**1. Introduction**

There exists a progressive increase of data linking specific levels of risk factors in prenatal life with cardiovascular disease outcomes in children and adolescents. Recent epidemiologic and experimental data substantially indicate that children descending from pregnancies complicated by gestational hypertension (GH), preeclampsia (PE), or fetal growth restriction (FGR) have an unique, lifetime cardiovascular risk profile that is present from early life. Young offspring of pregnancies complicated by GH or PE already have increased body mass index (BMI) and wider waist circumference [1,2]. Systolic and/or diastolic blood pressures (BP) were also reported to be higher in offspring of mothers with GH or PE compared with offspring of mothers without hypertensive disorders of pregnancy [1–5]. These differences were even consistent till the age of 18 years, as the patterns of blood pressure change did not differ between children of hypertensive and normotensive pregnancies [6]. Offspring from pregnancies with early PE (onset < 34 weeks) had at the age of 6 to 13 years a higher systolic BP and higher nocturnal systolic and diastolic BP than those born to late onset PE [7]. Maternal central pulsatile BP components (systolic BP and pulse pressure) during pregnancy were associated with higher BP in the offspring of women with PE. This positive correlation was already evident at 3 years old children [8]. These results suggested a possible association between maternal hypertensive disorders of pregnancy and offspring BP that may be driven by genetics or familial non-genetic risk factors particular to BP [5]. In addition, PE leaves a persistent alteration in the systemic and the pulmonary circulation of the children. Pulmonary artery pressure was roughly 30% higher and flow-mediated dilation was 30% smaller in children of PE-affected mothers than in controls. This alteration predisposes children to exaggerated hypoxic pulmonary hypertension already during childhood and may cause premature cardiovascular disease in the systemic circulation at some time in the future [9].

Sarvari et al. [10] reported that FGR induced cardiac remodeling persists until preadolescence (8–12 years of age) with findings similar to those reported in their prenatal life and childhood. Echocardiography and three-dimensional shape computational analysis revealed a more spherical and smaller hearts, decreased longitudinal motion and impaired relaxation in children affected with FGR [10]. Yiallourou et al. [11] revealed that preterm FGR children aged 5–12 years had smaller left ventricular lengths, ascending aorta, and left ventricular outflow tract diameter and vascular compliance was positively correlated with gestational age. These findings result in the hypothesis of FGR caused primary cardiac programming for explaining the association between low birth weight and later cardiovascular risk [10].

Birth weight influences childhood BP as well, but the effects may vary depending on ethnic group. FGR and early gestational age were associated with higher BP in white but not African American children at the age of 5 years [12].

Altogether, childhood obesity, hypertension, diabetes, and cardiac remodeling are the most prevalent intermediate and long-standing health consequences of undernutrition of the fetus caused by insufficiency of the placenta [13,14].

Although, health factors such as lipid levels, BMI, and BP normally change with age, growth, and development, children affected by pregnancy complications including GH, PE, and FGR represent a population that would benefit from implementation of early primary prevention strategies. At least modification of diet and physical activity are first-line interventions. Appropriate pharmacological intervention may be also considered when lifestyle change is not successful [15].

The goal of the study was to evaluate an epigenetic profile for the detection of cardiovascular risk in whole peripheral blood of children at the age of 3 to 11 years born out of pregnancies complicated by GH, PE, and FGR. Postnatal epigenetic profiling of microRNAs playing a role in pathogenesis of diverse cardiovascular/cerebrovascular diseases (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-92a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-210-3p, miR-221-3p, miR-342-3p, miR-499a-5p, and miR-574-3p) was the subject of our interest. We focused mainly on those microRNAs known to be involved in the onset of dyslipidaemia [16,17], hypertension [18–20], vascular inflammation [21,22], insulin resistance and diabetes [23], atherosclerosis [24,25], angiogenesis [26,27], coronary artery disease [19,22,26,28], myocardial infarction and heart failure [18,29–32], stroke [33], intracranial aneurysm [34], pulmonary arterial hypertension [35], and peripartum cardiomyopathy [36].

MicroRNAs are the members of the family of small noncoding RNAs that regulate expression of genes at the posttranscriptional level by blocking translation or degrading of target messenger RNA [37]. MicroRNA analyses indicate that under pathological conditions a variety of tissues display diverse microRNA expression profiles, which may be used in clinical diagnostics [38]. Recent studies have demonstrated that GH, PE, and FGR are associated with alterations in microRNA expression in the maternal circulation, placenta, and umbilical cord blood [39–43].

To the best of our knowledge, any study on expression profiling of microRNAs associated with cardiovascular and cerebrovascular diseases in whole peripheral blood of children descending from GH, PE, and FGR affected pregnancies has not been carried out.
