Samantha J. Benton

Redefining Preeclampsia Using Placenta-Derived Biomarkers

Preeclampsia affects 3% to 8% of all pregnancies.1 Acute maternal complications include eclampsia, stroke, placental abruption, disseminated intravascular coagulation, HELLP (hemolysis, elevated liver enzymes, low platelets), liver hemorrhage or rupture, pulmonary edema, adult respiratory distress syndrome, acute renal failure, and death.2 Preeclampsia complications account for more than 50 000 maternal deaths annually.2,3 In developing countries, where lack of access to appropriate maternal care is a major problem, maternal death rates are as high as 15% as compared with 0% to 1.8% in industrialized countries.2 Perinatal consequences include stillbirth, preterm delivery, fetal growth restriction (FGR), neonatal complications, and later sequelae.4 Long-term maternal risks include chronic hypertension, diabetes mellitus, coronary artery disease,5 neurological deficit, and premature death.2 Here, we argue that the classic definitions of preeclampsia, based on concepts that are now more than 50 years old, have become outdated and that the definition could be modernized to take account of our current understanding of disease pathophysiology. We propose a first step that incorporates the placental biomarker placenta growth factor (PlGF), but we allow for the possibility that the definition may need to be expanded to include other factors, such as the antiangiogenic factors, soluble fms-like tyrosine kinase-1 (sFLT1) or soluble endoglin (sENG),6 in due course. This is intended as an exploratory rather than a final development. Diseases may be defined and classified by cause, pathogenesis, or by clinical findings. Clear definitions and classification are difficult when pathogenesis is unknown. As a result, diagnostic labels may reflect only a set of symptoms and signs, defining a syndrome. Syndromes are never precise, because the features are multiple, nonspecific, and therefore may have diverse causes. Preeclampsia is a syndrome of new onset hypertension and proteinuria in the second half of pregnancy, that was defined …

Can placental growth factor in maternal circulation identify fetuses with placental intrauterine growth restriction

OBJECTIVE We investigated whether decreased concentrations of placental growth factor (PlGF) in maternal circulation differentiated placental intrauterine growth restriction (IUGR) from constitutionally small fetuses. Excluding congenital syndromes, infection, and aneuploidy, we assumed IUGR with an abnormal placental pathology to be of placental origin. STUDY DESIGN The study design included a single site, case-control study of 16 cases (9 placental IUGR, 7 constitutionally small) and 79 normal controls with singleton pregnancies. Plasma PlGF was measured by Triage PlGF immunoassay according to the product insert. A positive PlGF test was defined as a concentration less than the fifth percentile for gestational age for normal pregnancy. RESULTS A positive PlGF test was found in 9 of 9 placental IUGR cases, 1 of 7 constitutionally small fetuses, and 4 of 79 controls (P < .0001). PlGF identified placental IUGR from constitutionally small fetuses with 100% sensitivity and 86% specificity (P = .0009). CONCLUSION These preliminary data suggest PlGF may identify placental IUGR antenatally.

Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays

OBJECTIVE Placental growth factor and soluble Fms-like tyrosine kinase-1 may be potential diagnostic markers of preeclampsia. We compared performances of 2 immunoassays, the Triage placental growth factor assay and the Elecsys soluble Fms-like tyrosine kinase-1/placental growth factor ratio in diagnosing preeclampsia. STUDY DESIGN A single site, case-control study of 44 patients with preeclampsia and 84 matched normal pregnant controls. Samples were collected at the time of diagnosis. Assays were performed according to product inserts. RESULTS Both assays had optimal performance in diagnosing early-onset preeclampsia with area under the receiver operating characteristic curves of 0.99 (Triage: 100% sensitivity, 96% specificity; Elecsys: 64% sensitivity, 100% specificity for early-onset preeclampsia). Reassignment of the Elecsys cutoff for a positive test based on receiver operating characteristic curves increased sensitivity to 92%. CONCLUSION Using product insert cutoffs, Triage appears to have greater sensitivity at only a small reduction in specificity compared with Elecsys in the diagnosis of early-onset preeclampsia. A different cutoff may improve Elecsys sensitivity.

Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia

Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervised clustering to this combined data set identified 3 clinically significant probable etiologies of PE: “maternal”, with healthy placentas and term deliveries; “canonical”, exhibiting expected clinical, ontological, and histopathologic features of PE; and “immunologic” with severe fetal growth restriction and evidence of maternal antifetal rejection. Moreover, these groups could be distinguished using a small quantitative polymerase chain reaction panel and demonstrated varying influence of maternal factors on PE development. An additional subclass of PE placentas was also revealed to form because of chromosomal abnormalities in these samples, supported by array-based comparative genomic hybridization analysis. Overall, our findings represent a new paradigm in our understanding of the origins and maternal–placental contributions to the pathology of PE. The study of PE represents a unique opportunity to access human tissue associated with a complex hypertensive disorder, and our novel approach could be applied to other hypertensive and heterogeneous human diseases.

Abnormal Liver Function Tests as Predictors of Adverse Maternal Outcomes in Women With Preeclampsia

OBJECTIVES To evaluate whether (1) the absolute magnitude of liver function test values, (2) the percentage change in liver function test values over time, or (3) the rate of change in liver function test values over time predicts adverse maternal outcomes in women with preeclampsia. METHODS We used data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study, a prospective multicentre cohort study assessing predictors of adverse maternal outcomes in women with preeclampsia. Women with at least one liver function test performed at the time of hospital admission were included. Liver functions were tested by serum concentrations of aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), albumin, total bilirubin, and the international normalized prothrombin time ratio. Parameters investigated were absolute levels, change within 48 hours of hospital admission, change from admission to delivery or outcome, and rate of change from admission to delivery or outcome of each liver function test. The ability of these parameters to predict adverse outcomes was assessed using logistic regression analyses and by calculating the receiver operating characteristic (ROC) area under the curve (AUC). RESULTS Of the 2008 women, 1056 (53%) had at least one abnormal liver function test result. The odds of having an adverse maternal outcome were higher in women with any abnormal liver function test than in women with normal results. When test results were stratified into quartiles, women with results in the highest quartile (lowest quartile for albumin) were at higher risk of adverse outcomes than women in the lowest quartile for all parameters (highest for albumin). The absolute magnitude of AST, ALT, and LDH predicted adverse maternal outcomes (AST: ROC AUC 0.73 [95% CI 0.67 to 0.97]; ALT: ROC AUC 0.73 [95% CI 0.67 to 0.79]; LDH: ROC AUC 0.74 [95% CI 0.68 to 0.81]). Neither change of liver function test results, within 48 hours of admission or from admission to delivery or outcome, nor rate of change were predictive. CONCLUSION We found abnormal liver function test results to be associated with an increased risk for adverse maternal outcomes. Levels of AST, ALT, and LDH were found to be modestly predictive of these outcomes.

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).

Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms

BACKGROUND A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. METHODS Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied. RESULTS Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves. CONCLUSIONS We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes.

IFPA Meeting 2011 workshop report I: Placenta: Predicting future health; roles of lipids in the growth and development of feto-placental unit; placental nutrient sensing; placental research to solve clinical problems – A translational approach

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2011 there were twelve themed workshops, four of which are summarized in this report. These workshops related to both basic science and clinical research into placental growth and nutrient sensing and were divided into 1) placenta: predicting future health; 2) roles of lipids in the growth and development of feto-placental unit; 3) placental nutrient sensing; 4) placental research to solve clinical problems: a translational approach.

Measurement of sST2 is comparable to PlGF in the diagnosis of early-onset pre-eclampsia.

A diagnostic test to confirm pre-eclampsia would be beneficial for the clinical management of the syndrome. The Triage PlGF test is able to confirm pre-eclampsia with high accuracy, with the greatest efficacy at <35weeks gestation. We recently found that the anti-inflammatory protein sST2 is elevated in the plasma of pre-eclamptic women compared to normal controls. Here sST2 and PlGF are compared in early-onset and late-onset pre-eclamptic women. sST2 was found to be an equally good diagnostic tool for early-onset (sST2 AUC 0.944 versus PlGF AUC 0.995; not significant) but not late-onset disease.

Andrée Gruslin award lecture: Metabolomics as an important modality to better understand preeclampsia

Preeclampsia (PE) is a complex disorder that affects 3-5% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality. To date, the heterogeneity of clinical presentation, disease severity and outcomes have limited significant advances in early prediction, diagnosis, and therapeutic intervention of PE. The rapidly expanding field of metabolomics, which has the capacity to quantitatively detect low molecular weight compounds (metabolites) in tissue and biological fluids, shows tremendous promise in gaining a better understanding of PE. This review will discuss this emerging field and its contribution to recent advances in the understanding of PE pathophysiology, and identification of early predictive metabolic biomarkers for this complex disorder.