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Preeclampsia: Maternal Systemic Vascular Disorder Caused by Generalized Endothelial Dysfunction Due to Placental Antiangiogenic Factors.

Int J Mol Sci. 2019 Aug 30;20(17):

Authors: Tomimatsu T, Mimura K, Matsuzaki S, Endo M, Kumasawa K, Kimura T

Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries.

PMID: 31480243 [PubMed - indexed for MEDLINE]

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Matters of the Heart: Cardiovascular Health in Women Throughout Their Lifetimes.

Obstet Gynecol Clin North Am. 2019 Sep;46(3):515-525

Authors: Newman RA, Hameed AB

The authors' goal is to review the current recommendations for optimizing cardiovascular health beginning in adolescent years to adulthood, and to expand on the role that pregnancy complications may have as implications for future cardiovascular health. Attention to cardiac health begins in adolescence; however, most young patients are not screened. Pregnancy, with its increased cardiovascular demands and host of antepartum cardiopulmonary complications, may provide a window into future cardiac health. The distinct shift in cardiac risk that occurs once a woman enters menopause is largely ignored in routine screening guidelines.

PMID: 31378292 [PubMed - indexed for MEDLINE]

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Postpartum depression among women with pre-eclampsia and eclampsia in Tanzania; a call for integrative intervention.

BMC Pregnancy Childbirth. 2019 Jul 29;19(1):270

Authors: Mbarak B, Kilewo C, Kuganda S, Sunguya BF

BACKGROUND: Postpartum depression (PPD) complicates maternal wellbeing, maternal-infant bonding, and cognitive function in children and woman's relationship with her partner. Clinical observations suggest a higher risk of postpartum depression among those women with pre-eclampsia and eclampsia compared to the general population. However, the evidence is inconsistent and not from settings similar to Tanzanian. This study aimed to determine the magnitude and risk factors for PPD among women diagnosed with pre-eclampsia or eclampsia at Muhimbili National Hospital (MNH), Tanzania.
METHODS: This cross-sectional study was conducted among 390 women who had pre-eclampsia or eclampsia during pregnancy attending postnatal care clinic at MNH. PPD was assessed using Edinburg postnatal depression scoring scale (EPDS). Face to face interviews was conducted and data was analysed using descriptive and logistic regression analysis to address the two respective objectives.
RESULTS: PPD was prevalent among 20.5% of women who had pre-eclampsia or eclampsia but varied with severity. Factors associated with PPD included young age (AOR = 10.13 95% CI 1.99-52.02), being a single mother (AOR = 3.18 95% CI 1.02-9.95), having a lower level of education (AOR = 3.83 95% CI 1.45-10.16), having a perinatal death (AOR = 5.14 95% CI 2.53-10.45), lack of family support (AOR = 7.06 95% CI 1.25-39.90), and experience of stressful event during pregnancy (AOR = 15.14 95% CI 2.38-96.19).
CONCLUSION: One in five women with pre-eclampsia or eclampsia had PPD and the magnitude increased with the severity of the disease condition. To address PPD, efforts should be done to screen and provide treatment to pregnant women presenting with pre-eclampsia or eclampsia, especially those with young age, low education level, single marital status, perinatal loss, lack of family support, and those reported to have a stressful event during pregnancy.

PMID: 31357939 [PubMed - indexed for MEDLINE]

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A cross sectional study to assess the sFlt-1:PlGF ratio in pregnant women with and without preeclampsia.

BMC Pregnancy Childbirth. 2019 Jul 25;19(1):266

Authors: Pant V, Yadav BK, Sharma J

BACKGROUND: Preeclampsia is a multisystem disorder characterized by vascular endothelial malfunction occurring after 20 weeks of gestation. Placental soluble fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic factor and placental growth factor (PlGF) is a potent angiogenic factor. The imbalance between these factors during placenta and fetal development has been shown to play a role in endothelial damage in preeclampsia. Preeclampsia is the leading cause of maternal mortality in Nepal. This study was designed to compare the sFlt1:PLGF ratio in pregnant women with and without preeclampsia attending Tribhuvan University Teaching Hospital (TUTH).
METHOD: An observational cross-sectional study was performed in the Gynecology and Obstetrics Department of TUTH involving forty-four subjects with preeclampsia and forty-four age- and gestational-week-matched normal pregnant subjects as controls. Blood pressure, urinary protein levels, serum sFlt-1 levels, serum PlGF levels and the sFlt-1:PlGF ratio was compared in both the cases and control. The concentrations of sFlt-1 and PlGF were measured with commercially available ELISA kits. SPSS ver. 20.0 was used to analyze the data.
RESULTS: There was no significant difference in age or gestational age in either study group. The ratio of the sFlt-1 and PlGF concentrations was significantly higher in women with preeclampsia (31.6 ± 9.6) than in the controls (3.2 ± 1.3). Likewise, diastolic blood pressure was significantly associated (p-value 0.000), whereas the severity of proteinuria was not associated (p-value 0.773) with the sFlt-1:PlGF ratio in women with preeclampsia. The significantly higher ratio (35.51 ± 8.1 versus 25.4 ± 8.7) was found in women with preeclampsia who developed complications than the group of women with preeclampsia who did not develop complication.
CONCLUSION: The sFlt-1:PlGF ratio is significantly higher in Nepalese women with preeclampsia than in normal controls and this finding can be applied for further planned clinical trials.

