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Marleen MHJ van Gelder,1 Pim Beekers,1,2 Yrea RJ van Rijt-Weetink,3 Joris van Drongelen,4 Nel Roeleveld,1 Luc JM Smits5 1Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; 2National Health Care Institute, Diemen, the Netherlands; 3Netherlands Pharmacovigilance Centre Lareb,‘s-Hertogenbosch, the Netherlands; 4Department of Obstetrics & Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands; 5Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, the NetherlandsCorrespondence: Marleen MHJ van Gelder, Department for Health Evidence (HP 133), Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, the Netherlands, Tel +31 24 3615305, Fax +31 24 3613505, Email Marleen.vanGelder@radboudumc.nlPurpose: Preeclampsia is a leading cause of maternal morbidity and mortality. Calcium-based antacids and proton pump inhibitors (PPIs) are commonly used during pregnancy to treat symptoms of gastroesophageal reflux disease. Both have been hypothesized to reduce the risk of preeclampsia. We determined associations of calcium-based antacid and PPI use during pregnancy with late-onset preeclampsia (≥ 34 weeks of gestation), taking into account dosage and timing of use.Patients and Methods: We included 9058 pregnant women participating in the PRIDE Study (2012– 2019) or The Dutch Pregnancy Drug Register (2014– 2019), two prospective cohorts in The Netherlands. Data were collected through web-based questionnaires and obstetric records. We estimated risk ratios (RRs) for late-onset preeclampsia for any use and trajectories of calcium-based antacid and PPI use before gestational day 238, and hazard ratios (HRs) for time-varying exposures after gestational day 237.Results: Late-onset preeclampsia was diagnosed in 2.6% of pregnancies. Any use of calcium-based antacids (RR 1.2 [95% CI 0.9– 1.6]) or PPIs (RR 1.4 [95% CI 0.8– 2.4]) before gestational day 238 was not associated with late-onset preeclampsia. Use of low-dose calcium-based antacids in gestational weeks 0– 16 (< 1 g/day; RR 1.8 [95% CI 1.1– 2.9]) and any use of PPIs in gestational weeks 17– 33 (RR 1.6 [95% CI 1.0– 2.8]) seemed to increase risks of late-onset preeclampsia. We did not observe associations between late-onset preeclampsia and use of calcium-based antacids (HR 1.0 [95% CI 0.6– 1.5]) and PPIs (HR 1.4 [95% CI 0.7– 2.9]) after gestational day 237.Conclusion: In this prospective cohort study, use of calcium-based antacids and PPIs during pregnancy was not found to reduce the risk of late-onset preeclampsia.Keywords: extended Cox models, gestational hypertension, gastroesophageal reflux disease, longitudinal clustering methods, PRIDE study, The Dutch Pregnancy Drug Register

Objective: Obesity and pre‐eclampsia (PE) are both associated with vascular dysfunction, which translates into an increased risk for cardiovascular disease in later life. The aim of this study was to investigate whether there is an interaction between body mass index (BMI) and a history of PE in their effects on vascular health. Methods: This was an observational case–control study of 30 women with a history of PE who were compared with 31 age‐ and BMI‐matched controls who had an uncomplicated pregnancy. Flow‐mediated dilation (FMD), carotid intima–media thickness (cIMT) and carotid distensibility (CD) were measured 6–12 months postpartum. To evaluate the impact of physical fitness, maximum oxygen uptake capacity was assessed using a standardized maximum exhaustion cycling test using breath‐by‐breath analysis. To specify further BMI subgroups, metabolic syndrome constituents were assessed in all individuals. Results: Formerly pre‐eclamptic women had significantly lower FMD (5.1 ± 2.1% vs 9.4 ± 3.4%; P < 0.01), higher cIMT (0.59 ± 0.09 vs 0.49 ± 0.07 µm; P < 0.01) and lower CD (1.54 ± 0.37%/10 mmHg vs 1.80 ± 0.39%/10 mmHg; P < 0.01) compared with controls. In our study, population BMI correlated negatively with FMD (P = 0.04) but not with cIMT or CD. BMI and PE did not exhibit an interaction effect on these vascular parameters. Physical fitness was lower in women with a history of PE and in women with higher BMI. Constituents of the metabolic syndrome, including insulin, homeostasis model assessment for insulin resistance (HOMA‐ir), triglyceride, microalbuminuria and systolic and diastolic blood pressure, were