Pre-eclampsia is a pregnancy-specific, multisystem disorder that affects 3-5% of all pregnancies (Phillips and Boyd, 2016; Story and Chappell, 2017). It can affect many organs, including the kidneys, liver, vasculature, and brain, through reduced perfusion, endothelial damage, oedema, and ischaemia—all of which are highly detrimental to organ function and can result in maternal death (Dhariwal and Lynde, 2016). There are also adverse consequences for the fetus, because the pathology of pre-eclampsia is thought to originate in the placenta, and also because iatrogenic preterm birth is often necessary to prevent maternal and/or fetal demise (Story and Chappel, 2017). Pre-eclampsia is therefore a significant cause of maternal and perinatal morbidity and mortality worldwide (Dhariwal and Lynde, 2016; Roberts and Himes, 2017), although in high-income countries, maternal deaths due to pre-eclampsia have declined dramatically in recent years (Knight and Nair, 2017). However, in low-income countries, pre-eclampsia still represents a significant cause of maternal mortality (Bilano et al, 2014). Here, improved access to antenatal care can significantly reduce morbidity and mortality associated with this disease (Duley, 2009; Bilano et al, 2014).
There have been considerable advances in the understanding of the pathophysiology of and risk factors for pre-eclampsia, but this has not yet led to particularly effective treatment or predictive measures (Roberts and Bell, 2013; Myatt and Roberts, 2015; Mol et al, 2016). Screening is based on risk factors in a woman's medical and obstetric history (National Institute for Health and Care Excellence (NICE), 2010), but whether this is sufficiently efficacious is a matter of much debate, and screening methods have been developed that use maternal risk factors in combination with several biomarkers and biophysical measurements (Akolekar et al, 2013). These are proposed by some to be more effective at predicting pre-eclampsia (Tan et al, 2018); however, their potential in screening for pre-eclampsia is controversial (Mol et al, 2016). Apart from birth, the only known effective intervention is aspirin prophylaxis, which is administered to women determined by screening to be at at risk for the development of this disease, although the population that should be targeted for prophylaxis is also a matter of debate (Atallah et al, 2017).
Clinical manifestation
Pre-eclampsia is characterised by new-onset hypertension at or after 20 weeks' gestation together with proteinuria and/or other signs of the disease, such as visual disturbances, severe headache, epigastric pain and signs of haematological/biochemical abnormalities, including thrombocytopenia and impaired kidney or liver function tests (NICE, 2010; American College of Obstetricians and Gynecologists (ACOG), 2013) (Table 1). These widespread systemic effects are brought about by endothelial dysfunction, increased systemic vascular resistance, and decreased perfusion to many organs (Blackburn, 2017). This results in increased vascular permeability, oedema, and ischaemia. These effects are thought to arise as a result of the downstream effects of impaired placentation (Roberts and Bell, 2013; Chaiworapongsa et al, 2014a). Severe consequences can include renal failure, pulmonary oedema, HELLP (haemolysis, elevated liver enzymes, low platelets), disseminated intravascular coagulation and eclampsia, all of which impose the risk of maternal death (Chaiworapongsa et al, 2014a; Philips and Boyd, 2016). Fetal complications arise largely due to the impaired placentation (which can result in intrauterine growth restriction (IUGR)), as well as the implications of preterm birth, which is often necessary due to the acute risks to maternal health (Chaiworapongsa et al, 2014b; Story and Chappell, 2017). There are additional long-term implications, with an increased risk of future cardiovascular disease for both mother and child (Giguère et al, 2012; Hakim et al, 2013). Therefore, as well as preventing the immediate and potentially life-threatening complications, a treatment for pre-eclampsia could improve future health, for both mother and child.
| Pathophysiology | Presentation |
|---|---|
| Cardiovascular and haematological | |
| Vasoconstriction |
Hypertension |
| Central nervous system | |
| Hypertension |
Headache |
| Renal | |
| Endothelial damage |
Proteinuria |
| Hepatic | |
| Ischaemic cellular injury |
Epigastric pain |
| Fetoplacental unit | |
| Uteroplacental insufficiency |
Intrauterine growth restriction |
It is thought, however, that the clinical symptoms of pre-eclampsia represent the late stages of the disease, and that the pathophysiological changes begin long before these become evident (Redman and Sargent, 2010; Philips and Boyd, 2016), making it essential for mothers at risk for pre-eclampsia to be identified early in pregnancy. The pathophysiological mechanisms that produce the heterogenous clinical symptoms of pre-eclampsia have not yet been fully clarified, however; and it may be that the full elucidation of the pathways involved provide both targets for screening and for intervention. Given this heterogeneity in clinical presentation, it is likely that there are multiple combinations of pathophysiological pathways involved and that pre-eclampsia screening and treatment should therefore reflect this (Roberts and Bell, 2013; Chaiworapongsa et al, 2014a).
