancy BMI. In total, 378 mother–child pairs from the Maastricht Essential Fatty Acids Birth cohort (MEFAB) and 414 pairs from the Rhea Mother–Child cohort were followed up from early pregnancy to 6–7 years post-partum. At follow up, parents assessed their children’s behaviour, measured as total problems, internalizing and externalizing behaviours, with the Child Behaviour Checklist. We computed cohort- and subject-specific gestational weight gain trajectories using mixed-effect linear regression models. Fractional polynomial regressions, stratified by maternal pre-pregnancy BMI status, were then used to examine the association between gestational weight gain and childhood problem behaviours. Results In the pre-pregnancy overweight/obese group, greater gestational weight gain was associated with higher problem behaviours. On average, children of women with overweight/obesity who gained 0.5 kg/week scored 25 points higher (on a 0–100 scale) in total problems and internalizing behaviours, and about 18 points higher in externalizing behaviours than children whose mothers gained 0.2 kg/week. Inconsistent results were found in the pre-pregnancy normal weight group. Conclusions for Practice Excessive gestational weight gain in women with pre-pregnancy overweight/obesity might increase problem behaviours in school-age children. Particular attention should be granted to avoid excessive weight gain in women with a pre-pregnancy overweight or obesity.

Contains fulltext : 229441.pdf (Publisher’s version ) (Open Access) Background. Despite improved management, preeclampsia remains an important cause of maternal and neonatal mortality and morbidity. Low-dose aspirin (LDA) lowers the risk of preeclampsia. Although several guidelines recommend LDA prophylaxis in women at increased risk, they disagree about the definition of high risk. Recently, an externally validated prediction model for preeclampsia was implemented in a Dutch region combined with risk-based obstetric care paths. Objectives. To demonstrate the selection of a risk threshold and to evaluate the adherence of obstetric health care professionals to the prediction tool. Study Design. Using a survey (n = 136) and structured meetings among health care professionals, possible cutoff values at which LDA should be discussed were proposed. The prediction model, with chosen cutoff and corresponding risk-based care paths, was embedded in an online tool. Subsequently, a prospective multicenter cohort study (n = 850) was performed to analyze the adherence of health care professionals. Patient questionnaires, linked to the individual risk profiles calculated by the online tool, were used to evaluate adherence. Results. Health care professionals agreed upon employing a tool with a high detection rate (cutoff: 3.0%; sensitivity 75%, specificity 64%) followed by shared decision between patients and health care professionals on LDA prophylaxis. Of the 850 enrolled women, 364 women had an increased risk of preeclampsia. LDA was discussed with 273 of these women, resulting in an 81% adherence rate. Conclusion. Consensus regarding a suitable risk cutoff threshold was reached. The adherence to this recommendation was 81%, indicating adequate implementation.

Background Many colorectal cancer (CRC) survivors experience persisting health problems post-treatment that compromise their health-related quality of life (HRQoL). Prediction models are useful tools for identifying survivors at risk of low HRQoL in the future and for taking preventive action. Therefore, we developed prediction models for CRC survivors to estimate the 1-year risk of low HRQoL in multiple domains. Methods In 1458 CRC survivors, seven HRQoL domains (EORTC QLQ-C30: global QoL; cognitive, emotional, physical, role, social functioning; fatigue) were measured prospectively at study baseline and 1 year later. For each HRQoL domain, scores at 1-year follow-up were dichotomized into low versus normal/high. Separate multivariable logistic prediction models including biopsychosocial predictors measured at baseline were developed for the seven HRQoL domains, and internally validated using bootstrapping. Results Average time since diagnosis was 5 years at study baseline. Prediction models included both non-modifiable predictors (age, sex, socio-economic status, time since diagnosis, tumor stage, chemotherapy, radiotherapy, stoma, micturition, chemotherapy-related, stoma-related and gastrointestinal complaints, comorbidities, social inhibition/negative affectivity, and working status) and modifiable predictors (body mass index, physical activity, smoking, meat consumption, anxiety/depression, pain, and baseline fatigue and HRQoL scores). Internally validated models showed good calibration and discrimination (AUCs: 0.83–0.93). Conclusions The prediction models performed well for estimating 1-year risk of low HRQoL in seven domains. External validation is needed before models can be applied in practice.

