New lenses to look at preeclampsia

Hypertensive disorders of pregnancy (HDP) are associated with severe obstetric complications representing a leading cause of maternal mortality [1]. Furthermore, HDP can be related to pregnancy complications like iatrogenic preterm delivery, intrauterine growth restriction (IUGR) and perinatal death [2]. Traditional classification of HDP includes preeclampsia (PE), chronic hypertension with superimposed PE, gestational hypertension (GH) and chronic hypertension [3,4]. Its incidence greatly varies according to local population characteristics as a consequence of ethnicity, obesity, parity and other maternal risk factors. The incidence of PE alone is reported to be between 2% and 8% [5,6]. Scientific societies and committees attempted to improve the applicability of the traditional classification criteria of HDP to clinical practice by means of a detailed description of maternal functions and organs associated with hypertension in pregnancy [7,8]. The list of complications that classify GH as a preeclamptic phenotype had been recently enriched by IUGR, even in the absence of proteinuria [8]. In fact, beyond different maternal complications and despite intensive research in the past years, the diagnosis of PE is still based on clinical manifestations, as it has been defined many decades ago as a disease characterized by hypertension and proteinuria with or without organ failure [9]. An attempt to fit clinical phenotypes into this generalist criterion is the partition of HDP based on the temporal classification according to the gestational age at diagnosis (and in some cases gestational age at delivery) into earlyand late-onset, with 34 weeks of gestation as the most commonly used cut-off [10]. Although early-onset PE, which is more frequently associated with IUGR [10], is related with a higher rate of neonatal mortality and morbidity, the late-onset PE is almost three times more frequent and accounts worldwide for the substantial proportion of late preterm birth [11] and severe adverse outcome for the mother. Thus, it is not surprising that recently the members of the Global Pregnancy CoLaboratory [12] suggested a revision of the main phenotypes of PE based not only on gestational age at onset but also on the co-occurrence of IUGR, deficient angiogenic factors, maternal risk conditions such as obesity, diabetes and others. It is very likely, as it has been supported by histopathological and clinical studies since the late 1990s, that the common pathway underlying the clinical signs and symptoms of PE is represented by endothelial damage [13]. A recent contribution has been added by Baschat [14] and co-workers who revised in a seminal work the main risk profiles of pregnant women that might sum up to placental disease and trigger the development of cardiovascular and endothelial dysfunction. Maternal body mass index (BMI) and uterine arteries Doppler velocimetry resulted to be the two major determinants among the risk factors for PE. These findings on the role of BMI underline, on one side, the role of maternal predisposing conditions for metabolic syndrome, low-grade inflammation, the endothelial dysfunction that might be associated to late placental damage and hypertension not associated with IUGR. On the other side, shallow trophoblastic placentation, reflected by abnormal uterine arteries Doppler velocimetry, is at the basis of the trophoblastic oxidative stress and disbalance of angiogenic and anti-angiogenic factors [15,16]. The latter, ultimately, might damage maternal endothelium at the basis of systemic hypertension and/or cause other function or organ damage. In this case, the clinical manifestation will be associated with IUGR caused by placental insufficiency. These findings are in agreement with epidemiological studies [11] and with predictive studies as we will see in the next paragraph [15–19]. Indeed, the multi-facets clinical manifestations of HDP [9,10] could fit well into two different pathophysiological models and, consequently, two completely different patterns of placental damage and clinical phenotypes: on one hand, the placenta with incomplete spiral artery remodeling resulting in HDP associated with IUGR (HDP-IUGR), and on the other hand, the placenta with deregulated perfusion due to an over-expansion of terminal villi [20,21] resulting in HDP associated with fetuses with appropriate for gestational age growth (HDP-AGAf).