Publications by authors named "Chahinda Ghossein-Doha"

31 Publications

Better COVID-19 Intensive Care Unit survival in females, independent of age, disease severity, comorbidities, and treatment.

Sci Rep 2022 01 14;12(1):734. Epub 2022 Jan 14.

Department of Intensive Care Medicine, Maastricht University Medical Center + (Maastricht UMC+), P. Debyelaan 25, 6229 HX, Maastricht, the Netherlands.

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.
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http://dx.doi.org/10.1038/s41598-021-04531-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760268PMC
January 2022

Blood pressure adjustments throughout healthy and hypertensive pregnancy: A systematic review and meta-analysis.

Pregnancy Hypertens 2021 Dec 11;27:51-58. Epub 2021 Dec 11.

Department of Obstetrics and Gynecology, Maastricht University Medical Center, PO box 5800, 6202 AZ Maastricht, The Netherlands; Department of Obstetrics and Gynecology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Gestational hypertensive complications are preceded by deviant hemodynamic adjustments affecting blood pressure. Our objective was to determine the timing and magnitude of changes in blood pressure during singleton normotensive and hypertensive pregnancies. PubMed (NCBI) and Embase (Ovid) databases were searched for relevant studies up to November 2019. Studies reporting original blood pressure measurements during pregnancy together with a non-pregnant reference measurement were included. Studies including women with a history of cardiovascular or metabolic disease, or women using antihypertensive drugs were excluded. Pooled mean differences between pregnant and non-pregnant women, and absolute blood pressure values were calculated for predefined gestational intervals in normotensive and hypertensive pregnancy, using a random-effects model. Meta-regression analysis was used to analyze group differences in adjustments. In early normotensive pregnancy, both systolic and diastolic blood pressure decreased, reaching their maximum reduction of -4 mmHg (95%CI -6 to -1 mmHg) and -4 mmHg (95%CI, -5 to -3 mmHg), respectively in the second trimester. Thereafter, blood pressure gradually increased towards non-pregnant values. All absolute blood pressure measurements throughout normotensive pregnancy were below 130/80 mmHg. In hypertensive pregnancies, only diastolic blood pressure decreased early in pregnancy. In conclusion, this meta-analysis showed a clinically moderate, but significant mid-pregnancy drop in blood pressure during normotensive pregnancy. Reference curves with absolute values underscore the current liberal cut-off limit for gestational hypertension. A lack of a mid-pregnancy systolic blood pressure drop might reflect increased vascular resistance in women destined to develop hypertensive pregnancy complications.
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http://dx.doi.org/10.1016/j.preghy.2021.12.004DOI Listing
December 2021

Inappropriate left ventricular mass after HELLP syndrome inappropriate LVM after HELLP syndrome.

Pregnancy Hypertens 2021 Nov 12;27:16-22. Epub 2021 Nov 12.

Department of Obstetrics and Gynecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands; Department of Cardiology, Heart & Vascular Centre, Maastricht University Medical Center (MUMC), the Netherlands.

Objectives: Excessive left ventricular mass (LVM) results in inefficient LV work with energy waste leading to a negative prognostic effect. We aimed at investigating the presence of inappropriate LVM and calculating the myocardial mechano-energetic efficiency index (MEEi) in former pre-eclamptic (PE) women (with or without HELLP syndrome) compared to women who experienced HELLP syndrome without PE.

Study Design: In this cross-sectional study, women with a history of normotensive HELLP (n = 32), PE without HELLP (n = 59), and PE with HELLP (n = 101) underwent echocardiography as part of the clinical CV work-up after their complicated pregnancies from 6 months to 4 years postpartum. We excluded women with comorbidities, including chronic hypertension, hypercholesterolemia, and obesity.

Main Outcome Measures: LVM excess was calculated as the ratio between observed LVM and predicted LVM (by sex, stroke work and height), while MEEi was considered as the ratio between stroke work and "double product" (to approximate energy consumption), indexed to LVM.

Results: LV hypertrophy was present in 8-14% and concentric remodeling in 31-42% of women, without intergroup difference. LVM was inappropriate in one-third of normotensive former HELLP and in about one-half of PE with or without HELLP, with no difference among groups. Accordingly, without nominal difference, MEEi showed a tendency towards lower values in former pre-eclamptic individuals.

Conclusions: Women with a history of HELLP syndrome, independently from the presence/absence of PE, showed inappropriate LVM in the first 4 years after delivery, which may partially explain the elevated CV risk in these women compared to the general female population.
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http://dx.doi.org/10.1016/j.preghy.2021.11.003DOI Listing
November 2021

Differences and Similarities Among Coronavirus Disease 2019 Patients Treated in Seven ICUs in Three Countries Within One Region: An Observational Cohort Study.

Crit Care Med 2021 10 12. Epub 2021 Oct 12.

Department of Intensive Care, Ziekenhuis Oost-Limburg, Genk, Belgium. UHasselt, Faculty of Medicine and Life Sciences, Diepenbeek, Belgium. Department of Intensive Care, Maastricht University Medical Center +, Maastricht, The Netherlands. Department of Intensive Care, Laurentius Ziekenhuis, Roermond, The Netherlands. Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands. Department of Intensive Care, Jessa Hospital, Hasselt, Belgium. Department of Intensive Care, VieCuri Medisch Centrum, Venlo, The Netherlands. Department of Intensive Care, Zuyderland Medisch Centrum, Heerlen/Sittard, The Netherlands. Department of Surgery, Maastricht University Medical Center +, Maastricht, The Netherlands. School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands. Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands. Division for Acute and Emergency Medicine, Maastricht University Medical Center +, Maastricht, The Netherlands. Department of Intensive Care, University Hospital Rheinisch Westfälische Hochschule Aachen, Aachen, Germany.

Objectives: To investigate healthcare system-driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries.

Design: Multicenter observational cohort study.

Setting: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany.

Patients: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave.

Interventions: None.

Measurements And Main Results: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 (p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 (p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively (p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications.

