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Introduction: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis. Objective: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia. Methods: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared. Results: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility. Conclusions: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders. [Copyright &y& Elsevier]

Introduction: Blood pressure levels during pregnancy are important risk factors for gestational hypertensive disorders. Non-pregnant women from ethnic minority groups are found to have higher blood pressure levels compared to white women. Little is known about variation in blood pressure development during pregnancy across different ethnic groups. Objectives: To investigate ethnic differences in blood pressure levels in each trimester of pregnancy and the risk of gestational hypertensive disorders and the degree to which such differences can be explained by education and lifestyle related factors. Methods: The study included 6215 women participating in a population-based prospective cohort study from early pregnancy onwards in Rotterdam, The Netherlands. Ethnicity was assessed at enrolment. Blood pressure was measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Lifestyle factors included smoking, alcohol, caffeine intake, folic acid supplementation, sodium and energy intake, body mass index and maternal stress. Associations and explanatory pathways were investigated using linear and logistic regression analysis. Results: Dutch pregnant women had higher systolic blood pressure levels as compared to women in other ethnic groups in each trimester of pregnancy. Compared to Dutch women, Turkish and Moroccan women had lower diastolic blood pressure levels in each trimester. These differences remained after adjusting for education and lifestyle factors. Turkish and Moroccan women had a lower risk of gestational hypertension as compared to Dutch women (OR 0.32; 95% CI: 0.18, 0.58 and OR 0.28; 95% CI: 0.14, 0.58) and Cape Verdean women had an elevated risk of preeclampsia (OR 2.22; 95% CI: 1.22, 4.07). Differences could not be explained by education or lifestyle. Conclusion: Substantial ethnic differences were observed in blood pressure levels in each trimester of pregnancy and risk of gestational hypertensive disorders. A wide range of potential explanatory variables could not explain these differences. [Copyright &y& Elsevier]

Introduction: The prevalence of overweight and obesity among women of reproductive age is increasing. Maternal obesity seems to be associated with short-term and long-term adverse outcomes. Excessive gestational weight gain might also influence the risk of adverse pregnancy outcomes. Not much is known about risk factors of maternal obesity and excessive gestational weight gain. Also, little is known about critical periods of gestational weight gain in relation to adverse pregnancy outcomes. Objectives: We aimed to determine risk factors and maternal, fetal and childhood consequences of maternal obesity and excessive gestational weight gain. Furthermore, we examined the associations of trimester-specific weight gain with the risk of adverse pregnancy outcomes. Methods: The study was embedded in a population-based prospective cohort study among 6959 mothers and their children. Maternal anthropometrics were measured in each trimester of pregnancy. Information about maternal weight just before pregnancy, maximum weight during pregnancy and potential socio-demographic and lifestyle related determinants was obtained from questionnaire. Information about gestational hypertensive disorders and birth outcomes was obtained from medical records. Multivariate linear and logistic regression analyses were used. Results: Maternal lower educational level, lower household income, multiparity, and FTO risk allel were associated with an increased risk of maternal obesity, whereas maternal European ethnicity, nulliparity, higher total energy intake, and smoking during pregnancy were associated with an increased risk of excessive gestational weight gain (all p-values <0.05). As compared to normal weight, maternal obesity was associated with increased risks of gestational hypertension (OR 6.31 (95% CI 4.30,9.26)), preeclampsia (OR (3.61 (95% CI 2.04,6.39)), gestational diabetes (OR 6.28 (95%CI 3.01,13.06)), caesarean delivery (OR 1.91 (95% CI 1.46,2.50)), delivering large size for gestational age infants (OR 2.97 (95% CI 2.16,4.08)), and childhood obesity (OR 5.02 (95% CI:2.97,8.45)). Weaker associations of excessive gestational weight gain with these outcomes were observed, with the strongest effects for first trimester weight gain. Weight gain in first and third trimester was associated with the risk of gestational hypertension (OR 1.24 (95% CI 1.12,1.39) and OR 1.27 (95% CI 1.06,1.51) per standard deviation of change in gestational weight gain per week, respectively), whereas weight gain in third trimester was associated with the risk of preeclampsia (OR 1.35 (95% CI 1.08,1.69), per standard deviation of change in gestational weight gain per week). Conclusion: Our study shows that maternal obesity and excessive weight gain during pregnancy are associated with socio-demographic, lifestyle, and genetic factors and with increased risks of adverse maternal, fetal and childhood health outcomes. As compared to prepregnancy overweight and obesity, excessive gestational weight gain has a limited influence on adverse pregnancy outcomes. [Copyright &y& Elsevier]