Normal placentation
The pathology of pre-eclampsia is thought to originate in the placenta, during the establishment of the uteroplacental circulation (Powe et al, 2011; Roberts and Bell, 2013; Chaiworapongsa et al, 2014a). Under normal circumstances, this involves the transformation of maternal spiral arteries from small-diameter, high-resistance arteries into low-resistance, high-capacity vessels that can effectively perfuse the intervillous space (Powe et al, 2011). This begins at 8-10 weeks' gestation (Philips and Boyd, 2016) when cytotrophoblasts invade the uterine wall and take on the characteristics of the cells of blood vessels. Cytotrophoblasts up-regulate proteins typical of endothelial and smooth muscle cells, and down-regulate those of epithelial cells, giving them an endothelial, or smooth muscle phenotype, described by Fisher (2015) as ‘vascular mimicry’. As they migrate through the stroma of the uterine wall, they breach the walls of spiral arteries and migrate up these blood vessels, replacing the endothelial lining and part of the smooth muscle layer. The loss of these layers transforms spiral arteries into high-capacity, low-resistance blood vessels (Chaiworapongsa et al, 2014a; Philips and Boyd, 2016; Story and Chappell, 2017). In addition, as much of the neuromuscular component is lost, the vasculature is no longer responsive to modulators, resulting in a sustained high-volume, but low-velocity, flow to the intervillous space (Roberts and Bell, 2013).
Impaired placentation in pre-eclampsia
In pre-eclampsia, the process of transformation of spiral arteries is incomplete (Figure 1). Cytotrophoblasts fail to fully penetrate many spiral arteries and many are incompletely transformed or are not transformed at all (Powe et al, 2011). Normally, remodelling of spiral arteries extends into the myometrium; however, in pre-eclampsia, the myometrial portion of many arteries is left unaltered. As a result, many of the arteries still have thick muscular walls with a functional adrenergic nerve supply (Wylie and Bryce, 2016; Blackburn, 2017) and they are left as narrow, high-resistance vessels that provide high-pressure, pulsatile flow to the placenta. In addition, blood flow to the placenta can still be modified by adrenergic input (Dhariwal and Lynde, 2016). Therefore, the placenta is under-perfused by a high pressure blood flow that is subject to vasoconstriction (Blackburn, 2017). This results in placental ischaemia-reperfusion injury and as a result, oxidative stress. This is believed to result in the release of cytokines and anti-angiogenic proteins into the maternal circulation, including sFLT-1 and endoglin, which alter vascular growth and permeability (Myatt and Roberts, 2015; Dhariwal and Lynde, 2016). Furthermore, due to the high-pressure blood flow that perfuses the intervillous space, syncytiotrophoblast particles may also be released into the maternal circulation (Roberts and Bell, 2013; Cadavid, 2017). It is thought that it is these products of placental stress that cause the maternal syndrome of endothelial damage, altered haemostasis and coagulation, and increased systemic vascular resistance (Phillips and Boyd, 2016; Blackburn, 2017). However, the precise pathophysiological mechanisms linking placental hypoxia, ischaemia and oxidative stress to the maternal syndrome of endothelial dysfunction and hypertension are unclear (Figure 1).
Normally in pregnancy, there is a balanced production of the lipid-soluble mediators thromboxane (TXA2) and prostacyclin (PGI2), which act locally to alter cell function in a variety of ways. TXA2 is produced by platelets and induces vasoconstriction and platelet aggregation, while PGI2 is produced by endothelial cells, and has actions that oppose those of TXA2, stimulating vasodilation and inhibiting platelet aggregation (Rang et al, 2016). The balance between these mediators is regulated during pregnancy, in favour of vasodilation, to allow sufficient blood flow to the placenta while maintaining peripheral vasoreactivity (Blackburn, 2017; Atallah et al, 2017). However, in pre-eclampsia, the ratio of these mediators becomes altered in favour of TXA2, resulting in increased platelet aggregation (causing thrombocytopaenia due to platelet consumption) and vasoconstriction (increasing peripheral vascular resistance). This imbalance between TXA2 and PGI2 is the target for aspirin prophylaxis (Rang et al, 2016; Atallah et al, 2017), which will be explored in more detail later in this review. Research is underway to determine whether the imbalance in the anti-angiogenic mediators discussed above can also be exploited either for screening for pre-eclampsia, or as a target for drug therapy (Dhariwal and Lynde, 2016).
