Pattern of compounds in blood may indicate severity of gestational hypertension and preeclampsia

Preeclampsia, a complication of pregnancy characterized by high blood pressure and high levels of protein in the urine (proteinuria), indicating damage to the kidneys or other organ damage, is the main cause of maternal-fetal death in Brazil and the runner-up worldwide. In a Brazilian study published in the journal PLOS ONE, the pattern of substances present in patient blood samples varied according to the severity of the preeclampsia concerned.

The findings from the study, which was supported by FAPESP, expand scientific knowledge of preeclampsia and the mechanisms whereby damage to the kidneys, lungs, liver and brain can occur, paving the way for future therapeutic strategies to prevent such damage.

The study sample comprised 173 pregnant women, divided into four categories: healthy; gestational hypertension; preeclampsia; and severe preeclampsia. Blood samples were submitted to metabolomic analysis for detection of metabolites (small molecules made when the body breaks down food, drugs, chemicals or its own tissue).

“In our investigation of what happened to the metabolism in these women, we succeeded in showing not only that it was altered but also that the patterns of alteration correlated with clinical variables. This is important because it opens up possibilities of a better understanding of preeclampsia, especially with regard to organ damage,” Valeria Cristina Sandrim, last author of the article and a professor at São Paulo State University’s Botucatu Institute of Biosciences (IBB-UNESP), told Agência FAPESP.

“The metabolites signal the metabolic pathways that are activated or inactivated, so we plan to conduct a second stage of the study in which we’ll look at why the metabolic alterations occur and how we can intervene pharmacologically.”

The blood samples were collected at the general and teaching hospital (Hospital das Clínicas) run by the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP). Researchers at UNESP São José do Rio Preto and the State University of Campinas (UNICAMP) performed the metabolomics portion of the study.

The study was the first to use hydrogen nuclear magnetic resonance spectroscopy (1H NMR) to identify metabolites in patients with severe preeclampsia and gestational hypertension. The multiuser equipment involved was purchased by FAPESP. The technique, which is non-destructive and does not require chemical manipulation of samples, provides accurate information about the molecular structure and concentration of all compounds present in the subject’s metabolism.

The researchers identified 19 metabolites and noted that 11 were different across the four groups. For example, the group with severe preeclampsia had higher levels of acetate, N,N-dimethylglycine, glutamine, alanine, valine and creatine than the group with gestational hypertension and the control group (healthy women).

A comparison between the groups with preeclampsia and severe preeclampsia showed that higher levels of N,N-dimethylglycine, glutamine, alanine and valine correlated with greater severity and that higher levels of specific metabolites, including N,N-dimethylglycine, alanine and valine were associated with increased blood pressure, worse obstetric outcomes, and poorer end-organ function, particularly renal and hepatic damage.

The metabolomic analysis of the women with preeclampsia also indicated heightened disturbances in nitrogen metabolism, methionine, and urea cycles.

“The exacerbated metabolic disturbances may point to renal impairment and hepatic dysfunction, as evidenced by elevated levels of creatine and alanine. These findings not only contribute novel insights but also provide a more comprehensive understanding of the pathophysiological mechanisms at play in cases of preeclampsia with signs of severity,” Sandrim said.

Translational science

The authors will now pursue two lines of research based on these results. First, they will conduct in vitro experiments involving cultured cells to find out which metabolic pathways are altered in preeclampsia patients and see if any suitable drugs exist for treating these alterations. The second line of research, which will be conducted with support from FAPESP as part of the doctoral candidacy of Julyane Kaihara, will investigate biomarkers for predicting the risk of preeclampsia.

“We will collect blood samples from another group of pregnant women before they’re diagnosed with preeclampsia to try to identify possible prior metabolic alterations. This is important because we know not all cities have maternity hospitals that specialize in control of hypertension, and if we can identify marker metabolites that serve to predict preeclampsia, it will be possible to monitor these at-risk pregnant women more effectively,” Sandrim said.

Reference:

Julyane N. S. Kaihara,Fabio Rogerio de Moraes,Priscila Rezeck Nunes,Marco G. Alves,Ricardo C. Cavalli,Ljubica Tasic,Valeria Cristina Sandrim, Plasma metabolic profile reveals signatures of maternal health during gestational hypertension and preeclampsia without and with severe features, PLOS One, https://doi.org/10.1371/journal.pone.0314053