Subphenotypes of severe early-onset pre-eclampsia at hospital admission. A Latin American single-center exploratory latent class analysis.

OBJECTIVES: To identify distinct subphenotypes of severe early-onset pre-eclampsia in Latin America and analyze biomarker and hemodynamic trends between subphenotypes after hospital admission. METHODS: A single-center prospective cohort study was conducted in Colombia. The latent class analysis identified subphenotypes using clinical variables, biomarkers, laboratory tests, and maternal hemodynamics. Class-defining variables were restricted to measurements at and 24 h after admission. Primary and secondary outcomes were severe maternal and perinatal complications. RESULTS: Among 49 patients, two subphenotypes were identified: Subphenotype 1 (34.7%) had a higher likelihood of an sFlt-1/PlGF ratio ≤ 38, maternal age > 35, and low probability of TPR > 1400, CO <8, and IUGR; Subphenotype 2 (65.3%) had a low likelihood of an sFlt-1/PlGF ratio < 38, maternal age > 35, and high probability of TPR > 1400, CO <8, and IUGR. At 24 h postadmission, 64.7% of subphenotype 1 patients changed to subphenotype 2, while 25% of subphenotype 2 patients were reclassified as subphenotype 1. Subphenotype 1 displayed significant changes in CO and TPR, while subphenotype 2 did not. Maternal complications were more prevalent in subphenotype 2, with an odds ratio of 5.3 (95% CI: 1.3-22.0; P = 0.02), but no significant differences in severe neonatal complications were observed. CONCLUSIONS: We identified two distinct subphenotypes in a Latin American cohort of patients with severe early-onset pre-eclampsia. Subphenotype 2, characterized by higher TPR, sFlt-1, and serum creatinine and lower CO and PlGF at admission, was associated with worse maternal outcomes and appeared less modifiable after in-hospital treatment.

Comprehensive analyses of DNA methylation of the TIMP3 promoter in placentas from early-onset and late-onset preeclampsia.

Preeclampsia (PE) is classified into late-onset (LOPE) or early-onset (EOPE) according to gestational age of onset (≥34 or <34 weeks, respectively), and into preterm and term (delivery at <37 or ≥37 weeks, respectively). An imbalanced expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) impairs proper placentation in PE, and DNA methylation (DNAm) may affect their expression. We performed comprehensive analyses of DNAm and TIMP3 expression in placentas from PE reclassified into EOPE, LOPE, and term PE. We identified significant differentially methylated probes at the TIMP3 promoter in PE (28), EOPE (38), LOPE (20), and term PE (4) compared to controls, and in EOPE vs. LOPE (8). Moreover, we found a hypomethylation >70% in all groups (except EOPE vs. LOPE) and an increased TIMP3 expression in corresponding placental samples from PE, EOPE and LOPE compared to controls (p<0.05). Our findings highlight the role of DNAm of the TIMP3 promoter region regarding an epigenetic mechanism in PE.

Nocturnal hypertension and risk of developing early-onset preeclampsia in high-risk pregnancies.

To test the hypothesis that nocturnal hypertension identifies risk for early-onset preeclampsia/eclampsia (PE), we conducted an historical cohort study of consecutive high-risk pregnancies between 1st January 2016 and 31st March 2020. Office blood pressure (BP) measurements and ambulatory blood pressure monitoring (ABPM) were performed. The cohort was divided into patients without PE or with early- or late-onset PE (<34 and ≥34 weeks of gestation, respectively). The relative risks of office and ABPM hypertension for the development of late- or early-onset PE were estimated with multinomial logistic regression using no PE as a reference category. Four hundred and seventy-seven women (mean age 30 ± 7 years, with 23 ± 7 weeks of gestation at the time of the BP measurements) were analyzed; 113 (23.7%) developed PE, 69 (14.5%) developed late-onset PE, 44 (9.2%) developed early-onset PE. Office and ambulatory BP increased between the groups, and women who developed early-onset PE had significantly higher office and ambulatory BP values than those with late-onset PE or without PE. Hypertension prevalence increased across groups, with the highest values in early-onset PE. Nocturnal hypertension was the most prevalent finding and was highly prevalent in women who developed early-onset PE (88.6%); only 1.6% of women without nocturnal hypertension developed early-onset PE. Additionally, nocturnal hypertension was a stronger predictor for early-onset PE than for late-onset PE (adjusted OR, 5.26 95%CI 1.67-16.60) vs. 2.06, 95%CI 1.26-4.55, respectively). In conclusion, nocturnal hypertension was the most frequent BP abnormality and a significant predictor of early-onset PE in high-risk pregnancies.

