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Preterm birth, preeclampsia and miscarriage can be predicted from peripheral blood throughout the first trimester with high reliability

      Objective

      The Great Obstetrical Syndromes include the major disorders of pregnancy that include miscarriage, preeclampsia, preterm labor, and low birthweight. These complications pose a serious risk to both maternal and infant health and cost billions annually in increased health care cost in the USA alone. Although our understanding of these pathologies is increasing, prevention remains a significant challenge in obstetrics. Clinical symptoms generally manifest in the second to third trimesters of pregnancy, while underlying pathology begins within the placental bed beginning early in the first trimester. Previous studies directed to quantification of plasma biomarkers shed from placenta have failed. Instead, we propose examination of biomarkers related to the placental bed. We provide data showing that quantification of microRNA within peripheral blood cells correlates with outcome throughout the first trimester.

      Design

      We investigated the capacity of immune cell microRNAs isolated from peripheral blood in the first trimester to assess their ability to predict preeclampsia, preterm birth and miscarriage. We combined results from our four previous published studies to assess the reproducibility and robustness of the MicroRNA risk assessment method. The four published studies comprise a total of 160 births. The first study consisted of 34 pregnancies, (7 preeclampsia of late onset, 8 miscarriage and 19 normal), the second consisted of 39 pregnancies (12 preeclampsia, 8 miscarriage, 19 normal), the third consisted of 39 pregnancies (14 preterm, 25 full term) and the last consisted of 48 pregnancies (8 preeclampsia, 40 normal).

      Materials and Methods

      Quantitative rtPCR was performed on of 30 microRNAs selected from an original pool of 852 microRNAs from blood samples drawn at various time points the early first trimester of pregnancy. MicroRNA Risk Scores were calculated for each of the study groups and AUC-ROC calculations derived.

      Results

      For Study 1, the microRNA Risk Score AUC-ROC was 0.90 for miscarriage and 0.90 for late preeclampsia (p<0.0001). For Study 2, the AUC-ROC was 0.92 for miscarriage and 0.90 for preeclampsia (p<0.0001). For Study 3, the AUC-ROC was 0.98 for early preterm (<34 weeks) and 0.92 for late preterm (34-<38 weeks) (p<0.0001). For Study 4 the AUC-ROC for preeclampsia was 0.91 (p<0.0001), 0.94 for late onset preeclampsia (p<0.0001) and 0.82 for early onset preeclampsia (p=0.01).

      Conclusions

      Our combined analysis supports the idea that the Great Obstetrical Syndromes have a common biological origin early in the first trimester that can be detected throughout the first trimester using peripheral blood cell microRNA. Ours is the first to use microRNA in peripheral blood immune cells to successfully predict multiple placental bed related pregnancy disorders with high sensitivity and specificity. Early assessment allows use with other new first trimester screening methods, such as NIPT so comprehensive risk assessment package can be offered to the patient.

      Financial Support

      None
      References:
      • 1.
        Winger, E.E., Reed, J.L. and Ji, X., 2014. First trimester PBMC microRNA predicts adverse pregnancy outcome. Am J Reprod Immunol 2014;72:515-526.
      • 2.
        Winger, E.E., Reed, J.L. and Ji, X., 2015. First-trimester maternal cell microRNA is a superior pregnancy marker to immunological testing for predicting adverse pregnancy outcome. J Reprod Immunol 2015;110:22-35.
      • 3.
        Winger EE, Reed JL, Ji X. PLOSone 2017. Early first trimester peripheral blood cell microRNA predicts risk of preterm delivery in pregnant women: proof of concept. http://dx.doi.org/10.1371/journal.pone.0180124.
      • 4.
        Winger EE, Reed JL, Ji X. Nicolaides, K. First trimester peripheral blood maternal cell microRNA predicts preeclampsia outcome (unpublished).