Conclusions: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems' organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019.
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http://dx.doi.org/10.1097/CCM.0000000000005314DOI Listing
October 2021

Hemostasis and fibrinolysis in COVID-19 survivors 6 months after intensive care unit discharge.

Res Pract Thromb Haemost 2021 Aug 24;5(6):e12579. Epub 2021 Sep 24.

Central Diagnostic Laboratory Maastricht University Medical Centre+ Maastricht the Netherlands.

Background: The prothrombotic phenotype has been extensively described in patients with acute coronavirus disease 2019 (COVID-19). However, potential long-term hemostatic abnormalities are unknown.

Objective: To evaluate the changes in routine hemostasis laboratory parameters and tissue-type plasminogen activator (tPA) rotational thromboelastometry (ROTEM) 6 months after COVID-19 intensive care unit (ICU) discharge in patients with and without venous thromboembolism (VTE) during admission.

Methods: Patients with COVID-19 of the Maastricht Intensive Care COVID cohort with tPA ROTEM measurement at ICU and 6-month follow-up were included. TPA ROTEM is a whole blood viscoelastic assay that illustrates both clot development and fibrinolysis due to simultaneous addition of tissue factor and tPA. Analyzed ROTEM parameters include clotting time, maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT).

Results: Twenty-two patients with COVID-19 were included and showed extensive hemostatic abnormalities before ICU discharge. TPA ROTEM MCF (75 mm [interquartile range, 68-78]-59 mm [49-63];  ≤ .001), LOT (3690 seconds [2963-4418]-1786 seconds [1465-2650];  ≤ .001), and LT (7200 seconds [6144-7200]-3138 seconds [2591-4389];  ≤ .001) normalized 6 months after ICU discharge. Of note, eight and four patients still had elevated fibrinogen and D-dimer concentrations at follow-up, respectively. In general, no difference in median hemostasis parameters at 6-month follow-up was observed between patients with (n=14) and without (n=8) VTE, although fibrinogen appeared to be lower in the VTE group (VTE-, 4.3 g/L [3.7-4.7] vs VTE+, 3.4 g/L [3.2-4.2];  = .05).

Conclusions: Six months after COVID-19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased D-dimer and fibrinogen concentrations persist up to 6 months in some patients, warranting further exploration of the role of hemostasis in long-term morbidity after hospital discharge.
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http://dx.doi.org/10.1002/rth2.12579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463660PMC
August 2021

Maternal myocardial dysfunction after hemolysis, elevated liver enzymes, and low platelets syndrome: a speckle-tracking study.

J Hypertens 2021 10;39(10):1956-1963

Department of Obstetrics and Gynecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), The Netherlands.

Objectives: Pregnancy complicated by pre-eclampsia (PE) and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is associated with an increased risk of cardiovascular (CV) diseases later in life. Subclinical cardiac alterations precede eminent CV diseases. Speckle-tracking echocardiography (STE) is an effective method to assess subclinical myocardial dysfunction. We performed a myocardial speckle tracking study to investigate the prevalence of subclinical myocardial dysfunction in former PE patients (with and without HELLP syndrome) compared to normotensive women affected by HELLP syndrome.

Methods: In this cross-sectional retrospective study, women with a history of normotensive HELLP (n = 32), PE without HELLP (n = 59), and PE with HELLP (n = 101) underwent conventional and STE as part of the clinical CV work-up after their complicated pregnancies from 6 months to 4 years postpartum. We excluded women with comorbidities, including chronic hypertension, hypercholesterolemia, and obesity.

Results: Women with a history of PE with HELLP syndrome were characterized by a higher prevalence of altered left ventricular circumferential and global longitudinal two-dimensional (2D) strain (74 and 20%, respectively), altered right ventricular longitudinal 2D strain (37%), and left atrial (LA) 2D strain (57%). Moreover, a higher proportion of alterations of biventricular and LA strains was also present in former PE without HELLP as well as in the normotensive HELLP group.

Conclusions: In the first years after a pregnancy complicated by HELLP syndrome, irrespective of whether there was concomitant PE, a higher rate of abnormal STE myocardial function is observed. Therefore, these women may benefit from CV risk management.
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http://dx.doi.org/10.1097/HJH.0000000000002901DOI Listing
October 2021

7T dynamic contrast-enhanced MRI for the detection of subtle blood-brain barrier leakage.

J Neuroimaging 2021 09 23;31(5):902-911. Epub 2021 Jun 23.

Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.

Background And Purpose: Dynamic contrast-enhanced MRI (DCE-MRI) can be employed to assess the blood-brain barrier (BBB) integrity. Detection of BBB leakage at lower field strengths (≤3T) is cumbersome as the signal is noisy, while leakage can be subtle. Utilizing the increased signal-to-noise ratio at higher field strengths, we explored the application of 7T DCE-MRI for assessing BBB leakage.

Methods: A dual-time resolution DCE-MRI method was implemented at 7T and a slow injection rate (0.3 ml/s) and low dose (3 mmol) served to obtain signal changes linearly related to the gadolinium concentration, that is, minimized for T degradation effects. With the Patlak graphical approach, the leakage rate (K ) and blood plasma volume fraction (v ) were calculated. The method was evaluated in 10 controls, an ischemic stroke patient, and a patient with a transient ischemic attack.

Results: K and v were significantly higher in gray matter compared to white matter of all participants. These K values were higher in both patients compared to the control subjects. Finally, for the lesion identified in the ischemic stroke patient, higher leakage values were observed compared to normal-appearing tissue.

Conclusion: We demonstrate how a dual-time resolution DCE-MRI protocol at 7T, with administration of half the clinically used contrast agent dose, can be used for assessing subtle BBB leakage. Although the feasibility of DCE-MRI for assessing the BBB integrity at 3T is well known, we showed that a continuous sampling DCE-MRI method tailored for 7T is also capable of assessing leakage with a high sensitivity over a range of K values.
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http://dx.doi.org/10.1111/jon.12894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519128PMC
September 2021

Adaptation of left ventricular diastolic function to pregnancy: a systematic review and meta-analysis.

J Hypertens 2021 10;39(10):1934-1941

Department of Cardiology, Maastricht University Medical Center (MUMC+), The Netherlands.

