Circulating angiogenic factors and HIV among pregnant women in Zambia: a nested case–control study

Background Maternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway. Methods In a case-control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth). Results Compared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens. Conclusions We present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes. Keywords: HIV, Placental growth factor, Soluble fms-like tyrosine kinase-1, Preterm birth, Stillbirth