Early Pregnancy Serum Metabolite Profiles Associated with Hypertensive Disorders of Pregnancy in African American Women: A Pilot Study

Abstract

Hypertensive disorders of pregnancy (HDP) are the most common cardiometabolic complications of pregnancy, affecting nearly 10% of US pregnancies and contributing substantially to maternal and infant morbidity and mortality. In the US, women of African American race are at increased risk for HDP. Early biomarkers that reliably identify women at risk for HDP remain elusive, yet are essential for the early identification and targeting of interventions to improve maternal and infant outcomes. We employed high-resolution metabolomics (HRM) to identify metabolites and metabolic pathways that were altered in early (8-14 weeks) gestation serum samples of pregnant African American women who developed HDP after 20 weeks' gestation (n = 20)-either preeclampsia (PE; n = 11) or gestational hypertension (gHTN; n = 9)-compared to those who delivered full term without complications (n = 80). We found four metabolic pathways that were significantly (p < 0.05) altered in women who developed PE and five pathways that were significantly (p < 0.05) altered in women who developed gHTN compared to women who delivered full term without complications. We also found that four specific metabolites (p < 0.05) were distinctly upregulated (retinoate, kynurenine) or downregulated (SN-glycero-3-phosphocholine, 2'4'-dihydroxyacetophenone) in women who developed PE compared to gHTN. These findings support that there are systemic metabolic disruptions that are detectable in early pregnancy (8-14 weeks of gestation) among pregnant African American women who develop PE and gHTN. Furthermore, the early pregnancy metabolic disruptions associated with PE and gHTN are distinct, implying they are unique entities rather than conditions along a spectrum of the same disease process despite the common clinical feature of high blood pressure.

Conflict of interest statement

There are no conflicts of interest to declare by any author.

Copyright © 2020 Erin P. Ferranti et al.

Figures

Figure 1

Metabolic profiles of women with PE versus healthy controls. (a) Type 1 Manhattan plot, -log10p vs. mass-to-charge ratio. 470 m/z features were found significant at p value 0.05. No metabolites were significant by false discovery rate (FDR) q value 0.20. Red dots represent those features upregulated in preeclampsia (PE), and the blue dots represent features that were downregulated in PE; the dashed line represents significance cut-off of p value < 0.05. (b) Type 2 Manhattan plot, -log10p vs. retention time, the majority of features had retention time below 2 minutes; the dashed line represents significance cut-off of p value < 0.05. (c) 2-way hierarchical cluster analysis, PE is represented in green and healthy full term in red across the x-axis; significant features are clustered on the y-axis. (d) Principal component analysis. (e) Mummichog-enriched pathways at p value < 0.05 represented by the green dotted line.

Figure 2

Metabolic profiles of women with gestational hypertension versus healthy controls. (a) Type 1 Manhattan plot, -log10p vs. mass-to-charge ratio. 388 m/z features were found significant at p value 0.05. No metabolites were significant by false discovery rate (FDR) q value 0.20. Red dots represent those features downregulated in gestational hypertension (gHTN), and the blue dots represent features that were downregulated in healthy full-term women; the dashed line represents significance cut-off of p value < 0.05. (b) Type 2 Manhattan plot, -log10p vs. retention time. Majority of features had retention time below 2 minutes; the dashed line represents significance cut-off of p value < 0.05. (c) 2-way hierarchical cluster analysis. gHTN is represented in red and healthy full term in green across the x-axis; significant features are clustered on the y-axis; there is a clean separation seen between biological samples. (d) Principal component analysis. (e) Mummichog-enriched pathways at p value < 0.05 represented by the green dotted line.

Figure 3

Preeclampsia vs. gestational hypertension. (a) Type 1 Manhattan plot, -log10p vs. mass-to-charge ratio. 486 m/z features were found significant at p value 0.05. No metabolites were significant by false discovery rate (FDR) q value 0.20. Red dots represent those features downregulated in gestational hypertension (gHTN), and the blue dots represent features that were downregulated in PE. (b) Type 2 Manhattan plot, -log10p vs. retention time. (c) 2-way hierarchical cluster analysis. gHTN is represented in red and preeclampsia in green across the x-axis; significant features are clustered on the y-axis; there is clear separation between the two groups of women. (d) Principal component analysis.

Figure 4

Gestational hypertension vs. preeclampsia. (a) Partial least squares-discriminant analysis (PLS-DA). This supervised discriminatory analysis shows preeclampsia (PE) in orange triangles and gestational hypertension (gHTN) in blue circles. (b) Venn diagram showing 169 overlapping significant features between linear regression (p value < 0.05) and PLS-DA (VIP > 2). (c) Box and whisker plots for 4 significant verified features (from left to right) SN-glycero-3-phosphocholine (m/z 258.1094; RT 76 s), retinoate (m/z 301.2174; RT 28 s), L-kynurenine (m/z 209.0922; RT 40 s), and 2′4′-dihydroxyacetophenone (m/z 153.0577; RT 42 s).