significantly higher in formerly pre‐eclamptic women. BMI affected glucose metabolism but not lipids or blood pressure. BMI and PE positively interacted in their effect on insulin (P = 0.04) and HOMA‐ir (P = 0.02). Conclusions: Both BMI and a history of PE have negative effects on endothelial function, insulin resistance and physical fitness. In formerly pre‐eclamptic women, the effect of BMI on insulin resistance was particularly high, suggesting a synergistic effect. Additionally, independently of BMI, a history of PE was associated with reduced FMD and CD and increased cIMT and blood pressure. Recognizing the cardiovascular risk profile is important for informing patients and encouraging targeted lifestyle modifications. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objectives: Fetal endoscopic tracheal occlusion (FETO) improves neonatal survival of fetuses with congenital diaphragmatic hernia (CDH). However, FETO also increases the risk of preterm prelabor rupture of membranes (PPROM) and preterm delivery (PTD), as fetal membrane defects after fetoscopy do not heal. To solve this issue, an advanced sealing plug for closing the membrane defect is being developed. Using early‐stage health economic modeling, we aimed to estimate the potential value of this innovative plug in terms of costs and effects, and to determine the properties required for it to become cost‐effective. Methods: Early‐stage health economic modeling was applied to the case of performing FETO in women with a singleton pregnancy whose fetus is diagnosed prenatally with CDH. We simulated a cohort of patients using a state‐transition model over a 45‐year time horizon. In our best‐case‐scenario analysis, we compared the current‐care strategy with the perfect‐plug strategy, which reduces the risk of PPROM and PTD by 100%, to determine the maximum quality‐adjusted life years (QALYs) gained and costs saved. Using threshold analysis, we determined the minimum percentage reduction in the risk of PPROM and PTD required for the plug to be considered cost‐effective. The impact of model parameters on outcome was investigated using a sensitivity analysis. Results: Our model indicated that a perfect‐plug strategy would yield on average an additional 1.94 QALYs at a cost decrease of €2554 per patient. These values were influenced strongly by the percentage of cases with early PTD (27–34 weeks). Threshold analysis showed that, for €500 per plug, the plug strategy needs a minimum percentage reduction of 1.83% in the risk of PPROM and PTD (i.e. reduction in the risk from 47.50% to 46.63% for PPROM and from 71.50% to 70.19% for PTD) to be cost‐effective. Conclusions: Our model‐based approach showed clear potential of the plug strategy when applied in the context of FETO for CDH fetuses, as only a minor reduction in the risk of PPROM and PTD is needed for the plug to be cost‐effective. Its value is expected to be even higher when used in conditions associated with a higher rate of early PTD. Continued investment in research and development of the plug strategy appears to provide value for money. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This article discusses a study that explores the potential benefits of using sonographic tomography (ST) compared to conventional two-dimensional ultrasound (2D) for first trimester anomaly screening (FTAS) in pregnancy. The study developed an early-stage health economic model and simulated the outcomes for a theoretical cohort of 180,000 people. The results showed that ST could be a more cost-effective option, saving €90,000,000 annually in the Netherlands. However, further research is needed to estimate the consequences more precisely and determine the optimal test characteristics for ST. [Extracted from the article]

This article discusses a randomized controlled trial comparing the effectiveness of cervical pessary and vaginal progesterone in preventing preterm birth in multiples with a short cervix. The study was conducted in the Netherlands and included asymptomatic individuals with a multiple pregnancy and a mid-gestation cervical length of less than 38mm. The primary outcome was a composite of adverse perinatal outcomes, and the secondary outcomes included rates of preterm birth at various gestational ages. The study found that neither the pessary nor the progesterone treatment resulted in statistically significant differences in the prevention of adverse perinatal outcomes. [Extracted from the article]

