Does increase in arterial stiffness and wave reflection precede development of placental-mediated complications in pregnancy?

Placental-mediated pregnancy complications, such as preeclampsia, fetal growth restriction, and placental abruption, are somewhat unique to the human species [1] and affect 2–8% of pregnancies worldwide [2–5]. Although the risk factors for these complications are well established [5–7], current clinical screening tests are not predictive in nature and only serve to identify at risk individuals for further diagnostic testing or monitoring [8,9]. Given the large impact placental-mediated diseases have on maternal and fetal morbidity and mortality [10], there is a need for predictive tests that can be easily performed in the early stages of pregnancy to facilitate early interventions for management and potentially prevention of these complications. Such predictive tests should be simple, noninvasive, and cost-effective to ensure ease of clinical adoption. Normal pregnancy is associated with an array of cardiovascular adaptations that are necessary for coping with the increased blood flow demand to the placenta [11], and disruptions to placental blood flow is often associated with compromised pregnancies [12]. Furthermore, it has been shown that increased arterial stiffness and wave reflection are associated with placental-mediated diseases, such as preeclampsia [13]. Given the ease of noninvasive assessment of arterial stiffness and wave reflection by way of pulse wave velocity (PWV) measurement and arterial pulse wave analysis (PWA), there has been increasing research into the potential predictive value of arterial stiffness and wave reflection indices in pregnancy for the development of placental-mediated diseases [14–16]. In this issue of the Journal of Hypertension, Osman et al.[17] present a first systematic review and meta-analysis of published observational studies investigating the differences in PWV and augmentation index (AIx), indices of arterial stiffness and wave reflection, in pregnant women who subsequently developed placental-mediated diseases as compared with those with normal pregnancies. Measurement of PWV and AIx by way of PWA can be readily obtained using applanation tonometry [14], cuff-based oscillometry [18], or ultrasound [19]. In many of the studies included in the review by Osman et al.[17], both PWV and AIx were taken as indices of arterial stiffness. Where PWV is a measure of the wave speed at which the arterial pulse travels along the arterial wall and is thus a direct surrogate measure of arterial stiffness [20], AIx is a measure of systolic pressure augmentation and is affected by both the stiffness of the arteries and peripheral wave reflection [21]. Furthermore, AIx is influenced by other cardiovascular factors, such as heart rate (HR), in the absence of any change in arterial stiffness [22]. As such, AIx is not an index of arterial stiffness per se[21], but rather an index of wave reflection. This distinction would be important in the understanding of the different changes observed in PWV and AIx throughout the gestational period in both normal and compromised pregnancies. In addition, PWV and AIx are both affected by age and blood pressure (BP) [23,24]. These parameters must also be taken into account when interpreting changes in PWV and AIx. Previous studies have demonstrated that normal pregnancy is associated with a decrease in AIx [25] and PWV [26] throughout the gestational period, although aortic stiffness is slightly increased in the third trimester when compared with healthy nonpregnant controls [11,26]. These changes are consistent with the vasodilation of peripheral vessels, decrease in peripheral resistance, and increase in HR that occur in normal pregnancy [27]. When compared with their healthy pregnant counterparts, women with established preeclampsia presented with increased PWV [28,29] and AIx [30], suggesting a possible disruption to the normal regulatory response to increased blood flow demand associated with pregnancy due to endothelial dysfunction or oxidative inflammation [13]. Increased wave reflection as measured by AIx has also been shown to be negatively correlated with birth weight [31]. These findings prompted investigators to ask the question: are these differences in arterial stiffness and wave reflection a result of the placental-mediated diseases, or do they precede the development of such complications and may therefore have predictive value? To answer this question, measurements of PWV and AIx must be obtained prior to the development of these complications. As demonstrated in the review by Osman et al.[17], there are currently only a small number of studies that have explored the predictive value of arterial stiffness and wave reflection for the development of preeclampsia and small for gestational age (SGA) babies, and none have explored their associations with placental abruption or intrauterine fetal death. Despite this, the meta-analysis performed by Osman et al.[17] showed that both PWV and AIx, when corrected to a HR of 75 bpm (AIx-75), were significantly higher in women who subsequently developed preeclampsia or delivered SGA babies, and that differences in AIx-75 could be detected as early as the first trimester of pregnancy. However, various techniques were used to obtain PWV and AIx in the different studies, and not all studies adjusted for confounding factors. In particular, BP was significantly different between the healthy control group and the disease group in a few of the included studies; thus, it remains unclear whether the overall observed differences in PWV and AIx between the groups were independent of BP. The review and meta-analysis by Osman et al.[17] demonstrates the potential predictive value of assessing arterial stiffness and wave reflection, by way of PWV and AIx measurement, for the development of preeclampsia and delivery of SGA babies. It also highlights the importance of distinguishing between arterial stiffness and wave reflection indices to better understand potential underlying mechanisms associated with the hemodynamic changes preceding development of placental-mediated diseases. In addition, the review highlights the need for a more standardized method of assessment of arterial stiffness and wave reflection in pregnant women, particularly if these indices were to be used as a predictive tool in clinical screening for preeclampsia and other placental-mediated diseases. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.