Maternal pre-pregnancy weight has been related with young singletons’ cognitive and behavioral development, but it is not clear if it has an effect on temperament. We used a twin cohort to evaluate the association between maternal pre-pregnancy body mass index (BMI) and infants’ temperament. The mothers of 834 twins answered questions regarding their pre-pregnancy BMI and their 0- to 18-month-old children’s temperament using the Revised Infant Behavior Questionnaire. Three temperamental dimensions were examined: activity level, distress to limitation and duration of orienting. The relationship between maternal pre-pregnancy BMI and each temperamental component was investigated by means of multilevel mixed-effects linear regression analysis. We found no clear evidence of an association of maternal pre-pregnancy BMI with twins’ temperament. The development of temperament is influenced by a large number of factors, probably different from those influencing children’s emotional and behavioral development.

Introduction We performed an independent validation study of all published first trimester prediction models, containing non‐invasive predictors, for the risk of gestational diabetes mellitus. Furthermore, the clinical potential of the best performing models was evaluated. Material and methods Systemically selected prediction models from the literature were validated in a Dutch prospective cohort using data from Expect Study I and PRIDE Study. The predictive performance of the models was evaluated by discrimination and calibration. Clinical utility was assessed using decision curve analysis. Screening performance measures were calculated at different risk thresholds for the best model and compared with current selective screening strategies. Results The validation cohort included 5260 women. Gestational diabetes mellitus was diagnosed in 127 women (2.4%). The discriminative performance of the 12 included models ranged from 68% to 75%. Nearly all models overestimated the risk. After recalibration, agreement between the observed outcomes and predicted probabilities improved for most models. Conclusions The best performing prediction models showed acceptable performance measures and may enable more personalized medicine‐based antenatal care for women at risk of developing gestational diabetes mellitus compared with current applied strategies.

STUDY QUESTION To what extent are endometriosis and its related physical and mental symptoms associated with the perceived level of sexual functioning in women and their male partners? SUMMARY ANSWER Dyspareunia and depressive symptoms are associated with impaired sexual functioning in women with endometriosis, whereas sexual functioning in their male partners is not affected. WHAT IS KNOWN ALREADY Women with endometriosis suffer from more dyspareunia, lower sexual functioning, and lower quality of life. In qualitative studies, partners of women with endometriosis report that endometriosis affected their quality of life and produced relational distress. STUDY DESIGN SIZE, DURATION In this cross-sectional study, sexual functioning in women with endometriosis (n = 83) and their partners (n = 74) was compared with sexual functioning in a control group of women attending the outpatient department for issues related to contraception (n = 40), and their partners (n = 26). PARTICIPANTS/MATERIALS, SETTING, METHODS Women and partners were recruited in the Maastricht University Medical Centre (MUMC) and the VieCuri Medical Centre Venlo between June 2011 and December 2012. All participants were asked to complete a set of online questionnaires. MAIN RESULTS AND THE ROLE OF CHANCE Response rates were 59.3% (83/140) for women with endometriosis and 52.3% (74/140) for their partners. Response rates in the control group were respectively 43.2% and 27.4% (41/95 and 27/95), of whom 40 women and 26 partners could be included in the study. Women with endometriosis as compared with the control group, reported significantly more frequent pain during intercourse (53% versus 15%, P