Types of pre-eclampsia
There are proposed to be two broad subtypes of pre-eclampsia: an early form that manifests before 34 weeks, and a late form that culminates after 34 weeks (Myatt and Roberts, 2015; Dhariwal and Lynde, 2016; Phillips and Boyd, 2016). The early form is much less common and is associated with more severe perinatal and maternal outcomes; it is proposed that defective placentation is more relevant to this form of the disease. The late form accounts for the majority of cases of pre-eclampsia and is relatively mild. It is believed that maternal factors (such as underlying hypertension or metabolic disease) have more of an influence in the development of this form (Chaiworapongsa et al, 2014a; Myatt and Roberts, 2015) (Table 2). That these presentations are associated with differing mechanisms is supported by data that demonstrates that early onset pre-eclampsia is more consistently associated with abnormal uterine and umbilical artery Doppler waveforms, IUGR and placental lesions indicative of insufficient placental perfusion (Nelson et al, 2014; Park et al, 2015). The differing aetiologies of these presentations suggests that diverse approaches to their detection, prevention, and treatment may be required (Roberts and Bell, 2013; Roberge et al, 2017). Indeed, prophylactic aspirin therapy appears to be efficacious in preventing early but not late onset pre-eclampsia (Roberge et al, 2017; Rolnik et al, 2017). However, it may be that these presentations represent the culmination of different combinations of influencing factors, which include the severity of the underlying placental insufficiency, the timing of its establishment, and various underlying maternal co-morbidities and risk factors.
| Early onset pre-eclampsia | Late onset pre-eclampsia |
|---|---|
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|
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Risk factors
Risk factors that have found to be associated with an increased chance of developing of pre-eclampsia include chronic hypertension, diabetes, a family history or previous history of pre-eclampsia, advanced maternal age (≥40 years), raised BMI (≥35 kg/m2), multiple gestation, autoimmune diseases such as lupus erythematosus, chronic kidney disease, primiparity, and premipaternity (NICE, 2010; Powe et al, 2011; Chaiworapongsa et al, 2014a; Bartasch et al, 2016). Insights into the pathophysiology of pre-eclampsia can be gained from some of these risk factors (Bilano et al, 2014; Fisher, 2015):
Interestingly, the chances of successful implantation and placentation may be increased by prior exposure to paternal antigens, via exposure to seminal plasma (Redman and Sargent, 2010; Saftlas et al, 2014). This is implicated with the higher risk of pre-eclampsia with nulliparity and with premipaternity, which are associated with decreased exposure to paternal semen. Reproductive practices that limit exposure to paternal semen (such as barrier contraception) are also associated with an increased risk. An immune maladaptation mechanism for pre-eclampsia has therefore been proposed (Saftlas et al, 2014). When cytotrophoblasts invade the myometrium and spiral arteries, there is a close interaction and association between fetal cells, carrying both fetal and paternal antigens, and maternal cells. For this to be successful, it is essential that these fetal cells are not rejected by the maternal immune system. It is therefore suggested that prior exposure to paternal antigens present in semen would allow the maternal immune system to later recognise and accept the presence of these antigens, allowing this interaction to take place (Redman and Sargent, 2010). Immune adaptations may therefore allow and control the invasion of cytotrophoblasts and their interaction with maternal blood vessels, and prior exposure to paternal antigens (through exposure to paternal semen, or as a result of a previous pregnancy with the same father) may be required for this to be efficacious (Redman and Sargent, 2010; Saftlas et al, 2014) (Figure 2). Furthermore, genes that have been implicated in the development of pre-eclampsia include those that encode HLA-C, the fetal cell surface molecule that presents paternal antigens to maternal immune cells (Mol et al, 2016), further implying a role for immune maladaptation in pre-eclampsia.
