Association between micronutrients, oxidative stress biomarkers and angiogenic growth mediators in early and late-onset preeclamptic Ghanaian women.

Objectives: Micronutrients, especially calcium (Ca) and magnesium (Mg) are reported to reduce preeclampsia events via several factors such as endothelial cell control, optimal oxidative stress and a balanced angiogenic growth mediator. We evaluated the association of micronutrients with oxidative stress biomarkers, and angiogenic growth mediators in early-onset preeclampsia and late-onset preeclampsia. Methods: This case-control study recruited 197 preeclampsia (early-onset preeclampsia = 70 and late-onset preeclampsia = 127) as cases and 301 normotensive pregnant women as controls from the Komfo Anokye Teaching Hospital, Ghana. Samples were collected after 20 weeks of gestation for both cases and controls and estimated for Ca, Mg, soluble fms-like tyrosine kinase-1, placental growth factor, vascular endothelial growth factor-A, soluble endoglin, 8-hydroxydeoxyguanosine, 8-epiprostaglandinF2-alpha and total antioxidant capacity. Results: Early-onset preeclampsia women had significantly lower levels of Ca, Mg, placental growth factor, vascular endothelial growth factor-A and total antioxidant capacity but higher levels of soluble fms-like tyrosine kinase-1, soluble endoglin, 8-epiprostaglandinF2-alpha, 8-hydroxydeoxyguanosine, soluble fms-like tyrosine kinase-1/placental growth factor ratio, 8-epiprostaglandinF2-alpha /placental growth factor ratio, 8-hydroxydeoxyguanosine/placental growth factor ratio and soluble endoglin/placental growth factor ratio than late-onset preeclampsia and normotensive pregnant women (p < 0.0001). Among the early-onset preeclampsia women, the first and second quartile for serum placental growth factor, first quartile for vascular endothelial growth factor-A and total antioxidant capacity and the fourth quartiles for serum sEng, serum sFlt-1, 8-epiPGF2α and 8-OHdG were independently associated with low Ca and Mg (p < 0.05). Among late-onset preeclampsia women, the fourth quartile for soluble fms-like tyrosine kinase-1 was independently associated with low Ca and Mg (p < 0.05). Conclusion: Magnesium and calcium are associated with an imbalance in angiogenic growth mediators and oxidative stress biomarkers among preeclampsia women, particularly early-onset preeclampsia. Serial and routine measurement of these micronutrients would allow the monitoring of poor placental angiogenesis while enabling an understanding of the triggers of increased oxidative stress and reduced antioxidant in preeclampsia.

Placental lesions and differential expression of pro-and anti-angiogenic growth mediators and oxidative DNA damage marker in placentae of Ghanaian suboptimal and optimal health status pregnant women who later developed preeclampsia.