Item does not contain fulltext STUDY QUESTION: Does embryo culture medium influence pregnancy and perinatal outcome in IVF? SUMMARY ANSWER: Embryo culture media used in IVF affect treatment efficacy and the birthweight of newborns. WHAT IS KNOWN ALREADY: A wide variety of culture media for human preimplantation embryos in IVF/ICSI treatments currently exists. It is unknown which medium is best in terms of clinical outcomes. Furthermore, it has been suggested that the culture medium used for the in vitro culture of embryos affects birthweight, but this has never been demonstrated by large randomized trials. STUDY DESIGN, SIZE, DURATION: We conducted a multicenter, double-blind RCT comparing the use of HTF and G5 embryo culture media in IVF. Between July 2010 and May 2012, 836 couples (419 in the HTF group and 417 in the G5 group) were included. The allocated medium (1:1 allocation) was used in all treatment cycles a couple received within 1 year after randomization, including possible transfers with frozen-thawed embryos. The primary outcome was live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples that were scheduled for an IVF or an ICSI treatment at one of the six participating centers in the Netherlands or their affiliated clinics. MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rate was higher, albeit nonsignificantly, in couples assigned to G5 than in couples assigned to HTF (44.1% (184/417) versus 37.9% (159/419); RR: 1.2; 95% confidence interval (CI): 0.99-1.37; P = 0.08). Number of utilizable embryos per cycle (2.8 +/- 2.3 versus 2.3 +/- 1.8; P < 0.001), implantation rate after fresh embryo transfer (20.2 versus 15.3%; P < 0.001) and clinical pregnancy rate (47.7 versus 40.1%; RR: 1.2; 95% CI: 1.02-1.39; P = 0.03) were significantly higher for couples assigned to G5 compared with those assigned to HTF. Of the 383 live born children in this trial, birthweight data from 380 children (300 singletons (G5: 163, HTF: 137) and 80 twin children (G5: 38, HTF: 42)) were retrieved. Birthweight was significantly lower in the G5 group compared with the HTF group, with a mean difference of 158 g (95% CI: 42-275 g; P = 0.008). More singletons were born preterm in the G5 group (8.6% (14/163) versus 2.2% (3/137), but singleton birthweight adjusted for gestational age and gender (z-score) was also lower in the G5 than in the HTF group (-0.13 +/- 0.08 versus 0.17 +/- 0.08; P = 0.008). LIMITATIONS, REASONS FOR CAUTION: This study was powered to detect a 10% difference in live births while a smaller difference could still be clinically relevant. The effect of other culture media on perinatal outcome remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Embryo culture media used in IVF affect not only treatment efficacy but also perinatal outcome. This suggests that the millions of human embryos that are cultured in vitro each year are sensitive to their environment. These findings should lead to increased awareness, mechanistic studies and legislative adaptations to protect IVF offspring during the first few days of their existence. STUDY FUNDING/COMPETING INTERESTS: This project was partly funded by The NutsOhra foundation (Grant 1203-061) and March of Dimes (Grant 6-FY13-153). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NTR1979 (Netherlands Trial Registry). TRIAL REGISTRATION DATE: 1 September 2009. DATE OF FIRST PATIENT'S ENROLMENT: 18 July 2010.

Introduction: This study will compare former obstetric care as usual Expect I with risk-dependent care using a prediction tool Expect II. The Expect I study externally validated 39 prediction models using data of 2,614 women prospectively included from 2013 to 2015. Clinically useful models were embedded in a prediction tool. At the same time, risk-dependent care paths were developed by gynaecologists and midwives of Limburg southern province of the Netherlands. In risk-dependent care antenatal care is tailored to the results of individual risk assessments. Furthermore, these care paths stimulate integrated obstetric care by intensifying the collaboration between midwives outpatient clinics and gynecologists hospitals. Risk-dependent care is currently embedded in Limburg. Methods: A multicenter prospective cohort study will be performed from 2017 to 2018, enrolling women who will receive risk-dependent obstetric care Expect II. Obstetric risk profiles will be calculated using a web-based prediction tool comprising validated prediction models. Primary outcomes are adherence of healthcare professionals and compliance of women to key recommendations which were inadequate in former care as usual; e.g. recommendations regarding calcium intake to all women Expect I: adequate calcium intake in 34% of women and low dose aspirin treatment to women with an elevated preeclampsia risk Expect I: actual use in the high-risk group: 1.5%. Secondary outcomes are patient satisfaction and healthcare costs. Health outcomes such as neonatal adverse events will be analyzed in the second part of the Expect II study using registry data of the region. Preliminary results: Seven months after introduction we estimate that our prediction tool is used in ~40% of all pregnant women in participating regions. At the moment, 150 women are included in our cohort. Recommendations about calcium intake during pregnancy were given to 112 women 74%, 91 of these women 61% reported the intention to comply with the recommendations received. In case of an elevated preeclampsia risk n=62 preventive aspirin treatment was recommended to 41 women 66%, 18 of these women 29% reported the intention to comply. Discussion: Implementing new guidelines takes time and requires an additional effort of healthcare professionals. Especially if these guidelines reorganize the logistic structure of healthcare and include new strategies such as a prediction tool. Conclusion: The preliminary results of this study indicate that risk-dependent care has already been implemented by a reasonable proportion of healthcare professionals. Furthermore, risk-dependent care combined with a web-based prediction tool appears to increase usage of preventive interventions. Lessons learned: Since this abstract reveals preliminary results it is too soon to draw conclusions about any lessons learned. Limitations: These results are based on preliminary data, thus a relatively large proportion of participants are included by healthcare professionals who immediately started using our tool. Therefore, the preliminary results may suffer from a selective response of healthcare professionals in the early stages of our study.