Objective: To meta-analytically determine the adaptation of left ventricular diastolic function (LVDF)-indices to singleton normotensive pregnancies.

Methods: Literature was retrieved from PubMed and Embase. We included studies that reported a nonpregnant reference measurement and LVDF indices (mitral inflow signals, left atrial volume and tissue Doppler measurements). Mean differences between pregnant and reference measurements and weighted means of absolute values were calculated using a random-effects model.

Results: We included 34 eligible studies. Normotensive pregnancies were characterized by an initially larger increase in the passive left ventricular filling (E-wave peak velocity, 13%) compared to active left ventricular filling during diastole (A-wave peak velocity, 6%) resulting in a 16% increase of the E/A ratio in the first trimester. The E/A ratio progressively decreased during advancing gestation to -18% at term, resulting from stabilizing E-wave peak velocity and increased A-wave peak velocity. The E/e' ratio was increased between 22 and 35 weeks (a maximal increase of 13%) in normotensive pregnancy. Left atrial volume (LAV) progressively increased from 15 weeks onwards with a maximal increase of 30% between 36 and 41 weeks.

Conclusion: LVDF in normotensive pregnancy was improved in the first trimester after which LVDF progressively worsened. Large-scale studies in normotensive and hypertensive complicated pregnancies are needed for a more precise insight into LVDF changes during pregnancy.
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http://dx.doi.org/10.1097/HJH.0000000000002886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452327PMC
October 2021

Preventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to Pregnancy.

Hypertension 2021 06 5;77(6):2045-2053. Epub 2021 Apr 5.

Department of Obstetrics and Gynecology (E.G.M., E.C., V.A.L.v.B., V.M.M.M.S., R.J.A., M.E.A.S.), Maastricht University Medical Centre, the Netherlands.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16502DOI Listing
June 2021

Cardiac dysfunction after preeclampsia; an overview of pro- and anti-fibrotic circulating effector molecules.

Pregnancy Hypertens 2021 Mar 24;23:140-154. Epub 2020 Dec 24.

Department of Obstetrics and Gynecology, Maastricht University Medical Centre (MUMC+), The Netherlands; Department of Cardiology, Maastricht University Medical Centre (MUMC+), The Netherlands.

Preeclampsia (PE) is strongly associated with heart failure (HF) later in life. The aberrant cardiac remodelling is likely initiated or amplified during preeclamptic pregnancy. Aberrant remodelling often persists after delivery and is known to relate strongly to cardiac fibrosis. This review provides an overview of pro- and anti- fibrotic circulating effector molecules that are involved in cardiac fibrosis and their association with PE. Women with PE complicated pregnancies show increased ANG-II sensitivity and elevated levels of the pro-fibrotic factors IL-6, TNF-α, TGs and FFAs compared to uncomplicated pregnancies. In the postpartum period, PE pregnancies compared to uncomplicated pregnancies have increased ANG-II sensitivity, elevated levels of the pro-fibrotic factors IL-6, TNF-α, LDL cholesterol and leptin, as well as decreased levels of the anti-fibrotic factor adiponectin. The review revealed several profibrotic molecules that associate to cardiac fibrosis during and after PE. The role that these fibrotic factors have on the heart during and after PE may improve the understanding of the link between PE and HF. Furthermore they may provide insight into the pathways in which the relation between both diseases can be understood as potential mechanisms which interfere in the process of cardiovascular disease (CVD). Unravelling the molecular mechanism and pathways involved might bring the diagnostic and therapeutic abilities of those factors a step closer.
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http://dx.doi.org/10.1016/j.preghy.2020.12.001DOI Listing
March 2021

Study protocol for the randomized controlled EVA (early vascular adjustments) trial: tailored treatment of mild hypertension in pregnancy to prevent severe hypertension and preeclampsia.

BMC Pregnancy Childbirth 2020 Dec 12;20(1):775. Epub 2020 Dec 12.

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, PO box 5800, 6202, AZ, Maastricht, the Netherlands.

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.
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http://dx.doi.org/10.1186/s12884-020-03475-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733247PMC
December 2020

The "sex gap" in COVID-19 trials: a scoping review.

EClinicalMedicine 2020 Dec 30;29:100652. Epub 2020 Nov 30.

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.

Background: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses.

Methods: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated.

Findings: 30 studies were eligible for inclusion, investigating remdesivir ( = 2), lopinavir/ritonavir ( = 5), favipiravir ( = 1), umifenovir ( = 1), hydroxychloroquine/chloroquine ( = 8), convalescent plasma ( = 6), interleukin-6 (IL-6) pathway inhibitors ( = 5), interleukin-1 (IL-1) pathway inhibitors ( = 1) and corticosteroids ( = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females.

Interpretation: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care.

Funding: None.
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http://dx.doi.org/10.1016/j.eclinm.2020.100652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701906PMC
December 2020

Decreased serial scores of severe organ failure assessments are associated with survival in mechanically ventilated patients; the prospective Maastricht Intensive Care COVID cohort.

J Crit Care 2021 04 17;62:38-45. Epub 2020 Nov 17.

Department of Intensive Care, Maastricht University Medical Centre+, P. Debyelaan 25, 6202 AZ Maastricht, the Netherlands; Care and Public Health Research Institute (CAPHRI), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, the Netherlands. Electronic address:

Background: The majority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are admitted to the Intensive Care Unit (ICU) for mechanical ventilation. The role of multi-organ failure during ICU admission as driver for outcome remains to be investigated yet.

Design And Setting: Prospective cohort of mechanically ventilated critically ill with SARS-CoV-2 infection.

Participants And Methods: 94 participants of the MaastrICCht cohort (21% women) had a median length of stay of 16 days (maximum of 77). After division into survivors (n = 59) and non-survivors (n = 35), we analysed 1555 serial SOFA scores using linear mixed-effects models.

Results: Survivors improved one SOFA score point more per 5 days (95% CI: 4-8) than non-survivors. Adjustment for age, sex, and chronic lung, renal and liver disease, body-mass index, diabetes mellitus, cardiovascular risk factors, and Acute Physiology and Chronic Health Evaluation II score did not change this result. This association was stronger for women than men (P-interaction = 0.043).

