A new study published in the journal scientific reportYeah reported that circulating microparticle (CMP) proteins predict pregnancies complicated by placenta accreta spectrum (PAS).
The primary pathogenic feature of PAS is that the placenta does not spontaneously separate from the uterus after delivery. Therefore, PAS can have devastating consequences that can even lead to death. Antenatal diagnosis of PAS can reduce PAS-related maternal morbidity by up to 80% by allowing early multidisciplinary care. However, a significant number of PAS cases cannot be diagnosed before birth.
PAS risk is currently under investigation with historical/clinical risk factors and radiological evaluation. An easily available biomarker for PAS would provide unprecedented clinical benefit, particularly in rural and low-resource settings. CMPs are micro to nano-sized extracellular lipid bilayer vesicles that mediate cell signaling and communication. CMPs are promising in obstetric research, especially in preterm births and preeclampsia.
Studies: Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum. Image Credit: Blue Planet Studio / Shutterstock
Study and findings
In this study, researchers in the United States investigated whether CMPs could predict pregnancies complicated by PAS. Plasma samples from average 26 and 35 weeks of gestation were collected from the LIFECODES pregnancy biobank at Brigham and Women’s Hospital, Boston, between 2007 and 2020. Eligible subjects were patients 18 years of age or older who received antenatal care and planned to give birth at the indicated hospital.
Pregnancy was confirmed by ultrasound at ≤ 12 weeks of gestation. Cases were individual with clinical or histological grade 1 – 3 PAS. Possible cases were identified using specific search terms in electronic medical records (EMR) between 2007 and 2020. Controls were subjects without a diagnosis of PAS and were randomly matched 2:1 according to gestational age and number of fetuses.
Subjects with cancer/documented fetal chromosomal abnormality or using immunomodulators were excluded. Thirty-five cases and 70 controls were included; 27 cases had grade 1, seven cases had grade 2 and one had grade 3 PAS. Clinical criteria defined approximately 66% of PAS cases. CMPs were isolated using size exclusion chromatography and identified by liquid chromatography with tandem mass spectrometry.
The team implemented a two-step iterative workflow to identify CMP proteins that would serve as markers for PAS risk during the second and third trimesters, using regular regression (L1) and logistic regression for cross-validation. The same workflow was repeated with random allowed samples to simulate random chance.
The mean of all areas under the curves (AUCs) differed significantly between the observed and allowable panels in second trimester samples. The best performing CMP panel distinguished PAS from controls with an average of 0.83 AUC. This includes the following CMP proteins: cartilage acidic protein 1 (CRAC1), hemoglobin subunit gamma 2 (HBG2), sulfhydryl oxidase 1 (QSOX1) and. histone 4 (H4) and isthmin-2 (ISM2).
Similarly, the mean of all AUCs for third trimester samples differed significantly between the observed and allowable panels. The four best performing proteins – ISM2, immunoglobulin (Ig) lambda variants 10–54, Ig-like domain-containing protein and ubiquitin carboxyl terminal hydrolase differentiated PAS from controls with a mean of 0.78 AUC.
The team also applied mastery pathway analysis (IPA) to determine the biological function of identified proteins differentially expressed by PAS status. The analysis revealed significant overrepresentation of upstream regulators, canonical pathways, and cellular and molecular functions.
Recommended canonical pathways, upstream regulators, and molecular and cellular function analyzes during the second and third trimesters lead to morbid placental adhesion. Figure created with BioRender.com.
Proteomic changes in PAS during the second trimester led to overrepresentation of canonical pathways, including erythropoietin and iron homeostasis signaling. In addition, cellular and molecular functions around erythrocyte function and iron utilization were in agreement with the canonical erythropoietin and iron homeostasis signaling pathways revealed by IPA.
Similarly, IPA revealed significant overrepresentation of upstream regulators, canonical pathways, and cellular and molecular functions in the third quarter. Proteomic changes in PAS during the third trimester revealed significant overrepresentation of extracellular and immune signaling pathways, particularly those involving interleukin-15 (IL-15).
Cellular and molecular functional analyzes identified 24 selected annotated functions that were significantly overrepresented in the third trimester. However, there was some agreement between canonical pathways and cellular and molecular functions, particularly around cytoskeletal/cellular growth and immune signaling functions.
In summary, the team identified five and four CMP proteins that classify PAS in the second and third trimesters, respectively. The findings suggested that the markers had higher predictive value in the second quarter than in the third quarter. Further analysis revealed an overrepresentation of processes related to oxygenation and blood cell function during the second trimester, and abnormal immune cell and IL-15 signaling during the third trimester.
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