Abstract

Objective

The study used both subjective, Suboptimal Health Status (SHS) concept along with objective, biomarkers of oxidative stress (OS): 8-OHdG, 8-epi-PGF2α and total antioxidant capacity (TAC); and angiogenic growth mediators (AGMs): VEGF-A, sFlt-1, PlGF and soluble endoglin (sEng) for predicting early-onset (EO) and late-onset (LO) preeclampsia (PE)

Design

A Hospital-based longitudinal nested case-control study

Setting

Obstetrics and Gynaecology Department at Komfo Anokye Teaching Hospital, Ghana

Population/Sample

Singleton normotensive pregnancies (NTN-P) at baseline W1 (10-20th week gestation) (n= 593) of which 498 (197 developed PE) completed the study.

Methods:

The overall health status of the NTN-P participants was assessed at W1 and categorised as SHS and optimal health status (OHS) using a validated SHS questionnaire-25. Participants were followed at W2 (21-31st week, mid-pregnancy) and 32-42nd week. Samples were collected and analysed for biomarkers of OS and AGMs at the three-time points.

Main Outcome Measures

Receiver operative characteristics curve analysis was performed for the single and combined W1 and W2 biomarkers of OS and AGMs for predicting PE and its subtypes (EO-PE and LO-PE)

Results

Compared to single biomarkers of OS and AGMs, their combined ratios particularly, the W2 8-OHdG/PIGF ratio was a potent biomarker for PE [AUC=0.93]. Additionally, 8-OHdG/PIGF ratio best identified SHS-pregnant women who later developed EO-PE [AUC=0.97] and LO-PE [AUC=0.93]. Moreover, 8-OHdG/PIGF ratio best identified OHS-pregnant women who later developed EO-PE [AUC=0.94] and LO-PE (AUC=0.94).

Conclusion

Combination of biomarkers of OS and AGMs, particularly, mid-pregnancy 8-OHdG/PlGF ratio is a potent biomarker for PE and its subtypes.
Keywords: Preeclampsia, suboptimal health status, optimal health status, prognostics accuracies, combined biomarkers, oxidative stress, angiogenic growth mediator, discriminating powerIntroduction
Preeclampsia (PE) is a disorder of pregnancy characterised by hypertension and proteinuria, noticeable after 20 weeks gestation.1 The condition is easily treatable, as seen in developed countries—in the U.K. for example, PE is fatal in only one out of every million birth.2 In many other countries, however, particularly those in developing countries, this condition still poses a formidable threat to maternal-foetal health.2, 3 In Ghana, for example, roughly 18 maternal deaths are due to this condition, which translates to more than 570 deaths per 100,000 live births.3
In a retrospective study at the Komfo Anokye Teaching Hospital (KATH), Ghana, 26.4% of all maternal deaths were associated with hypertensive disorders of pregnancy.4 The prevalence of PE was 48.8%, being the highest amongst all the hypertensive disorders of pregnancy evaluated in a recent cross-sectional study at KATH.5 The prevalence rate is gradually increasing in developing countries, particularly in Ghana due to delayed detection and diagnosis.5 In most developing countries, resource constraints hamper early detection and effective diagnosis.6 Aside from the numerous treatment options available for managing PE, the delivery of the placenta and the baby under intensive care is another remedy that can avert PE onset.7
Until now, the diagnosis of PE has been based on blood pressure and proteinuria measurements, but these measures have not proven to predict the course and progression of the condition.6 This is because, PE is multifactorial, leaving the exact aetiology unknown. Researchers have been exploring avenues to understand the exact pathophysiology and develop promising biomarkers for early PE onset, even though the disorder has not been fully elucidated.8 Accumulating evidence, however, indicates that oxidative stress (OS), poor placental angiogenesis and incomplete maternal artery remodelling are among the leading contributing factors.9, 10 Thus, evaluating their markers may be useful for understanding the condition.
OS, which is an imbalance between pro-oxidants and antioxidants, has been reported among pregnant women who develop PE with increased levels of 8-epi-PGF2α (a marker of endogenous lipid peroxidation) and 8-OHdG (a marker of oxidative DNA damage) and a correspondingly reduced total antioxidant capacity (TAC) compared to normotensive pregnant women.11 Aside from the involvement of OS in the pathophysiology of PE, OS plays a central role in placental angiogenesis and vasculogenesis. 9, 10 Also, complete placental angiogenesis and vasculogenesis are key to maternal well-being and growth of the foetus. However, an incomplete placental vascular development may result in placental hypoxia and ischaemia, which subsequently stimulates an increased OS response. 9The result is an increased release of sFlt-1, an anti-angiogenic factor which antagonizes both PIGF and VEGF-A to drive high blood pressure and endothelial dysfunction in PE.12 Reduced levels of PlGF and VEGF-A and increased levels of sEng and sFlt-1 have been reported at the time of PE diagnosis 13 and in early gestational age, even before the clinical manifestation of PE.14, 15
Even though the roles of OS and AGMs are synergistic to the development of PE, longitudinal evaluation of both biomarkers throughout pregnancy is not available in Ghana, to the best of our current knowledge. A previous study has evaluated the potential of these markers in isolation.10 In this study, the suboptimal health status (SHS) concept was introduced to understand the independent role of OS and AGMs in PE. The concept has been previously used to identify pregnancies at increased risk of incidence PE and adverse pregnancy outcomes.16, 17 Similarly, SHS pregnancies were associated with increased OS, unbalanced pro- and AGMs.16 This signifies that the SHS concept can be integrated as an additional health assessment approach to identify early signs of OS and high-risk populations of pregnant women likely to develop PE. Thus, combining the concept of SHS and biomarkers (OS and AGMs) identification will be a better approach to predicting and monitoring the progression of PE. This study, therefore, used SHS concept to identify pregnant women though clinical normotensive but having poor health using SHSQ-25 and evaluated the prognostic accuracies o f early second trimester (10-20 weeks gestation) and mid-pregnancy (21-31weeks gestation) of single and combined biomarkers of OS and AGMs for preeclampsia (PE) and its subtypes: early-onset and late-onset PE in a Ghanaian Prospective Cohort birth Study.