PMID: 31345176 [PubMed - indexed for MEDLINE]

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Maternal age and the risk of adverse pregnancy outcomes: a retrospective cohort study.

BMC Pregnancy Childbirth. 2019 Jul 23;19(1):261

Authors: Londero AP, Rossetti E, Pittini C, Cagnacci A, Driul L

BACKGROUND: The increased potential for negative pregnancy outcomes in both extremes of reproductive age is a well-debated argument. The aim of this study was to analyze the prevalence and the outcome of pregnancies conceived at extreme maternal ages.
METHODS: This retrospective study considered all single consecutive pregnancies delivered in a tertiary referral center between 2001 and 2014. Patients were categorized into 4 groups according to maternal age at delivery (< 17 years; 18-28 years; 29-39 years; > 40 years). The following outcomes were considered (amongst others): pregnancy-related hypertensive disorders (PRHDs), neonatal resuscitation (NR), neonatal intensive care unit (NICU) admission, periventricular leucomalacia (PVL), and grade 3 and 4 intraventicular hemorrhage (IVH).
RESULTS: During the considered period 22,933 single pregnancies gave birth in our unit. We observed 71 women aged < 17 years, and 1552 aged > 40 years. In each year throughout the study period, there was a significant increment in maternal age of 0.041 years (95% CI 0.024-0.058) every new year. Multivariate analysis concluded out that maternal age over 40 years was an independent risk factor for preterm delivery (OR 1.36 95% CI 1.16-1.61, p < 0.05, PRHDs (OR 2.36 95% CI 1.86-3.00, p < 0.05), GDM (OR 1.71 95% CI 1.37-2.12, p < 0.05) cesarean section (OR 1.99 95% CI 1.78-2.23, p < 0.05), abnormal fetal presentation (OR 1.29 95% CI 1.03-1.61, p < 0.05), and fetal PVL (OR 3.32 95% CI 1.17-9.44, p < 0.05). We also observed that maternal age under 17 years or over 40 years was an independent risk factor for grade 3 or 4 neonatal IVH (OR 2.97 95% CI 1.24-7.14, p < 0.05).
CONCLUSIONS: These findings confirm a negative impact of extreme maternal ages on pregnancy. These results should be carefully taken into account by maternal care providers in order to inform women adequately, supporting them in understanding potential risks associated with their procreation choices, and to improve clinical surveillance.

PMID: 31337350 [PubMed - indexed for MEDLINE]

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Interactions between the complement and endothelin systems in normal pregnancy and following placental ischemia.

Mol Immunol. 2019 10;114:10-18

Authors: Regal JF, Lund JM, Wing CR, Root KM, McCutcheon L, Bemis LT, Gilbert JS, Fleming SD

Preeclampsia is characterized by new onset hypertension and fetal growth restriction and is associated with aberrant activation of the innate immune complement system and stressed or ischemic placenta. Previous studies have suggested a role for both endothelin and complement system activation products in new onset hypertension in pregnancy, but inter-relationships of the pathways are unclear. We hypothesized that complement activation following placental ischemia stimulates the endothelin pathway to cause hypertension and impair fetal growth. The Reduced Uterine Perfusion Pressure (RUPP) model results in hypertension and fetal growth restriction in a pregnant rat due to placental ischemia caused by mechanical obstruction of blood flow to uterus and placenta. The effect of inhibitor of complement activation soluble Complement Receptor 1 (sCR1) and endothelin A receptor (ETA) antagonist atrasentan on hypertension, fetal weight, complement activation (systemic circulating C3a and local C3 placental deposition) and endothelin [circulating endothelin and message for preproendothelin (PPE), ETA and endothelin B receptor (ETB) in placenta] in the RUPP rat model were determined. Following placental ischemia, sCR1 attenuated hypertension but increased message for PPE and ETA in placenta, suggesting complement activation causes hypertension via an endothelin independent pathway. With ETA antagonism the placental ischemia-induced increase in circulating C3a was unaffected despite inhibition of hypertension, indicating systemic C3a alone is not sufficient. In normal pregnancy, inhibiting complement activation increased plasma endothelin but not placental PPE message. Atrasentan treatment increased fetal weight, circulating endothelin and placental ETA message, and unexpectedly increased local complement activation in placenta (C3 deposition) but not C3a in circulation, suggesting endothelin controls local placental complement activation in normal pregnancy. Atrasentan also significantly decreased message for endogenous complement regulators Crry and CD55 in placenta and kidney in normal pregnancy. Results of our study indicate that complement/endothelin interactions differ in pregnancies complicated with placental ischemia vs normal pregnancy, as well as locally vs systemically. These data clearly illustrate the complex interplay between complement and endothelin indicating that perturbations of either pathway may affect pregnancy outcomes.