Conclusions: The decrease in SOFA score associated with survival suggests multi-organ failure involvement during mechanical ventilation in patients with SARS-CoV-2. Surviving women appeared to improve faster than surviving men. Serial SOFA scores may unravel an unfavourable trajectory and guide decisions in mechanically ventilated patients with SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jcrc.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669472PMC
April 2021

Spiral artery blood flow during pregnancy: a systematic review and meta-analysis.

BMC Pregnancy Childbirth 2020 Nov 11;20(1):680. Epub 2020 Nov 11.

Department of Obstetrics and Gynecology, Maastricht University Medical Centre (MUMC+), P. Debeyelaan 25, 6229 HX, Maastricht, The Netherlands.

Background: Downstream remodeling of the spiral arteries (SpA) decreases utero-placental resistance drastically, allowing sustained and increased blood flow to the placenta under all circumstances. We systematically evaluated available reports to visualize adaptation of spiral arteries throughout pregnancy by ultra-sonographic measurements and evaluated when this process is completed.

Methods: A systematic review and meta-analysis of spiral artery flow (pulsatility index (PI), resistance index (RI) and peak systolic velocity (PSV)) was performed. English written articles were obtained from Pubmed, EMBASE and Cochrane Library and included articles were assessed on quality and risk of bias. Weighted means of Doppler indices were calculated using a random-effects model.

Results: In healthy pregnancies, PI and RI decreased from 0.80 (95% CI: 0.70-0.89) and 0.50 (95% CI: 0.47-0.54) in the first trimester to 0.50 (95% CI: 0.45-0.55, p < 0.001) and 0.39 (95% CI: 0.37-0.42, p < 0.001) in the second trimester and to 0.49 (95% CI: 0.44-0.53, p = 0.752) and 0.36 (95% CI: 0.35-0.38, p = 0.037) in the third trimester, respectively. In parallel, PSV altered from 0.22 m/s (95% CI: 0.13-0.30 m/s) to 0.28 m/s (95% CI: 0.17-0.40 m/s, p = 0.377) and to 0.25 m/s (95% CI: 0.20-0.30 m/s, p = 0.560) in the three trimesters. In absence of second and third trimester Doppler data in complicated gestation, only a difference in PI was observed between complicated and healthy pregnancies during the first trimester (1.49 vs 0.80, p < 0.001). Although individual studies have identified differences in PI between SpA located in the central part of the placental bed versus those located at its periphery, this meta-analysis could not confirm this (p = 0.349).

Conclusions: This review and meta-analysis concludes that an observed decrease of SpA PI and RI from the first towards the second trimester parallels the physiological trophoblast invasion converting SpA during early gestation, a process completed in the midst of the second trimester. Higher PI was found in SpA of complicated pregnancies compared to healthy pregnancies, possibly reflecting suboptimal utero-placental circulation. Longitudinal studies examining comprehensively the predictive value of spiral artery Doppler for complicated pregnancies are yet to be carried out.
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http://dx.doi.org/10.1186/s12884-020-03150-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656690PMC
November 2020

Serial measurements in COVID-19-induced acute respiratory disease to unravel heterogeneity of the disease course: design of the Maastricht Intensive Care COVID cohort (MaastrICCht).

BMJ Open 2020 09 29;10(9):e040175. Epub 2020 Sep 29.

Department of Intensive Care, Maastricht University Medical Center+, Maastricht, The Netherlands.

Introduction: The course of the disease in SARS-CoV-2 infection in mechanically ventilated patients is unknown. To unravel the clinical heterogeneity of the SARS-CoV-2 infection in these patients, we designed the prospective observational Maastricht Intensive Care COVID cohort (MaastrICCht). We incorporated serial measurements that harbour aetiological, diagnostic and predictive information. The study aims to investigate the heterogeneity of the natural course of critically ill patients with a SARS-CoV-2 infection.

Methods And Analysis: Mechanically ventilated patients admitted to the intensive care with a SARS-CoV-2 infection will be included. We will collect clinical variables, vital parameters, laboratory variables, mechanical ventilator settings, chest electrical impedance tomography, ECGs, echocardiography as well as other imaging modalities to assess heterogeneity of the course of a SARS-CoV-2 infection in critically ill patients. The MaastrICCht is also designed to foster various other studies and registries and intends to create an open-source database for investigators. Therefore, a major part of the data collection is aligned with an existing national intensive care data registry and two international COVID-19 data collection initiatives. Additionally, we create a flexible design, so that additional measures can be added during the ongoing study based on new knowledge obtained from the rapidly growing body of evidence. The spread of the COVID-19 pandemic requires the swift implementation of observational research to unravel heterogeneity of the natural course of the disease of SARS-CoV-2 infection in mechanically ventilated patients. Our study design is expected to enhance aetiological, diagnostic and prognostic understanding of the disease. This paper describes the design of the MaastrICCht.

Ethics And Dissemination: Ethical approval has been obtained from the medical ethics committee (Medisch Ethische Toetsingscommissie 2020-1565/3 00 523) of the Maastricht University Medical Centre+ (Maastricht UMC+), which will be performed based on the Declaration of Helsinki. During the pandemic, the board of directors of Maastricht UMC+ adopted a policy to inform patients and ask their consent to use the collected data and to store serum samples for COVID-19 research purposes. All study documentation will be stored securely for fifteen years after recruitment of the last patient. The results will be published in peer-reviewed academic journals, with a preference for open access journals, while particularly considering deposition of the manuscripts on a preprint server early.

Trial Registration Number: The Netherlands Trial Register (NL8613).
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http://dx.doi.org/10.1136/bmjopen-2020-040175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526030PMC
September 2020

Circulating miR-216a as a biomarker of metabolic alterations and obesity in women.

Noncoding RNA Res 2020 Sep 22;5(3):144-152. Epub 2020 Aug 22.

Department of Obstetrics and Gynecology, School for Oncology & Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre (MUMC+), the Netherlands.

