N-terminal pro B-type natriuretic peptide as biomarker to predict pre-eclampsia and maternal-fetal complications.

A soluble fms-like tyrosine kinase-1 (sFlt-1)-to-placental growth factor (PlGF) ratio cut-off of 38 is currently considered optimal for ruling out pre-eclampsia (PE); however, implementation of this ratio in clinical practice is limited. N-terminal pro B-type natriuretic peptide (NT-proBNP) is elevated in PE owing to the cardiovascular effects of this disease. This study aimed to identify the predictive performance of NT-proBNP to detect PE and placental complications within 1 week after assessment, and compare it with the predictive performance of the sFlt-1/PlGF ratio. High-sensitivity troponin T (hs-TnT) and uric acid were also evaluated. This was a prospective nested case-control study conducted in five Spanish centers between March 2018 and December 2020, and comprised women with a singleton pregnancy and suspected PE between 24 + 0 and 41 + 0 weeks' gestation. We evaluated the ability of the sFlt-1/PlGF ratio, NT-proBNP, hs-TnT and uric acid to predict the development of any-onset (at any gestational age), early-onset (before 34 weeks) or term (at or after 37 weeks) PE within 1 week or 4 weeks after assessment. Predictive performance was assessed by estimating negative predictive values, positive predictive values, sensitivity, specificity and areas under the receiver-operating-characteristics curves (AUCs) for these biomarkers, with corresponding 95% CIs. We performed post-hoc exploratory analyses of associations between the sFlt-1/PlGF ratio, NT-proBNP, hs-TnT and uric acid in women who developed PE, as well as in women who developed complicated PE (PE plus fetal growth restriction, stillbirth or placental abruption) within 1 week and 4 weeks after assessment. A total of 323 women with suspected PE at or before 41 + 0 weeks were enrolled in the study, of whom seven were lost to follow-up. The final analysis included 316 eligible participants, with 424 samples. The overall incidence of PE was 23.4% (n = 74) and early-onset PE developed in 8.5% (n = 27) of cases. The sFlt-1/PlGF ratio and NT-proBNP exhibited similar abilities to predict early-onset PE within 1 week after assessment (AUC, 0.970 (95% CI, 0.932-1.000) and 0.971 (95% CI, 0.942-1.000), respectively). hs-TnT and uric acid demonstrated inferior predictive capability compared with the sFlt-1/PlGF ratio for the prediction of any-onset PE, early-onset PE and term PE within 1 week and 4 weeks after assessment. The optimal cut-off for NT-proBNP was 116 pg/mL. At this cut-off, NT-proBNP showed a sensitivity of 90.9% (95% CI, 70.8-98.9%) and a specificity of 94.3% (95% CI, 91.2-96.5%), with a positive predictive value of 5.7% (95% CI, 3.7-8.7%) and a negative predictive value of 99.9% (95% CI, 99.9-100%) in predicting early-onset PE within 1 week of assessment, which was comparable with that of the sFlt-1/PlGF ratio. Participants with PE-related complications had higher levels of all biomarkers, but only NT-proBNP showed a similar predictive ability to the sFlt-1/PlGF ratio for complicated PE within 1 week after assessment (AUC, 0.818 (95% CI, 0.706-0.930) vs 0.822 (95% CI, 0.723-0.921), respectively). An NT-proBNP cut-off value of 116 pg/mL has a similar diagnostic performance to that of the sFlt-1/PlGF ratio in predicting the diagnosis of early-onset PE within 1 week after assessment. Thus, NT-proBNP could be used in clinical practice for the early identification and management of PE, particularly in cases for which the sFlt-1/PlGF ratio is not available. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.

Nan MN ，Garrido-Giménez C ，Garcia-Osuna Á ，Garcia Manau P ，Ullmo J ，Mora J ，Sanchez-Garcia O ，Platero J ，Cruz-Lemini M ，Llurba E ， on behalf of the EuroPE working group ... -  《-》

Intermanufacturer assessment of diagnostic performance of angiogenic ratio vs glycosylated fibronectin in women with suspected pre-eclampsia.

