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American Journal of Obstetrics &... Jan 2023This expert review aimed to assess current literature on the effect and tracking of physical activity during pregnancy and associated outcomes. Self-reported physical... (Review)
Review
This expert review aimed to assess current literature on the effect and tracking of physical activity during pregnancy and associated outcomes. Self-reported physical activity may be inaccurate given the subjective nature of the questionnaires. The accelerometer ActiGraph is considered the "gold standard" to objectively measure physical activity. However, other more user-friendly wearable devices are now widely available and may accurately track physical activity. Conclusive data from both validated activity questionnaires and accelerometers indicate that physical activity is safe during pregnancy. In addition, studies of physical activity during pregnancy that evaluate pregnancy outcomes have found reduced risks of preterm birth, preeclampsia, and gestational diabetes mellitus and improved mental health among individuals who regularly engage in physical activity. In the United States, approximately 48% of pregnant individuals gain more than the recommended amount of weight during pregnancy; excessive gestational weight gain is associated with an increased risk of maternal and fetal complications, including preterm birth, preeclampsia, and gestational diabetes mellitus, and corresponding higher adverse short- and long-term maternal and offspring health outcomes. Although physical activity is safe during pregnancy and may reduce excessive gestational weight gain and resultant pregnancy complications, further research is needed to determine the frequency and duration of specific types of physical activity during pregnancy. Providers should encourage physical activity before and during pregnancy and educate patients regarding the benefits and safety of physical activity.
Topics: Pregnancy; Female; Humans; Infant, Newborn; Diabetes, Gestational; Gestational Weight Gain; Premature Birth; Pre-Eclampsia; Exercise; Weight Gain
PubMed: 36174931
DOI: 10.1016/j.ajogmf.2022.100758 -
Ultrasound in Obstetrics & Gynecology :... Jul 2019Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to...
OBJECTIVE
Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre-eclampsia, to identify high-value avenues for future research and to minimize future research waste in this field.
METHODS
MEDLINE, EMBASE and The Cochrane Library including DARE (Database of Abstracts of Reviews of Effects) databases, from database inception to March 2017, and bibliographies of relevant articles were searched, without language restrictions, for systematic reviews and meta-analyses on the prediction of pre-eclampsia. The quality of the included reviews was assessed using the AMSTAR tool and a modified version of the QUIPS tool. We evaluated the comprehensiveness of search, sample size, tests and outcomes evaluated, data synthesis methods, predictive ability estimates, risk of bias related to the population studied, measurement of predictors and outcomes, study attrition and adjustment for confounding.
RESULTS
From 2444 citations identified, 126 reviews were included, reporting on over 90 predictors and 52 prediction models for pre-eclampsia. Around a third (n = 37 (29.4%)) of all reviews investigated solely biochemical markers for predicting pre-eclampsia, 31 (24.6%) investigated genetic associations with pre-eclampsia, 46 (36.5%) reported on clinical characteristics, four (3.2%) evaluated only ultrasound markers and six (4.8%) studied a combination of tests; two (1.6%) additional reviews evaluated primary studies investigating any screening test for pre-eclampsia. Reviews included between two and 265 primary studies, including up to 25 356 688 women in the largest review. Only approximately half (n = 67 (53.2%)) of the reviews assessed the quality of the included studies. There was a high risk of bias in many of the included reviews, particularly in relation to population representativeness and study attrition. Over 80% (n = 106 (84.1%)) summarized the findings using meta-analysis. Thirty-two (25.4%) studies lacked a formal statement on funding. The predictors with the best test performance were body mass index (BMI) > 35 kg/m , with a specificity of 92% (95% CI, 89-95%) and a sensitivity of 21% (95% CI, 12-31%); BMI > 25 kg/m , with a specificity of 73% (95% CI, 64-83%) and a sensitivity of 47% (95% CI, 33-61%); first-trimester uterine artery pulsatility index or resistance index > 90 centile (specificity 93% (95% CI, 90-96%) and sensitivity 26% (95% CI, 23-31%)); placental growth factor (specificity 89% (95% CI, 89-89%) and sensitivity 65% (95% CI, 63-67%)); and placental protein 13 (specificity 88% (95% CI, 87-89%) and sensitivity 37% (95% CI, 33-41%)). No single marker had a test performance suitable for routine clinical use. Models combining markers showed promise, but none had undergone external validation.
