Pre-eclampsia is a global health problem, which complicates 2–8% of all pregnancies and contributes to 15% of preterm births and 9–26% of maternal deaths worldwide (World Health Organization (WHO), 2005; Duley, 2009; Steegers et al, 2010). The incidence of pre-eclampsia is likely to have increased yet further with the global increase in maternal age, obesity, assisted reproductive techniques and medical comorbidities that predispose women to pre-eclampsia, such as diabetes, hypertension and renal disease.
In simple terms, pre-eclampsia is thought to arise from failure of the normal development of the maternal–fetal interface in the placenta (Redman, 1991; Roberts and Redman, 1993; Granger et al, 2001); however, the precise mechanism remains unknown. Rapid advances in understanding have opened up new avenues of exploration in screening for, and prevention of, pre-eclampsia with the potential to significantly improve outcomes in the future. The aetiology of the disease is multifactorial and interventions for prevention and management will need to address a wide range of factors incorporating lifestyle and diet modification, and multidisciplinary care. Pre-eclampsia is a risk to health not only in the immediate peripartum period—women who have suffered from pre-eclampsia are at increased risk of cardiovascular disease throughout life (Irgens et al, 2001; Smith et al, 2001; Ray et al, 2005; Bellamy et al, 2007).
Hypertensive disorders of pregnancy
Hypertensive disorders of pregnancy may be subclassified into four groups (Chappell et al, 2008; Bramham et al, 2014):
The International Society for the Study of Hypertension in Pregnancy (ISSHP) has published guidelines to establish global unity in nomenclature referring to the hypertensive disorders of pregnancy, with the most recent guidance being released in 2014 (Tranquilli et al, 2014).
Accuracy of measurements
Blood pressure
Blood pressure should be measured with the woman at rest and the arm held at the level of the heart. If the woman is supine she should be in the left lateral position (Petrie et al, 1986). An appropriately sized cuff should always be used. In pregnancy, diastolic pressure is measured at the 5th Korotkoff sound.
Proteinuria
Proteinuria is best measured using a 24-hour urine collection, although even this test is susceptible to error (Chappell and Shennan, 2008). In practical terms the necessary delay in obtaining a result makes this test suboptimal for facilitating rapid decision-making. A spot protein creatinine ratio provides a more rapid result. A value of 30 mg/mmol or more indicates significant proteinuria (Chappell and Shennan, 2008). A negative protein creatinine ratio test (i.e. less than 30 mg/mmol) has a high negative predictive value (the woman is very unlikely to have pre-eclampsia), but a positive test should ideally be followed-up by a 24-hour urine collection to measure proteinuria.
Often in clinical practice, neither a 24-hour urine collection nor a spot protein creatinine ratio is readily available, and clinical management may be based on dipstick assessment for proteinuria. In women in whom pre-eclampsia is strongly suspected, a negative urine dipstick test should be interpreted with caution because its sensitivity is poor (negative predictive ratio 0.6 (Chappell and Shennan, 2008)) and many cases of pre-eclampsia would be missed if relying on dipstick testing alone.
Definitions of the hypertensive disorders of pregnancy
Chronic hypertension
Any woman presenting at booking with hypertension may have pre-existing chronic hypertension. Women with chronic hypertension should be referred early to an obstetric medicine service for the management of their pregnancy, as they are at increased risk of pre-eclampsia.
Gestational hypertension
Hypertension detected for the first time after 20 weeks of pregnancy and in the absence of any other features of pre-eclampsia is classified as gestational hypertension. However, there is a significant risk of progression to pre-eclampsia of around 25% (Tranquilli et al, 2014). Therefore, women with gestational hypertension require increased monitoring throughout pregnancy.
Pre-eclampsia
The classical definition of pre-eclampsia has been new onset hypertension associated with pregnancy after 20 weeks with proteinuria (bearing in mind that in both pre-eclampsia and gestational hypertension the presentation may occur postpartum). The most common presentation of pre-eclampsia is hypertension detected at a routine antenatal visit in an asymptomatic woman. The common symptoms of pre-eclampsia may present late and overlap to some degree with those of normal pregnancy—epigastric pain, nausea and vomiting, peripheral and facial oedema, headache with or without visual scotomas or blurred vision. On examination, women may be hyper-reflexic and may have marked clonus, an altered mental state or right upper quadrant tenderness on palpation.
