Preeclampsia (PE) is a major obstetrical syndrome affecting 3–5 % of pregnancies contributing to maternal and perinatal morbidity and mortality [1], [2], [3]. While PE is diagnosed after 20 weeks of pregnancy, the pathophysiological mechanisms are present long before the clinical signs and symptoms [4], [5]. Prophylactic low-dose aspirin introduced before 16 weeks was shown to prevent some complications of PE, among which a reduced risk of preterm preeclampsia and several perinatal complications such as preterm delivery, low birth weight and stillbirth [6], [7]. However, the universal use of aspirin remains debated as compliance with treatment needs to be considered, as well as the cost of universal use of aspirin and the existing risk of antepartum and postpartum hemorrhage associated with universal use of aspirin [8], [9], [10]. It is thus necessary to identify rapidly women who would benefit the most from targeted preventive treatment and thus improve both neonatal and perinatal outcomes [8].

Maternal characteristics are essential clinical components of obstetric follow-up and some are considered early markers of PE [11], [12]. Unfortunately, most women who develop PE are not receiving prophylaxis because they are not considered at high risk based on their clinical factors only [12]. Algorithms are proposed in the literature, combining clinical risk factors with maternal biomarkers (pregnancy-associated protein A (PAPP-A), Doppler ultrasound parameters or angiogenic markers (placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1, (sFlt1)) [13], [14], [15]. These algorithms performed well for pre-term PE, which is the rarest form of PE [12], [13], [15], [16]. Therefore, no known risk factors taken alone or in combination with other biomarkers are considered robust enough to predict women who would benefit from initiating prophylaxis early in pregnancy [13], [17]. The identification of biomarkers detected before 16 weeks of pregnancy could improve the prediction of PE as well as our understanding of the underlying mechanisms [17].

MicroRNAs (miRNAs) are an emerging class of biomarkers that may participate in PE pathophysiology [18]. They are small non-coding RNA molecules about 19–24 nucleotides long that regulate gene expression at the post-transcriptional levels. By binding to their mRNA targets, they regulate many biological processes and are possibly involved in various pathologies including PE [18], [19]. MiRNAs are also secreted in blood from organs and tissues, including the placenta [20], [21]. Circulating miRNAs also vary in abundance during pregnancy and fluctuate according to gestational age [22]. Previous studies have uncovered miRNAs associated with PE onset, with inconsistent results [19], [23], [24], [25]. Elements such as sample size, case-control design, miRNA profiling techniques, sampling timing, and absence of replication could explain this heterogeneity.

We hypothesized that women who develop PE are characterized by a unique circulating miRNA profile as early as the first trimester of pregnancy. Our objectives were to identify first trimester circulating miRNAs associated with PE and to assess their predictive value in addition to known clinical risk factors, in two independent pregnancy cohorts.