CONCLUSIONS
This review of reviews calls into question the need for further aggregate meta-analysis in this area given the large number of published reviews subject to the common limitations of primary predictive studies. Prospective, well-designed studies of predictive markers, preferably randomized intervention studies, and combined through individual-patient data meta-analysis are needed to develop and validate new prediction models to facilitate the prediction of pre-eclampsia and minimize further research waste in this field. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Adult; Biomarkers; Body Mass Index; Female; Humans; Mass Screening; Meta-Analysis as Topic; Placenta Growth Factor; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Complications; Prospective Studies; Pulsatile Flow; Risk Factors; Sensitivity and Specificity; Ultrasonography; Uterine Artery
PubMed: 30267475
DOI: 10.1002/uog.20117 -
Ageing Research Reviews Jan 2022Women live longer than men but experience greater disability and a longer period of illness as they age. Despite clear sex differences in aging, the impact of pregnancy... (Review)
Review
Women live longer than men but experience greater disability and a longer period of illness as they age. Despite clear sex differences in aging, the impact of pregnancy and its complications, such as preeclampsia, on aging is an underexplored area of geroscience. This review summarizes our current knowledge about the complex links between pregnancy and age-related diseases, including evidence from epidemiology, clinical research, and genetics. We discuss the relationship between normal and pathological pregnancy and maternal aging, using preeclampsia as a primary example. We review the results of human genetics studies of preeclampsia, including genome wide association studies (GWAS), and attempted to catalog genes involved in preeclampsia as a gateway to mechanisms underlying an increased risk of later life cardio- and neuro- vascular events. Lastly, we discuss challenges in interpreting the GWAS of preeclampsia and provide a functional genomics framework for future research needed to fully realize the promise of GWAS in identifying targets for geroprotective prevention and therapeutics against preeclampsia.
Topics: Aging; Female; Genome-Wide Association Study; Genomics; Geroscience; Humans; Male; Pre-Eclampsia; Pregnancy
PubMed: 34871806
DOI: 10.1016/j.arr.2021.101535 -
Journal of Reproductive Immunology Sep 2019Early-onset preeclampsia has been linked to poor placentation and fetal growth restriction, whereas late-onset preeclampsia was suggested to result from maternal... (Review)
Review
Early-onset preeclampsia has been linked to poor placentation and fetal growth restriction, whereas late-onset preeclampsia was suggested to result from maternal factors. We have proposed an alternative model, suggesting that both early- and late-onset preeclampsia result from placental syncytiotrophoblast stress. This stress represents a common endpoint of several Stage 1 processes, promoting the clinical stage 2 of preeclampsia (new-onset hypertension and proteinuria or other signs of end-organ dysfunction), but the causes and timing of placental malperfusion differ. We have suggested that late-onset preeclampsia, without evidence of poor spiral artery remodelling, may be secondary to intraplacental (intervillous) malperfusion due to mechanical restrictions. As the growing placenta reaches its size limit, malperfusion and hypoxia occurs. This latter pathway reflects what is observed in postmature or multiple pregnancies. Our revised two-stage model accommodates most risk factors for preeclampsia including primiparity, chronic pre-pregnancy disease (e.g. obesity, diabetic-, chronic hypertensive-, and some autoimmune diseases), and pregnancy risk factors (e.g. multiple or molar pregnancies, gestational diabetes or hypertension, and low circulating Placental Growth Factor). These factors may increase the risk of progressing to the second stage of preeclampsia (both early- and late-onset) by affecting one of or both pathways leading to Stage 1, as well as potentially accelerating the steps towards Stage 2, including priming the maternal cardiovascular susceptibility to inflammatory factors shed by the placenta. This paper reviews previous preeclampsia findings and concepts, which fit with the revised two-stage model, and argues that "maternal" preeclampsia does not exist, as all preeclampsia requires a placenta.