BACKGROUND: Angiogenic growth mediators (AGMs) and oxidative stress (OS) both play essential roles in normal placental vascular development and as such, placental alterations in these factors contribute to pre-eclampsia (PE). Suboptimal health status (SHS), an intermediate between health and disease, has been associated with imbalanced AGMs and OS biomarkers. Thus, SHS pregnant women may be at increased risk of developing PE and may present abnormal placental alteration and expression of AGMs and OS compared to optimal health status (OHS) pregnant women. We examined the histopathological morphology, immunohistochemical expression of AGMs antibodies and oxidative DNA damage marker in the placentae of SHS and OHS pregnant women who developed early-onset PE (EO-PE) and late-onset (LO-PE) compared to normotensive pregnancy (NTN-P). METHODS: This nested case-control study recruited 593 singleton normotensive pregnant women at baseline (10-20 weeks gestation) from the Ghanaian Suboptimal Health Status Cohort Study (GHOACS) undertaken at the Komfo Anokye Teaching Hospital, Ghana. Socio-demographic, clinical and obstetrics data were collected, and a validated SHS questionnaire-25 (SHSQ-25) was used in classifying participants into SHS (n = 297) and OHS (n = 296). Participants were followed until the time of PE diagnosis and delivery (32-42 weeks gestation). Blood samples were collected at the two-time points and were assayed for AGMs; soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PIGF), vascular endothelial growth factor-A (VEGF-A), and soluble endoglin (sEng), and OS biomarkers; 8-hydroxydeoxyguanosine (8-OHdG), 8-epiprostaglandinF2-alpha (8- epi-PGF2α) and total antioxidant capacity (TAC) using ELISA. Placental samples were collected for histopathological and immunohistochemical analysis. RESULTS: Of the 593 pregnant women, 498 comprising 248 SHS and 250 OHS women returned for delivery and were included in the final analysis. Of the 248 SHS women, 56, 97 and 95 developed EO-PE, LO-PE and NTN-P, respectively, whereas 14, 30 and 206 of the 250 OHS mothers developed EO-PE, LO-PE and NTN-P, respectively. At baseline, SHS_NTN pregnant women had a significant imbalance in AGMs and OS biomarkers compared to OHS_NTN pregnant women (p<0.0001). At the time of PE diagnosis, SHS_NTN-P women who developed EO-PE, LO-PE, and NTN-P had lower serum levels of P1GF, VEGF-A and TAC and correspondingly higher levels of sEng, sFlt-1, 8-epiPGF2α, and 8-OHdG than OHS-NTN-P women who developed EO-PE and LO-PE, NTN-P (p<0.0001). A reduced placental size, increased foetal/placental weight ratio, and a significantly higher proportion of fibrinoid necrosis, infarction, villous fibrin, syncytial knots, calcification, chorangiosis, tunica media/vascular wall hypertrophy and chorioamnionitis was associated with the SHS group who developed PE (EO-PE>LO-PE) more than OHS groups who developed PE (EO-PE>LO-PE) when all were compared to NTN-P (p<0.0001). The intensity of antibody expression of PIGF and VEGF-A were significantly reduced, whereas Flt-1, Eng and 8-OHdG were significantly increased in placentae from SHS-pregnant women who developed EO-PE>LO-PE more than OHS- pregnant women who developed EO-PE>LO-PE when all were compared to NTN-P (p<0.0001). CONCLUSION: Increased lesions, oxidative DNA damage, and imbalanced expression between pro-and anti-AGMs are associated more with SHS-embodied PE placentae rather than OHS-embodied PE subtypes, thus potentially allowing differential evaluation of PE.

Early gestational profiling of oxidative stress and angiogenic growth mediators as predictive, preventive and personalised (3P) medical approach to identify suboptimal health pregnant mothers likely to develop preeclampsia.