Obesity leads to an amplified risk of disease and contributes to the occurrence of type 2 diabetes, fatty liver disease, coronary heart disease, stroke, chronic kidney disease and various types of cancer. MicroRNAs (miRNAs), small non-coding RNA molecules of 20-25 nucleotides, can remain stable in plasma and have been studied as potential (predictive) biomarkers for obesity and related metabolic disorders. The aim of this study was to identify circulating miRNAs as biomarkers for obesity status and metabolic alterations in women. Circulating miR-216a and miR-155-5p were selected by miRNA expression profiling and validated by real time quantitative PCR in a validation cohort of 60 obese women and 60 normal weight-age-matched control women. This was supplemented by correlation analysis of the candidate miRNA and anthropometric variables, blood biochemistry and lipid profile markers. Circulating miR-216a was validated as a biomarker of obesity status with significantly reduced levels in obese women. Interestingly, this was associated with a negative correlation between the plasma miR-216a content and body mass index (BMI), waist circumference, mean arterial pressure (MAP), triglycerides, ratio of total cholesterol/high density lipoprotein (HDL)-cholesterol and high sensitivity-C reactive protein (hs-CRP).Taken together, we provide evidence for an abnormally expressed circulating miRNA, miR-216a, with additive value as a predictive marker for obesity that correlates with metabolic alterations presented by lipid profile and inflammatory markers.
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http://dx.doi.org/10.1016/j.ncrna.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479169PMC
September 2020

Low Plasma Volume and Increased Pressure Load Relate to Concentric Left Ventricular Remodeling After Preeclampsia: A Longitudinal Study.

J Am Heart Assoc 2020 10 13;9(19):e015043. Epub 2020 Sep 13.

Department of Obstetrics and Gynecology Research School GROW Maastricht University Medical Center Maastricht the Netherlands.

Background During uncomplicated pregnancy, left ventricular remodeling occurs in an eccentric way. In contrast, during preeclamptic gestation, the left ventricle hypertrophies concentrically, concurrent with loss in circulatory volume and increased blood pressure. Concentric cardiac structure persists in a substantial proportion of women and may be associated with pressure and volume load after preeclampsia. We hypothesize that low volume load, as indicated by plasma volume (PV) after preeclampsia and increased pressure load, is associated with remote concentric remodeling. Methods and Results In this longitudinal cohort study, we included 100 formerly preeclamptic women. Two visits were performed: at 0.8 years postpartum and at 4.8 years postpartum. During visit 1, we measured blood pressure and PV (I dilution technique, low PV ≤48 mL/kg lean body mass). During the second visit, we assessed cardiac geometry by cardiac ultrasound. Concentric remodeling was defined as relative wall thickness >0.42 and left ventricular mass index ≤95 g/m. We adjusted multivariable analysis for primiparity, systolic blood pressure, PV mL/kg lean body mass, and antihypertensive medication at visit 1. Low PV is associated with remote concentric remodeling (odds ratio [OR], 4.37; 95% CI, 1.06-17.40; and adjusted OR, 4.67; 95% CI, 1.02-21.42). Arterial pressure load (systolic, diastolic, and mean arterial pressure) is also associated with development of concentric remodeling (OR, 1.15 [95% CI, 0.99-1.35]; OR, 1.24 [95% CI, 0.98-1.58]; and OR, 1.20 [95% CI, 0.98-1.47], respectively). Conclusions In former preeclamptic women, development toward left ventricular concentric remodeling is associated with low volume load and increased pressure load.
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http://dx.doi.org/10.1161/JAHA.119.015043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792392PMC
October 2020

Maternal myocardial dysfunction after normotensive fetal growth restriction compared with hypertensive pregnancies: a speckle-tracking study.

J Hypertens 2020 10;38(10):1955-1963

Department of Obstetrics and Gynecology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC), The Netherlands.

Objective: Pregnancy complicated by preeclampsia and fetal growth restriction (FGR) relates to increased risk of cardiovascular disease later in life, but to different extents. Subclinical cardiac alterations precede eminent cardiovascular disease. Speckle-tracking echocardiography is an elegant method to assess subclinical myocardial dysfunction. We performed a myocardial speckle tracking study to evaluate the prevalence of subclinical myocardial dysfunction in former preeclampsia patients (with and without FGR) compared with normotensive women with FGR.

Methods: For this cross-sectional study, we retrospectively selected women with a history of normotensive FGR (n = 17), preeclampsia with FGR (n = 26) and preeclampsia without FGR (n = 134) who underwent conventional echocardiography as part of the clinical cardiovascular work-up after complicated pregnancies between 6 months and 4 years postpartum in Maastricht, The Netherlands. We excluded women with chronic hypertension, hypercholesterolemia and obesity.

Results: Women with normotensive FGR showed subclinical left ventricular (LV) impairment in systodiastolic function with concentric remodeling, slight alteration in right ventricular systolic function and left atrial strain, similarly to the preeclampsia group independently from the fetal growth. LV hypertrophy was only present in about 10% of cases who experienced preeclampsia (independently from the fetal growth) but not in those with normotensive FGR.

Conclusion: Similar to women with a history preeclampsia, women with a history of normotensive pregnancy but with FGR have abnormal myocardial function, shown with speckle-tracking echocardiography. Therefore, both preeclampsia and normotensive FGR should be viewed upon as risk indicator for subclinical myocardial impairment that may benefit from cardiovascular risk management.
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http://dx.doi.org/10.1097/HJH.0000000000002496DOI Listing
October 2020

Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury.

Sci Rep 2020 08 18;10(1):13945. Epub 2020 Aug 18.

Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R 0.04, R = 0.21, p = 0.001, 95% CI 0.103-0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF.
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http://dx.doi.org/10.1038/s41598-020-70848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435264PMC
August 2020

Accuracy and precision of USCOM versus transthoracic echocardiography before and during pregnancy.

Pregnancy Hypertens 2019 Jul 16;17:138-143. Epub 2019 Apr 16.

