Pre-eclampsia is a pregnancy-specific disorder, characterised by hypertension and multi-organ system involvement, that occurs in approximately 2-8% of pregnancies worldwide. Hypertensive disorders, including pre-eclampsia, remain one of the leading causes of maternal morbidity and a great contributor of maternal and perinatal mortality. Globally, approximately ten million women develop pre-eclampsia each year, and an estimated 76 000 pregnant women die annually from pre-eclampsia and related hypertensive disorders. There is also a high relative risk of fetal death in pregnancies diagnosed with pre-eclampsia. Despite ongoing research, the pathogenesis of pre-eclampsia remains unclear. This article will focus on the diagnosis, risk factors and aetiology of pre-eclampsia, while attempting to outline the collaborative management options for treatment and prevention.
Diagnosis of pre-eclampsia
Traditionally, pre-eclampsia is diagnosed as a new onset of hypertension and proteinuria after 20 weeks of gestation (Chaiworapongsa et al, 2014a). Hypertension in pregnancy is classified as a systolic blood pressure greater than or equal to 140 mmHg, and a diastolic blood pressure greater than or equal to 90 mmHg on two separate measurements taken 4–6 hours apart (Tannetta and Sargent, 2013). A diagnosis of proteinuria in pregnancy is when the total weight of protein in urine is greater than or equal to 300 mg in a 24-hour period (Chaiworapongsa et al, 2014b). Although hypertension is an essential element in the diagnosis of pre-eclampsia, the presence of proteinuria is not critical, and as a result, pre-eclampsia can be separated into non-proteinuric or proteinuric pre-eclampsia (Shennan, 2016). Non-proteinuric pre-eclampsia involves new onset of hypertension and the existence of systemic disease, which may include liver involvement, renal insufficiency, neurological and haematological complications, fetal growth restriction and uteroplacental dysfunction (Mol et al, 2016). The rationale for the exclusion of proteinuria in the diagnosis of pre-eclampsia is that pre-eclampsia may be evident before renal involvement has occurred (Chaiworapongsa et al, 2014a).
Numerous risk factors have been identified that may predict the onset of pre-eclampsia in pregnant women. A recent large systematic review and meta-analysis of 92 studies recognised several risk factors that identified women at high risk of developing pre-eclampsia (Bartsch et al, 2016). Factors that were considered high risk for the development of pre-eclampsia included previous history of pre-eclampsia; chronic hypertension in pregnancy; autoimmune conditions (such as systematic lupus erythematous); pre-gestational Type 1 or Type 2 diabetes mellitus; the use of reproductive technology; and a body mass index (BMI) greater than 30 (Bartsch et al, 2016). Other risk factors considered moderate risk for developing pre-eclampsia include an interval of more than 10 years between pregnancies; polycystic ovary syndrome; multiple pregnancies; and a family history of pre-eclampsia (Mol et al, 2016). Interestingly, nulliparity is also a risk factor for developing pre-eclampsia. This is thought to be caused by the mechanism of the maternal immune system towards seminal fluid and/or spermatozoa. When the maternal immune system is repeatedly exposed to the same spermatozoa and seminal fluid, it builds a tolerance towards the paternal antigens residing in the semen (Chaiworapongsa et al, 2014b). Therefore, prolonged exposure to the same semen is thought to decrease a women's risk of developing pre-eclampsia. Women with only one kidney are more than twice as likely to develop pre-eclampsia than women who have two kidneys; however, approximately 30% of women with any of the risk factors mentioned above will present clinically with a diagnosis of pre-eclampsia (Mol et al, 2016).
Aetiology of pre-eclampsia
Eclampsia was first thought to be a convulsive disorder of pregnancy, and due to the rapid onset of convulsions and seizures in pregnant women. The term ‘eclampsia’ originates from the Greek word eklampsis (meaning ‘lightning’) (Orjuela and Ruland, 2016). In 1840, the presence of albumin in urine was noted in women with eclampsia, and nearly 50 years later, hypertension was also recognised in this group of women. Subsequently, the term ‘pre-eclampsia’ was introduced to describe the state which precedes eclampsia.
Despite years of research, the exact underlying cause and progression of pre-eclampsia still remains poorly understood. A central theory that substantiates knowledge of pre-eclampsia is that the disorder results from placental ischaemia, in which a reduction in perfusion results in a number of bioactive factors being released into the maternal blood stream, which then initiates the clinical signs and symptoms that are often associated with pre-eclampsia (Shah and Khalil, 2015).
The first stage of pre-eclampsia occurs early in the first trimester of pregnancy, when the blastocyst is implanting into the myometrium of the uterus. In a normal pregnancy, the trophoblast cells on the leading edge of the blastocyst invade the arterial wall of the uterus, initiating the formation and remodelling of the spiral arteries, which allow the inter-villous space of the placenta to be adequately perfused (Tannetta and Sargent, 2013). In pre-eclampsia, the spiral arteries fail to undergo this physiological transformation, leading to the inadequate perfusion of the placenta, known as uteroplacental ischaemia (Palei et al, 2013). However, this failure of the spiral arteries to undergo physiological transformation is not specific to pre-eclampsia alone, and has also been observed in other conditions associated with pregnancy, including placental abruption, preterm premature rupture of membranes and intrauterine growth restriction (Chaiworapongsa et al, 2014a).