STUDY QUESTION: Do embryo culture media used during an IVF/ICSI treatment have an effect on cognitive development of singleton IVF children at 9 years of age?SUMMARY ANSWER: Cognitive development of children born after culture in two different embryo culture media is comparable.WHAT IS KNOWN ALREADY: Previously, we have shown that the culture medium used in an IVF/ICSI treatment affects birthweight and weight at 2 years of age after alternating assignment to embryo culture in either K-SCICM (Cook) or G1™ Version 3 (Vitrolife). Children with low birthweight are known to have an increased risk for learning disabilities. Data on cognitive development in general of children born after ART are still conflicting, and the only study reporting on the effects of culture medium on cognitive development shows significant differences in cognitive development between two culture medium groups.STUDY DESIGN SIZE DURATION: In this observational cohort follow-up study (MEDIUM-KIDS), parents of all singletons from our abovementioned study were approached after the ninth birthday of their child to participate in an additional follow-up study. Of the 294 eligible children included in the original study, 119 children (70 Vitrolife and 49 Cook) participated in the current study.PARTICIPANTS/MATERIALS SETTING METHODS: All follow-up measurements were performed between March 2014 and December 2016. CITO (Dutch Central Institute for Test Development) developed the Dutch pupil monitoring system, which involves nationwide independent, standardized, academic achievement score tests to monitor the child's school performance twice a year at fixed time points from third grade onward. The tests include language skills (vocabulary and orthography), mathematics and reading capability and comprehension. Results from the tests performed between third and sixth grades, expressed as ability scores, were obtained from the school. To investigate school performance development over the years, we used a mixed effects multilevel model. The least complex model with the best fit was selected to analyze whether culture medium affects cognitive development in our cohort. The study had enough power to detect a difference in ability score that reflects at least one performance category between the two groups.MAIN RESULTS AND THE ROLE OF CHANCE: No differences were seen in baseline characteristics between participants and non-participants (both parental and children characteristics). For all domains, the random intercept model was used. All analyses showed comparable results for the two culture medium groups. No significant differences were observed for any of the cognitive development domains, even after correction for potential confounders. Parental level of education was higher in the IVF group (45%) if compared to the national average level of education (35%), which most likely explains the higher CITO scores for the IVF children if compared to the National ability scores.LIMITATIONS REASONS FOR CAUTION: A limitation of the study was its pseudo-randomized design and the relatively low participation rate of 40.5%. This and the number of missing data prevent us from drawing robust causal conclusions. However, as this is the first and therewith oldest cohort of children where culture medium was allocated alternatingly and used in a blinded setting, in the same period, with all other conditions identical this study gives up until now the best available evidence.WIDER IMPLICATIONS OF THE FINDINGS: Our study analyzes the effects of culture medium on school performance of children born after IVF/ICSI in a prospective cohort study. Although further research on long-term academic skills and also on behavior is essential, our results are reassuring and should make parents of children born after IVF/ICSI feel comfortable with their children's cognitive development.STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the March of Dimes (Grant no. #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.TRIAL REGISTRATION NUMBER: NTR4220.