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, the Netherlands. Electronic address:

Objective: Monitoring hemodynamic status throughout pregnancy may help in identifying women with maladaptation predisposing to hypertensive complications. The Ultrasonic Cardiac Output Monitor (USCOM) is an easy-to-operate device for measuring cardiac output (CO) quickly. Our aim was to assess agreement between USCOM and transthoracic echocardiography (TTE) in: 1) non-pregnant women to correct for possible sources of discrepancy; 2) women longitudinally over the course of the pregnancy.

Study Design: High-risk women admitted for cardiovascular risk factor evaluation before pregnancy and multiple times during pregnancy, were included. CO was measured by TTE directly followed by USCOM measurements.

Main Outcome Measures: Bias, limits of agreement (LOA) and percentage error between the two methods by Bland-Altman analysis.

Results: Despite comparable non-pregnant CO levels (4.6 L/min), LOA and percentage error between the two methods improved moderately by optimizing the measurements using only the highest quality USCOM recordings in 132 non-pregnant women (percentage error of 39% and 30%, respectively). During pregnancy, in total 83, 106, 96 and 77 measurements were evaluated at respectively 12, 16, 20 and 30 weeks gestational age. Mean CO in USCOM was about 0.6 L/min higher compared to TTE in all trimesters; percentage error ranged from 35% to 45%. Linear mixed model analysis showed no association between bias and moment of measurement.

Conclusion: Agreement between USCOM and TTE in pregnancy was outside our a priori determined level of acceptability and therefore absolute values of USCOM and TTE cannot be used interchangeably. Future research should focus on the agreement of USCOM and TTE in clinical decision-making.
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http://dx.doi.org/10.1016/j.preghy.2019.04.003DOI Listing
July 2019

Early-Pregnancy Circulating Antioxidant Capacity and Hemodynamic Adaptation in Recurrent Placental Syndrome: An Exploratory Study.

Gynecol Obstet Invest 2019 29;84(6):616-622. Epub 2019 Jul 29.

Department of Obstetrics, UMC Utrecht, Division "Vrouw and Baby", Utrecht, The Netherlands.

Background/aims: Placental syndromes (PS) refer to pregnancy complications that include gestational hypertension, (pre)eclampsia, HELLP syndrome, and/or placental insufficiency-induced fetal growth restriction. These disorders are characterized by increased oxidative stress. This study aims to test the hypothesis that the abnormal hemodynamic adaptation to pregnancy, typical for early PS pregnancy, is accompanied by abnormal maternal levels of antioxidants relative to those in normal pregnancy.

Methods: Before, and at 12, 16, and 20 weeks pregnancy, we measured trolox equivalent antioxidant capacity (TEAC), uric acid (UA), and TEACC (TEAC corrected for UA) in maternal serum of former PS patients, who either developed recurrent PS (rPS; n = 16) or had a normal next pregnancy (non-rPS; n = 23). Concomitantly, we also measured various hemodynamic variables.

Results: rPS differed from non-rPS by higher TEACC levels before pregnancy (178 vs. 152 µM; p = 0.02) and at 20 weeks pregnancy (180 vs. 160 µM; p = 0.04). Only non-rPS responded to pregnancy by significant rises in hemodynamic measures.

Conclusion: These data indicate that rPS pregnancies are preceded by an increase in antioxidant capacity, presumably induced by subclinical vascular injury and low-grade chronic inflammation.
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http://dx.doi.org/10.1159/000501254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888971PMC
February 2020

Inappropriate left ventricular mass after preeclampsia: another piece of the puzzle Inappropriate LVM and PE.

Hypertens Res 2019 04 14;42(4):522-529. Epub 2018 Dec 14.

Maternal Fetal Medicine Unit, Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy.

Excessive left ventricular (LV) mass (LVM) increase results in inefficient LV work with high energy waste and a negative prognostic effect. We aimed to investigate the presence of inappropriate LVM and to calculate the myocardial mechanoenergetic efficiency index (MEEi) in asymptomatic women with a history of early-onset (EO) or late-onset (LO) pre-eclampsia (PE). Among all women diagnosed with PE in the years 2009-2013, after applying inclusion/exclusion criteria and cost-effectiveness analysis, we randomly selected thirty women who experienced EO-PE, thirty with a previous LO-PE and thirty healthy controls to undergo echocardiography from 6 months to 4 years after delivery. Data regarding gestational age (GA) and mean uterine artery (UtA) pulsatility index (PI) at PE onset were collected from medical records. All women were free from cardiovascular risk factors. LVM excess was calculated as the ratio between observed LVM and predicted LVM (by sex, stroke work and height), while MEEi was calculated as the ratio between stroke work and "double product" (to approximate energy consumption), indexed to LVM. Concentric remodeling was present in 60% of EO-PE and 53% of LO-PE. LVM excess was significantly more often present in the EO-PE group than in the control group. LVM was inappropriate in 52% of EO-PE and 17% of LO-PE. MEEi showed a tendency towards lower values in the EO-PE group. Multivariate regression analysis showed that both LVM excess and MEEi were independently associated with lower GA and higher mean UtA PI at PE onset. Inappropriate LVM with a tendency towards reduced MEEi in the first 4 years after delivery may partially explain the elevated cardiovascular risk in former pre-eclamptic women compared to the general population.
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http://dx.doi.org/10.1038/s41440-018-0163-9DOI Listing
April 2019

Recurrence rates of preeclampsia over the past 20 years in women assessed for non-pregnant cardiovascular risk factors.

Pregnancy Hypertens 2018 Oct 22;14:150-155. Epub 2018 Sep 22.

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, the Netherlands. Electronic address:

Objective: Several efforts to reduce recurrent preeclampsia have been implemented in clinical practice in the past decades. We assessed whether recurrence rates of preeclampsia and related offspring complications decreased in the past 20 years in women who received tailored preventive advices.

Study Design: In this observational cohort study, we included 752 women who had their first pregnancy complicated by preeclampsia between 1996 and 2012, and who participated in a non-pregnant risk factor assessment. A questionnaire was sent to women to follow-up on their next pregnancy outcome.

Main Outcome Measures: Prevalence of preeclampsia and related offspring complications in the subsequent pregnancy.

