Pregnancy involves an interplay between maternal and fetal factors affecting changes to maternal anatomy and physiology to support the developing fetus and ensure the well-being of both the mother and offspring. A century of research has provided evidence of the imperative role of the placenta in the development of preeclampsia. Recently, a growing body of evidence has supported the adaptations of the maternal cardiovascular system during normal pregnancy and its maladaptation in preeclampsia. Debate surrounds the roles of the placenta vs the maternal cardiovascular system in the pathophysiology of preeclampsia. We proposed an integrated model of the maternal cardiac-placental-fetal array and the development of preeclampsia, which reconciles the disease phenotypes and their proposed origins, whether placenta-dominant or maternal cardiovascular system-dominant. These phenotypes are sufficiently diverse to define 2 distinct types: preeclampsia Type I and Type II. Type I preeclampsia may present earlier, characterized by placental dysfunction or malperfusion, shallow trophoblast invasion, inadequate spiral artery conversion, profound syncytiotrophoblast stress, elevated soluble fms-like tyrosine kinase-1 levels, reduced placental growth factor levels, high peripheral vascular resistance, and low cardiac output. Type I is more often accompanied by fetal growth restriction, and low placental growth factor levels have a measurable impact on maternal cardiac remodeling and function. Type II preeclampsia typically occurs in the later stages of pregnancy and entails an evolving maternal cardiovascular intolerance to the demands of pregnancy, with a moderately dysfunctional placenta and inadequate blood supply. The soluble fms-like tyrosine kinase-1-placental growth factor ratio may be normal or slightly disturbed, peripheral vascular resistance is low, and cardiac output is high, but these adaptations still fail to meet demand. Emergent placental dysfunction, coupled with an increasing inability to meet demand, more often appears with fetal macrosomia, multiple pregnancies, or prolonged pregnancy. Support for the notion of 2 types of preeclampsia observable on the molecular level is provided by single-cell transcriptomic survey of gene expression patterns across different cell classes. This revealed widespread dysregulation of gene expression across all cell types, and significant imbalance in fms-like tyrosine kinase-1 (FLT1) and placental growth factor, particularly marked in the syncytium of early preeclampsia cases. Classification of preeclampsia into Type I and Type II can inform future research to develop targeted screening, prevention, and treatment approaches.

This study aimed to: (1) identify all relevant studies reporting on the diagnostic accuracy of maternal circulating placental growth factor) alone or as a ratio with soluble fms-like tyrosine kinase-1), and of placental growth factor-based models (placental growth factor combined with maternal factors±other biomarkers) in the second or third trimester to predict subsequent development of preeclampsia in asymptomatic women; (2) estimate a hierarchical summary receiver-operating characteristic curve for studies reporting on the same test but different thresholds, gestational ages, and populations; and (3) select the best method to screen for preeclampsia in asymptomatic women during the second and third trimester of pregnancy by comparing the diagnostic accuracy of each method.
A systematic search was performed through MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform databases from January 1, 1985 to April 15, 2021.
Studies including asymptomatic singleton pregnant women at >18 weeks\' gestation with risk of developing preeclampsia were evaluated. We included only cohort or cross-sectional test accuracy studies reporting on preeclampsia outcome, allowing tabulation of 2×2 tables, with follow-up available for >85%, and evaluating performance of placental growth factor alone, soluble fms-like tyrosine kinase-1- placental growth factor ratio, or placental growth factor-based models. The study protocol was registered on the International Prospective Register Of Systematic Reviews (CRD 42020162460).
Because of considerable intra- and interstudy heterogeneity, we computed the hierarchical summary receiver-operating characteristic plots and derived diagnostic odds ratios, β, θi, and Λ for each method to compare performances. The quality of the included studies was evaluated by the QUADAS-2 tool.
The search identified 2028 citations, from which we selected 474 studies for detailed assessment of the full texts. Finally, 100 published studies met the eligibility criteria for qualitative and 32 for quantitative syntheses. Twenty-three studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the second trimester, including 16 (with 27 entries) that reported on placental growth factor test alone, 9 (with 19 entries) that reported on the soluble fms-like tyrosine kinase-1-placental growth factor ratio, and 6 (16 entries) that reported on placental growth factor-based models. Fourteen studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the third trimester, including 10 (with 18 entries) that reported on placental growth factor test alone, 8 (with 12 entries) that reported on soluble fms-like tyrosine kinase-1-placental growth factor ratio, and 7 (with 12 entries) that reported on placental growth factor-based models. For the second trimester, Placental growth factor-based models achieved the highest diagnostic odds ratio for the prediction of early preeclampsia in the total population compared with placental growth factor alone and soluble fms-like tyrosine kinase-1-placental growth factor ratio (placental growth factor-based models, 63.20; 95% confidence interval, 37.62-106.16 vs soluble fms-like tyrosine kinase-1-placental growth factor ratio, 6.96; 95% confidence interval, 1.76-27.61 vs placental growth factor alone, 5.62; 95% confidence interval, 3.04-10.38); placental growth factor-based models had higher diagnostic odds ratio than placental growth factor alone for the identification of any-onset preeclampsia in the unselected population (28.45; 95% confidence interval, 13.52-59.85 vs 7.09; 95% confidence interval, 3.74-13.41). For the third trimester, Placental growth factor-based models achieved prediction for any-onset preeclampsia that was significantly better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1-placental growth factor ratio (placental growth factor-based models, 27.12; 95% confidence interval, 21.67-33.94 vs placental growth factor alone, 10.31; 95% confidence interval, 7.41-14.35 vs soluble fms-like tyrosine kinase-1-placental growth factor ratio, 14.94; 95% confidence interval, 9.42-23.70).
Placental growth factor with maternal factors ± other biomarkers determined in the second trimester achieved the best predictive performance for early preeclampsia in the total population. However, in the third trimester, placental growth factor-based models had predictive performance for any-onset preeclampsia that was better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1-placental growth factor ratio. Through this meta-analysis, we have identified a large number of very heterogeneous studies. Therefore, there is an urgent need to develop standardized research using the same models that combine serum placental growth factor with maternal factors ± other biomarkers to accurately predict preeclampsia. Identification of patients at risk might be beneficial for intensive monitoring and timing delivery.

The sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio is a helpful tool for the prediction and diagnosis of preeclampsia (PE). Current data even show that the ratio has the potential to predict adverse pregnancy outcomes (APO) caused by placental pathologies. The aim of this article is to give a brief overview of recent findings on APO predictions based on the sFlt-1/PlGF ratio. The focus is on obstetric pathologies related to placental dysfunction (PD) such as PE and/or fetal growth restriction (FGR). New uses of the sFlt-1/PlGF ratio as a predictor of APO demonstrate its potential with regard to planning hospitalization and corticosteroid administration and the optimal timing of delivery. However, prospective interventional studies are warranted to define the exact role of the sFlt-1/PlGF ratio as a predictor of adverse pregnancy outcomes caused by placental pathologies.
Der sFlt-1-(lösliche Fms-ähnliche Tyrosinkinase-1)/PlGF-(plazentarer Wachstumsfaktor-)Quotient ist ein nützliches Werkzeug für die Prognose und Diagnose einer Präeklampsie (PE). Aktuelle Daten zeigen sogar, dass der Quotient das Potenzial hat, durch plazentare Pathologien hervorgerufene ungünstige perinatale Outcomes (APO) vorherzusagen. Dieser Artikel gibt einen kurzen Überblick über die neuesten Erkenntnisse zu APO-Vorhersagen, die auf dem Einsatz des sFlt-1/PlGF-Quotienten basieren. Im Mittelpunkt stehen geburtshifliche Pathologien, die durch eine plazentare Dysfunktion (PD) wie PE und/oder fetale Wachstumsrestriktion (FGR) hervorgerufen werden. Neue Einsatzfelder für den sFlt-1/PlGF-Quotienten als Prädiktor von APO zeigen sein Potenzial bei der Planung einer Einweisung ins Krankenhaus bzw. der Verabreichung von Kortikosteroiden sowie für die optimale Terminierung einer Entbindung. Prospektive interventionelle Studien sind notwendig, um die präzise Rolle des sFlt-1/PlGF-Quotienten als Prädiktor von ungünstigen Schwangerschaftsergebnissen, die durch plazentare Pathologien hervorgerufen werden, zu ermitteln.

Impaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur more frequently in pregnancies with fetal CHD. One of the most important factors influencing the life of children with CHD is neurodevelopmental delay, which seems to start already in utero. Delayed neurodevelopment in utero may be correlated or even (partly) explained by impaired placentation in CHD cases. This systematic review provides an overview of published literature on placental development in pregnancies with fetal CHD. A systematic search was performed and the Newcastle-Ottawa scale was used to access data quality. Primary outcomes were placenta size and weight, vascular and villous architecture, immunohistochemistry, angiogenic biomarkers and/or placental gene expression. A total of 1161 articles were reviewed and 21 studies were included. Studies including CHD with a genetic disorder or syndrome and/or multiple pregnancies were excluded. Lower placental weight and elevated rates of abnormal umbilical cord insertions were found in CHD. Cases with CHD more frequently showed microscopic placental abnormalities (i.e. abnormal villous maturation and increased maternal vascular malperfusion lesions), reduced levels of angiogenic biomarkers and increased levels of anti-angiogenic biomarkers in maternal serum and umbilical cord blood. Altered gene expression involved in placental development and fetal growth were found in maternal serum and CHD placentas. In conclusion, abnormal placentation is found in CHD. More extensive studies are needed to elucidate the contribution of impaired placentation to delayed neurodevelopment in CHD cases.

