Early Pregnancy Biomarkers in Pre-Eclampsia: A Systematic Review and Meta-Analysis

Abstract

Pre-eclampsia (PE) complicates 2%-8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39-0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE.

Keywords: early pregnancy biomarkers; meta-analysis; pre-eclampsia.

Figure 1

Flowchart of selection process. GA: gestational age.

Figure 2

QUADAS-2 Quality score. QUADAS: Quality Assessment of Diagnostic Accuracy Studies.

Figure 3

Distribution of studied laboratory biomarkers (n = 401) in included articles (n = 147). PlGF: Placental growth factor; PAPP-A: Pregnancy associated plasma protein A; PP-13: Placental protein 13; ADAM-12: a disintegrin and metalloprotease 12; CRP: C-reactive protein; sFlt: Soluble fms-like tyrosine kinase-1; MMP-9: Matrix metallopeptidase 9; TNF-R1: Tumour-necrosis factor receptor-1; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; SHBG: Sex hormone-binding globulin.

Figure 4

Meta-analysis of single laboratory biomarkers in PE (both EOPE and LOPE). Legend: (1) activin-A; (2) ADAM-12; (3) α fetoprotein; (4) α-1-macroglobulin; (5) anti-CD63 (GP53, lysosomal secretion); (6) chemerin; (7) C-reactive protein; (8) cystatin C; (9) endoglin; (10) E-selectin; (11) fetal DNA; (12) fetal hemoglobin (ratio); (13) fibronectin; (14) free β-hCG; (15) free leptin index; (16) GRP78 (glucose regulated protein) ratio C-term/full length; (17) Htr-A1 (High-Temperature Requirement A1); (18) inhibin-A; (19) NGAL (neutrophil gelatinase-associated lipocalin); (20) PAPP-A; (21) PBMC (peripheral blood mononuclear cell) miRNA; (22) PlGF; (23) PP-13; (24) P-selectin; (25) soluble endoglin; (26) sFLT/PlGF ratio; (27) sFlt-1; (28) sVEGFR-1 (vascular endothelial growth factor); (29) TNF-R1 (tumor necrosis factor receptor). PE: Pre-eclampsia; EOPE: early-onset PE; LOPE: late-onset PE.

Figure 5

Summary of receiver operating characteristics curve of single laboratory biomarkers in PE (both EOPE and LOPE).

Figure 6

Meta-analysis of combination of laboratory and clinical makers in PE (both EOPE and LOPE). Legend: (1) PAPP-A, AFP, uE3, hCG (total or free β), inhibin-A; (2) mean PI + activin-A; (3) PlGF/sEng-ratio; (4) PAPP-A and free leptin index; (5) PP-13, UA-PI, AIx-75 (measure of arterial stiffness); (6) cystatin-C, CRP, uterine artery resistance index; (7) HbF ratio and A1M; (8) activin-A, inhibin-A, PlGF and UA-PI; (9) African American race, systolic blood pressure, BMI, education level, ADAM12, PAPP-A, PlGF; (10) BMI, education mother and HtrA1; (11) maternal characteristics, PlGF; (12) maternal characteristics, ADAM12; (13) maternal characteristics, PlGF; (14) sFLT-1, PlGF, PAPP-A, inhibin A, BMI, MAP; (15) PlGF, MAP, BMI, high fruit intake, uterine artery Doppler resistive index (UA-RI) * validation cohort; (16) PlGF, MAP, BMI, high fruit intake, UA-RI * training cohort.

Figure 7

Summary of receiver operating characteristics curve of combination model of laboratory and makers in PE (both EOPE and LOPE).