Objectives: In a previous mass spectrometry study of our research group, 25 proteins were found to be differentially expressed in cerebrospinal fluid of patients with preeclampsia compared to controls. The objective of the current study was to investigate DNA methylation of the genes encoding for the former mentioned proteins in an independent dataset., Study Design: In a nested case-control study of the Rotterdam Periconceptional Cohort, placental tissue, umbilical cord white blood cells and human umbilical vein endothelial cells (HUVEC) were obtained of 13 patients with early-onset preeclampsia, 16 patients with late-onset preeclampsia and 83 normotensive controls (27 patients with fetal growth restriction, 20 patients with spontaneous preterm birth and 36 uncomplicated pregnancies). DNA methylation of 783 CpGs in regions of 25 genes was measured., Main Outcome Measures: DNA methylation of selected candidate genes in early- and late-onset preeclampsia compared to fetal growth restriction, spontaneous preterm birth and uncomplicated controls., Results: From the 783 CpGs of the 25 selected genes, 15 CpGs were differentially methylated between early-onset preeclampsia and spontaneous preterm birth (3.80 E-5 ≤ p ≤ 0.036). Four CpGs were differentially methylated between early-onset preeclampsia and fetal growth restriction (0.0002 ≤ p ≤ 0.037) and 13 CpGs were differentially methylated between early onset preeclampsia and uncomplicated controls (0.0001 ≤ p ≤ 0.04)., Conclusion: Differences in DNA methylation were found in placental tissue, umbilical cord white blood cells and HUVEC of patients with early onset preeclampsia compared to (un)complicated controls, but not in patients with late-onset preeclampsia. The genes showing the largest differential methylation encode insulin-like growth factor 2 binding protein and receptor and cadherin 13., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the feasibility and effectiveness of a postpartum lifestyle intervention after pregnancies complicated by preeclampsia, fetal growth restriction (FGR) and/or gestational diabetes mellitus (GDM) to improve maternal risk factors for future cardiometabolic disease., Methods: Women following a complicated pregnancy were included six months postpartum in this specific pre-post controlled designed study. It has been conducted in one tertiary and three secondary care hospitals (intervention group) and one secondary care hospital (control group). The program consisted of a computer-tailored health education program combined with three individual counselling sessions during seven months. Primary outcome measures were the proportion of eligible women and weight change during the intervention., Results: Two hundred and six women were willing to participate. The proportion of eligible women who complied with the intervention was 23%. Major barrier was lack of time. Adjusted weight change attributed to lifestyle intervention was -1.9 kg (95%-CI -4.3 to -0.3). Further changes were BMI (-0.9 kg/m 2 (95%-CI -1.4 to -0.3)), waist-to-hip ratio (-0.04 cm/cm (95%-CI -0.06 to -0.03)), blood pressure medication use (19% (95%-CI 9% to 28%)), HOMA2-score (59 %S (95%-CI 18 to 99)) and total fat intake (-2.9 gr (95%-CI -4.6 to -1.2))., Conclusions: The results support feasibility and effectiveness of a lifestyle intervention after complicated pregnancies to improve maternal cardiometabolic risk factors. Further randomized controlled studies are needed with longer follow-up to evaluate durability. In the meantime, we suggest health care professionals to offer lifestyle interventions to women after complicated pregnancies., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging., Methods: Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied., Results: Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves., Conclusions: We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes., (Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The aetiology of pre-eclampsia is thought to originate from aberrant spiral artery remodelling and invasion evoking cellular oxidative stress. Previously, we discovered differentially expressed proteins in trophoblast cells of pre-eclamptic pregnancies. One of these proteins is calcyclin (S100A6); a Ca(2+)-binding protein associated with cellular stress response. By immunohistochemistry on formalin-fixed paraffin-embedded placental tissue, calcyclin expression was compared between women with early pre-eclampsia (n=72) and non-hypertensive control patients (n=66) (χ(2), p=0.006) blindly by two observers. Significantly more intense staining was seen in trophoblast cells of pre-eclamptic pregnancies compared to control placentas suggesting that trophoblast calcyclin is elevated in early pregnancy., (Copyright © 2013 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: Studies on the association of preeclampsia (PE) with thrombophilias (TRPH) are