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.