Background: In‐depth insight into haemodynamic changes during normotensive pregnancy may help identify women at risk for gestational hypertensive complications. Objectives: To determine the magnitude of changes in cardiac output and its determinants stroke volume and heart rate, and total peripheral vascular resistance during singleton normotensive and hypertensive pregnancies. Search strategy: PubMed (NCBI) and Embase (Ovid) databases were searched from their inception up to November 2019. Selection criteria: Studies reporting original measurements of haemodynamic parameters during pregnancy together with a non‐pregnant reference measurement. Studies including women using antihypertensive medication were excluded. Data collection and analysis: Pooled mean differences between pregnant and non‐pregnant women, and absolute values of haemodynamic parameters were calculated for predefined gestational intervals using a random‐effects model in normotensive and hypertensive pregnancy. Meta‐regression analysis was used to analyse group differences in adjustments and absolute values during pregnancy. Main results: In normotensive pregnancies, cardiac output increased from the first weeks on, reaching its highest level early in the third trimester (mean difference, 1.41 l·min1; 95% CI 1.18–1.63 l·min). In parallel, vascular resistance decreased progressively until its nadir in the early third trimester (mean difference, −331 dyn·sec–1·cm–5; 95% CI −384 to −277 dyn·sec–1·cm–5) and then increased slightly at term. In hypertensive pregnancies, the initial cardiac output increase was higher and vascular resistance did not change throughout gestation compared with reference values. Conclusions: Hemodynamic changes in women who eventually develop hypertensive complications are substantially different. Serial monitoring and plotting against developed normograms can identify women at risk and may allow timely intervention. Monitoring haemodynamic changes in pregnancy helps identify women at risk for hypertensive complications. Monitoring haemodynamic changes in pregnancy helps identify women at risk for hypertensive complications. [ABSTRACT FROM AUTHOR]

Introduction: An increasing number of women becomes pregnant while suffering from chronic kidney disease (CKD). As a result of decreased renal function, uremic solutes circulate at high levels in the maternal circulation. This study aimed to acquire more knowledge about the placental transfer of uremic solutes across the human placenta.Methods: Placental transfer was studied in healthy term placentas, via the ex vivo dual-side human cotyledon perfusion technique (closed-closed set-up for both maternal and fetal circulations). Uremic solute concentrations in maternal and fetal perfusates were measured via LC-MS/MS over 180 min of perfusion.Results: We found that the studied compounds demonstrated different degrees of placental transfer. Fetal-to-maternal perfusate ratios at t = 180 min were for anthranilic acid 1.00 ± 0.02, indole-3-acetic acid 0.47 ± 0.08, hippuric acid 0.36 ± 0.18, l-arabinitol 0.33 ± 0.04, indoxyl sulfate 0.33 ± 0.11, neopterin 0.28 ± 0.14 and kynurenic acid 0.13 ± 0.03. All uremic solutes studied also emerged in the perfusates when cotyledons were perfused in the absence of uremic solute concentrations added to the maternal reservoir. For kynurenin these concentrations were so high, it complicated the calculation of a transfer ratio for the exogenously administered compound.Discussion: After 180 min of exposure the extent of placental transfer differs substantially for the solutes studied, reflecting different transfer rates. Future studies should investigate to what extent specific uremic solutes reach the fetal circulation in vivo and how they may interfere with organ function and development of the unborn child. [ABSTRACT FROM AUTHOR]

