Systematic review supports the role of DNA methylation in the pathophysiology of preeclampsia: a call for analytical and methodological standardization.

BACKGROUND: Studies have recently examined the role of epigenetic mechanisms in preeclampsia pathophysiology. One commonly examined epigenetic process is DNA methylation. This heritable epigenetic marker is involved in many important cellular functions. The aim of this study was to establish the association between DNA methylation and preeclampsia and to critically appraise the roles of major study characteristics that can significantly impact the association between DNA methylation and preeclampsia. MAIN BODY: A systematic review was performed by searching PubMed, Web of Science, and EMBASE for original research articles published over time, until May 31, 2019 in English. Eligible studies compared DNA methylation levels in pregnant women with vs. without preeclampsia. Ninety articles were included. Epigenome-wide studies identified hundreds of differentially methylated places/regions in preeclamptic patients. Hypomethylation was the predominant finding in studies analyzing placental tissue (14/19), while hypermethylation was detected in three studies that analyzed maternal white blood cells (3/3). In candidate gene studies, methylation alterations for a number of genes were found to be associated with preeclampsia. A greater number of differentially methylated genes was found when analyzing more severe preeclampsia (70/82), compared to studies analyzing less severe preeclampsia vs. controls (13/27). A high degree of heterogeneity existed among the studies in terms of methodological study characteristics including design (study design, definition of preeclampsia, control group, sample size, confounders), implementation (biological sample, DNA methylation method, purification of DNA extraction, and validation of methylation), analysis (analytical method, batch effect, genotyping, and gene expression), and data presentation (methylation quantification measure, measure of variability, reporting). Based on the results of this review, we provide recommendations for study design and analytical approach for further studies. CONCLUSIONS: The findings from this review support the role of DNA methylation in the pathophysiology of preeclampsia. Establishing field-wide methodological and analytical standards may increase value and reduce waste, allowing researchers to gain additional insights into the role of DNA methylation in the pathophysiology of preeclampsia.

Preclinical atherosclerosis at the time of pre-eclamptic pregnancy and up to 10 years postpartum: systematic review and meta-analysis.

OBJECTIVES: Pre-eclampsia (PE) is a pregnancy-specific hypertensive disorder that has been associated with cardiovascular risk factors and vascular changes, such as acute atherosis in placental blood vessels, similar to early-stage atherosclerosis. The objective of this study was to determine whether women with PE have increased atherosclerotic burden, as determined by the carotid intima-media thickness (CIMT), compared with women without PE. METHODS: We conducted a systematic review and meta-analysis of studies that reported CIMT, a non-invasive, ultrasound-based measure of subclinical atherosclerosis, in women who did vs those who did not have PE. Studies were eligible if they had been conducted during pregnancy or during the first decade postpartum, and if CIMT was measured in the common carotid artery. Studies published before 7 March 2016 were identified through PubMed, EMBASE and Web of Science. Two reviewers used predefined forms and protocols to evaluate independently the eligibility of studies based on titles and abstracts and to perform full-text screening, data abstraction and quality assessment. Heterogeneity was assessed using the I2 statistic. Standardized mean difference (SMD) was used as a measure of effect size. RESULTS: Fourteen studies were included in the meta-analysis. Seven studies were carried out during pregnancy complicated by PE, 10 were carried out up to 10 years postpartum and three included measurements obtained at both time periods. Women who had PE had significantly higher CIMT than did those who did not have PE, both at the time of diagnosis (SMD, 1.10 (95% CI, 0.73-1.48); P < 0.001) and in the first decade postpartum (SMD, 0.58 (95% CI, 0.36-0.79); P < 0.001). CONCLUSIONS: Atherosclerotic load is present at the time of PE and may be a mechanism associated with the disease. Measurement of CIMT may offer an opportunity for the early identification of premenopausal women with atherosclerotic burden after a PE pregnancy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Resumen Objetivos: La preeclampsia (PE) es un trastorno hipertensivo específico del embarazo que ha sido asociada con factores de riesgo cardiovascular y cambios vasculares, tales como aterosis aguda en los vasos sanguíneos de la placenta, similares a las primeras etapas de la aterosclerosis. El objetivo de este estudio fue determinar si las mujeres con PE han aumentado la carga aterosclerótica, según lo determinado por el espesor del complejo íntima-media de la arteria carótida (CIMT, por sus siglas en inglés), en comparación con las mujeres sin PE. MÉTODOS: Se realizó una revisión sistemática y un metaanálisis de estudios que reportaron el CIMT, una medida no invasiva de la aterosclerosis subclínica obtenida mediante ecografía, comparando mujeres con PE y mujeres sin ella. Solo se incluyeron estudios llevados a cabo durante el embarazo o durante la primera década después del parto, y en los que se midió el CIMT en la arteria carótida común. Se usaron las bases de datos de PubMed, EMBASE y Web of Science para identificar estudios publicados antes del 7 marzo de 2016. Dos revisores utilizaron formularios y protocolos preestablecidos para evaluar de forma independiente la elegibilidad de los estudios, a partir de los títulos y los resúmenes, y para realizar un cribado del texto completo, un resumen de los datos y una evaluación de calidad. La heterogeneidad se evaluó mediante el test estadístico I2 . Se usó la diferencia de medias estandarizada (SMD, por sus siglas en inglés) como una medida de la magnitud del efecto. Resultados: En el metaanálisis se incluyeron catorce estudios. Siete de los estudios se llevaron a cabo durante embarazos complicados por PE, 10 se realizaron hasta 10 años después del parto y tres incluyeron mediciones tomadas en ambos períodos. Las mujeres con PE tuvieron un CIMT significativamente mayor que aquellas que no la tenían, tanto en el momento del diagnóstico (SMD 1,10 (I 95%, 0,73-1,48), P <0,001) como en la primera década después del parto (SMD 0,58 (IC 95%, 0,36-0,79), P <0,001). Conclusiones: La carga aterosclerótica está presente en el momento de la PE y podría ser un mecanismo asociado con esta enfermedad. La medición del CIMT puede ofrecer una oportunidad para la identificación temprana de mujeres premenopáusicas con carga aterosclerótica después de un embarazo con PE. : (pre-eclampsia,PE),,,。-(carotid intima-media thickness,CIMT),PEPE,。 : PEPECIMTmeta,CIMT、。:10CIMT。PubMed、EMBASEWeb of Science,201637。,,、。I2 。(SMD)。 : meta14。7PE,1010,3。PEPE,[SMD,1.10(95% CI,0.73~1.48);P<0.001]10[SMD,0.58(95% CI,0.36~0.79);P<0.001] CIMT。 : PE,。CIMT,PE。.