conflicting. Clinical heterogeneity of PE may be one of the explanations., Objectives: The present study addresses the question whether different phenotypes of PE are associated with subtypes of TRPH., Methods: In this retrospective cohort study between 1985 until 2010 women with PE were offered postpartum screening for the following TRPH: anti-phospholipid antibodies (APA), APC-resistance, protein C deficiency and protein S deficiency (PSD), hyperhomocysteinemia (HCY), factor V Leiden and Prothrombin gene mutation., Results: 890 Women with PE were screened for TRPH. 49% Also had HELLP, 60% had IUGR, 71% delivered before the 34th week. One or more TRPH factors were present in 31% of the women. Severe PE was associated with PSD (p=0.01). IUGR (p<0.01) was associated with APA (p<0.01) and PSD (P=0.03). Early onset PE was associated with APA (P, 0.01). More than 10% of placental infarction was associated with APA (p<0.01). Placental weight below the 5th percentile was associated with HCY (p=0.03). Other phenotypes of PE and TRPH were not associated., Conclusion: Severe and early onset PE, especially if complicated by IUGR, are associated with APA and PSD. Other phenotypes of PE, especially HELLP syndrome, were not associated with TRPH. We advise to screen for APA and PSD after severe and early onset PE, especially if complicated by IUGR. We do not recommend screening for TRPH in other phenotypes of PE., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: Evidence indicates a gender specific interaction between the mother, placenta and fetus in which maternal adaptation to pregnancy and outcome partly depends on fetal gender., Objectives: This study assesses fetal gender specific differences in placental biomarkers and uteroplacental vascular resistance. Methods Within the Generation R Study, in 1st and 2nd trimester (median 13.3 and 20.4 wks) blood samples were drawn to assess soluble fms-like tyrosine kinase (s-Flt1), placental growth factor (PLGF) and plasminogen activator inhibitor 2 (PAI-2). Uteroplacental resistance was assessed by mean pulsatility index (PI) of the uterine and umbilical arteries in the 2nd trimester. Mann-Whitney U and Student's t-test were performed to assess associations of gender on the above mentioned factors., Results: In total 8631 women were included (4274 female and 4357 male fetuses). From these women, 172 had a pregnancy complicated by pre-eclampsia (1.9%). Fetal sex related differences in placental biomarkers, being most pronounced in non pre-eclamptic pregnancies (Table 1). Differences were also observed between early (<34wks) and late onset pre-eclamptic women (>34wks)., Conclusion: This study shows that maternal adaptation to pregnancy varies by fetal gender, suggesting gender specific differences in placentation and placental function. The differences between pre-eclamptic and non pre-eclamptic women, and among pre-eclamptic women, suggest that different mechanisms apply to pre-eclamptic pregnancies., (Copyright © 2013. Published by Elsevier B.V.)

Background: Preeclampsia (PE), foetal growth restriction (FGR) and preterm birth (PTB) are associated with an increased risk on the development of cardiovascular disease in offspring. Abnormal programming of the embryonic and extra-embryonic vasculature may be involved. The umbilical cord could be a good model for studying foetal vascular development., Objectives: We examined the morphology of the umbilical cord vasculature in complicated (PE, FGR, PTB) and uncomplicated pregnancies., Methods: In a case-control study, we included 105 patients consisting of PE (n=31), FGR (n=26), PTB (n=24) and controls (n=24). Macroscopic measurements were performed and tissue samples were formalin-fixed within 1 hour after birth, for microscopic analysis of digitised paraffin sections., Results: The macroscopic evaluation showed shorter umbilical cords in PE than in controls. Microscopic measurements revealed a smaller total cord area in all complicated pregnancies compared to controls. The artery wall area was smaller in PE and IUGR, and a smaller vein wall area was present in PE only, compared to controls. The percentage of elastic fibres in the vein was lower in PE and IUGR than in controls (Table 1)., Conclusion: Our study demonstrates umbilical cord vascular abnormalities in PE, FGR and PTB, suggesting early vascular damage. Future studies should focus on similar structural changes in foetal vasculature and associations with cardiovascular disease in later life., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: Women with a pregnancy complicated by preeclampsia, intra-uterine growth restriction and/or gestational diabetes are at increased risk of future cardiovascular and metabolic disease. Lifestyle intervention may help these women to effectively lower these risks., Objectives: To test if offering lifestyle intervention after a complicated pregnancy significantly improves saturated fat-intake and exercise (primary objectives) and/or smoking habits (secondary objective)., Methods: The Pro-Active study (Postpartum Rotterdam Appraisal of Cardiovascular health and Tailored Intervention) is a feasibility study to develop and evaluate a postpartum lifestyle intervention program. In