Melanie Griffin

Diagnostic Accuracy of Placental Growth Factor in Women With Suspected Preeclampsia A Prospective Multicenter Study

Background— Hypertensive disorders of pregnancy are a major contributor to death and disability for pregnant women and their infants. The diagnosis of preeclampsia by using blood pressure and proteinuria is of limited use because they are tertiary, downstream features of the disease. Placental growth factor (PlGF) is an angiogenic factor, a secondary marker of associated placental dysfunction in preeclampsia, with known low plasma concentrations in the disease. Methods and Results— In a prospective multicenter study, we studied the diagnostic accuracy of low plasma PlGF concentration (<5th centile for gestation, Alere Triage assay) in women presenting with suspected preeclampsia between 20 and 35 weeks’ gestation (and up to 41 weeks’ gestation as a secondary analysis). The outcome was delivery for confirmed preeclampsia within 14 days. Of 625 women, 346 (55%) developed confirmed preeclampsia. In 287 women enrolled before 35 weeks’ gestation, PlGF <5th centile had high sensitivity (0.96; 95% confidence interval, 0.89–0.99) and negative predictive value (0.98; 0.93–0.995) for preeclampsia within 14 days; specificity was lower (0.55; 0.48–0.61). Area under the receiver operating characteristic curve for low PlGF (0.87, standard error 0.03) for predicting preeclampsia within 14 days was greater than all other commonly used tests, singly or in combination (range, 0.58–0.76), in women presenting with suspected preeclampsia (P<0.001 for all comparisons). Conclusions— In women presenting before 35 weeks’ gestation with suspected preeclampsia, low PlGF has high sensitivity and negative predictive value for preeclampsia within 14 days, is better than other currently used tests, and presents an innovative adjunct to management of such women.

Diagnostic Biomarkers in Women With Suspected Preeclampsia in a Prospective Multicenter Study

OBJECTIVE: To evaluate 47 biomarkers (selected from the current medical literature), in isolation or in combination with placental growth factor (PlGF), to determine the need for delivery within 14 days, in women presenting with suspected preterm preeclampsia. METHODS: In a prospective, multicenter observational study, 47 biomarkers were measured in 423 women presenting with suspected preterm preeclampsia (in two prespecified groups: group 1 at less than 35 weeks of gestation and group 2 presenting between 35 0/7 and 36 6/7 weeks of gestation) to evaluate their ability to determine the primary endpoint: preeclampsia requiring delivery within 14 days. Using factor analysis and stepwise logistic regression, we sought one or more additional biomarkers for optimal determination of the primary endpoint. RESULTS: In women presenting at less than 35 weeks of gestation (n=286), the best performing combination of PlGF, podocalyxin, endoglin, procalcitonin (receiver operating curve [ROC] area 0.90, 95% confidence interval [CI] 0.86–0.93) was not statistically better than PlGF alone (ROC 0.87, 95% CI 0.83–0.92; P=.43) for preeclampsia requiring delivery within 14 days. Two other single markers had test performance that was not significantly different to PlGF (soluble fms-like tyrosine kinase-1 [sFlt-1] ROC 0.83, 95% CI 0.78–0.88; endoglin ROC 0.83, 95% CI 0.79–0.88). Similar findings were found in women presenting between 35 0/7 and 36 6/7 weeks of gestation (n=137): ROC for PlGF alone 0.75 (95% CI 0.67–0.83); ROC for PlGF, cystatin, pregnancy-associated plasma protein A in combination 0.81 (95% CI 0.74–0.88; P=.40). CONCLUSION: This study supports the growing body of evidence that a single angiogenesis-related biomarker (PlGF, sFlt-1, or endoglin) alone represents a useful diagnostic test for women presenting with suspected preterm preeclampsia.

Diagnostic accuracy of placental growth factor and ultrasound parameters to predict the small-for-gestational-age infant in women presenting with reduced symphysis-fundus height.

To assess the diagnostic accuracy of placental growth factor (PlGF) and ultrasound parameters to predict delivery of a small‐for‐gestational‐age (SGA) infant in women presenting with reduced symphysis–fundus height (SFH).

Prediction of delivering a small for gestational age infant and adverse perinatal outcome in women with suspected pre-eclampsia

To evaluate the test performance of 47 biomarkers and ultrasound parameters for the prediction of delivery of a small‐for‐gestational‐age (SGA) infant and adverse perinatal outcome in women presenting with suspected pre‐eclampsia.

Clinical applications of biomarkers in preeclampsia

Preeclampsia remains a significant cause of maternal morbidity and mortality worldwide. Prediction, diagnosis and management continue to be challenging but advances in the understanding of the pathophysiological processes underlying the disease has enabled identification of multiple biomarkers, some of which aid prediction of those at risk. Even in isolation, some of these biomarkers have demonstrated sufficient test performance for incorporation into clinical practice. A combination of the most promising biomarkers and clinical factors may improve risk prediction, and aid diagnosis and subsequent management through development of integrated clinical risk models. This article aims to review the literature relating to biomarkers in preeclampsia and summarize the possible clinical applications of these findings.

