Pre-Eclampsia Mechanisms Flashcards
What is pre-eclampsia?
Who does it affect?
Is it improving?
- An abnormal condition of pregnancy characterised by onset of acute hypertension after the 24th week of gestation
- It is estimated to affect 2-8% of all pregnancies and if left untreated, can develop into eclampsia (NHS, 2015)
- There has been a reduction in the maternal mortality in developed which can be attributed to an improvement in assessing risk and the level of prenatal care as well as improvement in management – leading to only 2 women between 2012-2014 dying due to preeclampsia (Shennan et al., 2017)
Aetiology of pre-eclampsia
- The common risk factors for pre-eclampsia include nullparity, increasing age, obesity, pregestational diabetes, a family history and other pre-existing diseases such as anti-phospholipid syndrome
- The underlying mechanisms for pre-eclampsia are debated with many theories as to why it develops in pregnancy
Mechanism of pre-eclampsia - pathophysiology
In normal pregnancy, extravillous trophoblasts (EVTs) deeply invade the uterine spiral arteries, disrupt the muscular coat and elastica, and replace the vascular endothelial cells
This remodeling dilates the spiral arteries and triggers increased uteroplacental blood flow.
Therefore, failed remodeling at this stage leads to reduced uteroplacental blood flow and hypoxic stress to the fetus and placenta.
Endothelial damage releases VEGF and co-receptors for TGF-β1 and -β3, which induces maternal intravascular systemic inflammatory responses and endothelial dysfunction, resulting in hypertension and proteinuria after 20 weeks’ gestation.
What are the three mechanisms of pre-eclampsia?
Placental iscahemia
Oxidative Stress
Autoimmune
What is placental ischaemia?
- Central hypothesis governing our understanding of pre-eclampsia is that the disorder results from ischaemia of the placenta, which in turn releases factors into maternal circulation
Evidence of contribution of endoplasmic stress in pre-eclampsia
Lian et al., 2011
- Endoplasmic reticulum (ER) stress has been implicated in both pre-eclampsia (PE), Lian et al. (2011) evaluate the contribution of ER stress in the pathogenesis of PE compared levels of ER stress markers in decidual tissue from pregnancies complicated by PE
- Whole-genome transcriptional profiling showed increased ER stress and western blot analyses showed ATF6 marker immunoreactivity in most (>80%) extravillous trophoblasts, decidual cells and macrophages associated with PE
Evidence against placental ischaemia being a cause
Ayuk, 2006
- Argued that placental ischaemia is a consequence rather than a cause
- There is a strong association between pre-eclampsia and small (rather than large) placentas - which would have less ischaemia
- Failed trophoblast invasion of the spiral arteries is not specific to pre-eclampsia and occurs in other pregnancy complications and in up to 40% of biopsies from normal pregnancies
- Evidence shows that the risk of a woman developing pre-eclampsia is almost entirely dependent on maternal factors
Nizard et al., 2003
- Backed this up by showing that ligation of hypogastric artery during pregnancy did not impair fertility or pregnancy outcomes
- Would be expected to if placental ischaemia was implicated in cause of disease
What is the process of oxidative stress?
- Production of ROS overwhelms the intrinsic antioxidant defence mechanisms
- In preeclampsia it induces the release of proinflammatory cytokines and chemokines as well as trophoblast debris
- Thought to be due to intermittent hypoxia and reoxygenation, probably resulting from deficient conversion of the myometrial segment of the spiral arteries
Evidence of oxidative stress causing pre-eclampsia
Cindrova-Davies et al., 2007
- Examined activation of signaling pathways during hypoxia-reoxygenation of villous explants in vitro.
- Hypoxia-reoxygenation activated the p38 and stress-activated mitogen-activated protein kinase (MAPK) pathways.
- Downstream effects include increased tissue concentrations and secretion of TNF-alpha and IL-1B, increased expression of COX-2, and apoptosis
- Administration of vitamins C and E to explants blocked activation of pathways
- Concluded that oxidative stress is a potent inducer of placental synthesis and release of proinflammatory factors and identified pathways involved
Evidence of prevention of oxidative stress - AAT levels correlate to PE
Feng et al., 2016
- AAT levels are significantly decreased in placenta tissues from women with PE compared that of healthy women
- Mice model of preeclampsia prepared by injection and AAT was added with control groups
- AAT injection can relieve the high blood pressure and reduce urine protein levels in a dose-dependent manner, and thus improve PE
- AAT injection inactivated PE mediated activation of signaling such as P38 and MAPK - agrees with Cindrova-Davies 2007
- A potential therapeutic target?
What is the mechanism of autoimmune disease in PE?
- Trophoblast invasion depends in part on plasminogen activators to convert plasminogen into plasmin, PAI-1 is an inhibitor which negatively controls plasminogen activator levels and is the most abundant
- Leads to shallow invasion, characteristic of pre-eclampsia
Evidence that autoantibodies contributed to PE
Xia et al., 2003
- Included preeclampsia women and a control group to study the role of Angiotensin 2 receptor (AT1) autoantibodies
- IgG AT1-AA purified from patients 90% of pre-eclampsia patients were able to contract the myocytes which is due to downstream pathway
- Activation of AT1 receptors by AT1-AA was blocked by losartan (an AT1 receptor antagonist) – proves it is that specific receptor
- In vitro activation of AT1 receptors by AT1-AA resulted in decreased trophoblast invasiveness
- Findings suggest maternal autoantibody with the ability to activate AT1 receptors may account for features of preeclampsia
Evidence that antibodies to AT1 receptor caused PE
Zhou et al., 2008
- Further evidence that it is due to autoimmune disease, IgG from women with preeclampsia stimulated the synthesis and secretion of sFlt-1 via AT1 receptor activation in pregnant mice
- Resulted in inhibition of endothelial cell migration and capillary tube formation in vitro.
Diagnosis of PE
It is made upon regular check ups in pregnancy where blood pressure is monitored, any rise in BP is treated with suspicion and a urine sample will be performed if suspected to detect proteinuria.
Treatment of PE
If the BP is over 140/90 then the woman generally needs to be hospitalised according to NICE, hypertensive treatment can be started if severely high BP (labetalol preferred)
Bed rest – close monitoring with BP checked over 4 times-a-day
Magnesium sulphate – given if severe to prevent seizures occurring
High protein diet – to replace the lost protein in urin
The only true cure for preeclampsia is delivery – for example if you’re near term, an emergency C-section can be performed