IMPORTANCE Autologous fat transfer (AFT or fat grafting) has become an invaluable tool for the correction of disfiguring deformities after breast cancer surgery. However, clinical and animal studies have shown conflicting results regarding its oncologic safety.OBJECTIVE To determine whether exposure to AFT vs conventional breast reconstruction is associated with increased rates of cancer relapse in patients with breast cancer.DESIGN, SETTING, AND PARTICIPANTS This matched cohort study involved retrospective medical record review to identify all patients in a local patient database receiving AFT between 2006 and 2014. Each AFT case was matched with a nonexposed control patient with similar baseline characteristics. The mean (SD) follow-up of patients receiving AFT was 9.3 (4.9) years including 5.0 (1.7) years following AFT. Control patients were followed up for a mean (SD) of 8.6 (1.8) years from the primary surgery. Patients were identified through the local patient database of the Tergooi Hospital in Hilversum, the Netherlands. A total of 287 patients with breast cancer (300 affected breasts) who received AFT for breast reconstruction after cancer were included in the intervention group. Each AFT case was matched with a respective control patient based on age, type of oncologic surgery, tumor invasiveness, and disease stage. In addition, individual AFT-control pairs were selected to have the same locoregional recurrence-free interval at baseline. Data were analyzed between 2016 and 2017.EXPOSURES Reconstruction with AFT vs conventional breast reconstruction or none.MAIN OUTCOMES AND MEASURES Primary end pointswere the cumulative incidences of oncologic events in AFT and control patients and their respective hazard ratios.RESULTS Of the 587 total patients, all were women and the mean age was 48.1 years for the patients undergoing AFT and 49.4 years for the control patients. Eight locoregional recurrences were observed in the treatment group (287 patients) and 11 among the control group (300 patients), leading to an unadjusted hazard ratio of 0.63 (95% CI, 0.25-1.60; P =.33). No increased locoregional recurrence rates were seen in relevant subgroups based on the type of oncological surgery, tumor invasiveness, or pathological stage. In addition, no increased risks with AFT were detected with respect to distant recurrences or breast cancer-specific mortality.CONCLUSIONS AND RELEVANCE No significant differences in the locoregional recurrence rates between the AFT and control groups were observed after 5 years of follow-up. These findings confirm the results of previous studies; therefore, clinical evidence suggesting that AFT is associated with increased risk for cancer relapse is still lacking.

Introduction: This study assessed the external validity of all published first trimester prediction models for the risk of preeclampsia (PE) based on routinely collected maternal predictors. Moreover, the potential utility of the best-performing models in clinical practice was evaluated. Material and Methods: Ten prediction models were systematically selected from the literature. We performed a multicenter prospective cohort study in the Netherlands between July 1, 2013, and December 31, 2015. Eligible pregnant women completed a web-based questionnaire before 16 weeks’ gestation. The outcome PE was established using postpartum questionnaires and medical records. Predictive performance of each model was assessed by means of discrimination (c-statistic) and a calibration plot. Clinical usefulness was evaluated by means of decision curve analysis and by calculating the potential impact at different risk thresholds. Results: The validation cohort contained 2,614 women of whom 76 developed PE (2.9%). Five models showed moderate discriminative performance with c-statistics ranging from 0.73 to 0.77. Adequate calibration was obtained after refitting. The best models were clinically useful over a small range of predicted probabilities. Discussion: Five of the ten included first trimester prediction models for PE showed moderate predictive performance. The best models may provide more benefit compared to risk selection as used in current guidelines.

One of the goals of a pilot study is to identify unforeseen problems, such as ambiguous inclusion or exclusion criteria or misinterpretations of questionnaire items. Although sample size calculation methods for pilot studies have been proposed, none of them are directed at the goal of problem detection. In this article, we present a simple formula to calculate the sample size needed to be able to identify, with a chosen level of confidence, problems that may arise with a given probability. If a problem exists with 5% probability in a potential study participant, the problem will almost certainly be identified (with 95% confidence) in a pilot study including 59 participants.

