This webinar was sponsored by Thermo Fisher Scientific. He is Professor and recently appointed head of the Department of Obstetrics and Gynaecology, Groote Schuur Hospital, University of Cape Town. He has extensive experience as Consultant Obstetrician and Gynaecologist at tertiary level Groote Schuur Hospital. Prof Matjila is serving a second term on the National Health Research Committee – the Ministerial Advisory Committee on Research for Health and is current chair of the Policy and Strategy Subcommittee of the NHRC. He is also serving a second term as chair of the Academic Liaison Committee of the South African Society of Obstetricians and Gynaecologists and is Senate Member of the Colleges of Medicines of South Africa and Council Member of the College of Obstetricians and Gynaecologists.
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The following article is based on Prof Matjila’s presentation.
Hypertensive disorders of pregnancy (HDPs) affect 2%-8% of pregnancies globally. Of HDPs, preeclampsia contributes the most to adverse maternal and perinatal outcomes.
Preeclampsia is characterised by development of new-onset hypertension and proteinuria after 20 weeks’ gestation although proteinuria is no longer a necessary diagnostic requirement. It is a multi-factorial disorder, which manifests with systemic endothelial dysfunction in various organs.
Preeclampsia contributes significantly to maternal and perinatal morbidity and mortality.
The developing world bears the brunt of severe disease and adverse maternal and perinatal outcomes. About 99% of the estimated annual global maternal and perinatal pre-eclampsia-related deaths occur in LMICs.
For such an impactful disease, the diagnosis of preeclampsia is still based on non-specific signs: proteinuria and new onset hypertension, for which there exists a list of differential diagnoses or mimickers.
Imitators of preeclampsia
Several disorders have previously proved to imitate preeclampsia since they share some of the clinical and laboratory findings.
The pathophysiologic causes of these conditions include vasospasm, platelet activation or destruction, microvascular thrombosis, endothelial cell dysfunction, and reduced tissue perfusion. These imitators include acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, haemolytic uremic syndrome, systemic lupus erythematosus, severe hypothyroidism, sepsis, and now covid.
Additionally, the prognostication in terms of prediction of adverse maternal and perinatal morbidity and mortality in women with the diagnosis of preeclampsia has remained a challenge.
The potential role of biomarkers in the management of preeclampsia
Placental hypo-perfusion and hypoxia result in release of circulatory factors into the maternal circulation.
It is important to recognise that molecular pathways implicated in placental dysfunction are diverse.
VEGF family and its receptors
sFlt-1 is a soluble truncated variant of the VEGFR-1 receptor, which lacks the cytoplasmic and trans-membrane domains, but conserves the ligand-binding domain.
Towards term, the distinction between PET and normal pregnancy (sFlt-1/PlGF) becomes blurred.
Establishing diagnosis and baseline assessment of maternal organ system function and foetal assessment
Initial hospital admission and work-up for confirmation of diagnosis includes the exclusion of organ dysfunction with biochemical and haematological testing and serial measurement of blood pressure and urine. Twenty-four two-hour urine collection is necessary for quantification of proteinuria or protein/creatine ratio. Foetal sonography will look at biometry, growth, amniotic fluid index and umbilical artery dopplers.
Biomarkers can distinguish between type of disease (HTD) and onset.
A word of caution
Placental-based disorders (PBD) are heterogeneous, hence other PBD and pathological entities may result in perturbed biomarker levels beyond preeclampsia. Disrupted angiogenesis only explains certain phenotypes of these disorders. Other pathways include lack of immune tolerance, permissive cell adhesion profiles, syncitiotrophoblast ageing and fatigue, placental programming, placental microbiomes, and non-coding RNAs.
Conditions associated with abnormal angiogenesis:
- Vascular malformations:
- TGF-B (AV malformations in hereditary telangiectasia)
- Tie2 (venous malformations)
- VEGF-R3 mutations (congenital lymphoedema)
- Obesity – insulin and leptin have an effect on VEGF and FGF expression.
Summary and conclusion
The definition for preeclampsia is constantly evolving. Maternal and perinatal morbidity and mortality are heightened in the presence of preeclampsia. The burden is most palpable in LMICs and relates to early onset disease. The pathophysiology for early onset disease involves dysfunctional placentation and its dissemination.
The molecular pathways involved in dysfunctional placentation are numerous and complex. Recent focus has been on disturbance of the angiogenic pathway (mainly PlGF and sFlt-1). These are likely to enhance clinical precision, in conjunction with clinical acumen, particularly for the exclusion of preeclampsia in patients with suspected disease. This is also the case for characterisation of preeclampsia, and prognostication of maternal and perinatal outcomes. As a result, the classification of HDP and preeclampsia is likely to incorporate biomarkers.
However, caution needs to be exercised in the presence of pathology involving the angiogenic pathway and other placental mediated disorders. This offers an opportunity for research, given the continental and national burden of preeclampsia.