PMID: 31326653 [PubMed - indexed for MEDLINE]

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Placental sFLT1 is associated with complement activation and syncytiotrophoblast damage in preeclampsia.

Hypertens Pregnancy. 2019 Aug;38(3):193-199

Authors: Yonekura Collier AR, Zsengeller Z, Pernicone E, Salahuddin S, Khankin EV, Karumanchi SA

The immune complement system protects against pathogens; however, excess activation results in disease like hemolytic uremic syndrome, a clinical imitator of preeclampsia. Vascular endothelial factor (VEGF) protects against aberrant complement activation and is inhibited by soluble fms-like tyrosine kinase-1 (sFLT1) in other organs. We hypothesize that sFLT1 promotes complement-mediated placental damage through VEGF inhibition in preeclampsia. Objective: Quantify placental complement activity and sFLT1 expression in preeclampsia, and the subgroup of preeclampsia with hemolysis elevated liver enzymes low platelets (HELLP) syndrome. Methods: Placental complement activation marker C4d, membrane attack complex (MAC), and sFLT1 expression was quantified using immunofluores cence microscopy. Results: Placentas from 18 controls, 25 preeclampsia, including 6 cases of HELLP syndrome were identified. Placental C4d expression was greater in PE (median 6.4 [IQR: 5.1, 8.3]) compared to controls (4.4 [3.6, 5.5]; p = 0.003). MAC expression was also increased in preeclampsia compared to controls (6.5 [5.8, 8.7]; 5.4 [2.9, 5.9], p = 0.001). Placental sFLT1 expression was also higher in preeclampsia (p <0.0001). C4d and MAC were strongly correlated with sFLT1 levels in the placenta (R = 0.72; p < 0.0001 and R = 0.59; p = 0.01, respectively). Complement and sFLT1 expression was elevated in HELLP compared to preeclampsia without laboratory abnormalities, but this difference did not reach statistical significance. Conclusion: Increased placental complement activation and damage was seen in preeclampsia and correlates with sFLT1 expression. Our findings support the importance of the complement pathway in preeclampsia.

PMID: 31291799 [PubMed - indexed for MEDLINE]

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Screening of serum biomarkers of preeclampsia by proteomics combination with bioinformatics.

Hypertens Pregnancy. 2019 Aug;38(3):184-192

Authors: Ling Y, Su J, Lin J, Wang S

Objective: To screen for novel predictive serum markers of preeclampsia (PE). Method: Blood samples were collected from seven women with PE and five with healthy pregnancies. Serum proteins were identified using isobaric tags for relative and absolute quantitation (iTRAQ) technology combined with liquid chromatography mass spectrometry analysis. The differentially expressed proteins in the PE samples were identified using the SwissProt database, and functionally annotated by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The upregulated proteins from iTRAQ result were verified by ELISA. Results: We identified 121 differentially expressed proteins, of which 76 were upregulated and 45 were downregulated, and 14 were differentially expressed by more than two-folds. The top GO terms for Cellular Components (CC) were high-density lipoprotein particles and plasma lipoprotein particles, defense response for Biological Processes (BP), and glycosaminoglycan binding, heparin binding and sulfur compound for Molecular functions (MF). The pathway hsa04979 for Cholesterol metabolism was significantly enriched among the upregulated proteins, while the structural domain was enriched in immunoglobulin subtype 2. The dysregulation of pregnancy-specific beta-1-glycoprotein 2 (PSG2) was confirmed by ELISA. Conclusion: PE pathogenesis is related to lipid metabolism and inflammation, and proteins related to these pathways are potential early diagnostic markers for PE.PSG2 may be a marker of PE.

PMID: 31284791 [PubMed - indexed for MEDLINE]

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The association between abnormal coagulation testing in preeclampsia, adverse pregnancy outcomes, and placental histopathology.