Diagnostic Accuracy of Placental Growth Factor in Women With Suspected Preeclampsia

Background— Hypertensive disorders of pregnancy are a major contributor to death and disability for pregnant women and their infants. The diagnosis of preeclampsia by using blood pressure and proteinuria is of limited use because they are tertiary, downstream features of the disease. Placental growth factor (PlGF) is an angiogenic factor, a secondary marker of associated placental dysfunction in preeclampsia, with known low plasma concentrations in the disease. Methods and Results— In a prospective multicenter study, we studied the diagnostic accuracy of low plasma PlGF concentration (<5th centile for gestation, Alere Triage assay) in women presenting with suspected preeclampsia between 20 and 35 weeks’ gestation (and up to 41 weeks’ gestation as a secondary analysis). The outcome was delivery for confirmed preeclampsia within 14 days. Of 625 women, 346 (55%) developed confirmed preeclampsia. In 287 women enrolled before 35 weeks’ gestation, PlGF <5th centile had high sensitivity (0.96; 95% confidence interval, 0.89–0.99) and negative predictive value (0.98; 0.93–0.995) for preeclampsia within 14 days; specificity was lower (0.55; 0.48–0.61). Area under the receiver operating characteristic curve for low PlGF (0.87, standard error 0.03) for predicting preeclampsia within 14 days was greater than all other commonly used tests, singly or in combination (range, 0.58–0.76), in women presenting with suspected preeclampsia (P<0.001 for all comparisons). Conclusions— In women presenting before 35 weeks’ gestation with suspected preeclampsia, low PlGF has high sensitivity and negative predictive value for preeclampsia within 14 days, is better than other currently used tests, and presents an innovative adjunct to management of such women.

8.3 Placental growth factor (PLGF) and ultrasound parameters for predicting the small for gestational age infant (SGA) in suspected small for gestational age: pelican FGR study

The SGA infant is at increased risk of short and long-term health complications. Identifying the SGA fetus remains challenging. Placental insufficiency contributes to pathogenesis and it has been proposed that markers of placental function such as PlGF may improve prediction. PELICAN FGR, a large multicentre, prospective observational study measuring PlGF in women with reduced symphysis fundal height (SFH), assessed the ability of PlGF and ultrasound parameters to predict delivery of an SGA infant. 592 women with singleton pregnancies and reduced SFH between 24–37 weeks’ gestation across 11 sites in UK and Canada were analysed. Plasma PlGF was measured at enrolment and ultrasound data recorded. Plasma PlGF concentration <5th centile, estimated fetal weight <10th centile (EFW10), umbilical artery Doppler pulsatility index > 95th centile and oligohydramnios were compared as predictors for an SGA infant <3rd (SGA3) and <10th (SGA10) customised birthweight centiles. Test performance statistics were calculated for all parameters in isolation and combination. Sensitivity and negative predictive value (NPV) of EFW10 for SGA3 (n = 78) were 61% and 93% respectively; for SGA10 (n = 192) they were 49% and 77% respectively. PlGF had sensitivity of 37% and NPV of 90% for SGA3. In combination, PlGF and EFW10 had sensitivity of 69% and NPV of 93% for SGA3. In women presenting with reduced SFH, EFW10 and other ultrasound parameters have modest test performance for prediction of a subsequent SGA infant. PlGF performed no better than EFW10 in determining delivery of an SGA infant. Incorporating PlGF with ultrasound parameters provided modest improvements in test performance.

Diagnostic Accuracy of Placental Growth Factor in Women With Suspected PreeclampsiaClinical Perspective: A Prospective Multicenter Study

Background— Hypertensive disorders of pregnancy are a major contributor to death and disability for pregnant women and their infants. The diagnosis of preeclampsia by using blood pressure and proteinuria is of limited use because they are tertiary, downstream features of the disease. Placental growth factor (PlGF) is an angiogenic factor, a secondary marker of associated placental dysfunction in preeclampsia, with known low plasma concentrations in the disease. Methods and Results— In a prospective multicenter study, we studied the diagnostic accuracy of low plasma PlGF concentration (<5th centile for gestation, Alere Triage assay) in women presenting with suspected preeclampsia between 20 and 35 weeks’ gestation (and up to 41 weeks’ gestation as a secondary analysis). The outcome was delivery for confirmed preeclampsia within 14 days. Of 625 women, 346 (55%) developed confirmed preeclampsia. In 287 women enrolled before 35 weeks’ gestation, PlGF <5th centile had high sensitivity (0.96; 95% confidence interval, 0.89–0.99) and negative predictive value (0.98; 0.93–0.995) for preeclampsia within 14 days; specificity was lower (0.55; 0.48–0.61). Area under the receiver operating characteristic curve for low PlGF (0.87, standard error 0.03) for predicting preeclampsia within 14 days was greater than all other commonly used tests, singly or in combination (range, 0.58–0.76), in women presenting with suspected preeclampsia (P<0.001 for all comparisons). Conclusions— In women presenting before 35 weeks’ gestation with suspected preeclampsia, low PlGF has high sensitivity and negative predictive value for preeclampsia within 14 days, is better than other currently used tests, and presents an innovative adjunct to management of such women.