The second stage of pre-eclampsia arises in the second half of the second trimester of pregnancy, and into the third. As the fetus grows, the oxygen demand on the placenta increases. The placenta begins to struggle with the intermittent or inadequate blood supply, which results in oxidative stress and hypoxia. This then leads to the blastocyst excessively releasing anti-angiogenic factors and microparticles to compensate for the placental ischaemia (Snydal, 2014). These factors and particles trigger the release of inflammatory cytokines, leading to a widespread inflammatory response and the aggravation of endothelial cells throughout the body (Palei et al, 2013). The entire circulatory system is lined with endothelial cells, whose dysfunction can cause vascular excitability, resulting in the symptoms associated with pre-eclampsia. The more extensive the placental dysfunction is, the earlier the symptoms of pre-eclampsia manifest in pregnancy (Snydal, 2014).
The clinical presentation of pre-eclampsia varies significantly among women. Often, women with pre-eclampsia are asymptomatic and are frequently diagnosed during routine antenatal care (Townsend, et al, 2015). During routine antenatal assessment, monitoring of blood pressure and assessing for proteinuria are used to screen for pre-eclampsia. Women with pre-eclampsia may present with involvement of one or more organ systems, including cardiovascular, renal, hepatic, neurological and cardiopulmonary (Rosser and Katz, 2013).
The systemic hypertension associated with pre-eclampsia results from vascular hyperactivity, which is caused by the excessive inflammation and endothelial dysfunction. The effect of endothelial malfunction is excessive blood-clotting and leukocyte activation, which can lead to widespread fluid leakage from the interstitial space and thrombocytopenia (Brennan et al, 2014). Oedema may also be present in the lower extremities, due to the failure of the normal vasodilatory function and increased haemoconcentration caused by pregnancy.
Renal involvement in pre-eclampsia is caused by the hypertrophy and swelling of endothelial cells lining the glomerulus (Müller-Deile and Schiffer, 2014). This hypertrophy results in a reduction of glomerular filtration and the presence of proteinuria in urine, reducing filtration and the presence of proteinuria may progress into oliguria and severe renal failure.
Women with hepatic involvement may present with epigastric, shoulder or right upper quadrant abdominal pain and tenderness on palpation of the liver (Snydal, 2014). This pain is often related to areas of infarction and necrosis within the liver itself. This cell death is a direct result of haemolysis and a build-up of fibrin deposits caused by the destruction of the small blood vessels within the liver (Banerjee, 2017). In severe cases, liver damage may lead to disseminate intravascular coagulation and increased incidence of postpartum haemorrhage.
Central nervous system involvement includes eclampsia, stroke, and reversible ischaemic neurological deficits. Eclampsia is the onset of seizures and an extremely serious progression of pre-eclampsia, and it is thought that the endothelial lining of the cranial blood vessels may malfunction, causing fluid to leak into the brain and leading to cerebral oedema (Mol et al, 2016). The blood vessels overreact as a result of the increased stress, which leads to vasospasm and seizures occurring. Women with neurological involvement may also present with headaches or visual disturbances, including loss of vision.
Endothelial dysfunction in pre-eclampsia may also result in cardiopulmonary complications and respiratory distress. Endothelial dysfunction in the capillaries surrounding the alveoli of the lungs may cause fluid leakage from the blood vessels and into the alveoli. This fluid build-up results in pulmonary oedema, leading to reduced oxygen saturations and shortness of breath (Snydal, 2014). Pulmonary oedema may also progress into a pregnancy-related acute respiratory distress syndrome (ARDS), which has a very high mortality rate (Lapinsky, 2017). This pulmonary oedema often occurs in the postpartum period for women with pre-eclampsia.
Clinical presentation of pre-eclampsia involving the fetus includes oligohydramnios, intrauterine growth restriction and the absence of, or reverse direction of, end diastolic flow of the placental cord (Hu et al, 2016).
The clinical presentation and diagnosis of women with pre-eclampsia is suggestive of underlying multisystem organ dysfunction and morbidity. Women with severe pre-eclampsia may develop life-threatening complications, often known as HELLP syndrome, which is comprised of three components: haemolysis, elevated liver enzymes and low platelet count. HELLP syndrome has an acute onset with rapid deterioration, and may occur with or without severe hypertension or proteinuria (Mol et al, 2016).
Collaborative management and treatment of pre-eclampsia
The most effective treatment for pre-eclampsia is the birth of both the baby and placenta (Amaral et al, 2015). There are a number of effective treatment options in the antenatal, intrapartum and postnatal period that successfully prevent complications of pre-eclampsia from occurring; however, these treatment options do not halt the underlying disease process of pre-eclampsia.
