Our study showed that high-risk pregnant women with SUA > 4 mg/dL had higher daytime and nocturnal ABPM values. Furthermore, high SUA levels had a synergic effect with nocturnal hypertension on the risk for PE; ~50% of pregnant women with both, high SUA and nocturnal hypertension, developed PE. We have previously communicated that nocturnal hypertension increases ~ 5 times the relative risks for PE. These results expand our previous findings showing that the combination of high SUA with nocturnal hypertension duplicates the risk compared with those women with nocturnal hypertension alone.
Studies designed to determine “normal” values of SUA in high-risk pregnant women are scanty. Consequently, we decided to divide the cohort according to SUA quartiles and define the top quartile as high SUA. Using this approach, a low cut-point value was identified (4.04 mg/dL). Remarkably, in the general population, data from the Pamela's study shows that SUA levels were associated with new onset left ventricular hypertrophy from values as low as 4.1 mg/dL [20]. In our cohort, lineal correlations between SUA and ABPM were significant but weak, higher for nighttime than daytime ABPM. These low linear correlations could be partially due o the finding that BP values remain stable trough quartiles 1 to 3 and increase abruptly in quartile 4.
In the whole cohort, women with SUA in the upper quartile had > 2 times more risk to develop PE (OR 2.66 95%CI 1.70–4.20). However, when only women without nocturnal hypertension were considered (group 2), the increased risk associated with high SUA was lower and did not reach statistical significance (p = 0.108). Conversely, in women with nocturnal hypertension, high SUA increases the risk remarkably. Indeed, the highest risk was observed with the combination of both, high SUA and nocturnal hypertension.
The pathophysiological mechanisms involved in the relationships between uric acid, nocturnal hypertension, and PE are not yet completely known. Because of placental hypoxia, trophoblasts produce massive amounts of soluble fms-like tyrosine kinase-1 (sFlt-1) that circulate systemically in the mother, leading to endothelial dysfunction, and finally overt clinical disease with hypertension, proteinuria, liver damage, hemolysis, and low platelet count [21]. Moreover, deleterious cardiovascular and renal effects of the imbalance between antiangiogenic and angiogenic placental factors have been described in the general population [22]. Thus, we can hypothesize that both the increase in SUA and nighttime BP could be early manifestations of systemic endothelial dysfunction. A recently published study conducted in high-risk pregnancies showed that sFlt-1 was positively correlated with systolic and diastolic daytime and nighttime BP while PlGF was negatively associated with nighttime BP [23].
Beyond these pathophysiological considerations, our study supports the utility of SUA (a cheap and widely available blood test) as predictor of PE, specifically in high-risk pregnant women with nocturnal hypertension. While the incidence of PE was 6.5% pregnancies in women with uric acid < 4 mg/dL and nighttime BP < 120/70 mmHg, it increased to nearly 50% pregnancies with the combination of both, SUA > 4mg/dL and nocturnal hypertension. It must be highlighted that SUA elevations and nocturnal hypertension seems to precede for several weeks the development of overt clinical disease. Other biochemical marker, the sFlt-1/PlGF ratio, has been also proposed to identify early women who subsequently developed PE [24]; it has been used to exclude PE in the next 7 days because of their good negative predictive value. However, the positive predictive value is low. Furthermore, the measurements are expensive and not available in low resource settings. Based in the data of the present study, the combination of nocturnal hypertension and SUA > 4 mg/dl could be an alternative approach to identify women who at risk for PE.
Although the results of our study are straightforward, certain limitations must be highlighted. First, this study was performed on a cohort of high-risk pregnant women; therefore, our findings are not necessarily applicable to pregnancies without this condition. Indeed, the high prevalence of PE observed may be explained by selection bias. Second, the diagnosis of hypertension by ABPM was achieved using the same threshold as for the general population. However, a published study of pregnant women in a southern Chinese population defined similar ABPM thresholds using a maternal and fetal outcome-based approach [25]. Third, although women with history of renal disease were excluded, more subtle renal damage might be present influencing SUA levels. Fourth, our SUA threshold was defined specifically for our cohort and could be not appropriate for women of other ethnicities or with lesser risk. However, in previously studies, similar values were related with left ventricular hypertrophy [20] general population and with markers of insulin resistance in non-pregnant healthy women [26]. Finally, this is an observational, real word study, and some bias could be not discharged. Thus, the use of low doses of ASA, calcium supplements, or antihypertensive drugs may influence the results. However, the OR values were not altered by adjustment for covariates.
In conclusion, despite these limitations, our study conducted in high-risk pregnancies shows a relationship between SUA and nighttime BP, and that those women who have both, high SUA and nocturnal hypertension, are at very high risk to develop PE in the next few weeks. Thus, the results suggest that the measurement of SUA in conjunction with ABPM performed at ~ 30 weeks of gestation is a simple and suitable approach in order to identify women at high risk for PE.