Pregnancy: A delicate physiological balance
This type of impaired placentation is not limited to pre-eclampsia; it is also seen in preterm birth and IUGR, and on its own is not necessarily sufficient to cause pre-eclampsia (Chaiworapongsa et al, 2014a). This has led to the suggestion that maternal and fetal factors might further drive impaired placentation towards the pathophysiological processes involved in pre-eclampsia (Roberts and Bell, 2013; Fisher, 2015; Myatt and Roberts, 2015). These factors may influence the outcome of impaired placentation and include maternal factors such as obesity and diabetes, and fetal factors such as unrecognised antigens and a large placental mass (Table 4). Therefore, various combinations of maternal and fetal factors could tip the balance towards pre-eclampsia, placing additional stress on systems that are already stressed, exacerbating the pathophysiology imposed by impaired placentation (Figure 2). Roberts and Bell (2013) suggest that if placentation is sufficiently aberrant, pre-eclampsia may develop without additional influencing factors, or the balance might be sufficiently tipped towards pre-eclampsia by maternal or fetal factors alone, without impaired placentation. It may therefore be that the early and late forms of pre-eclampsia are not so different after all, but that early onset pre-eclampsia has the additional burden of impaired placentation imposed upon it, or that the impaired placentation has more involvement in the pathophysiology. In either case, maternal physiology must contend with the stress imposed by pregnancy that is superimposed with maternal and fetal factors—the combination, timing, and severity of which may determine the nature and outcome of the pathology.
Long term effects
As well as the immediate risks, pre-eclampsia carries an increased likelihood of later exposure to cardiovascular disease (Giguère et al, 2012; Hakim et al, 2013). This may be because pre-eclampsia and cardiovascular disease share the same risk factors and likely similar pathological processes (obesity, hypertension, hypercoagulation, endothelial dysfunction) (Giguère et al, 2012), or because pre-eclampsia exposes underlying vascular disease (Myatt and Roberts, 2015). In line with this, Foo et al (2017) found that women who developed pre-eclampsia had significantly higher blood pressure and peripheral vascular resistance, and lower cardiac output preconception, compared to those who did not. There is also an increased risk for the child of developing cardiovascular disease (Hakim et al, 2013), and these adverse consequences add to the need for a treatment for pre-eclampsia.
Management and treatment
The only known treatment for pre-eclampsia is birth, and it is perhaps with the precise elucidation of the pathological mechanisms involved that specific targets for drug therapy will be identified. However, the clinical manifestations of pre-eclampsia usually do not develop until the third trimester (Story and Chappell, 2017) and it is thought that by this time many of the pathophysiological changes have already occurred and may be irreversible (Roberts and Bell, 2013; Phillips and Boyd, 2016). Thus, it is essential that women who may be at risk of pre-eclampsia are identified early in pregnancy so that prophylactic preventative therapy can begin. Low-dose aspirin has been found to reduce the incidence of pre-eclampsia among women found to be at-risk (Askie et al, 2007; Atallah, 2017; Roberge et al, 2017; Roberts et al, 2017), and 75 mg daily from 12 weeks' gestation is advised for all women considered at risk of developing pre-eclampsia (NICE, 2010) (Table 3). Aspirin acts by rectifying the altered thromboxane (TXA2): prostacyclin (PGI2) ratio that is thought to occur in pre-eclampsia. It inhibits the enzyme cyclo-oxygenase, which is responsible for the production of these mediators from cell membrane phospholipids (Figure 3). TXA2 is produced in platelets, which have no nucleus, and therefore are unable to produce new cyclo-oxygenase to overcome this block and re-synthesise TXA2. PGI2, however, is produced in endothelial cells, which are quickly able to synthesise new cyclo-oxygenase and therefore regain the capacity to produce PGI2. This restores the imbalance in favour of prostacyclin, inhibiting platelet aggregation and vasoconstriction, and promoting vasodilation (Rang et al, 2016; Atallah et al, 2017).
| High risk | Moderate risk |
|---|---|
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NB: Women with any one risk factor that puts them at high risk for developing pre-eclampsia, or with more than one moderate risk factor are advised to take aspirin from 12 weeks' gestation until the birth of their baby.