Objectives: To review systematically current literature on kidney function changes during pregnancy, in order to estimate the extent of adaptation over the course of both healthy physiological and complicated singleton pregnancies, and to determine healthy pregnancy reference values.Methods: PubMed (NCBI) and EMBASE (Ovid) electronic databases were searched, from inception to July 2017, for studies on kidney function during uncomplicated and complicated pregnancies. Included studies were required to report a non-pregnant reference value of kidney function (either in a non-pregnant control group or as a prepregnancy or postpartum measurement) and a pregnancy measurement at a predetermined and reported gestational age. Kidney function measures assessed were glomerular filtration rate (GFR) measured by inulin clearance, GFR measured by creatinine clearance and serum creatinine level. Pooled mean differences between pregnancy measurements and reference values were calculated for predefined intervals of gestational age in uncomplicated and complicated pregnancies using a random-effects model described by DerSimonian and Laird.Results: Twenty-nine studies met the inclusion criteria and were included in the analysis. As early as the first trimester, GFR was increased by up to 40-50% in physiological pregnancy when compared with non-pregnant values. Inulin clearance in uncomplicated pregnancy was highest at 36-41 weeks, with a 55.6% (53.7; 95% CI, 44.7-62.6 mL/min) increase when compared with non-pregnant values, and creatinine clearance was highest at 15-21 weeks' gestation, with a 37.6% (36.6; 95% CI, 26.2-46.9 mL/min) increase. Decrease in serum creatinine level in uncomplicated pregnancy was most prominent at 15-21 weeks, with a 23.2% (-0.19; 95% CI, -0.23 to -0.15 mg/dL) decrease when compared with non-pregnant values. Eight studies reported on pregnancies complicated by a hypertensive disorder. Meta-regression analysis showed a significant difference in all kidney function parameters when comparing uncomplicated and hypertensive complicated pregnancies.Conclusions: In healthy pregnancy, GFR is increased as early as the first trimester, as compared with non-pregnant values, and the kidneys continue to function at a higher rate throughout gestation. In contrast, kidney function is decreased in hypertensive pregnancy. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: Prepregnancy reduced plasma volume (PV) increases the risk of subsequent pre-eclamptic pregnancy. Reduced PV is thought to reflect venous reserve capacity, especially when venous vasculature is constricted and sympathetic tone is elevated. As obesity might affect these variables, and is associated with pre-eclampsia, increased body weight may underlie these observations. The aim of this study was to determine whether the relationship between reduced venous reserve and pre-eclampsia is independent of body mass index (BMI).Methods: This was an observational case-control study in which venous reserve capacity in 30 formerly pre-eclamptic, but currently non-pregnant, women divided equally into three groups based on BMI (BMI 19.5-24.9, 25.0-29.9 or ≥ 30.0 kg/m2 ), was compared with that in 30 healthy parous, non-pregnant controls. Cases and controls were matched for BMI, age and parity. Venous reserve capacity was quantified by assessing PV and venous compliance (VeC). The autonomic nervous system regulating venous capacitance was evaluated using heart rate (HR) variability analysis, with the women in a resting supine position and during positive head-up tilt (HUT).Results: Compared with controls, formerly pre-eclamptic women had, when in a resting supine position, lower PV (1339 ± 79 vs 1547 ± 139 mL/m2 (P < 0.0001)), lower VeC (0.04 ± 0.02 vs 0.07 ± 0.02 mL/dL/mmHg (P < 0.0001)), higher sympathetic tone (1.9 ± 1.1 vs 1.2 ± 0.7 (P = 0.002)) and lower baroreceptor sensitivity (BRS; 8.7 ± 3.8 vs 19.0 ± 1.7 ms/mmHg (P < 0.0001)). During HUT, women with a history of pre-eclampsia had less modulatory capacity over VeC and BRS, while HR and sympathetic tone remained consistently higher.Conclusions: Women with a history of pre-eclampsia had reduced venous reserve capacity compared with that in BMI-matched controls. This is reflected by lower PV and VeC, with the autonomic balance being shifted towards sympathetic dominance and lower BRS. This suggests that underlying reduced venous reserve, but not BMI, relates to pre-eclampsia. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: The aim of this systematic review and meta-analysis was to describe comprehensively the pattern of cardiac remodeling during normotensive human singleton pregnancy and to compare it with that of pregnancy complicated by hypertension.Methods: We performed a meta-analysis of the current literature on cardiac remodeling during normotensive and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies needed to report a reference measurement (matched non-pregnant control group, prepregnancy or postpartum) and measurements made during predetermined gestational-age intervals. Mean differences between reference and pregnancy data were calculated using the random-effects model described by DerSimonian and Laird.Results: Forty-eight studies were included in the meta-analysis, with publication dates ranging from 1977 to 2016. During normotensive pregnancy, most geometric indices started to increase in the second trimester. Left ventricular mass (LVM) increased by 28.36 (95% CI, 19.73-37.00) g (24%), and relative wall thickness (RWT) increased by 0.03 (95% CI, 0.02-0.05) (10%) compared with those in the reference group. During hypertensive pregnancy, LVM and RWT increased more than during normotensive pregnancy (92 (95% CI, 75.46-108.54) g (95%) and 0.14 (95% CI, 0.09-0.19) (56%), respectively).Conclusions: During normotensive pregnancy, most cardiac geometric indices change from the second trimester onwards. Both LVM and RWT increase, by 20% and 10%, respectively, consistent with concentric rather than eccentric remodeling. Cardiac adaptation in hypertensive pregnancy deviates from that in healthy pregnancy by a greater change in LVM (95% increase from reference) and RWT (56% increase from reference). Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

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Objective: To describe the physiological pattern of gestational plasma volume adjustments in normal singleton pregnancy and compare this with the pattern in pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction.Methods: We performed a meta-analysis of the current literature on plasma volume adjustments during physiological and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies reported both reference plasma volume measurements (non-pregnant, prepregnancy or postpartum) and measurements obtained during predetermined gestational ages. Mean differences bet ween the reference and pregnancy plasma volume measurements were calculated for predefined intervals of gestational age using a random-effects model described by DerSimonian and Laird.Results: Thirty studies were included in the meta-analysis with publication dates ranging from 1934 to 2007. Plasma volume increased in the first weeks of pregnancy, with the steepest increase occurring during the second trimester. Plasma volume continued to increase in the third trimester with a pooled maximum increase of 1.13 L (95% CI, 1.07-1.19 L), an increase of 45.6% (95% CI, 43.0-48.1%) in physiological pregnancies compared with the reference value. The plasma volume expansion in gestational hypertensive and growth-restricted pregnancies was 0.80 L (95% CI, 0.59-1.02 L), an increase of 32.3% (95% CI, 23.6-41.1%) in the third trimester, a smaller increase than in physiological pregnancies (P < 0.0001).Conclusions: During physiological pregnancy, plasma volume increases by, on average, more than 1 L as compared with non-pregnant conditions. In pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction, plasma volume increase in the third trimester is 13.3% lower than in normal pregnancy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Adaptación fisiológica del volumen del plasma materno durante el embarazo: una revisi\xF3n sistemática y metaanálisis RESUMEN OBJETIVO: Describir el patrón fisiológico de los cambios en el volumen del plasma gestacional en embarazos normales con feto único y compararlo con el patrón en los embarazos complicados por hipertensión gestacional, preeclampsia o restricción del crecimiento fetal. MÉTODOS: Se realizó un metaanálisis de la literatura actual sobre los cambios en el volumen de plasma durante embarazos complicados y fisiológicos. La literatura se obtuvo de las bases de datos PubMed (NCBI) y EMBASE (Ovid). Los estudios incluidos mencionaban tanto mediciones de referencia del volumen plasmático (no embarazada, antes del embarazo o después del parto) como mediciones tomadas a edades gestacionales predeterminadas. Se calcularon las medias de las diferencias entre las mediciones de referencia y las del embarazo