To compare the diagnostic performance of different manufacturers' immunoassays for the soluble fms-like tyrosine kinase-1 (sFlt-1)-to-placental growth factor (PlGF) ratio with that of a point-of-care (PoC) test for glycosylated fibronectin (GlyFn) in women with suspected pre-eclampsia (PE). This was a prospective, single-center, double-blinded, non-interventional study of East Asian women with a singleton pregnancy who presented with hypertension with or without clinical features of PE after 20 weeks' gestation between January 2020 and March 2022. Maternal serum samples were collected at the time of presentation, and subsequent management followed the departmental protocol, based on gestational age, severity of hypertension, fetal condition and presence of severe PE features. Women diagnosed with PE at presentation were excluded. PE was diagnosed according to the 2018 International Society for the Study of Hypertension in Pregnancy classification. Levels of sFlt-1 and PlGF were measured using the Cobas e411 (Roche Diagnostics), BRAHMS KRYPTOR (ThermoFisher Scientific) and iMAGIN 1800 (Ningbo Aucheer) platforms. GlyFn levels were measured using the Lumella™ GlyFn PoC test (DiabetOmics Inc.). The predictive performance of each test to rule out PE within 7 days and rule in PE within 28 days from the date of presentation was assessed. Based on the PROGNOSIS study, a sFlt-1/PlGF ratio of ≤ 38 on the Roche platform was used to predict the absence of PE within 7 days. The sFlt-1/PlGF ratio was classified as high or low using platform-specific thresholds equivalent to a Roche sFlt-1/PlGF ratio of 38, which were derived using Passing-Bablok regression. GlyFn was categorized as high or low using two reported clinical management thresholds (263 μg/mL and 510 μg/mL). Overall, 236 women with suspected PE were included, of whom 70 (29.7%) were diagnosed with PE; 36 (51.4%) and 70 (100%) developed PE within 7 days and 28 days, respectively. Eighty-eight (37.3%) women had a sFlt-1/PlGF ratio of > 38 on the Roche platform, 79 (33.5%) women had a sFlt-1/PlGF ratio of > 55 on the KRYPTOR platform and 96 (40.7%) women had a sFlt-1/PlGF ratio of > 40 on the iMAGIN 1800 platform. Furthermore, 62 (26.3%) and four (1.7%) women had a GlyFn level of > 263 μg/mL and > 510 μg/mL, respectively. The negative predictive value (NPV) of the sFlt-1/PlGF ratio measured on the Roche, KRYPTOR and iMAGIN 1800 platforms to rule out PE within 7 days after presentation was 83.3%, 82.0% and 82.9%, respectively, while that for GlyFn > 263 μg/mL and > 510 μg/mL was 82.6% and 70.4%, respectively. The corresponding positive predictive values (PPV) to rule in PE within 28 days after presentation were 50.5%, 52.3% and 46.7%, respectively, for the sFlt-1/PlGF ratio, and 35.4% and 50.0%, respectively, for GlyFn > 263 μg/mL and > 510 μg/mL. The predictive performance of different manufacturers' assays for the sFlt-1/PlGF ratio to rule in and rule out PE were similar once standardized to a common threshold. Our findings suggest that the sFlt-1/PlGF ratio and GlyFn using a cut-off of 263 μg/mL can both be utilized to rule out PE within 7 days after assessment, with a moderate NPV. The PPV for ruling in PE within 28 days remains poor. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Wah IYM ，Sahota DS ，Wong NKL ，Lee NMW ，Liu CJ ，Lau CSL ，Leung HHY ，Poon LC ... -  《-》

Prognostic value of angiogenic markers in pregnancy with fetal growth restriction.

Pregnancies with fetal growth restriction (FGR) are at increased risk for pre-eclampsia. Angiogenic markers including soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by FGR, but their utility for predicting pre-eclampsia in growth-restricted pregnancies is uncertain. This study aimed to evaluate the prognostic value of angiogenic markers for predicting the development of pre-eclampsia in pregnancies with FGR and suspected pre-eclampsia. This was a retrospective study of singleton pregnancies with FGR, defined according to Delphi consensus criteria, which underwent sampling of sFlt-1 and PlGF for suspicion of pre-eclampsia at the Medical University of Vienna, Vienna, Austria, between 2013 and 2020. Women with an established diagnosis of pre-eclampsia at sampling were excluded. Cox regression analysis and logistic regression analysis were performed to evaluate the association of angiogenic markers with the development of pre-eclampsia at various timepoints. In this cohort of 93 women, pre-eclampsia was diagnosed in 14 (15.1%) women within 1 week after sampling, 21 (22.6%) within 2 weeks after sampling and 38 (40.9%) at any time after assessment. The sFlt-1/PlGF ratio consistently showed a stronger association with the development of pre-eclampsia compared to sFlt-1 or PlGF alone (pre-eclampsia within 1 week: area under the receiver-operating-characteristics curve, 0.87 vs 0.82 vs 0.72). Models including the sFlt-1/PlGF ratio were associated more strongly with pre-eclampsia hazard compared to models including sFlt-1 or PlGF alone (concordance index, 0.790 vs 0.759 vs 0.755). The risk classification capability of the sFlt-1/PlGF ratio decreased after the 2-week timepoint. The established cut-off value for the sFlt-1/PlGF ratio of < 38 was effective for ruling out pre-eclampsia within 2 weeks, with a negative predictive value of 0.933 and sensitivity of 0.952. Use of the sFlt-1/PlGF ratio is preferrable to the use of PlGF alone for the prediction of pre-eclampsia in pregnancies with FGR. Established cut-offs for ruling out the development of pre-eclampsia in the short term seem to be effective in these patients. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Palmrich P ，Kalafat E ，Pateisky P ，Schirwani-Hartl N ，Haberl C ，Herrmann C ，Khalil A ，Binder J ... -  《-》

Angiogenic factors alone or in combination with ultrasound Doppler criteria for risk classification among late-onset small fetuses with or without pre-eclampsia.

