title: First-trimester maternal cell microRNA is a superior pregnancy marker to immunological testing for predicting adverse pregnancy outcome.
abstract: Patients at risk of immune-mediated pregnancy complications have historically relied on the use of peripheral blood immunological assays for diagnosis and pregnancy monitoring. However, these tests often fail to identify many at-risk patients, achieving moderately predictive receiver operating characteristic (ROC) curve AUCs of 0.60-0.70. We previously demonstrated that a microRNA panel comprising 30 microRNAs successfully predicts pregnancy outcome in the first trimester. In our current study we constructed a smaller, more clinically useful seven-microRNA panel from the original panel of 30 microRNAs with equivalent sensitivity and specificity. To select optimal microRNAs for a smaller panel, quantitative RT-PCR on 30 microRNAs was first performed on 48 patients (191 samples) with concurrent immunological testing: TNFα/Il-10 ratio, IFNγ/Il-10, CD56+16+%, NK 50:1 cytotoxicity and T regulatory cells. MicroRNAs were separated into clusters associated with: Th1/Th2 response; T regulatory cell percent; pregnancy risk; treatment response. Seven most differentially expressed microRNAs were selected. The seven microRNA scoring system was then applied to 39 patient samples in the first trimester of pregnancy (19 healthy deliveries, 8 miscarriages, 12 preeclampsia [7 late-onset and 5 early-onset]) and 20 samples in the preconception period (2-10 weeks before conception). Predictive value was assessed. ROC curves for the seven-microRNA panel achieved AUC 0.92 for miscarriage and 0.90 for preeclampsia (blood drawn 34.9±19.2 days post-implantation). For samples measured preconception, ROC curve analysis demonstrated AUC 0.81 for adverse pregnancy outcome. Maternal PBMC microRNA can identify high-risk patients likely to benefit from immunotherapy with improved sensitivity and specificity compared with standard immune assays.
authors.affiliation: Laboratory for Reproductive Medicine and Immunology, 7013 Realm Dr, Ste A, San Jose, CA, USA. Electronic address: ewinger@sbcglobal.net.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Winger
authors.affiliation: Laboratory for Reproductive Medicine and Immunology, 7013 Realm Dr, Ste A, San Jose, CA, USA. Electronic address: reedjanel@yahoo.com.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Reed
authors.affiliation: Stanford University, Human Immune Monitoring Center, CCSR 0128, 1291 Welch Road, Stanford, CA, USA. Electronic address: xuhuai.ji@stanford.edu.
authors.forename: Xuhuai
authors.initials: X
authors.lastname: Ji
mesh_terms: D000022:Abortion, Spontaneous / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000097:blood*; D011225:Pre-Eclampsia / Q000097:blood*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First / Q000097:blood*
chemical_list: D016207:Cytokines; D035683:MicroRNAs
keywords: Implantation; Miscarriage; Natural killer cell; Preeclampsia; T regulatory cell; TNF-α/Il-10 ratio