Hypertens Pregnancy. 2019 Aug;38(3):176-183

Authors: Feldstein O, Kovo M, Tal O, Braunstein M, Grinstein E, Schreiber L, Bar J, Weiner E

Objective: We aimed to determine whether abnormal coagulation laboratory testing results in preeclampsia, are associated with adverse pregnancy outcomes and placental histopathology lesions. Methods: Demographic, labor, laboratory-testing, and placental histopathology reports of pregnancies complicated by preeclampsia were compared between those with and without abnormal coagulation profile (ACP). Results: Of 348 cases of preeclampsia 16.1% had ACP. There were no differences between the groups in GA at delivery, severe features, placental-abruption, SGA, composite adverse neonatal outcome and placental histopathology lesions. Conclusion: ACP in pregnancies complicated by preeclampsia was not associated with any of the studied outcomes. Our data question the usefulness of routine coagulation tests in the initial assessment of women presenting with preeclampsia.

PMID: 31271326 [PubMed - indexed for MEDLINE]

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Methylation profile of genes involved in inflammation, in the blood from pregnancies with maternal preeclampsia due to untreated gestational diabetes mellitus.

Hormones (Athens). 2019 Jun;18(2):173-178

Authors: Halvatsiotis P, Tsokaki T, Chrelias C, Kassanos D, Domali E, Gazouli M, Dimitriadis G, Kalantaridou S

PURPOSE: To investigate DNA methylation changes in peripheral blood from patients with gestational diabetes mellitus (GDM) and preeclampsia (PE) due to poorly treated GDM.
METHODS: Eighteen pregnant women participated in the study: 6 with GDM, 6 with PE, and 6 healthy controls. The promoter methylation status of genes was profiled using the Human Inflammatory Response and Autoimmunity EpiTect Methyl II Signature PCR Array profiles. The results were validated with quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS: Fewer inflammation-related genes were significantly hypomethylated in PE cases compared to healthy subjects than in GDM cases. Some of the examined genes show different methylation patterns between GDM and PE.
CONCLUSIONS: The epigenetic changes observed in this study indicate that GDM and PE exhibit specific DNA methylation profiles, with possible clinical applications.

PMID: 31154656 [PubMed - indexed for MEDLINE]

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Urinary neutrophil gelatinase-associated lipocalin is associated with preeclampsia in a cohort of Turkish women.

Hypertens Pregnancy. 2019 Aug;38(3):157-162

Authors: Yuksel S, Ozyurek SE, Acar DK, Ozdemir C, Guler S, Kiyak H, Gedikbasi A

Purpose: We investigated the optimal cut-off level for urinary neutrophil gelatinase-associated lipocalin (NGAL) in preeclamptic patients to confirm the diagnosis. Methods: Urinary NGAL concentrations were measured by specific enzyme-linked immunosorbent assay (ELISA). Results: Patients with preeclampsia had significantly higher urinary NGAL concentrations than controls (mean: 387 ng/ml vs. 188 ng/ml, respectively; P< 0.001). Using a cutoff value 252 ng/ml for urinary NGAL to confirm diagnosis of preeclampsia, sensitivity, and specificity were 92% and 91%, respectively. Conclusion: Urinary NGAL concentrations were significantly elevated in women with preeclampsia versus normotensive controls.

PMID: 31140344 [PubMed - indexed for MEDLINE]

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Is maternal lipid profile in early pregnancy associated with pregnancy complications and blood pressure in pregnancy and long term postpartum?

Am J Obstet Gynecol. 2019 08;221(2):150.e1-150.e13

Authors: Adank MC, Benschop L, Peterbroers KR, Smak Gregoor AM, Kors AW, Mulder MT, Schalekamp-Timmermans S, Roeters Van Lennep JE, Steegers EAP

BACKGROUND: An atherogenic lipid profile is a risk factor for the initiation and progression of atherosclerosis. This ultimately leads to cardiovascular disease. Women with a history of hypertensive disorders of pregnancy are at increased risk of sustained hypertension and cardiovascular disease later in life. Currently it is unclear whether dyslipidemia during pregnancy contributes to these risks.
OBJECTIVE: The objective of the study was to determine the associations between early pregnancy maternal lipid profile, hypertensive disorders of pregnancy, and blood pressure during and years after pregnancy.
STUDY DESIGN: We included 5690 women from the Generation R Study, an ongoing population-based prospective birth cohort. Two hundred eighteen women (3.8%) developed gestational hypertension and 139 (2.4%) preeclampsia. A maternal lipid profile consisting of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, remnant cholesterol, and non-high-density lipoprotein cholesterol was determined in early pregnancy (median, 13.4 weeks of gestation). Systolic and diastolic blood pressures were measured in early, mid-, and late pregnancy and 6 and 9 years after pregnancy.
RESULTS: Triglycerides and remnant cholesterol in early pregnancy were positively associated with preeclampsia. Maternal lipid levels in early pregnancy were not associated with gestational hypertension. Total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and especially triglycerides and remnant cholesterol were positively associated with blood pressure in pregnancy and 6 and 9 years after pregnancy. Triglycerides and remnant cholesterol are positively associated with sustained hypertension 6 and 9 years after pregnancy.
CONCLUSION: An atherogenic lipid profile in early pregnancy reflecting impaired triglyceride-rich lipoprotein metabolism is independently associated with preeclampsia and blood pressure throughout pregnancy but also with sustained hypertension long term postpartum. Lipid levels in early pregnancy may help to identify women at risk for future hypertension and perhaps also women at risk for future cardiovascular disease.

