Preeclampsia Clinical Trial
Official title:
Cardiac Biomarkers in Preeclampsia: Prediction of Disease and the Risk of Future Cardiovascular Events in Survivors
SUMMARY Background: Improvements in the management and prevention of obstetric haemorrhage
and sepsis, in addition to magnesium sulphate for preeclampsia have led to significant
reduction in global maternal mortality rates; thus leaving increasing number of survivors of
preeclampsia than previously. Preeclampsia is associated with inflammatory changes that alter
vascular integrity - an effect which may persist beyond pregnancy, resulting in
atherosclerosis which predisposes to myocardial ischemia, myocardial infarction and stroke.
Aim: To predict preeclampsia early in pregnancy and detect preeclampsia survivors at risk for
future cardiovascular disease and events using cardiac and gene markers.
Methods: a cohort study design with recruitment of participants at 3 stages; in the first
trimester of pregnancy, second half and the puerperium. Serum levels of fibrinogen, hsCRP,
apoA/apoB, triglycerides and other lipids, in addition to genetic studies would be compared
between those with preeclampsia and normal pregnancies, delivered mothers would be followed
up from puerperium, upto 5 years.
Data Analysis: would be performed using the Statistical Package for Social Sciences (SPSS)
software version 21.0. Numerical data would be expressed as mean ± standard deviation (SD).
Results from the two groups of women would be compared using the independent T-test, Analysis
of Variance (ANOVA) and the chi-square test while the Mantel Haenszel statistics would be
used to determine risks. The level of statistical significance would be set at p-value less
than 0.05.
Conclusion: Myocardial ischemia, myocardial infarction and stroke are major causes of sudden
death because their precursors; atherosclerosis and hypertension are asymptomatic.
Under-utilization of routine health care check further increases the risk of sudden death
from these conditions. Preeclampsia is a recognized risk factor and screening of survivors
would help to detect women at risk for cardiovascular diseases and offer early preventive
care.
Preeclampsia is a disease that is strongly linked with the risk of stroke and other
cardiovascular disease. This is a condition with greater prevalence in the Low and middle
income countries of the world especially sub-Saharan Africa, where the morbidity and
mortality is reportedly higher. Larger numbers of survivors are expected with the rising
global gains in maternal mortality reduction associated with preeclampsia. These
cardiovascular diseases myocardial ischemia, myocardial infarction and stroke are major
causes of sudden death because the precursor conditions; atherosclerosis and hypertension are
largely asymptomatic. There are established biomarkers for these conditions which can be used
as screening tools. The low utilization of routine health care check and the asymptomatic
nature of these events increase the risk of sudden premature death from these conditions. The
postnatal period offers a good opportunity for screening for these events to detect women at
risk and offer early preventive care.
Preeclampsia is essentially a disease of the trophoblast, it has also been shown to be
associated with oxidative stress, a phenomenon, which increases the levels of LDL cholesterol
peroxidation, leading to its increased uptake by macrophages, resulting in foam cell
formation and atherosclerosis. Preeclampsia is also associated with inflammatory changes that
alter vascular integrity - an effect which may persist beyond pregnancy, resulting in
atherosclerosis which predisposes to myocardial ischemia, myocardial infarction and stroke.
These changes in the vasculature are asymptomatic and unless hypertension is detected early
and vasoprotective or antithrombotic treatment commenced, sudden death may occur from stroke
or acute myocardial infarction.
Hypertensive heart disease refers to heart conditions that result from the effect of
hypertension. The heart in this instance now works under a higher pressure resulting in the
hypertrophy of cardiac muscle, thickening of the cardiac arterial vasculature (leading to
coronary arterial disease) and increased risk of myocardial ischemia and infarction. The
resulting cardiac muscle dysfunction leads to increasing levels of pro-inflammatory
cytokines, which can be detected in the blood stream and whose levels may correlate with the
presence and severity of the disease condition. Hypertension has similar effects on the
cerebral vasculature, where it can cause vessel rupture resulting in life-threatening
intracranial haemorrhage. The vessels under the influence of long standing hypertension may
undergo hypertrophy leading to thickening of the vessel wall with narrowing of lumen and then
cerebral ischemia, infarction and stroke.
There is a significant reduction in the risk of fatal and non-fatal stroke if hypertension is
detected early and effectively controlled with antihypertensive drugs. This preventive
strategy has been shown to be of more benefit when commenced at a younger age and especially
in women of the black race who are at higher risk and would benefit more.