Results: 467 (62%) women responded to the questionnaire of which two-thirds had a subsequent ongoing pregnancy. Recurrent preeclampsia occurred in 29% of women who delivered between 1997 and 2004, in 20% of women who delivered between 2005 and 2009, and in 24% of women who delivered between 2010 and 2016 (overall p-value = 0.319). Combined maternal complications did not change over time (OR 0.98 per year, 95% CI 0.93-1.04, p-value = 0.503). Offspring complications in the subsequent pregnancy decreased over time with an OR of 0.92 (95% CI 0.86-0.98, p = 0.009) per year.

Conclusion: Recurrence rates of preeclampsia did not decrease over the past 20 years in women who have been extensively assessed on cardiovascular risk factors. In the same period, foetal and neonatal outcomes improved substantially. Efforts to extend and improve strategies to reduce recurrence risk of preeclampsia still seem to be necessary.
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http://dx.doi.org/10.1016/j.preghy.2018.09.006DOI Listing
October 2018

Pre-Eclampsia: A Twilight Zone Between Health and Cardiovascular Disease?

J Am Coll Cardiol 2018 07;72(1):12-16

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, the Netherlands.

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http://dx.doi.org/10.1016/j.jacc.2018.04.049DOI Listing
July 2018

Circulating Fibronectin and Plasminogen Activator Inhibitor-2 Levels as Possible Predictors of Recurrent Placental Syndrome: An Exploratory Study.

Gynecol Obstet Invest 2017 20;82(4):355-360. Epub 2016 Sep 20.

Department of Pathology, Maastricht University Medical Centre, CAPHRI Research School, The Division 'Vrouw & Baby', Maastricht, The Netherlands.

Background/aim: Placental syndromes (PS) are characterized by endothelial dysfunction complicating placental dysfunction. Possible markers for endothelial dysfunction and amount of trophoblast are fibronectin and plasminogen activator inhibitor-2 (PAI-2), respectively. We aimed (1) to determine whether in women with recurrent PS (rPS), this complication is preceded by deviating fibronectin- and PAI-2-levels, and (2) whether this is dependent on pre-pregnant plasma volume (PV).

Methods: In 36 former patients, we determined fibronectin- and PAI-2-levels in blood-samples collected preconceptionally and at 12-16 weeks in their next pregnancy. Differences were analyzed between pregnancies with rPS (n = 12) and without rPS (non-rPS, n = 24) using linear mixed models, with subanalyses based on pre-pregnant normal or subnormal PV.

Results: We observed higher fibronectin-levels at 12-16 weeks (p < 0.05 and p < 0.01, respectively) and lower PAI-2-levels at 16 weeks (p < 0.01) in the rPS subgroup, the intergroup differences being larger in women with subnormal PV.

Conclusion: We showed that former PS patients who developed rPS have raised fibronectin- and reduced PAI-2-levels already in early/mid pregnancy. These deviations are even more prominent in women with subnormal pre-pregnant PV, supporting development of a 2-step screening program for former patients to identify the high-risk subgroup of women who may benefit from closer surveillance.
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http://dx.doi.org/10.1159/000449385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569709PMC
June 2018

A1. Volume load and pressure load both relate to relative wall thickness in former PE.

J Matern Fetal Neonatal Med 2016 Aug;29 Suppl 2:1-17

Aims: To study the relationship between volume and pressure load on the one hand and relative wall thickness (RWT) on the other hand in former preeclamptic women.

Methods: In 654 former PE women, blood pressure (BP) and PV (iodine 125 albumin indicator dilution technique) where measured. PV was indexed for body surface area (BSA). Echocardiography was performed to calculate RWT. The study population was divided in 4 subgroups consisting of women with either normal- or high-systolic BP (sysBP) (<140 versus ≥140mmHg, respectively) and normal- or low-PV index (>1373 versus ≤1373 ml/m2 respectively). Differences between the four subgroups where analyzed with ANOVA. Pearson's rho is calculated for the correlation between PV and sysBP on the one hand and RWT on the other hand.

Results: RWT was the lowest in the group with normal sysBP and normal PV and the highest in the subgroup with high sysBP and low PV subgroup (Table 1). Moreover, PVindex correlated negatively with RWT in the setting of both normal sysBP and high sysBP (Figure 1a and b) while systolic BP correlated positively with RWT in the setting of normal sysBP but not in the setting of high sysBP (Figure 1c and d).

Discussion: Raised RWT, as a measure for concentric remodelling, relates to both decreased volume load and increased pressure load.
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http://dx.doi.org/10.1080/14767058.2016.1189993DOI Listing
August 2016

Maternal metabolic syndrome, preeclampsia, and small for gestational age infancy.

Am J Obstet Gynecol 2015 Sep 22;213(3):370.e1-7. Epub 2015 May 22.

Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, The Netherlands.

Objective: We sought to explore to what extent the presence of cardiometabolic and cardiovascular risk constitutions differ between pregnancies complicated by small-for-gestational-age (SGA) infancy, preeclampsia (PE), or a combination of both.

Study Design: We conducted a cohort study in women after pregnancies complicated by placental syndrome with fetal manifestations (SGA infancy [n = 113]), maternal manifestations (PE [n = 729]), or both (n = 461). Independent sample t test was used to compare cardiometabolic and cardiovascular risk factors between groups. Logistic regression was used to calculate odds ratios and adjusted odds ratios of the prevalence of the metabolic syndrome and its constituents between groups. Adjustments were made for maternal age, parity, smoking, interval between delivery and measurements, and intrauterine fetal demise.

Results: The metabolic syndrome was present in 7.5% of women who delivered SGA infants, 15.6% of former PE women, and 19.8% of women after pregnancy complicated by both SGA and PE. Hypertension was observed in 25% of former PE women and 15% of women with solely SGA. Women who delivered a SGA infant had lower global vascular compliance compared to former PE women without SGA.

Conclusion: Cardiometabolic risk factors consistent with metabolic syndrome relate to the maternal rather than to the fetal presentation of placental syndrome. Nonetheless, highest incidence of metabolic syndrome was observed in women with both PE and SGA. PE relates to chronic hypertension, whereas increased arterial stiffness seems to be associated with women who deliver a SGA infant.
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http://dx.doi.org/10.1016/j.ajog.2015.05.045DOI Listing
September 2015

Long-Term Risk to Develop Hypertension in Women With Former Preeclampsia: A Longitudinal Pilot Study.