The overall aim of antenatal treatment of pre-eclampsia is to stabilise the mother and fetus until term gestation is reached. Antihypertensive medications are commonly administered to decrease blood pressure and to lower the risk of adverse outcomes occurring for both mother and fetus (Chaiworapongsa et al, 2014b). Optimal blood pressure for women with pre-eclampsia is a systolic blood pressure of 140–160 mmHg and a diastolic of 90–100 mmHg (Snydal, 2014). Methyldopa and labetalol are both considered the antihypertensive drugs of choice for the treatment of mild and moderate hypertension in pregnancy (Al Khaja et al, 2014). Both are considered safe in pregnancy and do not appear to be teratogenic. Corticosteroids, such as betamethasone, may also be administered antenatally to women diagnosed with pre-eclampsia in the event that they may progress to a pre-term birth. Betamethasone encourages fetal lung maturity and reduces the incidence of respiratory distress syndrome in babies (Brown and Garovic, 2014).
Another treatment option for women with pre-eclampsia is the administration of magnesium sulphate. Magnesium sulphate is considered the first-line drug of choice for controlling seizures in eclamptic women and seizure prophylaxis in pre-eclamptic women. Magnesium sulphate may be administered during the antenatal assessment of disease status, either pre-operatively before caesarean section or during the induction of labour, and may be continued postpartum following birth (Moroz et al, 2016). Magnesium sulphate has been shown to reduce the risk of eclampsia by more than 50% (Okusanya et al, 2016); however, it is not an antihypertensive medication and caution is advised when it is used for this purpose. Women who are given magnesium sulphate should be constantly assessed for signs of toxicity, which may include lethargy, hypotension, bradycardia and headaches (Moroz et al, 2016).
Timing of birth is also an important aspect that needs to be considered for the treatment of pre-eclampsia. The sooner the placenta is removed, the less likely the mother is to develop life-threatening or serious complications. The timing of birth is based on the neonatal risk of ending the pregnancy versus the maternal and neonatal risks associated with continuing the pregnancy (Mol et al, 2016).
Prevention of pre-eclampsia includes a broad range of interventions that have been considerably investigated in an attempt to reduce the risk of women developing pre-eclampsia. Interventions that have been tested include aspirin, low dose heparin, calcium supplementation, low salt diets, diuretics, antioxidants and fish oil tablets (Chaiworapongsa et al, 2014b). The administration of low dose aspirin has been extensively researched and is the only preventative intervention that may be given to women who are at high risk of developing pre-eclampsia (Brown and Garovic, 2014). Aspirin prevents platelets from producing thromboxane, which causes systemic inflammation; therefore, a daily dose of 75 mg of low dose aspirin is recommended from 12 weeks' gestation until birth.
Calcium supplementation has also been proposed as an intervention for reducing the risk of developing pre-eclampsia in pregnant women as calcium deficiency has previously been associated with the development of pre-eclampsia (Chaiworapongsa et al, 2014b). The use of calcium supplementation for the prevention of hypertensive disorders has been reported as halving the risk of pre-eclampsia and reducing the risk of preterm birth (Hofmeyr et al, 2014).
Long term implications of pre-eclampsia
Pre-eclampsia is a pregnancy specific disorder that usually disappears after the birth of the baby and the removal of the placenta. Women who have experienced a pregnancy complication, such as a hypertensive disorder, are at risk for cardiovascular disorders (Snydal, 2014). Women who have had multiple pregnancies affected by pre-eclampsia are at much greater risk of end-stage renal disease (Chaiworapongsa et al, 2014b). A diagnosis of pre-eclampsia identifies a vulnerable group of women who are at an increased risk of long term health implications, and as a result, may enable early prevention strategies to be initiated, including exercise, diet and pharmacological treatment.
Pre-eclampsia is a progressive disease that is unique to pregnancy and has many different identifiable risk factors. Despite years of research, the underlying mechanisms accountable for the pathogenesis of pre-eclampsia have not yet been identified. Pre-eclampsia can have serious consequences for both mother and fetus and can involve multiple organ systems including the renal, hepatic, neurological, cardiovascular and respiratory systems. As a result, blood pressure monitoring and urine testing should be completed as part of routine antenatal assessment of all women in order to appropriately screen for pre-eclampsia. Removal of the placenta remains the only curative treatment. The timing of birth must be accurately assessed with the risks associated with pre-term birth weighed against the risks of continuing a pregnancy for both mother and baby. Other treatment strategies try to prevent complications of pre-eclampsia occurring, and aim to stabilise the mother and fetus until term gestation is reached. Preventative interventions for pre-eclampsia are disappointing, and the only intervention that has promising results is the administration of low dose aspirin to high-risk women. Further research is required to identify the pathogenesis of pre-eclampsia and to identify more effective preventative management strategies.