| Influencing factors | Exacerbating pathophysiology | |
|---|---|---|
| Maternal factors | Hypertension |
Vasoconstriction |
| Fetal factors | Presentation of unrecognised antigens (primiparity, premipaternity) |
Immune maladaptation |
Assessment and screening
In order to begin aspirin prophylaxis, women at risk of pre-eclampsia need to be identified. This is based on the identification of risk factors in maternal medical and obstetric history (NICE, 2010) (Table 3). However, there are concerns over whether this method is sufficiently efficacious, due to a reportedly low successful detection rate (Tan et al, 2018), and combined testing has been widely suggested (Akolekar et al, 2013; Park et al, 2015; Wright et al, 2015; O'Gorman et al, 2016). This uses a combination of maternal characteristics, biophysical measurements (including uterine artery blood flow and mean arterial pressure) and biomarkers (such as pregnancy-associated plasma protein-A) to determine whether a mother is at increased risk of developing the disease. The screening programme for pre-eclampsia (SPREE) trial compared the proposed and accepted screening methods, and found the performance of and compliance with NICE screening to be low (Tan et al, 2018). The authors concluded that the identification of women at risk for developing pre-eclampsia is substantially improved by using maternal risk factors in combination with biochemical and biophysical measurements. However, it is argued that this is a resource-intensive method of screening that only identifies a small proportion of women at risk for early pre-eclampsia (Roberts and Hymes, 2017). Although the adverse consequences of this form of the disease are more severe, the majority of women who develop pre-eclampsia are affected by the late form of the disease, and the majority of morbidity and mortality is in low-resource settings where this form of screening would not be feasible (Roberts and Hymes, 2017).
Management
The management of pre-eclampsia revolves around the control of maternal blood pressure, prevention of seizures, and the determination of the optimal timing of birth (Chaiworapongsa et al, 2014b). While hypertension must be controlled to prevent the risk of severe cerebral complications, which can include eclamptic seizures and intracranial haemorrhage, artificial lowering of blood pressure can compromise the uteroplacental circulation, and therefore oxygen and nutrient delivery to the fetus (Chaiworapongsa et al, 2014b; Wylie and Bryce, 2016). Guidelines therefore differ regarding the blood pressure threshold at which antihypertensive therapy should commence (Chaiworapongsa et al, 2014b). In addition, decisions around timing of birth can be extremely challenging, given the risks associated with potential maternal demise, which must be balanced against those of preterm birth. Extreme care in the monitoring of maternal and fetal condition is required, as well as the use of magnesium sulphate either as prophylaxis or in the event of an eclamptic seizure (Wylie and Bryce, 2016).
Magnesium sulphate is a calcium antagonist, and although its mechanism of action in eclampsia is unclear, it reduces activity in excitable tissue, including arterial vasculature and neuronal tissue (Jordan, 2010; Hunter and Gibbins, 2011). It is believed therefore to inhibit eclamptic seizures by producing vasodilation and reducing neural activity, particularly excessive NMDA receptor activity, improving cerebral blood flow and reducing seizure activity (Hunter and Gibbins, 2011). However, its use is not without risk, as it produces widespread depression, and adverse effects can include respiratory depression and (although extremely rare) cardiac arrest (Jordan, 2010; Hunter and Gibbins, 2011). Vigilant attention to maternal and fetal condition is therefore critical and includes assessment of respiratory rate and patellar reflexes to monitor for signs of toxicity, and ensuring availability of calcium gluconate to reverse magnesium sulphate toxicity should this occur (Hunter and Gibbins, 2011; Wylie and Bryce, 2016). Magnesium sulphate crosses the placenta, and the neonate should also be closely monitored following birth, particularly for respiratory depression (Jordan, 2010). Interestingly, placental transfer of magnesium sulphate appears to have a neuroprotective effect for the fetus, preventing the development of cerebral palsy in the preterm neonate, possibly through its inhibitory action on fetal NMDA receptors, which protects against hypoxic stress (Crowther et al, 2017; Shepherd et al, 2017). There is however a critical need to prevent deterioration of maternal condition to the point where magnesium sulphate is required, although this is not always possible as an eclamptic seizure can occur suddenly, without any prior symptoms, and can occur postpartum.
Conclusion
It is likely that the heterogenous clinical presentations of pre-eclampsia result from disparate underlying pathophysiological pathways, which arise as a result of different combinations of timing, pre-existing comorbidities, and maternal and fetal risk factors. These comorbidities and risk factors may result in a predisposition to pre-eclampsia or determine its outcome, but result in a system that cannot withstand the cardiovascular stress imposed by impaired placentation, and a spectrum of clinical presentations ranging from mild, to extremely severe and a threat to life. It is therefore vital that women at risk for this pathophysiology are accurately identifed, for potential prevention, as well as increased surveillance. However, methods of screening and intervention appear to bypass women at low-risk for this disease, as well as those at risk of developing it later in pregnancy. In addition, apart from aspirin prophylaxis, the only option is stabilisation of maternal blood pressure to prevent delivery becoming necessary, or until it becomes necessary. Further elucidation of the pathophysiological mechanisms involved in the development of pre-eclampsia as well as its more severe adverse outcomes will perhaps allow the development of efficacious, targeted, therapeutic interventions against them.