Predictive value of serum PLGF/sFlt-1 combined with placental 3D-PDI in preeclampsia / 中国医科大学学报

Objective To investigate the predictive value of serum placental growth factor(PLGF)/soluble fms-like tyrosine kinase-1(sFlt-1),combined with the placental three-dimensional energy Doppler index(3D-PDI)in preeclampsia(PE).Methods From January 2021 to December 2022,120 pregnant women with PE risk factors were selected and followed up until 1 week after delivery.Serum PLGF and sFlt-1 levels were measured at routine prenatal check-ups at 14 to 20 weeks gestation.The PLGF/sFlt-1 ratio was calculated,and placental 3D-PDI was detected by ultrasound,including the vascularization index(VI),blood flow index(FI),and vascularization-blood flow index(VFI).Based on whether PE occurred after 20 weeks of pregnancy,cases were divided into PE(55 cases)and control groups(65 cases).The PE group was further divided into mild PE(35 cases)and severe PE groups(20 cases)based on the severity of the di-sease.The differences in PLGF/sFlt-1 and 3D-PDI between the groups were compared in terms of a statistical analysis of the correlation between PLGF,sFlt-1,and 3D-PDI.The receiver operating characteristic curve(ROC)was plotted,and the predictive value of each index on PE alone or in combination was analyzed.Results The systolic blood pressure(SBP),diastolic blood pressure(DBP),24 h protein-uria level,preterm birth rate,NICU admission rate,and preconception BMI in the PE group were higher than those in the control group(P＜0.05).The two groups had no differences in age,gestational age,pregnancy history,and fertility history(P＞0.05).The serum PLGF/sFlt-1 of the PE group was lower than that of the control group,and the serum PLGF/sFlt-1 of the severe group was lower than that of the mild group(P＜0.05).The 3D-PDI index of the PE group was lower than that of the control group,and the 3D-PDI index of the severe group was lower than that of the mild group(P＜0.05).Pearson's correlation analysis indicated that PLGF and VFI were signifi-cantly positively correlated(P＜0.01),and sFlt-1 was significantly negatively correlated with VFI(P＜0.01).ROC curve analysis showed that PLGF/sFlt-1,VI,FI,and VFI all had predictive value for PE and the value of VI,FI,and VFI jointly predicted PE,and was higher than that of various parameters(AUC = 0.951).Serum PLGF/sFlt-1,VI,FI,and VFI combined predicted the highest value(AUC=0.987).Conclusion In patients with PE,serum PLGF,sFlt-1,and placental VFI are significantly correlated.Serum PLGF/sFlt-1,placenta VI,FI,and VFI are reduced in early pregnancy,and the combined application of the four indicators has the highest efficacy in predicting PE,providing a possible reference for the early clinical screening or prediction of PE.

Diagnosis and Management of Preeclampsia: Suggested Guidance on the Use of Biomarkers / Diagnóstico e tratamento da pré-eclâmpsia: Sugestão para o uso adequado dos biomarcadores

Abstract Objective It is a challenge to consider preeclampsia (PE) diagnosis and management in low and middle-income settings, where it represents a major public health concern. The placenta is the underlying cause of disease, and the plasma concentrations of proangiogenic and antiangiogenic factors released by the placenta can reflect the risks of disease progression. Antiangiogenic proteins, such as soluble fms-like tyrosine kinase 1 (sFlt-1), and proangiogenic, like placental growth factors (PlGF), are directly and inversely correlated with the disease onset, respectively. Methods Narrative review on the use of biomarkers (sFlt-1 to PlGF ratio) with a suggested guidance protocol. Results Key considerations on the use of biomarkers: the sFlt-1/PlGF ratio is mainly relevant to rule out PE between 20 and 36 6/7 weeks in cases of suspected PE; however, it should not replace the routine exams for the diagnosis of PE. The sFlt-1/PlGF ratio should not be performed after confirmed PE diagnosis (only in research settings). In women with suspected PE, sFlt-1/PlGF ratio < 38 can rule out the diagnosis of PE for 1 week (VPN = 99.3) and up to 4 weeks (VPN= 94.3); sFlt-1/PlGF ratio > 38 does not confirm the diagnosis of PE; however, it can assist clinical management. In cases of severe hypertension and/or symptoms (imminent eclampsia), hospitalization is imperative, regardless of the result of the sFlt-1/PlGF ratio. Conclusion The use of biomarkers can help support clinical decisions on the management of suspected PE cases, especially to rule out PE diagnosis, thus avoiding unnecessary interventions, especially hospitalizations and elective prematurity

