Association of third-trimester N-terminal pro-brain natriuretic peptide levels and pre-eclampsia development

Abstract Background Pre-eclampsia shares numerous risk factors with cardiovascular diseases and is associated with postpartum cardiovascular complications. Natriuretic peptides, outside pregnancy valid biomarkers for detecting subclinical cardiac dysfunction, are typically elevated at the time of pre-eclampsia diagnosis. However, their role before disease manifestation is still puzzling. Aims To assess whether third-trimester natriuretic peptide levels are associated with a diagnosis of pre-eclampsia in pregnant individuals. Methods This study measured NT-proBNP levels in third-trimester samples of 1454 pregnant individuals prior to disease manifestation. Pre-eclampsia was diagnosed using the American College of Obstetrics and Gynecology (ACOG) criteria. Linear regression analyses were performed, and multivariable adjustments were done for age, body mass index (BMI), preexisting hypertension, diabetes, and chronic kidney disease. Odds ratios were calculated per doubling of NT-proBNP levels. Results Of the 1454 individuals, 118 (7.6 %) developed pre-eclampsia. The median week of gestation for blood sampling was 29.0 (IQR 28.4 – 29.4) in both groups (p = 0.68). Individuals with pre-eclampsia manifestation had higher BMI, were more often nulliparous, and had lower placental growth factor levels (all p < 0.01). Higher NT-proBNP levels were associated with a lower risk of pre-eclampsia, which persisted after controlling for confounders (adjusted odds ratio (OR), 0.84; 95 % CI, 0.70 - 1.00). This inverse relationship was particularly pronounced in cases of late-onset pre-eclampsia, defined as onset after 34 + 0 weeks of gestation. Specifically, for preterm pre-eclampsia between weeks 34 + 0 and 36 + 9, the adjusted OR was 0.78 (95 % CI, 0.56-1.09), and for term pre-eclampsia at or after week 37 + 0, the adjusted OR was 0.77 (95 % CI, 0.61 - 0.95). Conversely, a positive association was observed between NT-proBNP levels and the occurrence of early-onset pre-eclampsia < 34 + 0 weeks, with an adjusted OR of 1.69 (95 % CI, 1.00 - 2.91). Causal mediation analyses indicated that the association between higher BMI and pre-eclampsia mediated only a minor fraction (11.5 % [95 % CI, 4.3 % - 36.0 %, p < 0.01]) of the observed association. Conclusion These findings reveal the complex interplay between third-trimester NT-proBNP levels and the risk of pre-eclampsia. They unravel an inverse association for late-onset disease but a contrasting positive correlation for early-onset cases in temporal proximity to NT-proBNP assessment. The latter may reflect acute physiological responses to pre-eclampsia nearing diagnosis. However, the inverse relationship observed for later manifestations underscores the importance of further research to dissect the underlying pathophysiological mechanisms, which suggest cardiovascular maladaption to pregnancy prior to pre-eclampsia manifestation.