PMID: 30940559 [PubMed - indexed for MEDLINE]

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Protective effect of vitamin D supplementation in a rat modal of preeclampsia: a possible implication of chemerin.

Hypertens Pregnancy. 2019 Aug;38(3):149-156

Authors: Nassar SZ, Badae NM

Background: Preeclampsia (PE) is a disorder of pregnancy associated with vitamin D (VD) deficiency. Chemerin is an adipokine significantly increased in preeclampsia and is regulated by VD. Objectives: To determine whether VD supplementation would protect against development of PE through Chemerin reduction Methods: PE was induced in albino rats by injection of 12.5 mg of deoxycorticosterone (DOCA).   Rats were randomly divided into normal pregnant, PE group, VD supplemented PE group. Results: VD supplementation decreased systolic blood pressure, proteinuria and decreased serum Chemerin level. Conclusion: VD treatment reduced Chemerin level, and blood pressure in DOCA rat model of PE.

PMID: 30922121 [PubMed - indexed for MEDLINE]

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Lvrn expression is not critical for mouse placentation.

J Reprod Dev. 2019 Jun 14;65(3):239-244

Authors: Tobita T, Kiyozumi D, Muto M, Noda T, Ikawa M

Preeclampsia is a systemic disease caused by abnormal placentation that affects both mother and fetus. It was reported that Laeverin (LVRN, also known as Aminopeptidase Q) was up-regulated in the placenta of preeclamptic patients. However, physiological and pathological functions of LVRN remained to be unknown. Here we characterized Lvrn function during placentation in mice. RT-PCR showed that Lvrn is expressed in both fetus and placenta during embryogenesis, and several adult tissues. When we overexpressed Lvrn in a placenta-specific manner using lentiviral vectors, we did not see any defects in both placentae and fetuses. The mice carrying Lvrn overexpressing placentas did not show any preeclampsia-like symptoms such as maternal high blood pressure and fetal growth restriction. We next ablated Lvrn by CRISPR/Cas9-mediated genome editing to see physiological function. In Lvrn ablated mice, maternal blood pressure during pregnancy was not affected, and both placentas and fetuses grew normally. Collectively, these results suggest that, LVRN is irrelevant to preeclampsia and dispensable for normal placentation and embryonic development in mice.

PMID: 30745494 [PubMed - indexed for MEDLINE]

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Basal Chronic Villitis and Disorders of the Placental Basal Plate: A Possible Immunological Link Between Hypertensive Disorders of Pregnancy and Morbidly Adherent Placenta.

Pediatr Dev Pathol. 2019 Jul-Aug;22(4):334-339

Authors: Katzman PJ, Blitman J, Metlay LA

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a common cause for preterm delivery. Prior studies showed that chronic villitis (CV) is associated with intrauterine growth restriction, preeclampsia, intrauterine fetal death, and morbidly adherent placenta (MAP). The authors hypothesize that disorders of the placental basal plate, especially basal chronic villitis (BCV), are associated with HDP.
METHODS: The laboratory information system was queried over 12 years to identify placentas with or without the clinical history of HDP and with or without multifocal/focal CV or BCV. As a control for tissue sampling, a similar search was performed over 5 years for placentas evaluated for MAP.
RESULTS: Of 19,683 placentas identified, 14.8% had CV which was in 18.5% and 14.2% of placentas associated with or without HDP, respectively, a significant difference (P < .0001). BCV was present in 6.0% and 3.9% of placentas with or without HDP, respectively, also a significant difference (P < .0001). BCV was more likely than multifocal/focal CV to occur in HDP (32.4% vs 27.4%) when all cases of CV were analyzed (P = .025). Of 221 placentas with MAP, 64% had multifocal/focal CV and 36% had BCV.
CONCLUSIONS: BCV and CV are more common in placentas with HDP than in normotensive pregnancies. They are also seen in MAP, as supported by another recent study.

PMID: 30665335 [PubMed - indexed for MEDLINE]

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Diet and exercise for preeclampsia prevention in overweight and obese pregnant women: systematic review and meta-analysis.