Resumo Objetivo um desafio considerar o diagnóstico e o tratamento da pré-eclâmpsia (PE) em locais de baixa e média renda, onde a doença representa um grande problema de saúde pública. A placenta é a causa subjacente da doença, e as concentrações plasmáticas de fatores pró-angiogênicos e antiangiogênicos liberados pela placenta podem refletir os riscos de progressão da doença. Proteínas antiangiogênicas, como a tirosina quinase fms solúvel tipo 1 (sFlt-1), e pró-angiogênicas, como o fator de crescimento placentário (PlGF), estão direta e inversamente correlacionados com o início da doença, respectivamente. Métodos Revisão narrativa sobre o uso de biomarcadores (razão sFlt-1/PlGF) com sugestão de protocolo de orientação para uso clínico. Resultados Principais considerações sobre o uso de biomarcadores: a razão sFlt-1/PlGF é principalmente relevante para descartar PE entre 20 e 36 6/7 semanas em casos de suspeita de PE; entretanto, não deve substituir os exames de rotina para o diagnóstico de PE. A relação sFlt-1/PlGF não deve ser realizada após a confirmação do diagnóstico de PE (apenas em ambientes de pesquisa). Em mulheres com suspeita de PE, a razão sFlt-1/PlGF < 38 pode descartar o diagnóstico de PE por 1 semana (VPN = 99,3) e até 4 semanas (VPN = 94,3); A relação sFlt-1/PlGF > 38 pode auxiliar no manejo clínico. Em casos de hipertensão grave e/ou sintomas (eclâmpsia iminente), a hospitalização é imprescindível, independentemente do resultado da relação sFlt-1/PlGF. Conclusão O uso de biomarcadores pode auxiliar na tomada de decisões clínicas no manejo de casos suspeitos de PE, principalmente para afastar o diagnóstico da doença, evitando intervenções desnecessárias, tais como internações e prematuridade iatrogênica.

Progress in the study for pathogenesis and clinical treatment of preeclampsia / 解放军医学杂志

Preeclampsia (PE) is a serious complications during pregnancy, with a global incidence of 2%–8%. It is one of the important causes of the incidence and death of pregnant women and parturients. The main clinical manifestations are hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg), proteinuria (>0.3 g/24 h) can be accompanied by renal dysfunction, thrombocytopenia, liver dysfunction, pulmonary edema and other multi-system and multiple organ involvement. Antiphospholipid antibody syndrome, hypertension, diabetes, chronic kidney disease, obesity, PE family history, multiple pregnancy, maternal old age are the risk factors of PE. At present, the pathogenesis of PE is not completely clear, but more and more evidences suggest that the abnormal level of angiogenic factors and coagulation dysfunction are the main causes of the disease. The research progress in recent years has been reviewed in present paper in the pathogenesis and clinical treatment of PE, so as to provide a reference for clinical use.

Evaluation of sFlt-1/PlGF Ratio for Predicting and Improving Clinical Management of Pre-eclampsia: Experience in a Specialized Perinatal Care Center

BACKGROUND: Management of pregnant women at high risk of pre-eclampsia (PE) requires frequent monitoring, with referral to specialized perinatal care centers. Reliable tests are necessary to improve prediction of PE and related complications and to assess disease severity and progression. An imbalance in two biomarkers, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), is involved in PE pathogenesis. The sFlt-1 to PlGF ratio is increased in pregnant women before the onset of PE. An elevated ratio is highly predictive of PE, whereas the diagnosis of PE can be ruled out within one week for low ratios. The main objective of this study was to assess whether a low sFlt-1/PlGF ratio, below a cutoff of 38, can predict the absence of PE within one week. METHODS: We performed a prospective, monocentric, observational study to evaluate serum sFlt-1/PlGF ratio (Roche Diagnostics Cobas e411 system) for predicting -PE in a group of 67 high-risk pregnant women (20–37 gestation weeks). RESULTS: Among the 67 patients included, 53 had a sFlt-1/PlGF ratio lower than 38; none developed subsequent PE leading to a negative predictive value of 100%. Eight patients developed clinical PE. The positive predictive value was 21% at one week and 18% at four weeks, in accordance with previous studies. CONCLUSIONS: The serum sFlt-1/PlGF ratio showed highly predictive performances for ruling out PE. Using these biomarkers in routine management of PE may improve clinical care and avoid inappropriate hospitalization, which has a significant economic impact.

