Discussion
Main findings
In line with several other studies 14, 16, 18-22, this
study observed an imbalance in OS and AGMs markers in both OHS and SHS
pregnant women, who were likely to develop PE. But the effect was more
pronounced in the SHS group compared with the OHS group. When
we compared the prognostic accuracies of biomarkers of OS and AGMs at
Wave 1 and Wave 2 to predict SHS and OHS pregnant women who developed PE
and its subtypes (EO-PE and LO-PE), the single biomarkers of OS and AGMs
yielded fair predictive accuracies. However, the combined biomarkers of
OS and AGMs including sFlt-1/PlGF, 8-epiPGF2α/PlGF, 8-OHdG/PlGF and
sEng/PlGF yielded very good predictive accuracies. Particularly,
mid-pregnancy 8-OHdG/PlGF improved PE (all cases) prognosis by yielding
the best discriminating power and best predictive accuracy at a cut-off
value ≥0.80. Also, sFlt-1/PlGF and 8-epiPGF2α/PlGF ratio both yielded
very good discriminating powers.
Strengths and limitations
A previous longitudinal study by Kusanovic et al.,15 among pregnant Chilean women found the
“mid-trimester” as the gestation time for best predicting PE. This
finding is consistent with the pattern of results in the present study.
To the best of current knowledge, this is the first and largest
longitudinal nested case-control study among a Ghanaian population
reporting the prognostic potential of both single and combined
biomarkers of OS and AGMs for PE. Besides, the present study is the
first to identify the 8-OHdG/PlGF ratio as a promising prognostic marker
for PE. Furthermore, our ability to explore the prognostic accuracies of
the different subtypes of PE (early and late-onset PE) by incorporating
the public health concept of SHS is the first of its kind. Despite these
strengths, some limitations need to be improved upon for future studies.
Firstly, the study was undertaken in a single hospital, which means that
the present study may not have sampled representative participants
across the entire Ghanaian populace, therefore, ethnic bias may have
occurred. Secondly, the present study identified the best biomarkers for
the prediction of the onset of PE at mid-pregnancy (21-31 weeks, median
27 weeks gestation) which is relatively late in the disease progression.
Finally, the high AUC generated may be due to the high incidence rate of
PE and may not necessarily be because the combined biomarkers are
accurate. Therefore, it is recommended that future studies should
replicate the present study to validate the finding that the 8-OHdG/PlGF
ratio is a potent prognostic marker for PE.
Interpretation
The findings of our study demonstrate that OS and AGMs play a
significant role in the development of PE, and SHS mothers are at high
risk of defective angiogenesis and vasculogenesis. According to Prattet al., 23, these mechanisms may operate via
shallow extravillous trophoblast invasion and subsequent poor maternal
artery remodelling, resulting in placental under-perfusion and hypoxia.
The effect of this is stimulating the antagonistic activity of sFlt-1 to
impair the physiological function of PIGF and
VEGF-A.23 Also, sEng, an anti-AGM, interferes with
transforming growth factor-beta, which results in impaired nitric oxide
synthesis, consequent vasoconstriction, endothelial dysfunction and
clinical manifestation of PE.24, 25 Thus, the combined
concept of SHS and synergetic effect of OS and AGMs becomes important
and useful in pregnancy, especially among mothers from resourced limited
countries.
The finding that 8-OHdG/PlGF improved PE prediction is novel according
to the currently available information. The synergistic role of both OS
and abnormal placental angiogenesis in the pathophysiology of PE,
suggest that both factors may share a common pathway.9,
10 The strength of the 8-OHdG/PIGF ratio is that when the cut-off value
was applied in a logistic regression model, the mid-pregnancy mothers
were at 4.8-fold increased adjusted odds of developing PE, indicating
that its prognostic potential is independent of many confounding
factors. Similarly, to other combined ratios, there was significantly
increased levels of 8-OHdG/PlGF in both early 2ndtrimester (10-20 weeks) and mid-pregnancy (21-31 weeks) of pregnant
women who later developed PE compared to NTN-PW, suggesting that these
markers are of prognostic importance. The sFlt-1/PlGF ratio is
reported as the best marker by some studies 13, 19, 21,
26, even though another study by Park et al.,27 found that its predictive accuracy is, however,
comparable to the single AGMs.
The present study hypothesises that 8-OHdG/PlGF is an ideal prognostic
marker that gives a comprehensive understanding of the pathogenesis of
PE, unlike sFlt-1/PIGF, which is limited to detecting angiogenesis
alone. The abnormally increased 8-OHdG/PIGF ratio reflects the imbalance
between OS and AGMs, indicating that the increased oxidative DNA damage
has created disequilibrium in pro-angiogenic function. Hence, by
measuring this marker, the synergistic physiology of both OS and AGMs
may be known. Early detection of increased 8-OHdG/PIGF ratio will inform
clinicians of the need for antioxidant supplementation, which is likely
to reduce the circulatory ischaemic/hypoxic insult and enhance placental
angiogenesis. From a therapeutic standpoint, a combined antioxidant
supplement plus pro-angiogenic molecules could be the best therapeutic
approach for the management and prevention of PE.10
Early-onset PE (EO-PE) is the most severe subtype of PE and is mostly
linked with biochemical derangement and adverse perinatal outcomes as
opposed to late-onset PE (LO-PE).20, 28 In the present
study, compared to NTN-PW, a marked imbalance of both biomarkers of OS
and AGMs was observed at both early 2nd trimester
(10-20 weeks) and mid-pregnancy (21-31 weeks) in SHS rather than OHS
pregnant women who developed EO-PE, followed by those who developed
LO-PE. When the ROC curve analysis of biomarkers of OS and AGMs at early
2nd trimester and mid-pregnancy were tested to predict
SHS and OHS pregnant women who developed EO-PE and LO-PE, the
mid-pregnancy 8-epiPGF2α/PlGF ratio yielded the best prognostic
accuracies. Particularly, discriminating powers were 97.0% for SHS-PWLD
EO-PE, 93.0% for SHS-PWLD LO-PE and 94.0% for OHS-PWLD both EO-PE and
LO-PE. All these findings support the hypothesis that combined
biomarkers of OS and AGMs are a new approach to predicting and
diagnosing PE and its subtypes.