J Matern Fetal Neonatal Med. 2019 Oct;32(20):3495-3501

Authors: Syngelaki A, Sequeira Campos M, Roberge S, Andrade W, Nicolaides KH

Objective: To investigate the effect of diet and/or exercise in overweight or obese pregnant women on the risk of preeclampsia (PE). Methods: We performed a systematic review and meta-analysis of randomized controlled trials examining the effect of diet and/or exercise interventions in overweight and obese pregnant women on the risk of PE and hypertensive disorders. We completed a literature search through PubMed, Embase, Cinahl, Web of science, Cochrane CENTRAL Library from their earliest entries to November 2017 and from references of other systematic reviews. No language restrictions were applied. Relative risks (RR) with random effect were calculated with their 95% confidence intervals (CI). Results: There were 23 eligible trials (7236 participants), including 11 (5023 participants) investigating the effect of diet and three (387 participants) investigating the effect of exercise on risk of PE, 14 (4345 participants) investigating the effect of diet, five (884 participants) investigating the effect of exercise and one (304 participants) investigating the effect of diet and exercise on risk of hypertensive disorders. Most studies were considered to be at low risk of bias for random sequence allocation and incomplete outcome data but at high risk of bias for blinding of participant and personnel. The heterogeneity of the studies on PE was low (I2 = 0-11%), but the heterogeneity of the studies on hypertensive disorders was variable (I2 = 0-53%). In women randomized to diet and/or exercise, compared to expectant management, there was no significant difference in the risk of PE (RR 1.01, 95% CI 0.80-1.27; p = .96) or hypertensive disorders of pregnancy (RR 0.87, 95% CI 0.70-1.06; p = .17). In the intervention group, compared to expectant management, gestational weight gain was significantly lower (-1.47 kg, 95% CI -1.97 to -0.97; p < .00001). Metaregression weighted by the size of the studies showed no significant association between gestational weight gain and the risk of PE or hypertensive disorders (p = .314 and p = .124, respectively). Conclusions: Diet and exercise in overweight or obese pregnant women are beneficial in reducing gestational weight gain. However, these interventions do not reduce the risk of PE or hypertensive disorders of pregnancy.

PMID: 29792061 [PubMed - indexed for MEDLINE]

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The effect of prepregnancy body mass index on birth weight, preterm birth, cesarean section, and preeclampsia in pregnant women.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3818-3823

Authors: Mohammadi M, Maroufizadeh S, Omani-Samani R, Almasi-Hashiani A, Amini P

Objective: The objective of this study is to determine the impact of maternal prepregnancy BMI on birth weight, preterm birth, cesarean section, and preeclampsia among pregnant women delivering singleton life birth. Methods: A cross-sectional study of 4397 women who gave singleton birth in Tehran, Iran from 6 to 21 July 2015, was conducted. Women were categorized into four groups: underweight (BMI < 18.5 kg/m2), normal (BMI 18.5-25 kg/m2), overweight (BMI 25-30 kg/m2) and obese (BMI >30 kg/m2), and their obstetric and infant outcomes were analyzed using both univariate and multivariate logistic regression. Results: Prepregnancy BMI of women classified 198 women as underweight (4.5%), 2293 normal (52.1%), 1434 overweight (32.6%), and 472 as obese (10.7%). In comparison with women of normal weight, women who were overweight or obese were at increased risk of preeclampsia (odds ratio (OR) = 1.47, 95% CI = 1.06-2.02; OR = 3.67, 95% CI = 2.57-5.24, respectively) and cesarean section (OR = 1.21, 95% CI = 1.04-1.41; OR = 1.35, 95% CI = 1.06-1.72, respectively). Infants of obese women were more likely to be macrosomic (OR = 2.43, 95% CI = 1.55-3.82). Conclusion: Prepregnancy obesity is a risk factor for macrosomia, preeclampsia, and cesarean section and need for resuscitation.

PMID: 29768986 [PubMed - indexed for MEDLINE]

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Strategies for the prediction of late preeclampsia.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3729-3733

Authors: Mula R, Meler E, Albaiges G, Rodriguez I

Objectives: To evaluate different strategies for the prediction of late preeclampsia. Methods: A retrospective study was undertaken. A predictive model including maternal parameters (maternal age, maternal BMI, maternal history of preeclampsia or intrauterine growth restriction (PE/IUGR) or maternal chronic disease, and maternal arterial pressure) and mean pulsatility index (PI) of uterine Doppler was created. It was evaluated as an independent model in each trimester, considering 11-13.6 weeks, 20-22.6 weeks and 32-33.6 weeks consequently, and as an integrated model. Results: In the group of late preeclampsia, patients were more obese and had higher incidence of chronic hypertension. Uterine artery pulsatility index (UtA PI) and mean blood pressure were increased in all three trimesters. When evaluating all three models independently, third trimester model performed better than the other two with a sensitivity of 79% and specificity of 82%. The area under the receiver-operating characteristic (ROC) curve (AUC) was 0.86. The integration of all three determinations did not improve third trimester's model. Conclusion: Prediction of late preeclampsia at third trimester seems to be possible if maternal characteristics, blood pressure and UtA Doppler are included.