Objective To assess the effect on mode of delivery of the routine use of labour epidural analgesia (EA) compared with analgesia on request. Design Randomised non-inferiority trial. Setting One university and one non-university teaching hospital in The Netherlands. Population Women with a singleton pregnancy in cephalic presentation beyond 36 + 0 weeks' gestation. Methods Participants were randomly allocated to receive either routine EA or analgesia on request. Intention-to-treat (ITT) and per-protocol (PP) analyses were performed, with confidence intervals (CI) calculated for the differences in percentages or means. Main outcome measures Rate of operative delivery (instrumental vaginal or caesarean), labour characteristics, and adverse labour and neonatal outcomes. Results A total of 488 women were randomly allocated to the routine EA (n = 233) or analgesia on request group (n = 255). In the routine EA group, 89.3% (208/233) received EA. According to ITT analysis, 34.8% (81/233) women in the routine EA group had an operative delivery, compared with 26.7% (68/255) in the analgesia on request group (difference 8.1%, 95% CI −0.1 to 16.3). The difference in rate of operative deliveries according to the PP analysis was statistically significant (difference 8.9%, 95% CI 0.4 to 17.4). Inferiority of EA could not be rejected, as in both analyses the upper bound of the confidence interval exceeded the pre-specified inferiority criterion of +10%. Women in the routine EA group had more adverse effects, including hypotension (difference 9.5%, 95% CI 4.2 to 14.9), and motor blockade (difference 6.8%, 95% CI 1.1 to 12.5). Conclusion Non-inferiority of routine EA could not be demonstrated in this trial. Routine EA use is likely to lead to more operative deliveries and more maternal adverse effects. The results of our study do not justify routine use of EA.

Study question Does age of G-1 PLUS v5 embryo culture medium affect IVF outcome? Summary answer Birthweight of singletons born after IVF showed an inverse association with age of the embryo culture medium, while no association was found between age of culture medium and fertilization rate, embryonic development or ongoing pregnancy. What is known already It has been reported that IVF culture media can deteriorate during storage, which suggests that the capacity of culture media to support optimal embryo development decreases over time. Some animal studies showed an effect of storage time on embryo development, in contrast to other studies, while the effect of aging culture medium on IVF outcome in humans is unknown. Study design, size, duration We used data on outcome of 1832 IVF/ICSI cycles with fresh embryo transfer, performed in the period 2008-2012 to evaluate the association of fertilization rate, embryonic development, ongoing pregnancy and birthweight of singletons with age of the culture medium (Vitrolife AB G-1 PLUS v5). Participants/materials, setting, methods Age of the culture medium was calculated by subtracting the production date from the date of ovum retrieval. Data analysis included linear regression and logistic regression on continuous and categorical outcomes, respectively. Main results and the role of chance Age of the culture medium was not associated with fertilization rate (P = 0.543), early cleavage rate (P = 0.155), percentage of embryos containing four or more cells on Day 2 (P = 0.401), percentage of embryos containing eight or more cells on Day 3 (P = 0.175), percentage of embryos with multinucleated blastomeres (P = 0.527), or ongoing pregnancy (P = 0.729). However, birthweight of the newborn was inversely associated with age of the medium (β = -3.6 g, SE: 1.5 g, P = 0.021), after controlling for possible confounders (day of embryo transfer, number of transferred embryos, child's gender, gestational age at birth, parity, pregnancy complications, maternal smoking, height and weight, and paternal height and weight) and the association was not biased by year of treatment, time since first opening of the bottle or batch variations. This indicates a difference of 234 g in birthweight of newborns for media with an age difference of 65 days. Limitations, reasons for caution The results from this study may be specific for the G-1 PLUS v5 culture medium and extrapolation of the results to other media should be done with caution because of the differences in composition and shelf life. Wider implications of the findings Age of G-1 PLUS v5 medium used to culture human embryos affects birthweight of the respective newborn. This could imply that the preimplantation embryo adapts to its in vitro environment with lasting in vivo consequences. Therefore, it is important that companies are transparent about the exact composition of their embryo culture media, which will allow IVF clinics to further investigate the effects of the media or media components on the health of IVF children. Study funding/competing interests No funding and no competing interests declared. Trial registration number Not applicable.

