In Search of a Predictive Model for Preeclampsia: The Beat Goes On

Preeclampsia is a pregnancy-specific syndrome characterized by hypertension and proteinuria, or other target organ damage (TOD), occurring after 20 weeks of gestation. It affects 5–8% of pregnancies, and is a leading cause of maternal and fetal morbidity and mortality globally.¹ Although many clinical factors that increase a woman’s risk of developing preeclampsia have been identified, there is a need for improved risk prediction to identify women who require heightened surveillance during pregnancy as well as those who may benefit from interventions to reduce the incidence of preeclampsia or lessen the severity of disease.

High blood pressure (BP) that predates pregnancy, termed chronic hypertension, is one such clinical factor that is associated with a higher risk of developing preeclampsia. BP fluctuates throughout life. Historically, BP variability (BPV) was viewed as an artifact inhibiting the accurate measurement of mean BP. However, over the past 20+ years studies have identified BPV as an independent risk factor for TOD, cardiovascular disease and, more recently, suggested that it may be a target for pharmacological treatment. BPV is now divided into two types-- random variability and non-random variability which is related to biological or behavioral patterns—and can be assessed over long term (seasonal, visit-to-visit BPV), short term (24-hour, diurnal, nocturnal BPV), and very short-term (beat-to-beat BPV) intervals.²

In this issue of Hypertension, Nuckols et. al.³ present information about beat-to-beat BPV as a potential first trimester predictive tool for preeclampsia. The authors report BPV data from 139 women who were followed from <14 weeks gestation through delivery, of whom 18 (13%) developed preeclampsia. They found that as early as the first trimester, and consistently in the second and third trimesters, BPV was higher among women who developed preeclampsia compared to women who did not. They also found that systolic BP was elevated in all 3 trimesters among those with preeclampsia while diastolic BP and, as a consequence, mean arterial pressure (MAP) were similar to that of women without preeclampsia until the third trimester when preeclampsia became clinically overt. Although systolic BPV was correlated with systolic BP, the correlation was weak (r=0.23; P=0.01), and systolic BPV predicted preeclampsia independent of systolic BP (HR 1.72, 95% CI 1.10–2.70) and other potential confounders such as maternal age and body mass index. Unfortunately, the study was underpowered and multivariable regression models were not able to be executed. Using Receiver Operator Curve analysis, the authors found that the optimal cutoff of systolic BPV for prediction of preeclampsia was 3.9 mm Hg, which had a sensitivity of 86.7% and a specificity of 61.7%. Further, the study examined potential physiologic contributors to the observed alterations in BPV by concurrently measuring baroreflex sensitivity (BRS) and pulse wave velocity (PWV). They found that PWV was weakly correlated with systolic BPV and was elevated throughout pregnancy in women with preeclampsia, while there was no correlation between BRS and systolic BPV and little difference in BRS across pregnancy in women who developed preeclampsia compared to those who did not.

Pregnancy induces unique hemodynamic changes and the role of BPV in hypertensive disorders of pregnancy such as preeclampsia is not well established. While MAP is associated with risk of preeclampsia, MAP alone is not a useful predictor due to the significant overlap with controls and therefore, poor predictive value.⁴ In contrast, BPV is associated with both hypertension and TOD damage⁵ and, therefore, is a potentially meaningful biomarker for predicting preeclampsia. Few prior studies have identified beat-to-beat BPV, heart rate variability, and BRS as potential predictors of preeclampsia. In a study of 102 pregnancies the three aforementioned parameters measured during the second trimester better predicted preeclampsia in combination than pathological uterine perfusion alone.⁶ The largest positive predictive value for preeclampsia occurred when the variability measures were assessed in conjunction with uterine perfusion. In a secondary analysis of data from a prospectively enrolled cohort of 385 military women, Flood et al. demonstrated that low-frequency beat-to-beat BPV was a significant predictor of pregnancy-induced hypertension, but not preeclampsia.⁴ Taken in conjunction with the findings of the current study by Nuckols et al., this study suggests a possible ability to differentiate between hypertensive disorders of pregnancy with different etiologies. This is important as this ability may reduce unnecessary interventions or inappropriate preterm delivery.

Beat-to-beat BPV is thought to primarily reflect cardiovascular regulatory mechanisms and autonomic nervous system dysfunction (Figure).⁷ Many of the humoral and rheological factors that increase BPV are known to be altered in normotensive pregnancy with further derangements seen in the preeclamptic state. In particular, endothelin-1 is increased while nitric oxide levels and bradykinin-mediated vasodilation are reduced. Mechanistically, these factors contribute to the observed BP rise in preeclampsia, and their vasoconstrictive effects may similarly increase beat-to-beat BPV. There is a growing awareness of the role sleep disturbances and altered ventilation play in the pathogenesis of preeclampsia, and they are also potent effectors of beat-to-beat BPV.⁸ With respect to autonomic nervous system dysfunction, sympathetic output is known to be increased in pregnancy, with an exacerbation seen in hypertensive and preeclamptic pregnancies. While the current study found no alteration in BRS, one measure of sympathetic output, it did not examine central neural mechanisms or humoral or paracrine regulation of sympathetic activation, thus we cannot fully exclude altered sympathetic activation as a potential mechanism through which beat-to-beat BPV is increased in preeclampsia.

Figure. Contributors to beat to beat blood pressure variability.

The solid line indicates an association was found between decreased arterial compliance, assessed using pulse wave velocity, and increased blood pressure variability in the current study. The dotted line indicates no association was found between sympathetic output, assessed as baroreflex sensitivity, and blood pressure variability in the current study.

The fact that beat-to-beat BPV can be characterized over a short duration in a single visit without interrupting sleep may confer greater clinical utility of this metric over others in the context of pregnancy. An accurate tool to stratify pregnant women’s risk of developing preeclampsia is desperately needed for many reasons. Although preventive interventions for preeclampsia are somewhat limited, accurate noninvasive, low-cost early predictors may improve maternal and fetal outcomes through better risk prediction and proactive treatment. Currently, aspirin is the only recommended medication proven to reduce the incidence of preterm preeclampsia, though trials of metformin, pravastatin, and other agents are ongoing. Targeting these interventions to women with the greatest potential benefit to avoid exposing the fetus to unnecessary risk is essential. The study by Nuckols et. al. suggests that risk stratification may be improved by identifying women with early alterations in hemodynamic parameters, which is a novel finding. Further studies are needed to investigate whether BPV predicts preeclampsia in non-white women, given the marked racial differences in hypertension etiology, and to examine potential biological mechanisms contributing to increased BPV in preeclampsia.