Global DNA methylation in placental tissues from pregnant with preeclampsia: A systematic review and pathway analysis.

Pre-eclampsia (PE) is the major cause of fetal and maternal mortality and can be classified according to gestational age of onset into early-onset (EOPE, <34 weeks of gestation) and late- (LOPE, ≥34 weeks of gestation). DNA methylation (DNAm) may help to understand the abnormal placentation in PE. Therefore, we performed a systematic review to assess the role of global DNAm on pathophysiology of PE, focused on fetal and maternal tissues of placenta from pregnant with PE, including EOPE and LOPE. We searched the databases EMBASE, Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, Lilacs, Scielo and Google Scholar, and followed the MOOSE guidelines. Moreover, we performed pathway analysis with the overlapping genes from the included studies. Twelve out of 24 included studies in the qualitative analysis considered the classification into EOPE and LOPE. We did not found heterogeneity in the criteria used for diagnosis of PE, and a few studies evaluated whether confounding factors would influence placental DNAm. Fourteen out of 24 included studies showed hypomethylation in placental tissue from pregnant with PE compared to controls. The differences in DNAm are specific to genes or differentially methylated regions, and more evident in EOPE and preterm PE compared to controls, rather than LOPE and term PE. The overlapping genes from included studies revealed pathways relevant to pathophysiology of PE. Our findings highlighted the heterogeneous results of the included studies, mainly focused on North America and China. Replication studies in different populations should use the same placental tissues, techniques to assess DNAm and pipelines for bioinformatic analysis.

Maternal left ventricular hypertrophy and diastolic dysfunction and brain natriuretic peptide concentration in early- and late-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia (PE) is associated with maternal cardiac remodeling and diastolic dysfunction. The aim of this study was to assess and compare maternal left ventricular structure and diastolic function and levels of brain natriuretic peptide (BNP) in women with early-onset (< 34 weeks' gestation) vs those with late-onset (≥ 34 weeks' gestation) PE. METHODS: This was a prospective, cross-sectional, observational study of 30 women with early-onset PE, 32 with late-onset PE and 23 normotensive controls. Maternal cardiac structure and diastolic function were assessed by echocardiography and plasma levels of BNP were measured by enzyme immunoassay. RESULTS: Early- and late-onset PE were associated with increased left ventricular mass index and relative wall thickness compared with normotensive controls. In women with early-onset PE, the prevalence of concentric hypertrophy (40%) and diastolic dysfunction (23%) was also significantly higher (both P < 0.05) compared with women with late-onset PE (16% for both). Maternal serum BNP levels were significantly higher (P < 0.05) in women with early-onset PE and correlated with relative wall thickness and left ventricular mass index. CONCLUSIONS: Early-onset PE is associated with more severe cardiac impairment than is late-onset PE, as evidenced by an increased prevalence of concentric hypertrophy, diastolic dysfunction and higher levels of BNP. These findings suggest that early-onset PE causes greater myocardial damage, increasing the risk of both peripartum and postpartum cardiovascular morbidity. Although these cardiovascular effects are easily identified by echocardiographic parameters and measuring BNP, further studies are needed to assess their clinical utility. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Preeclampsia de inicio temprano y tardío: una antigua enfermedad, nuevas ideas

Las importantes diferencias que existen entre las manifestaciones de la preeclampsia, antes (inicio temprano) y después de la semana 34 (inicio tardío), plantean la posibilidad que se trate de dos enfermedades distintas. Basada en diferencias genéticas, epidemiológicas y placentarias, esta hipótesis cobra fuerza. Sin embargo, recientes estudios nos muestran la posibilidad de una continuidad clínico temporal entre ambos fenotipos. En este contexto los fenómenos antiangiogénicos y su relación con el feto podrían ser determinantes para esclarecer la interrogante.

Significant differences between preeclampsia manifestations before (early-onset) and after 34 weeks (late-onset) raise the possibility that these are two different diseases. This hypothesis is strengthened based on genetic, epidemiological and placental differences. However, recent studies show the possibility of temporal continuity between both clinical phenotypes. In this context antiangiogenic phenomena and their relation with the fetus may be crucial in clarifying this unanswered question.