Background: Implementation of non-invasive prenatal testing (NIPT) in Down syndrome screening programmes requires health policy decisions about its combination with other tests and its timing in pregnancy. Aim: Our aim was to aid health policy decision makers by conducting a quantitative analysis of different NIPT implementation strategies. Methods: Decision trees were created to illustrate all plausible alternatives in a theoretical cohort of 100,000 pregnant women in five screening programmes: classical screening by the first-trimester combined test (FCT), pre-selection of high-risk women prior to NIPT by the FCT, NIPT as the first screening test at 10 weeks and at 13 weeks, and the simultaneous conductance of NIPT and the FCT. Results: Pre-selection by FCT prior to NIPT reduces the number of amniocenteses to a minimum because of a reduction of false-positive NIPT results. If NIPT is the first screening test, it detects almost all fetal Down syndrome cases. NIPT at 10 weeks reassures women early in pregnancy, while NIPT at 13 weeks prevents unnecessary tests due to spontaneous miscarriages and allows for immediate confirmation by amniocentesis. Conclusion: Every implementation strategy has its advantages and disadvantages. The most favourable implementation strategy may be NIPT as the first screening test at 13 weeks, offering the most accurate screening test for Down syndrome, when the risk for spontaneous miscarriage has declined remarkably and timely confirmation by amniocentesis can be performed.

Purpose The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. Methods A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. Results Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0–9.0) in the BRCA group as a whole, 6.5 (IQR 4.0–8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5–9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0–11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). Conclusions Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve. Electronic supplementary material The online version of this article (doi:10.1007/s10815-017-1014-3) contains supplementary material, which is available to authorized users.

Background: A number of first-trimester prediction models addressing important obstetric outcomes have been published. However, most models have not been externally validated. External validation is essential before implementing a prediction model in clinical practice. Objective: The objective of this paper is to describe the design of a study to externally validate existing first trimester obstetric prediction models, based upon maternal characteristics and standard measurements (eg, blood pressure), for the risk of pre-eclampsia (PE), gestational diabetes mellitus (GDM), spontaneous preterm birth (PTB), small-for-gestational-age (SGA) infants, and large-for-gestational-age (LGA) infants among Dutch pregnant women (Expect Study I). The results of a pilot study on the feasibility and acceptability of the recruitment process and the comprehensibility of the Pregnancy Questionnaire 1 are also reported. Methods: A multicenter prospective cohort study was performed in The Netherlands between July 1, 2013 and December 31, 2015. First trimester obstetric prediction models were systematically selected from the literature. Predictor variables were measured by the Web-based Pregnancy Questionnaire 1 and pregnancy outcomes were established using the Postpartum Questionnaire 1 and medical records. Information about maternal health-related quality of life, costs, and satisfaction with Dutch obstetric care was collected from a subsample of women. A pilot study was carried out before the official start of inclusion. External validity of the models will be evaluated by assessing discrimination and calibration. Results: Based on the pilot study, minor improvements were made to the recruitment process and online Pregnancy Questionnaire 1. The validation cohort consists of 2614 women. Data analysis of the external validation study is in progress. Conclusions: This study will offer insight into the generalizability of existing, non-invasive first trimester prediction models for various obstetric outcomes in a Dutch obstetric population. An impact study for the evaluation of the best obstetric prediction models in the Dutch setting with respect to their effect on clinical outcomes, costs, and quality of life—Expect Study II—is being planned. Trial Registration: Netherlands Trial Registry (NTR): NTR4143; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4143 (Archived by WebCite at http://www.webcitation.org/6t8ijtpd9) [JMIR Res Protoc 2017;6(10):e203]

Item does not contain fulltext BACKGROUND: Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM((R))) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy. METHODS: In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM((R)) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry. RESULTS: Reference ranges were obtained for clotting time (CT), clot formation time (CFT), alpha-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm. INTEM: CT 109-225 s, CFT 40-103, and MCF 63-78 mm. FIBTEM: CT 31-79 s and MCF 13-45 mm. APTEM: CT 33-62 s, CFT 42-118, and MCF 61-79 mm. CONCLUSIONS: Reference values for ROTEM((R)) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515).

