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. 2023 Jul 11;23(1):508.
doi: 10.1186/s12884-023-05784-2.

Screening of placenta accreta spectrum disorder using maternal serum biomarkers and clinical indicators: a case-control study

Jiayi Zhou #  1   2 , Si Yang #  1   2   3 , Xingneng Xu  1   2 , Xiuting Xu  1   2 , Xuwei Wang  1   2 , Anqi Ye  3 , Yanhong Chen  1   2 , Fang He  1   2 , Bolan Yu  4   5   6
Affiliations

Screening of placenta accreta spectrum disorder using maternal serum biomarkers and clinical indicators: a case-control study

Jiayi Zhou et al. BMC Pregnancy Childbirth. .

Abstract

Background: Placenta accreta spectrum (PAS) disorder is a major cause of postpartum hemorrhage-associated maternal and fetal death, and novel methods for PAS screening are urgently needed for clinical application.

Methods: The purpose of this study was to develop new methods for PAS screening using serum biomarkers and clinical indicators. A total of 95 PAS cases and 137 controls were enrolled in a case-control study as cohort one, and 44 PAS cases and 35 controls in a prospective nested case-control study were enrolled as cohort two. All subjects were pregnant women of Chinese Han population. Biomarkers for PAS from maternal blood samples were screened based on high-throughput immunoassay and were further validated in three phases of cohort one. Screening models for PAS were generated using maternal serum biomarkers and clinical indicators, and were validated in two cohorts. The expression levels of biomarkers were analyzed using histopathological and immunohistochemical (IHC) techniques, and gene expression was examined by QPCR in the human placenta. Binary logistic regression models were built, and the area under the curve (AUC), sensitivity, specificity, and Youden index were calculated. Statistical analyses and model building were performed in SPSS and graphs were generated in GraphPad Prism. The independent-sample t test was used to compare numerical data between two groups. For nonparametric variables, a Mann-Whitney U test or a X2 test was used.

Results: The results demonstrated that the serum levels of matrix metalloproteinase-1 (MMP-1), epidermal growth factor (EGF), and vascular endothelial growth factor-A (VEGF-A) were consistently higher, while the level of tissue-type plasminogen activator (tPA) was significantly lower in PAS patients compared with normal term controls and patients with pre-eclampsia (PE) and placenta previa (PP). IHC and QPCR analysis confirmed that the expression of the identified biomarkers significantly changed during the third trimester in human placenta. The generated screening model combining serum biomarkers and clinical indicators detected 87% of PAS cases with AUC of 0.94.

Conclusions: Serum biomarkers can be used for PAS screening with low expense and high clinical performance; therefore, it may help to develop a practicable method for clinical prenatal PAS screening.

Keywords: Biomarkers; Placenta accreta spectrum; Screening model.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of this study. NOR, normal term controls; PAS, pregnant women with placenta accreta spectrum; PE, pregnant women with pre-eclampsia; PP, pregnant women with placenta previa; APO, adverse pregnancy outcomes. The figures between parentheses were the number of enrollment subjects
Fig. 2
Fig. 2
Expression levels of serum biomarkers in different groups. a MoMs of EGF, VEGF-A, tPA, and MMP1 in the serum from PAS and CON groups in Cohort one; (b) MoMs of EGF, VEGF-A, PAI-tPA, and MMP1 in the serum from PAS and CON groups in Cohort two; (c) comparison of the detected levels of EGF, VEGF-A, PAI-tPA, and MMP1 between serum and plasma. MoM: multiples of the median; CON: group of NOR, PE, and PP cases; PAS: PAS cases. *: P < 0.01. **: P < 0.001, compared with CON group
Fig. 3
Fig. 3
Diagnostic signature of each sample and ROC curve of three screening models in all subjects. (a) model M1; (b) model M2; (c) model M3; ROC: Receiver Operating Characteristic; AUC: the area under the curve; CON: group of NOR, PE, and PP cases; PAS: PAS cases. *: P < 0.01. **: P < 0.001, compared with CON group
Fig. 4
Fig. 4
Validation of the altered biomarkers in human placenta. a IHC analysis of EGF, VEGF, tPA, and MMP1 in placenta from PAS cases and controls (50 × magnification; black arrows indicate uterus muscle; red arrows indicate invasive placental trophoblasts) (b) QPCR analysis of EGF, VEGFA, PLAT(tPA), and MMP1 in placenta from PAS cases and controls. UM: Uterus muscle; CON: placenta from normal term controls; PAS: non-invasion area of placenta from PAS patients; PAS-i: invasion area of placenta from PAS patients
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