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.

Association of mid-trimester maternal angiogenic biomarkers with small-for-gestational-age infants in an urban Zambian cohort: a nested case-control study.

OBJECTIVE: To investigate whether angiogenic biomarker concentrations differ between women who deliver small-for-gestational-age (SGA) infants (<10th centile birth weight for gestational age) compared with controls, because identifying SGA risk early could improve outcomes. METHODS: This case-control study compared serum concentrations of angiogenic biomarkers before 24 weeks of pregnancy from 62 women who delivered SGA infants (cases) and 62 control women from an urban Zambian cohort. Odds of delivering an SGA infant were calculated using conditional logistic regression. RESULTS: Placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sEng) in controls were 37.74 pg/mL (interquartile range [IQR] 23.12-63.15), 2525.18 pg/mL (IQR 1502.21-4265.54) and 2408.18 pg/mL (IQR 1854.87-3017.94), respectively. SGA cases had higher PlGF (40.50 pg/mL, IQR 22.81-67.94) and sFLT-1 (2613.06 pg/mL, IQR 1720.58-3722.50), and lower sEng (2038.06 pg/mL, IQR 1445.25-3372.26). Participants with sEng concentration below and concomitant sFLT-1 concentration above their respective thresholds (n = 40) had five-fold higher odds of SGA (adjusted odds ratio 4.77, 95% confidence interval 1.61-14.1; P = 0.005). CONCLUSION: Biomarker concentrations were similar between cases and controls. Participants with concomitant low sEng and high sFLT-1 had the highest odds of SGA, suggesting that a combination of biomarkers may better for predicting SGA than single biomarkers.

Maternal HIV, antiretroviral timing, and spontaneous preterm birth in an urban Zambian cohort: the role of local and systemic inflammation.

OBJECTIVE: To assess plasma and vaginal inflammation in three antenatal groups (HIV-uninfected women, HIV-infected women entering care on preconceptional ART, and HIV-infected women not on preconceptional ART) and whether these measures are associated with spontaneous preterm birth (sPTB). DESIGN: Case--control study nested within a pregnancy cohort in Lusaka, Zambia. METHODS: We analyzed 11 pro-inflammatory and two anti-inflammatory markers in 207 women with paired plasma and vaginal specimens collected between 16 and 20 gestational weeks. Among 51 HIV-infected women, we repeated the assays in 24-34-week samples. We used confirmatory factor analysis to create inflammation scores and compared them among the three groups. RESULTS: At baseline, HIV-infected women not on ART had higher vaginal pro-inflammatory scores than HIV-uninfected women [mean 0.37 (95% CI -0.06 to 0.80) vs. -0.02 (-0.32 to 0.27), P = 0.02]. In repeat testing, women not on preconceptional ART had an increase in vaginal inflammation between the baseline and 24-34-week visits compared with those continuing preconceptional ART [mean 0.62 (95% CI -0.80 to 4.20) vs. -0.07 (-2.78 to 2.11), P = 0.04]. In multivariate analyses, baseline vaginal inflammation predicted sPTB (aOR 1.5; 95% CI 1.0-2.3; P = 0.02). Plasma inflammation did not differ by HIV or ART exposure and was not associated with sPTB. CONCLUSION: Women not receiving ART at entry into pregnancy care had more vaginal inflammation than women entering on treatment. They also experienced an increase in vaginal inflammation between the two sampling timepoints, possibly as a consequence of ART initiation. Vaginal (but not systemic) inflammation was associated with sPTB and offers a potential mechanistic insight into this important adverse birth outcome.