Reprod Sci 2014 Jul 18;21(7):846-853. Epub 2014 Jan 18.

Division "Vrouw & Baby", University Medical Center Utrecht, Utrecht, the Netherlands.

Introduction: Women with former preeclampsia (exPE) develop chronic hypertension 4 times more often than healthy parous controls. Women, destined to develop remote chronic hypertension, had increased left ventricular mass index (LVMI) and diastolic blood pressure (BP) prior to the onset of hypertension as compared to those remaining normotensive. However, longitudinal data on the progress of this increased LVMI in women destined to develop hypertension are lacking.

Methods: We included 20 women with exPE and 8 parous controls. At both 1- and 14-year postpartum (pp), we performed cardiac ultrasound and determined circulating levels of the metabolic syndrome variables. Of 14-year pp, 7 (35%) former patients had developed chronic hypertension. We compared these 7 former patients with both the 13 former patients who remained normotensive and the 8 parous controls using the Mann-Whitney U test and Kruskal-Wallis analysis.

Results: Women with hypertensive exPE differed from their normotensive counterparts by a higher incidence of early-onset preeclampsia (PE) in their index pregnancy and a higher rate of recurrence in next pregnancies. At 1-year pp, they also had high/normal BP and higher fasting insulin levels. At 14 years pp, the relative left ventricular wall thickness was higher, and the E/A ratio was lower, in the hypertensive group relative to those remaining normotensive.

Conclusion: Women with exPE are at increased risk of developing chronic hypertension, when (1) the PE in the index pregnancy had an early-onset and/or recurred in next pregnancies and (2) the 1-year pp. Blood pressure was high normal. We also noticed that at 14 years pp, the hypertensive group showed signs of concentric left ventricular remodeling along with a decreased E/A ratio.
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http://dx.doi.org/10.1177/1933719113518989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107566PMC
July 2014

Hypertension after preeclampsia is preceded by changes in cardiac structure and function.

Hypertension 2013 Aug 3;62(2):382-90. Epub 2013 Jun 3.

Department of Obstetrics and Gynecology, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, The Netherlands.

Preeclampsia is associated with a 4-fold higher risk for developing remote chronic hypertension. Preeclampsia is accompanied by left ventricular hypertrophy and decreased diastolic function, which may or may not resolve postpartum. We tested the hypothesis that increased measures of cardiac geometry and decreased cardiac function persisting for ≥ 6 months postpartum in normotensive women with a history of preeclampsia precede the development of later chronic hypertension. Formerly preeclamptic women (n=652) underwent echocardiography at 9 months (range, 6-19) postpartum. We excluded women with preexisting hypertension (n=42), hypertension at the postpartum screening (n=133), and those that did not return any checklist (n=128). Eventually, 349 women were included. Remote health was evaluated by a biennially checklist. We used Cox regression for analysis. Twenty-seven (8%) normotensive women had developed chronic hypertension during a medium follow-up period of 6 years. At screening they differed from their counterparts who remained normotensive by hazard ratio for left ventricular mass index (1.11; 95% confidence interval [CI], 1.03-1.18), diastolic blood pressure (1.13; 95% CI, 1.06-1.20), systolic blood pressure (1.07; 95% CI, 1.02-1.11), mean arterial pressure (1.11; 95% CI, 1.05-1.18), heart rate (1.05; 95% CI, 1.01-1.10), and E/A ratio (0.22; 95% CI, 0.06-0.85). Backward stepwise analysis showed independent hazard ratio for left ventricular mass index and diastolic blood pressure 1.08 (95% CI, 1.01-1.16) and 1.13 (95% CI, 1.06-1.21), respectively. In conclusion, the development of later chronic hypertension in initially normotensive formerly preeclamptic women is preceded by increased left ventricular mass index and diastolic blood pressure at postpartum screening.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01319DOI Listing
August 2013

PP056. Cardiac adaptation in the preclinical phase of recurrent preeclampsia in women with a history of early preeclampsia.

Pregnancy Hypertens 2013 Apr 6;3(2):87-8. Epub 2013 Jun 6.

Introduction: Preeclampsia is thought to be preceded by first trimester circulatory maladaptation. Early and late onset PE may exhibit two different cardiac and hemodynamic states. Moreover, early PE relates to postpartum impaired cardiac function. Incomplete resolved or impaired cardiac function may influence the pattern of cardiac adaptation in the next pregnancy and may relate to recurrent disease. We postulate that in women with a history of early PE, the pattern of early cardiac adaptation differs between those that do and those that do not develop recurrent disease.

Objectives: We hypothesize that after early onset PE, in the subsequent gestation, the pattern of cardiac adaptation differs between those that do and those that do not develop recurrent disease.

Methods: In this cohort study, we included 84 women with a history of early-onset PE. Former PE patients who concomitantly experienced HELLP-syndrome, fetal growth restriction and/or fetal demise, were excluded. The remaining 51 women underwent serial cardiac ultrasound and automated blood pressure and heart rate recordings, once before, and again at gestational age 12, 16 and 20 weeks. Post hoc, women were subdivided into those who did (RECUR) or did not develop recurrent PE (CONTR). We analyzed data using repeated measures analysis of variance.

Results: 14/51 (27%) women developed recurrent PE. Pre-pregnant heart rate was higher (71 vs 64 bpm, p<0.05) and stroke volume lower (68 vs 77mL, p<0.05) in RECUR as compared to CONTR. Even though LVM index was consistently lower in the RECUR group, the two subgroups responded to the next pregnancy with a comparable pattern of cardiac adaptation.

Conclusion: Despite consistently lower LVM and SV and higher HR, after early onset PE, the pattern of subsequent early pregnancy cardiac adaptation is comparable in those that do and do not develop recurrent disease.
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http://dx.doi.org/10.1016/j.preghy.2013.04.083DOI Listing
April 2013
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