PMID: 29764256 [PubMed - indexed for MEDLINE]

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Association study between variants in LHCGR DENND1A and THADA with preeclampsia risk in Han Chinese populations.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3801-3805

Authors: Zhang YJ, Li L, Wang ZJ, Zhang XJ, Zhao H, Zhao Y, Wang XT, Li CZ, Wan JP

Objective: To evaluate the association between preeclampsia and three single nucleotide polymorphisms (rs13405728 in LHCGR gene; rs13429458 in THADA gene, and rs2479106 in DENND1A gene) which were identified to be genetic variants of polycystic ovary syndrome (PCOS) by genome-wide association study in Han Chinese populations. Methods: A total of 784 northern Han Chinese women (378 controls and 406 cases) were genotyped for the three genetic variants by polymerase chain reaction and direct sequencing. Unconditional logistic regression analysis was used to adjust the impact of prepregnancy body mass index, primiparas, and maternal age. Results: No significant difference was found in the allele frequencies of the three genetic variants between cases and controls (p > .05), but genotype frequency of the SNP rs2479106 was significantly differ between cases and controls when analyzed under recessive models (p = .02). There was also a substantial difference in the genotype frequencies of the SNP rs13429458 between cases and controls under additive models (p = .01). Conclusions: Genetic variants of PCOS (rs13405728 in LHCGR gene; rs13429458 in THADA gene and rs2479106 in DENND1A gene) may not be involved in the development of preeclampsia in Han Chinese women.

PMID: 29727258 [PubMed - indexed for MEDLINE]

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QSOX1 regulates trophoblastic apoptosis in preeclampsia through hydrogen peroxide production.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3708-3715

Authors: Li J, Tong C, Xu P, Wang L, Han TL, Wen L, Luo X, Tan B, Zhu F, Gui S, Gao R, Qi H, Baker PN

Objective: Oxidative stress plays a significant role in the pathogenesis of preeclampsia (PE), by inducing trophoblast cell death and consequent placental dysfunction. Quiescin sulfhydryl oxidase 1 (QSOX1) is upregulated in many types of cancer cells; it promotes disulfide bond formation as well as hydrogen peroxide (H2O2) production. The aims of present study are to investigate the expression pattern of QSOX1 in placentae of pregnancies complicated by PE and the role of QSOX1 in the regulation of trophoblastic function, thus providing in-depth understanding of the putative involvement of QSOX1 in the development of PE. Methods: Human term placenta from normal pregnancies and from pregnancies complicated by PE was collected to measure QSOX1 expression and H2O2 levels. Down-regulation of QSOX1 in HTR-8/SVneo cells was achieved by siRNA interference. An in vitro cellular PE model was generated by hypoxic incubation. Protein expression levels were assessed by Western blotting, and H2O2 levels were determined in the cell culture medium as well as in the cell lysate. Trophoblast apoptosis was evaluated by TUNEL staining. Results: QSOX1 was overexpressed in the PE placenta. Inhibition of QSOX1 expression in HTR-8/SVneo cells attenuated cell apoptosis and intracellular H2O2 levels. Hypoxia-induced QSOX1 expression in HTR-8/SVneo cells and led to apoptosis of HTR-8/SVneo cells, and knock-down of QSOX1 rescued hypoxia-induced trophoblast apoptosis. Conclusions: Hypoxia-induced upregulation of QSOX1 and a consequent elevation in intracellular H2O2 increased apoptosis in placentae of pregnancies complicated by PE.

PMID: 29712536 [PubMed - indexed for MEDLINE]

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Analysis of preventability of hypertensive disorder in pregnancy-related maternal death using the nationwide registration system of maternal deaths in Japan.

J Matern Fetal Neonatal Med. 2019 Oct;32(20):3420-3426

Authors: Katsuragi S, Tanaka H, Hasegawa J, Nakamura M, Kanayama N, Nakata M, Murakoshi T, Yoshimatsu J, Osato K, Tanaka K, Sekizawa A, Ishiwata I, Ikeda T, Maternal Death Exploratory Committee in Japan and Japan Association of Obstetricians and Gynecologists