To investigate the prognostic value of maternal angiogenic factors in late-onset small fetuses, alone or in combination with the ultrasound and Doppler parameters currently used for the classification of low-risk small-for-gestational-age (SGA) fetuses or high-risk fetal growth restriction (FGR), overall and according to the presence or absence of pre-eclampsia. This was a prospective cohort study of women with a singleton pregnancy with a diagnosis of late-onset fetal smallness (defined as birth weight < 10th centile) and a gestational age of ≥ 34 weeks at delivery. Ultrasound assessment of estimated fetal weight (EFW) and Doppler assessment of uterine artery pulsatility index (UtA-PI) and cerebroplacental ratio (CPR) were performed every 1-2 weeks. Biochemical analysis of the angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in maternal peripheral venous blood samples was performed using enzyme-linked immunosorbent assay within 1-2 weeks after diagnosis of SGA or FGR. The primary outcome was adverse perinatal outcome, defined as a composite of emergency Cesarean section for non-reassuring fetal status, metabolic acidosis (umbilical artery pH < 7.0), neonatal unit admission and/or perinatal death. The predictive value of EFW < 3rd centile, Doppler parameters (UtA-PI > 95th centile and CPR < 5th centile) and sFlt-1/PlGF ratio > 95th centile, alone or in combination, was assessed using logistic regression analysis in the overall population and stratified by presence or absence of pre-eclampsia developing at any time before delivery. Among the 602 included cases, 91 (15.1%) developed pre-eclampsia and 511 (84.9%) did not. In the overall study population, all parameters were associated independently with adverse perinatal outcome: EFW < 3rd centile (adjusted odds ratio (aOR), 2.58 (95% CI, 1.67-4.00)), UtA-PI > 95th centile (aOR, 1.92 (95% CI, 1.25-2.94)), CPR < 5th centile (aOR, 2.35 (95% CI, 1.46-3.78)) and sFlt-1/PlGF ratio > 95th centile (aOR, 1.71 (95% CI, 1.09-2.69)). Only sFlt-1/PlGF ratio > 95th centile was associated independently with adverse perinatal outcome in cases with pre-eclampsia, whereas in those without pre-eclampsia, only EFW < 3rd centile and CPR < 5th centile were associated independently with adverse perinatal outcome. In the overall population, the detection rate (DR) and false-positive rate for adverse perinatal outcome were, respectively: 39.8% (95% CI, 31.7-47.9%) and 16.9% (95% CI, 10.7-23.1%) for sFlt-1/PlGF ratio > 95th centile alone; 86.8% (95% CI, 83.4-90.2%) and 61.9% (95% CI, 57.1-66.7%) for a combined model of EFW < 3rd centile, UtA-PI > 95th centile and CPR < 5th centile; 81.3% (95% CI, 77.3-85.3%) and 52.3% (95% CI, 47.1-57.5%) for a combined model of EFW < 3rd centile and sFlt-1/PlGF ratio > 95th centile; and 88.5% (95% CI, 85.4-91.6%) and 64.5% (95% CI, 59.8-69.2%) for a combined model including all the abovementioned observed parameters. sFlt-1/PlGF ratio alone had a low predictive value for adverse perinatal outcome, but when combined with EFW, its predictive performance was similar to that of EFW combined with Doppler parameters. Combining sFlt-1/PlGF ratio with EFW and Doppler criteria achieved the highest DR for adverse perinatal outcome, and additionally, might help to identify imminent pre-eclampsia in pregnancies complicated by fetal smallness. These findings support the use of angiogenic factors as an additional criterion to those currently used for identifying high-risk FGR among late-onset small fetuses, but do not support their use as a standalone biomarker. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.

Youssef L ，Crispi F ，Paolucci S ，Miranda J ，Lobmaier S ，Crovetto F ，Figueras F ，Gratacos E ... -  《-》

Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Espinoza J ，Calsavara VF ，Kilpatrick S ，Rana S ，Costantine MM ，Boggess K ，Wylie BJ ，Moore Simas TA ，Louis JM ，Gaw SL ，Murtha A ，Wiegand S ，Gollin Y ，Singh D ，Silver RM ，Durie DE ，Panda B ，Norwitz ER ，Burd I ，Plunkett B ，Scott RK ，Lemoine E ，Thadhani R ，Karumanchi SA ... -  《-》