Soluble fms-like tyrosine kinase-1 and soluble endoglin in HIV-associated preeclampsia

Govender, Nalini; Naicker, Thajasvarie; Rajakumar, Augustine; Moodley, Jagidesa

doi:10.1016/j.ejogrb.2013.05.021

Cited by 22 publications

(16 citation statements)

References 36 publications

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“…(51) However, the sample size in that study was small (27 HIV-negative women and 31 women living with HIV) and the authors did not specify if the subjects were receiving ART. By contrast, Govender et al reported no relationship between HIV infection and angiogenic factors measured in the third trimester of pregnancy, but provided no details concerning ART exposure (25). Even though our study is the first to report data on periconceptionnal and first trimester ART exposure, our results are consistent with those of a recent study in Uganda of 326 pregnant women living with HIV who began receiving ART in the second trimester.…”

supporting

confidence: 85%

“…Increased sFlt-1 and decreased free PlGF levels in maternal blood, or increased sFlt-1/ PlGF ratio are directly implicated in the pathophysiology of preeclampsia, including maternal endothelial dysfunction. (22)(23)(24)(25)(26)(27)(28)(29) A change in these factors is also associated with other complications during pregnancy, such as intrauterine growth restriction, (27,30) preterm delivery,(31) spontaneous abortion and stillbirth, (26,32,33), confirming the association between impaired placental perfusion and systemic changes in angiogenic factors. (34-36) These observations have been noted in cohorts of women living with HIV.…”

Section: Introductionmentioning

confidence: 83%

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No association between early antiretroviral therapy during pregnancy and plasma levels of angiogenic factors: a cohort study

Djeha

Girard

Trottier

et al. 2019

Preprint

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Background: Early antiretroviral therapy (ART) during pregnancy has dramatically reduced the risk of perinatal HIV transmission. However, studies have shown an association between premature delivery and the use of ART during pregnancy (particularly protease inhibitor (PI)-based therapies), which could be explained by placental dysfunction. The objective of this study was to evaluate the association of ART (class, duration of exposure and time of initiation) with placental function by using angiogenic factors placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) as biomarkers. Methods: Clinical and biological data from 159 pregnant women living with HIV were analyzed. Levels of each biomarker were measured in the first and second trimester of pregnancy. After logarithmic transformation, we compared these using generalized estimating equations according to (a) the type of ART; (b) the duration of exposure to ART; and (c) the time of initiation of ART. Results: After adjusting for variables such as ethnicity, maternal age, gestational age, body mass index, parity, smoking status, and sex of the fetus, we found no significant association between the class of ART (PI-based or not) and serum concentrations of PlGF or sFlt-1. Furthermore, no significant association was found between biomarker levels and the duration of ART exposure or the timing of ART initiation (pre- or post-conception). Conclusions: This study suggests that first and second trimester angiogenic factor levels are not significantly associated with ART, regardless of the duration or type (with or without PI). These observations seem reassuring when considering the use of ART during early pregnancy.

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supporting

confidence: 85%

Section: Introductionmentioning

confidence: 83%

No association between early antiretroviral therapy during pregnancy and plasma levels of angiogenic factors: a cohort study

Djeha

Girard

Trottier

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Whether cART use in pregnancy influences angiogenic processes and placenta vascular formation is still an open question. A small number of studies failed to observe an effect of HIV or cART on angiogenic dysregulation in the context of preeclampsia or stillbirth 24 , 25 . However, HIV protease inhibitors, a class of antiretrovirals that are often included in cART regimens used to treat HIV-positive (HIV+) pregnant women, were shown to decrease VEGF production and to inhibit angiogenesis in cancer cell lines and mouse cancer models, in part by impeding PI3K and Akt activation 26 – 31 .…”

Section: Introductionmentioning

confidence: 99%

HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation

Mohammadi

Papp

Cahill

et al. 2018

Sci Rep

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Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women.

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“…Angiogenic processes beginning in the second trimester induce remodeling of the underlying placental architecture to allow for increased blood flow and surface area for nutrient exchange. 14 , 15 Altered expression of angiogenic factors is associated with a number of complications in pregnancy including preeclampsia, 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 systemic lupus erythematosus and/or antiphospholipid antibodies, 28 fetal growth restriction, 22 , 29 , 30 preterm delivery, 31 and spontaneous abortion/stillbirth, 21 , 32 , 33 suggesting placental stress responses triggered by placental malperfusion can lead to systemic changes in angiogenic factors. 34 , 35 , 36 …”

Section: Introductionmentioning

confidence: 99%

Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV

Conroy

McDonald

Gamble

et al. 2017

American Journal of Obstetrics and Gynecology

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BackgroundAngiogenic processes in the placenta are critical regulators of fetal growth and impact birth outcomes, but there are limited data documenting these processes in HIV-infected women or women from low-resource settings.ObjectiveWe sought to determine whether angiogenic factors are associated with adverse birth outcomes in HIV-infected pregnant women started on antiretroviral therapy.Study DesignThis is a secondary analysis of samples collected as part of a clinical trial randomizing pregnant women and adolescents infected with HIV to lopinavir/ritonavir-based (n = 166) or efavirenz-based (n = 160) antiretroviral therapy in Tororo, Uganda. Pregnant women living with HIV were enrolled between 12-28 weeks of gestation. Plasma samples were evaluated for angiogenic biomarkers (angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin) by enzyme-linked immunosorbent assay between: 16-<20, 20-<24, 24-<28, 28-<32, 32-<36, 36-<37 weeks of gestation. The primary outcome was preterm birth.ResultsIn all, 1115 plasma samples from 326 pregnant women and adolescents were evaluated. There were no differences in angiogenic factors according to antiretroviral therapy group (P > .05 for all). The incidence of adverse birth outcomes was 16.9% for spontaneous preterm births, 25.6% for small-for-gestational-age births, and 2.8% for stillbirth. We used linear mixed effect modelling to evaluate longitudinal changes in angiogenic factor concentrations between birth outcome groups adjusting for gestational age at venipuncture, maternal age, body mass index, gravidity, and the interaction between treatment arm and gestational age. Two angiogenic factors–soluble endoglin and placental growth factor–were associated with adverse birth outcomes. Significantly higher concentrations of soluble endoglin throughout gestation were found in study participants destined to deliver preterm [likelihood ratio test, χ2(1) = 12.28, P < .0005] and in those destined to have stillbirths [χ2(1) = 5.67, P < .02]. By contrast, significantly lower concentrations of placental growth factor throughout gestation were found in those destined to have small-for-gestational-age births [χ2(1) = 7.89, P < .005] and in those destined to have stillbirths [χ2(1) = 21.59, P < .0001].ConclusionAn antiangiogenic state in the second or third trimester is associated with adverse birth outcomes, including stillbirth in women and adolescents living with HIV and receiving antiretroviral therapy.

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Soluble fms-like tyrosine kinase-1 and soluble endoglin in HIV-associated preeclampsia

Cited by 22 publications

References 36 publications

No association between early antiretroviral therapy during pregnancy and plasma levels of angiogenic factors: a cohort study

No association between early antiretroviral therapy during pregnancy and plasma levels of angiogenic factors: a cohort study

HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation

Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV

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