a prospective case-control setting we tested the effect of the lifestyle intervention. Women were included between April 2007 and August 2009. They were eligible if ⩾18 years old at time of inclusion, being able to understand and speak the Dutch language and not having pre-existing conditions that could interfere with the lifestyle intervention. Cases were offered lifestyle intervention by a trained counsellor between 6 and 10 months postpartum. During 3 private sessions, mainly exercise and fat-intake and to some extend smoking habits were discussed and aims were made to improve lifestyle. Controls did not receive these sessions, but were not restricted to improve lifestyle on their own. Lifestyle habits were scored at 6 and 13 months postpartum. For saturated fat-intake we used the Maastricht Fatlist. For exercise we used the International Physical Activity Questionnaire (IPAQ). For smoking habits we used a short version of the questionnaire of STIVORO (the Dutch anti-smoking association). We also performed a formative evaluation of the intervention program., Results: During our study 1121 women gave birth after a complicated pregnancy. 490 Women were eligible for the study of which 240 women (49%) gave informed consent to participate. 56 Women (23%) were lost-to-follow-up, leaving 186 women for the analysis. Between 6 and 13 months postpartum saturated fat-intake was significantly reduced by 3.6g/day (95%>CI 1.8-5.4) in cases compared to controls. Exercise was improved in cases compared to controls, but it did not reach significance (277 MET's (-2699-3254)). Although smoking decreased from 14.5% to 10.4% in cases, it was not significant and comparable to the decrease in controls (15.0% to 8.4%). The formative evaluation showed that the most important motivator to improve lifestyle was the increased risk of future cardiovascular and metabolic disease (70%) and the increased risk for recurrence in a next pregnancy (57%). Main barriers were an already busy life (40%), distance (35%) and duration (38%) of travelling to the hospital and to early postpartum to pay attention to lifestyle (26%)., Conclusion: Lifestyle intervention after complicated pregnancy may be effective in improving saturated fat-intake. Other interventions, specially aimed at postpartum women, are needed to improve exercise and smoking habits. More research is needed to develop lifestyle intervention program specifically aimed at these women. New possibilities of multimedia are promising., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Women with a pregnancy complicated by preeclampsia, intra-uterine growth restriction and/or gestational diabetes are at increased risk of future cardiovascular and metabolic disease. Lifestyle intervention may help these women to effectively lower these risks., Objectives: To test if offering lifestyle intervention after a complicated pregnancy significantly reduces weight (primary objective) and/or other cardiovascular and metabolic risk factors (secondary objective)., Methods: The Pro-Active study (Postpartum Rotterdam Appraisal of Cardiovascular health and Tailored Intervention) is a feasibility study to develop and evaluate a postpartum lifestyle intervention program. In a prospective case-control setting we tested the effect of the lifestyle intervention. Women were included between April 2007 and August 2009. They were eligible if ⩾18 years old at time of inclusion, being able to understand and speak the Dutch language and not having pre-existing conditions that could interfere with the lifestyle intervention. Cases were offered lifestyle intervention by a trained counsellor between 6 and 10 months postpartum. During 3 private sessions, mainly exercise and fat-intake and to some extend smoking habits were discussed and aims were made to improve lifestyle. Controls did not receive these sessions, but were not restricted to improve lifestyle on their own. Anthropometric and laboratory measurements were taken at 6 and 10 months postpartum and again at 13 months postpartum to test for durability of the effects., Results: During our study 1121 women gave birth after a complicated pregnancy. Four hundred and ninety Women were eligible for the study of which 240 women (49%) gave informed consent to participate. 56 Women (23%) were lost-to-follow-up, leaving 186 women for the analysis. Between 6 and 13 months postpartum weight was significantly reduced in cases compared to controls by 2.1kg (95%>CI 0.4-3.7), resulting in a 0.7kg/m(2) (0.1-1.3) lower BMI. Also systolic blood pressure (5.0mmHg(0.3-9.7)), waist circumference (4.6cm(2.6-6.6)) and waist-to-hip ratio (0.03(0.01-0.04)) were significantly improved in cases compared to controls. Heart rate, hip circumference and total cholesterol were significantly improved within cases, but not compared to controls. Diastolic blood pressure and fasting glucose were not improved., Conclusion: Lifestyle intervention after complicated pregnancy may be effective in lowering weight and improving other cardiovascular and metabolic risk factors. It suggests that now is prudent and justified to start a large-scale randomised controlled trial to validate our results., (Copyright © 2012. Published by Elsevier B.V.)