Predelivery maternal circulating neutrophil extracellular traps and deoxyribonuclease in placental dysfunction and...

Neutrophil extracellular traps consist of DNA and protein and are secreted by neutrophils upon activation. They are stable structures but may be degraded by deoxyribonucleases. Neutrophil extracellular traps can induce endothelial dysfunction, an important feature of the preeclampsia pathophysiology. However, the levels of neutrophil extracellular traps biomarkers and deoxyribonuclease in the maternal circulation during preeclampsia, gestational hypertension, and fetal growth restriction, as well as potential associations to placental dysfunction, remain to be elucidated.

We aimed to investigate levels of circulating neutrophil extracellular traps biomarkers and deoxyribonuclease in women with early-onset and late-onset preeclampsia, gestational hypertension, and isolated fetal growth restriction compared to clinically healthy pregnancies. Additionally, we aimed to compare these biomarkers with circulating placental dysfunction biomarkers and maternal as well as fetal clinical proxies of placental dysfunction in women with preeclampsia.

Plasma and serum samples from women categorized as having early-onset preeclampsia (n=49), late-onset preeclampsia (n=202), gestational hypertension (n=105), isolated fetal growth restriction (n=50), and normotensive, euglycemic controls (n=1126) were analyzed by immunoassays for the circulating neutrophil extracellular traps biomarkers citrullinated histone H3 and myeloperoxidase-DNA and deoxyribonuclease and for the placental dysfunction biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor. The Kruskal-Wallis H test was used to compare biomarker levels across groups. Post hoc pairwise comparisons were conducted using Dunn's test, with Bonferroni correction applied to adjust for multiple comparisons. In women with early-onset and late-onset preeclampsia, the residuals were not normally distributed. Therefore, univariable and multivariable quantile (median) regression for estimating models for the conditional median function were used to study associations between our biomarkers of interest and proxies for placental dysfunction. A 2-sided P value of <.05 was considered statistically significant.

Women with early-onset and late-onset preeclampsia, but not gestational hypertension or isolated fetal growth restriction, had lower median levels of circulating citrullinated histone H3 (both adjusted P<.001) and deoxyribonuclease (both adjusted P<.001) compared to controls. Women with late-onset preeclampsia had lower myeloperoxidase-DNA (adjusted P<.001) compared to controls. Univariable regression analyses within the preeclampsia group revealed positive associations between citrullinated histone H3 and placental growth factor (P=.004) and negative associations between citrullinated histone H3 and soluble fms-like tyrosine kinase-1 (P=.034) and between deoxyribonuclease and soluble fms-like tyrosine kinase-1 (P=.038). In multivariable regression analyses, citrullinated histone H3 and placental growth factor (P=.009) and deoxyribonuclease and gestational age at blood sampling (P=.001) were positively associated, whereas citrullinated histone H3 (P=.027) and deoxyribonuclease (P=.034) were negatively associated with systolic blood pressure. Finally, citrullinated histone H3 was associated with newborn weight ≤10th percentile, representing a fetal proxy for placental dysfunction (P=.036).

The lower levels of circulating neutrophil extracellular traps and deoxyribonuclease in women with preeclampsia, but not in gestational hypertension or isolated fetal growth restriction, as well as associations between citrullinated histone H3 and biomarkers of placental dysfunction may indicate that neutrophil extracellular traps play a role in the placental dysfunction that exclusively characterizes preeclampsia. Additionally, the association between low citrullinated histone H3, low deoxyribonuclease, and high maternal blood pressure may suggest that insufficient presence of circulating deoxyribonucleases contributes to the excessive vascular inflammation in women with preeclampsia.