Topics: Female; Humans; Models, Biological; Pre-Eclampsia; Pregnancy; Proteinuria; Trophoblasts
PubMed: 31301487
DOI: 10.1016/j.jri.2019.07.004 -
American Journal of Physiology. Heart... Sep 2020Preeclampsia is a major complication of pregnancy manifested as hypertension and often intrauterine growth restriction, but the underlying pathophysiological mechanisms... (Review)
Review
Preeclampsia is a major complication of pregnancy manifested as hypertension and often intrauterine growth restriction, but the underlying pathophysiological mechanisms are unclear. Predisposing genetic and environmental factors cause placental maladaptations leading to defective placentation, apoptosis of invasive cytotrophoblasts, inadequate expansive remodeling of the spiral arteries, reduced uteroplacental perfusion pressure, and placental ischemia. Placental ischemia promotes the release of bioactive factors into the maternal circulation, causing an imbalance between antiangiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and proangiogenic vascular endothelial growth factor, placental growth factor, and transforming growth factor-β. Placental ischemia also stimulates the release of proinflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin type 1 receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, causing generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels, leading to decreases in endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increases in vasoconstrictors such as endothelin-1 and thromboxane A. The bioactive factors also target vascular smooth muscle and enhance the mechanisms of vascular contraction, including cytosolic Ca, protein kinase C, and Rho-kinase. The bioactive factors could also target matrix metalloproteinases and the extracellular matrix, causing inadequate vascular remodeling, increased arterial stiffening, and further increases in vascular resistance and hypertension. As therapeutic options are limited, understanding the underlying vascular mechanisms and molecular targets should help design new tools for the detection and management of hypertension in pregnancy and preeclampsia.
Topics: Animals; Arterial Pressure; Female; Humans; Hypertension, Pregnancy-Induced; Hypoxia; Ischemia; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Risk Factors; Signal Transduction; Uterine Artery; Vascular Remodeling; Vascular Stiffness
PubMed: 32762557
DOI: 10.1152/ajpheart.00202.2020 -
Hypertension (Dallas, Tex. : 1979) Jun 2020Preeclampsia is a common pregnancy complication, affecting 2% to 8% of pregnancies worldwide, and is an important cause of both maternal and fetal morbidity and... (Review)
Review
Preeclampsia is a common pregnancy complication, affecting 2% to 8% of pregnancies worldwide, and is an important cause of both maternal and fetal morbidity and mortality. Importantly, although aspirin and calcium are able to prevent preeclampsia in some women, there is no cure apart from delivery of the placenta and fetus, often necessitating iatrogenic preterm birth. Preclinical models of preeclampsia are widely used to investigate the causes and consequences of preeclampsia and to evaluate safety and efficacy of potential preventative and therapeutic interventions. In this review, we provide a summary of the published preclinical models of preeclampsia that meet human diagnostic criteria, including the development of maternal hypertension, together with new-onset proteinuria, maternal organ dysfunction, and uteroplacental dysfunction. We then discuss evidence from preclinical models for multiple causal factors of preeclampsia, including those implicated in early-onset and late-onset preeclampsia. Next, we discuss the impact of exposure to a preeclampsia-like environment for later maternal and progeny health. The presence of long-term impairment, particularly cardiovascular outcomes, in mothers and progeny after an experimentally induced preeclampsia-like pregnancy, implies that later onset or reduced severity of preeclampsia will improve later maternal and progeny health. Finally, we summarize published intervention studies in preclinical models and identify gaps in knowledge that we consider should be targets for future research.
Topics: Animals; Disease Models, Animal; Female; Pre-Eclampsia; Pregnancy
PubMed: 32248704
DOI: 10.1161/HYPERTENSIONAHA.119.14598 -
Nature Jan 2022Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden. Yet the ability to assess underlying pathophysiology before...
Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.
