Sequential disruptions to inflammatory and angiogenic pathways and risk of spontaneous preterm birth in Malawian women

Abstract

Preterm birth is a leading cause of death in children under five years of age. We hypothesized that sequential disruptions to inflammatory and angiogenic pathways during pregnancy increase the risk of placental insufficiency and spontaneous preterm labor and delivery. We conducted a secondary analysis of inflammatory and angiogenic analytes measured in plasma samples collected across pregnancy from 1462 Malawian women. Women with concentrations of the inflammatory markers sTNFR2, CHI3L1, and IL18BP in the highest quartile before 24 weeks gestation and women with anti-angiogenic factors sEndoglin and sFlt-1/PlGF ratio in the highest quartile at 28-33 weeks gestation had an increased relative risk of preterm birth. Mediation analysis further supported a potential causal link between early inflammation, subsequent angiogenic dysregulation detrimental to placental vascular development, and earlier gestational age at delivery. Interventions designed to reduce the burden of preterm birth may need to be implemented before 24 weeks of gestation.

Keywords: Clinical finding; Health sciences; Pregnancy.

Graphical abstract

Figure 1

Flow chart of the patient population Breakdown of patients and samples included in the current study. ^a Madanitsa and colleagues [20]. ^b Elphinstone and colleagues [7].

Figure 2

Forest plot of adjusted relative risk (and 95% confidence interval) for preterm birth at each visit, according to inflammatory and angiogenic mediator concentration The adjusted relative risk (95% CI) for preterm birth for women in the highest quartile of each marker, relative to women in the lowest quartile, at each visit: (A) enrollment (13–23 weeks gestation) or (B) visit 2 (28–33 weeks gestation). Models were adjusted for blood pressure (systolic) at enrollment, gestational age at plasma collection for each respective visit, treatment group, maternal gravidity (primigravid: yes/no), socioeconomic status, and malaria during pregnancy (yes/no by PCR). Abbreviations: Adjusted relative risk (aRR), Angiopoietin-1 (Angpt-1), Angiopoietin-2 (Angpt-2), Angiopoietin-Like 3 (Angptl3), Chitinase-3-Like Protein-1 (CHI3L1), C-reactive protein (CRP), Interleukin-18 Binding Protein (IL18BP), Placental Growth Factor (PlGF), soluble Endoglin (sEng), soluble Fms-like tyrosine kinase 1 (sFlt-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR2).

Figure 3

Path diagrams for multiple mediator analysis of inflammatory analytes through angiogenic mediators Regression coefficients with 95% bootstrapped confidence intervals for each path in the multiple mediator models. Indirect (mediation) effects were calculated using the product of coefficients method (a₁b₁ or a₂b₂). c’ represents the direct effect of the inflammatory analytes (A) sTNFR2, (B) CHI3L1, or (C) IL18BP on gestational age at delivery, after controlling for mediators. Gestational age and blood pressure (systolic) at enrollment, as well as malaria during pregnancy (by PCR), were included as covariates. Positive estimates indicate the increase in outcome with a one unit increase in predictor. Negative estimates indicate the decrease in outcome with a one unit increase in predictor. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. Abbreviations: Chitinase-3-Like Protein-1 (CHI3L1), Interleukin-18 Binding Protein (IL18BP), Placental Growth Factor (PlGF), soluble Endoglin (sEng), soluble Fms-like tyrosine kinase 1 (sFlt-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR2).