In the general adult population, lipids and cardiac biomarkers have been shown to predict the
occurrence of these cardiovascular events. These biomarkers include: High sensitivity
C-reactive Protein (hsCRP), Apolipoproteins (LDL, Apo B-100, Apo A1), Lipoprotein a (Lp(a),
Oxidized LDL, Lipoprotein-associated phospholipase (A2-LpPLA2), Sphingosine-1-phosphate
(Sph-1-P), small dense low density lipoprotein (sdLDL) and Myeloperoxidase (MPO). A recent
systematic review on markers for primary cardiovascular events revealed that in terms of
correlation with the development of cardiovascular disease; C-reactive protein, fibrinogen,
cholesterol, apolipoprotein B, the apolipoprotein A/apolipoprotein B ratio, high density
lipoprotein, and vitamin D, were useful in the prediction of cardiovascular disease, while
for primary stroke; fibrinogen and serum uric acid were strong markers.
This study therefore aimed to determine the risk of future cardiovascular disease and events
in survivors of preeclampsia using these established biomarkers, in conjunction with testing
for gene markers.
Participants would include all consecutive participants who meet the inclusion criteria for
each group of study within the 12-month period at all sites. They would be educated about the
study and informed consent obtained from them or from relatives (when patient is unable to do
so). A 10ml sample of venous blood and a dry blood spot on filter paper would be obtained (by
doctors from all the participating sites) from all the participants for assay of cardiac,
lipid and gene markers of cardiovascular disease.
At the start of the study, training sessions on the study protocol and monitoring would be
held for all team members from the study sites and this would be done fortnightly until
completion of study to ensure uniformity.
Blood samples obtained would be centrifuged to obtain plasma and serum at each study site
which would then be transported in ice packs department of medical laboratory science of the
Babcock University, Ilishan-Remo for assay of lipid and cardiac biomarkers while the genetic
studies (DNA extraction and sequencing) would be done at the Centre for Advanced Medical
Research and Biotechnology (CAMRAB), laboratory at Babcock University Teaching Hospital,
Ilishan-Remo. All samples obtained would be coded such that the laboratory scientist is
blinded from the identity of the participants. The results obtained would then be transferred
into the pre-labelled proforma where other details of each participant including the biodata
and pregnancy history have already been entered. The participants details entered into the
proforma would also be entered directly into tablets linked with Redcap mobile application
for web hosting, which would then be exported later to SPSS for analysis. Twenty four-hour
telephone contact would be maintained with team members from all the study sites involved in
the study, through direct phone call and text message. A whatsapp chat group would be created
to link all four study sites for easy transmission of information. Twenty four-hour telephone
contact would be maintained with team members from all the study sites involved in the study.
The blood samples would be collected into lithium heparin and plain anticoagulant-free
containers and transported immediately in an ice container to the laboratory for analysis
where they would be centrifuged at 2,500 rpm for 5 minutes, at all sites, before transport of
both well labelled supernatant sera in plain bottles and plasma in lithium heparin bottles
after decanting from the packed red cells to Babcock University. Serum and plasma aliquots
would then be stored at -20ºC in Babcock University until further analysis. The drop of blood
spot obtained from each participant would be allowed to air-dry and then safely stored in a
cool dry storage refrigerator before transport to CAMRAB, where it would be maintained at
-80˚C until gene analysis. Serum and plasma samples that are not used would be stored at
-80˚C for 5 years.
Blood pressure measurements would be obtained by a trained nurse at each site with manually
operated mercury powered sphygmomanometer and these readings would be taken in the sitting
position. The Korotkoff sound V would be taken as the level for diastolic blood pressure in
all cases. The blood pressure would then be immediately entered into the study proforma for
each participant.
After explaining the procedure with the aid of the subject information form, obtaining
consent and completing the history segments of the proforma, 10ml of venous blood samples
would be obtained from the participants prior to the commencement of any intravenous therapy.
This sample would be collected from the contra-lateral upper limb of patients who are already
on intravenous infusion. The venous blood would be aspirated from the participant's
ante-cubital vein and placed in a lithium heparin vacuum tube (5mls) and a plain
anticoagulant-free bottle (5mls). At the time of blood collection, a drop of blood would be
made on a filter paper for genetic analysis.
All participants would be followed up till end of puerperium thus; observation for the
development of preeclampsia in women admitted within the first half of pregnancy, those
admitted with preeclampsia in pregnancy would be observed for the correlation of preeclampsia
severity with the levels of biomarkers and those recruited postpartum would have their levels
of cardiac and gene markers compared with those of women who had normal pregnancies.
Telephone contact of the participants and their next of kin would be obtained and they or
next of kin would be contacted at 1, 2, 5 and 10 year intervals for development of
cardiovascular events and repeat serum levels of biomarkers.
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