Angiogenic factors and oxidative stress biomarkers in gestational hypertension and preeclampsia

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Hypertensive disorders of pregnancy are multisystemic disorders whose etiology is still unknown. An Imbalance in angiogenic factors and oxidative stress (OS) biomarkers levels has been implicated. It is against this background that this study prospectively evaluated angiogenic factors and oxidative biomarkers and the role they play in the pathogenesis of gestational hypertension (GH) and preeclampsia (PE). This prospective study recruited 235 pregnant women at 20-40 week gestation from the Obstetrics and Gynaecology (O&G) department of the Komfo Anokye Teaching Hospital (KATH). Finally 150 (50 GH, 50 PE and 50 normal pregnant) gave informed consent and their course of pregnancy were followed until delivery. Serum levels of placental growth factor (PLGF), soluble fms-like tyrosine kinase 1 (sFlt-1) and 8-epi-prostaglandin F2alpha (8-epi-PGF2α) levels were estimated by ELISA and total antioxidant capacity (T-AOC) was measured spectrophotometrically. Median levels of sFlt-1, 8-epi-PGF2α and sFlt-1/PLGF ratio were significantly elevated while PLGF, T-AOC and PLGF/sFlt-1 ratio were significantly reduced in GH and PE compared to normal pregnant (NP) controls (p<0.05) at baseline. Conversely, levels of sFlt-1, 8-epi-PGF2α and sFlt-1/PLGF significantly decreased while PLGF and T-AOC were significantly increased after 48 hours delivery in all studied participant (p<0.05). Levels of sFlt-1, 8-epi-PGF2α and sFlt-1/PLGF tend to peak in the third trimester of pregnancy specifically at 32-36week gestation. Advanced maternal age (35-40 year) pregnant women were significantly associated with angiogenic and oxidative stress imbalance compared to age group 18-24 year (p<0.05). Increased proportion of adverse maternal and fetal outcomes such as preterm delivery, emergency caesarean section, placental previa, placental abruption, stillbirth, intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD), and postpartum hemorrhage (PPH), low birth weight (LBW), fetal distress, birth asphyxia and Apgar score below 7 after 5 minutes were significantly associated with preeclamptic pregnancies compared to normal control groups (p<0.05). A significant positive correlation (PIGF vs T-AOC; and sFlt-1 vs 8-epi-PGF2α) and a negative correlation (PLGF vs sFlt-1, sFlt-1 vs T-AOC, PLGF vs 8-epi-PGF2α, and T-AOC vs 8-epi-PGF2α) was observed among studied groups after adjusting for maternal age, BMI, gestational age and parity (p<0.05). Angiogenic profile and oxidative stress biomarkers were significantly associated with systolic and diastolic blood pressure, gestational BMI and adverse pregnancy outcomes such as IUGR, placental abruption, stillbirth, IUFD, and PPH after adjusting for maternal age and pregestational BMI (p<0.05). The best area under the curve obtained on analysis using ROC curve indicated that ratio of PLGF/sFlt-1 followed by sFlt-1/PLGF ratio and PLGF could be used as predictive markers for early onset third trimester pregnancy in PE. GH and thus PE create an imbalance in the levels of angiogenic factors and oxidative biomarkers as depicted by elevated levels anti-angiogenic factors and pro-oxidants and a reduced concentration of pro-angiogenic factors and antioxidants. Pharmacologic remedies of exogenous pro-angiogenic molecules, antioxidant supplements and inhibiting the action of anti-angiogenic molecules could provide inventive approaches to the management of GH and PE and potentially alleviate the adverse complications suffered by these patients
A thesis submitted in fulfillment of the requirements for the degree of Master of Philosophy in the Department of Molecular Medicine, School of Medical Sciences