Objective: Hypertensive disorder of pregnancy (HDP) is a major cause of maternal death. The goal of this study was to investigate factors associated with maternal death due to HDP. Study design: HDP-related maternal deaths in Japan reported to the Committee of the Ministry of Health, Labor and Welfare from 2010 to 2015 were examined. Results: Out of 47 cases of HDP, 30 were identified as the major cause of maternal death. The median maternal age was 34 years (range 24-45) and the mortality in women aged ≥40 years was seven times higher that than in women aged <34 years. The etiologies were intracerebral hemorrhage (n = 22), subarachnoid hemorrhage (n = 3), subcapsular hematoma of the liver (n = 2), peripartum cardiomyopathy (n = 2), and eclampsia (n = 1), and 19 cases were deemed preventable. The most frequent antepartum problems were delays in hospitalization, maternal transfer, and termination of pregnancy. In four cases, diagnosis of HELLP syndrome was too late because laboratory data were not checked, despite the patient reporting epigastric pain or showing elevation of blood pressure (BP). Treatment for lowering of BP was improper in 2/3 intrapartum cases, even though BP was elevated during pregnancy (144 versus 188 mmHg, p < .001). There was inadequate lowering of BP and lack of use of magnesium sulfate in 7/11 postpartum cases (64%), despite aspartate aminotransferase (AST) (p < .005), alanine aminotransferase (ALT) (p < .01), lactate dehydrogenase (LDH) (p < .005), and platelet count (PLT) (p < .01) all significantly worsening after delivery. Conclusion: HDP accounts for 11% of maternal deaths in Japan. Mothers aged ≥40 years are most at risk for HDP-related maternal death. Major concerns for preventabilities were late hospitalization, maternal transportation, and termination of pregnancy for term or near-term HDP. Regular vital checks and prompt lowering of BP were lacked during labor in most cases. HELLP syndrome should be managed at a general hospital with sufficient medical resources.

PMID: 29699420 [PubMed - indexed for MEDLINE]

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Maternal serum laeverin (aminopeptidase Q) measured in the first trimester of pregnancy does not predict preeclampsia.

J Matern Fetal Neonatal Med. 2019 Oct;32(20):3348-3351

Authors: Pihl K, Sørensen S, Nystad M, Acharya G, Jørgensen FS

Objective: The aim of this study was to compare the laeverin level in maternal serum from first trimester (11-14 weeks) of pregnancy between normal pregnancies and pregnancies that later developed preeclampsia (PE). Material and methods: This was a case-cohort study. The laeverin concentration was measured in cases with preterm PE (n = 55), term PE (n = 95), and a reference group of randomly selected women with normal pregnancy outcome (n = 200) in stored serum samples collected from the double-test as part of the combined first trimester trisomy 21 screening program. The samples were thawed and analyzed for laeverin. The median gestational age at blood sampling was 77 days (range 57-96 days). Multiple regression analysis was performed to establish a normal median. Concentrations were converted to multiples of the median (MoM) and groups were compared using the Mann-Whitney U-test. Results: In the reference group, laeverin was significantly correlated with gestational age (r = 0.18, p = .01) and its concentration ranged from 41-393 µg/L. No significant differences in the median laeverin MoM were found between the reference group (1.01 MoM) and cases with preterm PE (0.98 MoM) or term PE (0.96 MoM). Conclusions: First trimester maternal serum laeverin level cannot be used to predict preeclampsia.

PMID: 29681208 [PubMed - indexed for MEDLINE]

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Incidence and natural history of preeclampsia/eclampsia at the university maternity of Antananarivo, Madagascar: high prevalence of the early-onset condition.

J Matern Fetal Neonatal Med. 2019 Oct;32(19):3266-3271

Authors: Ratsiatosika AT, Razafimanantsoa E, Andriantoky VB, Ravoavison N, Andrianampanalinarivo Hery R, Boukerrou M, Iacobelli S, Robillard PY

Objectives: To investigate the incidence of early - (delivery <34 weeks) (EOP) versus late-onset (delivery ≥34 weeks) (LOP) in Madagascar. Study design: Eight months observational study of all preeclamptic/eclamptic women delivering at the maternity of the University Hospital of Befelatanana, Antananarivo, Madagascar. Sociodemographical and obstetrical risk factors are analyzed. Results: Over the study period, we found 142 combined preeclampsia/eclampsia among 4316 births (incidence 3.3% for singleton pregnancies), of which 65 eclampsia (1.5% of all deliveries). The rate of delivery <34 weeks of gestation in preeclamptic women was 37.3% and 38.5% in eclamptic ones. The overall rate of fetal and neonatal mortality was of 50% (71/142). In EO forms the infant death rate was 83% (44/53), of which approximately 33% were due to intrauterine fetal death. In LO forms, the infant death rate was 20% in preeclampsia (15% of fetal deaths), while in case of maternal eclamptic seizures the infant mortality rate was doubled (40%). There were seven maternal deaths (of which four were eclamptic women). Conclusions: We have in Madagascar a high rate of early-onset preeclampsia/eclampsia EOP (37% versus approximately 10% in international literature) and a consequent worrying rate of maternal-fetal mortality. We could find other high incidence of EOP in nine other geographical locations: Guadeloupe (31%), Réunion (31%), Mauritius (34%), Cameroon (37.4%), China (38%), Zimbabwe (58%), Thailand (34%), Turkey (29%), and India (26%). Emerging and tropical countries may belong to the "high rate of EOP standard." There is an urgent need to have additional data from these areas to confirm the hypothesis.

PMID: 29621911 [PubMed - indexed for MEDLINE]

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