Introduction This study evaluates former obstetric care as usual (Expect I) with risk-dependent care using a prediction tool (Expect II). The Expect I study externally validated 39 prediction models using data of 2,614 women prospectively included from 2013 to 2015. Clinically useful models were embedded in a web-based prediction tool. Additionally, risk-dependent care paths were developed, resulting in antenatal care tailored to the outcomes of individual risk assessments. Risk-dependent care was embraced by a consortium of obstetric healthcare professionals in the Dutch province of Limburg. Objective This part focuses on adherence of healthcare professionals and compliance of women to key recommendations; e.g. adequate calcium intake in all women and low-dose aspirin treatment in women at increased risk of preeclampsia. Methods Women receiving risk-dependent care are being enrolled in a prospective multicenter cohort (Expect II) and receive four questionnaires at intervals. Preliminary results Ten months after introduction our prediction tool is being used in an estimated 24–40% of pregnant women in our region. Currently, 435 women have been enrolled. Recommendations regarding calcium intake were discussed with 351 women (81%), of which 285 (81%) reported the intention to comply (Expect I, adequate calcium intake in 34% of women). In case of an elevated preeclampsia risk (n = 223) aspirin treatment was discussed with 180 women (76%), of which 52 (29%) intended to comply (Expect I, actual use in the high-risk group: 1.5%). Discussion The preliminary results indicate risk-dependent care has been implemented by a reasonable proportion of healthcare professionals. Furthermore, usage of the prediction tool increases recommendation of preventive interventions. Implementing new guidelines asks an additional effort of healthcare professionals, especially if it includes novel strategies such as a prediction tool. Future research should focus on barriers that hamper the adherence of healthcare professionals to risk-dependent care and on reasons for non-compliance of women.

Item does not contain fulltext OBJECTIVE: To develop and internally validate a model that predicts the outcome of an intended vaginal birth after caesarean (VBAC) for a Western European population that can be used to personalise counselling for deliveries at term. DESIGN: Registration-based retrospective cohort study. SETTING: Five university teaching hospitals, seven non-university teaching hospitals, and five non-university non-teaching hospitals in the Netherlands. POPULATION: A cohort of 515 women with a history of one caesarean section and a viable singleton pregnancy, without a contraindication for intended VBAC, who delivered at term. METHODS: Potential predictors for a vaginal delivery after caesarean section were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN OUTCOME MEASURES: Predictors for VBAC. For model validation, the area under the receiver operating characteristic curve (AUC) for discriminative capacity and calibration-per-risk-quantile for accuracy were calculated. RESULTS: A total of 371 out of 515 women had a VBAC (72%). Variables included in the model were: estimated fetal weight greater than the 90(th) percentile in the third trimester; previous non-progressive labour; previous vaginal delivery; induction of labour; pre-pregnancy body mass index; and ethnicity. The AUC was 71% (95% confidence interval, 95% CI = 69-73%), indicating a good discriminative ability. The calibration plot shows that the predicted probabilities are well calibrated, especially from 65% up, which accounts for 77% of the total study population. CONCLUSION: We developed an appropriate Western European population-based prediction model that is aimed to personalise counselling for term deliveries.

Item does not contain fulltext OBJECTIVE: To externally validate two models from the USA (entry-to-care [ETC] and close-to-delivery [CTD]) that predict successful intended vaginal birth after caesarean (VBAC) for the Dutch population. DESIGN: A nationwide registration-based cohort study. SETTING: Seventeen hospitals in the Netherlands. POPULATION: Seven hundred and sixty-three pregnant women, each with one previous caesarean section and a viable singleton cephalic pregnancy without a contraindication for an intended VBAC. METHODS: The ETC model comprises the variables maternal age, prepregnancy body mass index (BMI), ethnicity, previous vaginal delivery, previous VBAC and previous nonprogressive labour. The CTD model replaces prepregnancy BMI with third-trimester BMI and adds estimated gestational age at delivery, hypertensive disease of pregnancy, cervical examination and induction of labour. We included consecutive medical records of eligible women who delivered in 2010. For validation, individual probabilities of women who had an intended VBAC were calculated. MAIN OUTCOME MEASURES: Discriminative performance was assessed with the area under the curve (AUC) of the receiver operating characteristic and predictive performance was assessed with calibration plots and the Hosmer-Lemeshow (H-L) statistic. RESULTS: Five hundred and fifteen (67%) of the 763 women had an intended VBAC; 72% of these (371) had an actual VBAC. The AUCs of the ETC and CTD models were 68% (95% CI 63-72%) and 72% (95% CI 67-76%), respectively. The H-L statistic showed a P-value of 0.167 for the ETC model and P = 0.356 for the CTD model, indicating no lack of fit. CONCLUSION: External validation of two predictive models developed in the USA revealed an adequate performance within the Dutch population.