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Twin pregnancy is one of the key risk factors for the development of preeclampsia. Soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin are molecules involved in the process of angiogenesis with a proven role in the pathogenesis of preeclampsia. The aim of the review was to summarize available data on maternal serum levels of the biomarkers of angiogenesis and their usefulness in predicting preeclampsia in twin pregnancies. Most of available data suggest biomarkers concentrations differ between singleton and twin gestation and are related to chorionicity of twin pregnancy. Several algorithms including biomarkers of angiogenesis in prediction of PE in twin pregnancy are available and seem promising, however more large prospective surveys are necessary to assess their usefulness in general clinic use.

The most widely accepted theory for the development of preeclampsia is the \"two-stage theory\". An imbalance between antiangiogenic and proangiogenic factors is considered the link between the two stages. Nowadays, an increasing amount of data is available on the use of measurements of serum concentrations of these factors in the prediction, diagnosis and management of preeclampsia. The most useful, modern biochemical test that may help in making crucial clinical decisions in patients with preeclampsia is the sFlt-1/PlGF (soluble fms-like tyrosine kinase 1/placental growth factor) ratio. The aim of this review is to present the current use of different biochemical tests in the prediction, diagnosis and management of preeclampsia. Development of these diagnostic methods in recent years and a belief in their ground-breaking role in modern management of preeclampsia make this review especially important.

Background  Prenatal serum screening is an important modality to screen for aneuploidy in pregnancy. The addition of placental growth factor (PLGF) to screen for trisomy 21 remains controversial. Objective  To determine whether the addition of PLGF to combined serum aneuploidy screening improves detection rates (DRs) for trisomy 21. Study Design  We performed a systematic review of the literature until October 2019 to determine the benefits of adding PLGF to prenatal screening. We performed a goodness-of-fit test and retrieved the coefficient of determinations ( R 2 ) as a function of false positive rates (FPRs), providing mean-weighted improvements in the DRs after accounting for PLGF levels. Results  We identified 51 studies, of which 8 met inclusion criteria (834 aneuploidy cases and 105,904 euploid controls). DRs were proportional to FPR across all studies, ranging from 59.0 to 95.3% without PLGF and 61.0 to 96.3% with PLGF (FPR 1-5%). Goodness-of-fit regression analysis revealed a logarithmic distribution of DRs as a function of the FPR, with R 2  = 0.109 (no PLGF) and R 2  = 0.06 (PLGF). Two-sample Kolmogorov-Smirnov\'s test reveals a p -value of 0.44. Overall, addition of PLGF improves DRs of 3.3% for 1% FPR, 1.7% for 3% FPR, and 1.4% for 5% FPR, respectively. Conclusion  Addition of PLGF to prenatal screening using serum analytes mildly improves trisomy 21 DRs as a function of FPRs.

Despite extensive research, the pathophysiology and prevention of pre-eclampsia remain elusive, diagnosis is challenging, and pre-eclampsia remains associated with adverse maternal and perinatal outcomes. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing is increasingly being implemented in clinical practice in several countries. This review provides healthcare providers with an understanding of the evidence for PlGF-based testing and describes the practicalities and challenges to implementation. TWEETABLE ABSTRACT: Placental growth factor in pre-eclampsia: evidence and implementation of testing.

Multiple gestation is one of the key risk factors for the occurrence of preeclampsia (PE). Soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin are molecules involved in the process of angiogenesis with a proven role in the pathogenesis of PE. The aim of the review was to summarize available data on maternal serum levels of the above-mentioned factors and their usefulness in predicting PE in twin pregnancies. Only original research articles written in English were considered eligible. Reviews, chapters, case studies, conference papers, experts\' opinions, editorials, and letters were excluded from the analysis. No publication date limitations were imposed. The systematic literature search using PubMed/MEDLINE, Scopus, Embase, and Cochrane Library databases identified 338 articles, 10 of which were included in the final qualitative analyses. The included studies showed significant differences in maternal serum levels of the discussed factors between women with twin pregnancies with PE and those who did not develop PE, and their promising performance in predicting PE, alone or in combination with other factors. The identification of the most effective algorithms, their prompt introduction to the clinical practice, and further assessment of the real-life performance should become a priority.