BACKGROUND: Pregnant women, particularly in developing countries are facing a huge burden of preeclampsia (PE) leading to high morbidity and mortality rates. This is due to delayed diagnosis and unrecognised early targeted preventive measures. Adapting innovative solutions via shifting from delayed to early diagnosis of PE in the context of predictive diagnosis, targeted prevention and personalisation of medical care (PPPM/3 PM) is essential. The subjective assessment of suboptimal health status (SHS) and objective biomarkers of oxidative stress (OS) and angiogenic growth mediators (AGMs) could be used as new PPPM approach for PE; however, these factors have only been studied in isolation with no data on their combine assessment. This study profiled early gestational biomarkers of OS and AGMs as 3 PM approach to identify SHS pregnant mothers likely to develop PE specifically, early-onset PE (EO-PE) and late-onset PE (LO-PE). METHODS: A prospective cohort of 593 singleton normotensive pregnant (NTN-P) women were recruited at 10-20th (visit 1) and followed from 21 weeks gestation until the time of PE diagnosis and delivery. At visit 1, SHS was assessed using SHS questionnaire-25 (SHSQ-25) and women were classified as SHS and optimal health status (OHS). Biomarkers of OS (8-hydroxy-2-deoxyguanosine [8-OHdG], 8-epi-prostaglansinF2alpha [8-epi-PGF2α] and total antioxidant capacity [TAC]) and AGMs (vascular endothelial growth factor [VEGF-A], soluble Fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF] and soluble endoglin [sEng]) were measured at visit 1 and time of PE diagnosis. RESULTS: Of the 593 mothers, 498 (248 SHS and 250 OHS) returned for delivery and were included in the final analysis. Fifty-six, 97 and 95 of the 248 SHS mothers developed EO-PE, LO-PE and NTN-P respectively, versus 14 EO-PE, 30 LO-PE and 206 NTN-P among the 250 OHS mothers. At the 10-20th week gestation, unbalanced levels of OS and AGMs were observed among SHS women who developed EO-PE than LO-PE compared to NTN-P women (p < 0.0001). The combined ratios of OS and AGMs, mainly the levels of 8-OHdG/PIGF ratio at 10-20th week gestation yielded the best area under the curve (AUC) and highest relative risk (RR) for predicting SHS-pregnant women who developed EO-PE (AUC = 0.93; RR = 6.5; p < 0.0001) and LO-PE (AUC = 0.88, RR = 4.4; p < 0.0001), as well as for OHS-pregnant women who developed EO-PE (AUC = 0.89, RR = 5.6; p < 0.0001) and LO-PE (AUC = 0.85; RR = 5.1; p < 0.0001). CONCLUSION: Unlike OHS pregnant women, SHS pregnant women have high incidence of PE coupled with unbalanced levels of OS and AGMs at 10-20 weeks gestation. Combining early gestational profiling of OS and AGMs created an avenue for early differentiation of PE subtypes in the context of 3 PM care for mothers at high risk of PE.

Suboptimal health pregnant women are associated with increased oxidative stress and unbalanced pro- and antiangiogenic growth mediators: a cross-sectional study in a Ghanaian population.

Optimal oxidative stress (OS) is important throughout pregnancy; however, an increased OS may alter placental angiogenesis culminating in an imbalanced of angiogenic growth mediators (AGMs). Suboptimal Health Status (SHS), a physical state between health and disease, may be associated with increased OS and unbalanced AGMs. In this study, we explored the association between SHS, biomarkers of OS (BOS) and AGMs among normotensive pregnant women (NTN-PW) in a Ghanaian Suboptimal Health Cohort Study (GHOACS). This comparative GHOACS recruited 593 NTN-PW from the Komfo Anokye Teaching Hospital, Ghana. SHS was measured using a Suboptimal Health Status Questionnaire-25 (SHSQ-25). Along with the subjective SHS measure, objective BOS: 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-epiprostaglandinF2 alpha (8-epi-PGF2α), total antioxidant capacity (TAC), and AGMs: vascular endothelial growth factor-A (VEGF-A), soluble fms-like tyrosine kinase receptor 1 (sFlt-1), placental growth factor (PIGF) and soluble endoglin (sEng) were evaluated. Compared to optimal health NTN-PW, levels of PlGF, VEGF-A and TAC were significantly (p < 0.05) reduced and negatively associated with SHS whilst sEng, sFlt-1, 8-epiPGF2α, 8-OHdG, and combined ratios of sFlt-1/PlGF, 8-epiPGF2α/PlGF, 8-OHdG/PlGF, and sEng/PlGF were significantly increased and positively associated with SHS. The first quartile for PIGF (2.79-fold) and VEGF-A (5.35-fold), and the fourth quartile for sEng (4.31-fold), sFlt-1 (1.84-fold), 8-epiPGF2α (2.23-fold), 8-OHdG (1.90-fold) and urinary 8-OHdG (1.95-fold) were independently associated with SHS (p < 0.05). SHS is associated with increased OS and unbalanced AGMs. Early identification of SHS-related OS and unbalanced AGMs may inform clinicians of the need for therapeutic options.