Topics: Cell-Free Nucleic Acids; Female; Humans; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; RNA; Retrospective Studies; Sensitivity and Specificity
PubMed: 34987224
DOI: 10.1038/s41586-021-04249-w -
Biomolecules Jun 2020Preeclampsia (PE) is a serious pregnancy complication, affecting about 5-7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal... (Review)
Review
Preeclampsia (PE) is a serious pregnancy complication, affecting about 5-7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks' gestation and, if left untreated, can lead to serious complications and lifelong disabilities-even death-in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.
Topics: Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Vascular Endothelial Growth Factor Receptor-1
PubMed: 32599856
DOI: 10.3390/biom10060953 -
American Journal of Obstetrics and... Feb 2022Animal models have been critical in investigating the pathogenesis, mediators, and even therapeutic options for a number of diseases, including preeclampsia.... (Review)
Review
Animal models have been critical in investigating the pathogenesis, mediators, and even therapeutic options for a number of diseases, including preeclampsia. Preeclampsia is the leading cause of maternal and fetal morbidity and mortality worldwide. The placenta is thought to play a central role in the pathogenesis of this disease because it releases antiangiogenic and proinflammatory factors into the maternal circulation, resulting in the maternal syndrome. Despite the deleterious effects preeclampsia has been shown to have on the mother and baby during pregnancy and postpartum, there is still no effective treatment for this disease. Although clinical studies in patients are crucial to identify the involvement of pathogenic factors in preeclampsia, there are obvious limitations that prevent detailed investigation of the quantitative importance of time-dependent mechanisms involved in this syndrome. Animal models allow investigators to perform proof-of-concept studies and examine whether certain factors found in women with preeclampsia mediate hypertension and other manifestations of this disease. In this brief review, we summarize some of the more widely studied models used to investigate pathophysiological mechanisms that are thought to be involved in preeclampsia. These include models of placental ischemia, angiogenic imbalance, and maternal immune activation. Infusion of preeclampsia-related factors into animals has been widely studied to understand the specific mediators of this disease. These models have been included, in addition to a number of genetic models involved in overexpression of the renin-angiotensin system, complement activation, and trophoblast differentiation. Together, these models cover multiple mechanisms of preeclampsia from trophoblast dysfunction and impaired placental vascularization to the excess circulating placental factors and clinical manifestation of this disease. Most animal studies have been performed in rats and mice; however, we have also incorporated nonhuman primate models in this review. Preclinical animal models not only have been instrumental in understanding the pathophysiology of preeclampsia but also continue to be important tools in the search for novel therapeutic options for the treatment of this disease.
Topics: Animals; Disease Models, Animal; Female; Models, Genetic; Pre-Eclampsia; Pregnancy
PubMed: 33722383
DOI: 10.1016/j.ajog.2020.10.025 -
Journal of Extracellular Vesicles May 2023Preeclampsia (PE) is a multisystem disorder with high maternal morbidity and mortality rates. Currently, no practical therapeutic approach is available to prevent PE...
Preeclampsia (PE) is a multisystem disorder with high maternal morbidity and mortality rates. Currently, no practical therapeutic approach is available to prevent PE progression, except for early delivery. Gut dysbiosis is associated with PE development. Previous data showed that the abundance of Akkermansia muciniphila (Am) was lower in patients with PE than in normotensive pregnant women. Here, in this study, decreased abundance of Am was observed in a PE mouse model. Also, we found that administration with Am could significantly attenuate systolic blood pressure, promote foetal growth and improve the placental pathology in mice with PE. Moreover, Am-derived extracellular vesicles (AmEVs) were transferred from the gastrointestinal (GI) tract to the placenta and mitigated pre-eclamptic symptoms in PE mice. These beneficial effects of AmEVs were mediated by enhanced trophoblast invasion of the spiral artery (SpA) and SpA remodelling through activation of the epidermal growth factor receptor (EGFR)-phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT) signalling pathway. Collectively, our findings revealed the potential benefit of using AmEVs for PE treatment and highlighted important host-microbiota interactions.
Topics: Pregnancy; Female; Mice; Humans; Animals; Placentation; Placenta; Pre-Eclampsia; Extracellular Vesicles
PubMed: 37165987
DOI: 10.1002/jev2.12328