para el volumen plasmático a intervalos predefinidos de la edad gestacional, utilizando un modelo de efectos aleatorios descrito por DerSimonian y Laird.Resultados: En el metaanálisis se incluyeron treinta estudios con fechas de publicación entre 1934 y 2007. El volumen plasmático aumentó en las primeras semanas de embarazo y el mayor incremento se produjo durante el segundo trimestre. El volumen de plasma continuó aumentando en el tercer trimestre con un aumento combinado máximo de 1,13L (IC 95%, 1,7-1,19 L), lo que supone un aumento del 45,6% (IC 95%, 43,0-48,1%) en embarazos fisiológicas en comparación con el valor de referencia. El aumento del volumen plasmático en los embarazos con hipertensión y con crecimiento intrauterino restringido fue de 0,80L (IC 95%, 0,59-1,02 L), lo que supone un aumento del 32,3% (IC 95%, 23,6-41,1%) en el tercer trimestre, y un incremento menor que en los embarazos fisiológicos (P <0,0001).Conclusiones: Durante el embarazo fisiológico el volumen de plasma aumenta, en promedio, más de 1L, en comparación con el de las no embarazadas. En los embarazos complicados por hipertensión gestacional, preeclampsia o restricción del crecimiento fetal, el aumento del volumen plasmático en el tercer trimestre es un 13,3% menor que en el embarazo normal. :meta : ,、。 : meta。PubMed(NCBI)EMBASE(Ovid)。(、)。DerSimonianLaird,。 : Meta30,19342007。,。,1.13 L(95% CI,1.07~1.19 L),,45.6%(95% CI,43.0%~48.1%)。0.80 L(95%CI,0.59~1.02 L),32.3%(95% CI,23.6%~41.1%),(P<0.0001)。 : ,,1 L。、,13.3%。. [ABSTRACT FROM AUTHOR]

Background: To optimise the health of pregnant women and their children by evidence-based primary and secondary prevention, more scientific knowledge is needed. To overcome the methodological limitations of many studies on pregnancy and child health, which often use a retrospective design, we established the PRIDE (PRegnancy and Infant DEvelopment) Study.Methods and Results: The PRIDE Study is a large prospective cohort study that aims at including 150 000-200 000 women in early pregnancy to study a broad range of research questions pertaining to pregnancy complications, maternal and child health, and adverse developmental effects in offspring. Women are invited to participate by their prenatal care provider before or at their first prenatal care visit and are asked to fill out web-based questionnaires in gestational weeks 8-10, 17, and 34, as well as biannually throughout childhood. In addition, a food frequency questionnaire and a paternal questionnaire are administered and medical records are consulted. Multiple validation studies will be conducted and paper-and-pencil questionnaires are available for women who cannot or do not want to participate through the Internet. For subgroups of participants, blood and saliva samples for genetic and biochemical analyses are being collected. The pilot phase, which started in July 2011, showed a response rate of 47%. Recruitment will eventually cover all of the Netherlands.Conclusions: We expect that this study, which will be the largest birth cohort in the world so far, will provide new insights in the aetiology of disorders and diseases that originate in pregnancy. The PRIDE Study is open for collaboration. [ABSTRACT FROM AUTHOR]

Currently, tacrolimus is the most potent immunosuppressive agent for renal transplant recipients and is commonly prescribed during pregnancy. As data on placental exposure and transfer are limited, we studied tacrolimus placental handling in samples obtained from renal transplant recipients. We found transfer to venous umbilical cord blood, but particularly noted a strong placental accumulation. In patient samples, tissue concentrations in a range of 55–82 ng/g were found. More detailed ex vivo dual-side perfusions of term placentas from healthy women revealed a tissue-to-maternal perfusate concentration ratio of 113 ± 49 (mean ± SEM), underlining the placental accumulation found in vivo . During the 3 h ex vivo perfusion interval no placental transfer to the fetal circulation was observed. In addition, we found a non-homogeneous distribution of tacrolimus across the perfused cotyledons. In conclusion, we observed extensive accumulation of tacrolimus in placental tissue. This warrants further studies into potential effects on placental function and immune cells of the placenta. [ABSTRACT FROM AUTHOR]