Significancia del desbalance de los factores angiogénicos en preeclampsia

La participación de los factores antiangiogénicos, la forma soluble de la fms-semejante a la tirosina quinasa (Flt-1s) y la endoglina soluble (Engs), en el desarrollo de la preeclampsia (PE) se ha demostrado en múltiples estudios clínicos y experimentales. Estos estudios están complementados por estudios en animales, en los cuales la sobreexpresión de estos factores antiangiogénicos origina manifestaciones clínicas muy similares a la PE. El origen de esta enfermedad permanece desconocido. Sin embargo, factores genéticos, ambientales e inmunológicos parecen alterar el desarrollo normal de la placenta, lo cual conduce últimamente a la PE. Flt-1s y Engs inhiben la producción y las propiedades proangiogénicas del factor de crecimiento vascular endotelial (FCVE) y del factor de crecimiento placentario (FCP), necesarios para el desarrollo normal vascular de la placenta y las adaptaciones vasculares fisiológicas del embarazo. Cantidades exageradas de Flt-1s y Engs se producen en la placenta disfuncional y se liberan en la circulación materna. Altas concentraciones de Flt-1s y Engs se encuentran en la circulación materna semanas antes de que la enfermedad sea detectada clínicamente. Las capacidades de los factores angiogénicos para predecir PE en embarazos asintomáticos de riesgo bajo y alto son inconsistentes y no útiles para el uso clínico. Por otro lado, proporciones de los factores Flt-1s/FCP, FCP/Flt-1s, y FCP/Eng poseen valores predictivos más altos para diagnosticar PE y predecir sus complicaciones en mujeres con sintomatología de PE. En estas condiciones, el uso clínico de estos marcadores biológicos podría ser implementado en un futuro cercano. Las propiedades biológicas y farmacocinéticas de las estatinas las convierten en uno de los medicamentos con más potencial preventivo para la PE. Otros opciones terapéuticas que se están estudiando son medicamentos que directamente inhiban los factores antiangiogénicos circulantes. Estudios in vitro y estudios pilotos clínicos se están realizando actualmente examinando la seguridad materno-fetal, la transferencia placentaria y la efectividad de estas terapias.

The role of the antiangiogenic factors, the soluble form of the fms-like tyrosine kinase receptor 1 (sFlt1) and the soluble endoglin (sEng), in the development of preeclampsia (PE) has been demonstrated in multiple clinical and experimental studies. These studies are complemented by animal studies, in which overexpression of these antiangiogenic factors leads to clinical manifestations similar to PE. Although, the origin of this disease remains unknown, genetic, environmental, and immunological factors appear to affect the normal placental development, resulting ultimately in PE. sFlt-1 and sEng inhibit the proangiogenic properties of the vascular endothelial growth factor (VEGF) and the placental growth factor (PlGF), affecting the normal vascular development in the placenta and the physiological vascular adaptations that occur in pregnancy. Exaggerated amounts of sFlt-1 and sEng, produced in the dysfunctional placenta, are released into the maternal circulation and elevated circulating concentrations of these antiangiogenic factors are found several weeks prior to the clinical manifestations of the disease. Multiple studies have reported the capacity of circulating antiangiogenic factor concentrations to predict PE in asymptomatic low and high risk pregnancies. The reported predictive values of sFlt-1 and sEng are inconsistent across these studies and therefore their clinical use in this population is not recommended. On the other hand, maternal plasma concentrations of these factors appear to have a better performance in women with symptoms of PE. Among the possible combinations, the ratios of sFlt-1/PlGF, PlGF/sFlt-1, and PlGF/Engs seem to have the highest sensitivities and specificities to diagnose PE as well as the highest predictive values for PE-related adverse outcomes. These properties support their clinical use in this setting and it is likely those ancillary tests will be incorporated to the clinical practice in the near future. The participation of antiangiogenic factors in the pathogenesis of PE, also have stimulated investigation of new targeted therapies. The biological and pharmacokinetic properties of statins have converted them in one of the most promising preventive therapies for this disease. Others are investigating agents that directly inhibit the circulating antiangiogenic factors. In-vitro and pilot clinical studies are currently evaluating the effectiveness, maternal-fetal safety, and placental transference of these therapies.

Cord Blood Soluble fms-Like Tyrosine Kinase 1 and Placental Growth Factor in Preterm Infants with Maternal Preeclampsia / 이화의대지

OBJECTIVES: The purpose of this study was to investigate the relationship of cord blood levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) in preterm infants with maternal preeclampsia. METHODS: Thirty six preterm infants born at Ewha Womans University Mokdong Hospital from January 2006 to August 2006 were studied after prior parental consent at mid-pregnancy. sFlt-1, PlGF, and VEGF levels in the cord blood of preterm neonate, with or without maternal preeclampsia, were measured using enzyme-linked immunosorbent assay. RESULTS: There was no difference in sFlt-1 between infants with and without maternal preeclampsia. Infants with maternal preeclampsia had significantly lower PlGF levels (P=0.035) and higher sFlt-1/PlGF ratio (P=0.080) with borderline significance. Cord blood VEGF levels were not related to maternal preeclampsia. Infants with maternal preeclampsia had lower birth weight (P=0.030), lower neonatal platelet count without statistical significance (P=0.064) and more likely to be small for gestational age (P=0.057). Neonatal platelet count was significantly correlated with cord blood PlGF levels (r=0.674, P=0.032). CONCLUSION: Increased sFlt-1/PlGF ratio and decreased PlGF may not only be related to the pathophysiology of maternal preeclampsia but also affect the neonatal platelet count and birth weight.