Diagnostic Accuracy of Placental Growth Factor in Women With Suspected PreeclampsiaClinical Perspective

Background— Hypertensive disorders of pregnancy are a major contributor to death and disability for pregnant women and their infants. The diagnosis of preeclampsia by using blood pressure and proteinuria is of limited use because they are tertiary, downstream features of the disease. Placental growth factor (PlGF) is an angiogenic factor, a secondary marker of associated placental dysfunction in preeclampsia, with known low plasma concentrations in the disease. Methods and Results— In a prospective multicenter study, we studied the diagnostic accuracy of low plasma PlGF concentration (<5th centile for gestation, Alere Triage assay) in women presenting with suspected preeclampsia between 20 and 35 weeks’ gestation (and up to 41 weeks’ gestation as a secondary analysis). The outcome was delivery for confirmed preeclampsia within 14 days. Of 625 women, 346 (55%) developed confirmed preeclampsia. In 287 women enrolled before 35 weeks’ gestation, PlGF <5th centile had high sensitivity (0.96; 95% confidence interval, 0.89–0.99) and negative predictive value (0.98; 0.93–0.995) for preeclampsia within 14 days; specificity was lower (0.55; 0.48–0.61). Area under the receiver operating characteristic curve for low PlGF (0.87, standard error 0.03) for predicting preeclampsia within 14 days was greater than all other commonly used tests, singly or in combination (range, 0.58–0.76), in women presenting with suspected preeclampsia (P<0.001 for all comparisons). Conclusions— In women presenting before 35 weeks’ gestation with suspected preeclampsia, low PlGF has high sensitivity and negative predictive value for preeclampsia within 14 days, is better than other currently used tests, and presents an innovative adjunct to management of such women.

2.2 Plasma Placental Growth Factor (PlGF) in the Diagnosis of Women with Pre-Eclampsia Requiring Delivery Within 14 Days: The PELICAN Study

Introduction Evidence exists to suggest that the symptoms of pre-eclampsia are mediated by an imbalance of circulating angiogenic factors of placental origin; reduced concentrations of placental growth factor (PlGF) have been correlated with disease severity. Methods A prospective, observational, cohort study was undertaken in seven UK maternity units. Women presenting 20 + 0 to 40 + 6 weeks gestation with suspected pre-eclampsia had serum PlGF measurement. ISSHP definitions of hypertensive disease were assigned, blinded to PlGF values. Analysis of the enrolment sample was conducted to evaluate diagnostic accuracy for pre-eclampsia requiring delivery within 14 days for very low PlGF (<12 pg/ml) and low PlGF (>12 pg/ml < 5th centile) using PlGF high (>5th centile) as referent. Results Diagnosis of pre-eclampsia requiring delivery within 14 days using 5th centile as threshold. Conclusion In women presenting <35 weeks’ gestation with suspected pre-eclampsia, low PlGF level rules in women requiring delivery within 14 days and high PlGF rules out preterm delivery. Test performance falls off in women presenting over 35 weeks’ gestational. PlGF can assist diagnosis and identify women requiring increased care. Abstract 2.2 Table < 35+0 35+0 to 36+6 ≥37+0 N = 287 N = 137 N = 201 Sensitivity 0.95 (0.89–0.99)79/83 0.71 (0.59–0.82)47/66 0.59 (0.48–0.70)49/83 Specificity 0.56 (0.49–0.63)114/204 0.65 (0.53–0.76)46/71 0.77 (0.69–0.84)91/118 Positive Predictive Value 0.47 (0.39–0.55)79/169 0.65 (0.53–0.76)47/72 0.65 (0.53–0.75)49/76 Negative Predictive Value 0.97 (0.92–0.99)114/118 0.71 (0.58–0.81)46/65 0.73 (0.64–0.80)91/125 Positive Likelihood ratio 2.2 (1.8–2.5) 2.0 (1.4–2.9) 2.6 (1.8–3.8) Negative Likelihood ratio 0.09 (0.03–0.23) 0.4 (0.3–0.7) 0.5 (0.4–0.7)