Many women clearly have a pre-eclampsia-like syndrome with similar prognosis and outcomes but have either no hypertension or no proteinuria. All guidelines currently in use require hypertension in order to diagnose pre-eclampsia (WHO, 2011; American Congress of Obstetricians and Gynecologists (ACOG), 2013; Tranquilli et al, 2014). However, it should be noted that proteinuria is no longer required to establish the diagnosis in the presence of other maternal organ dysfunction or uteroplacental dysfunction (Tranquilli et al, 2014). This is because it is vital to recognise the breadth of presentation of pre-eclampsia and not dismiss, for example, a severely hypertensive woman with marked intra-uterine fetal growth restriction as having gestational hypertension.
Pre-eclampsia superimposed on chronic hypertension
If a woman with pre-existing hypertension develops superimposed pre-eclampsia, it may be difficult to diagnose, particularly if she also has pre-existing proteinuria due to renal disease. However, in general terms, if a woman with pre-pregnancy hypertension develops worsening hypertension in combination with either proteinuria, new organ dysfunction or uteroplacental dysfunction, then pre-eclampsia may be diagnosed.
Screening for pre-eclampsia
It is demonstrable that early identification and close monitoring of high-risk women produces better maternal and fetal outcomes, so effective screening is an urgent research priority. Historically, screening took the form of regular blood pressure and urine checks throughout pregnancy for all women. In the UK today the National Institute for Health and Care Excellence (NICE) recommends using maternal history, age, body mass index (BMI) and number of fetuses to select women for treatment with low-dose aspirin (NICE, 2010).
Using a risk-factor-based approach like this will identify a large number of women, most of whom do not go on to develop pre-eclampsia, and miss the considerable cohort of ‘low risk’ women who do manifest the disease. A number of novel strategies are under investigation.
First trimester screening
The primary intervention that has been shown to reduce the incidence of pre-eclampsia is low-dose aspirin started prior to 16 weeks of pregnancy (Villa et al, 2013). It is likely that any intervention that would prevent pre-eclampsia would also be most effective in the first trimester when placentation occurs. A screening test that would take advantage of that would need to provide a sensitive assessment of risk prior to 16 weeks.
Pre-eclampsia is known to be associated with a derangement of the serum markers of angiogenesis and these markers are thought to have potential value in screening for pre-eclampsia. Markers evaluated for screening include pregnancy-associated plasma protein A (PAPP-A) (Dugoff et al, 2004), placental protein 13 (PP-13) (Romero et al, 2008), homocysteine, asymmetric dimethylarginine (ADMA), a disintegrin and metalloprotease 12 (ADAM 12) (Poon et al, 2008), uric acid (Thangaratinam et al, 2006) and leptin. None of these has adequate predictive accuracy individually as a clinical test but several groups of researchers have proposed models that include a combination of factors to identify women at risk of pre-eclampsia (Poon and Nicolaides, 2014a). It has been shown that the combination of ultrasound assessment of uterine artery Dopplers, a variety of serum markers and maternal risk factors can provide a sensitive screening test in the second trimester (Onwudiwe et al, 2008).
A first trimester model incorporating mean arterial pressure (MAP), uterine artery resistance, PAPP-A and placental growth factor (PIGF) in the first trimester has reported detection rates as high as 96% for early-onset pre-eclampsia (Poon and Nicolaides, 2014b). Given that the greatest maternal and neonatal morbidity is associated with early-onset pre-eclampsia, screening tests like this could offer an opportunity to move the focus from diagnosing pre-eclampsia in the third trimester to preventing it in the first trimester (Poon et al, 2013).
PlGF triage
To improve detection later in pregnancy, the soluble Fms-like tyrosine kinase 1 (sFlt-1)/PIGF ratio has been evaluated as a diagnostic and screening test, and has been found to have high specificity and sensitivity for pre-eclampsia, particularly for early onset disease (Verlohren et al, 2010). Subsequent investigations have shown that it may be possible to discriminate between the hypertensive disorders of pregnancy using this ratio (Engels et al, 2013). This approach provides the possibility of rapid testing to predict or clarify a diagnosis of pre-eclampsia once clinical suspicion is present, and such a test is now commercially available. PlGF in isolation has been shown to predict among those presenting with suspected pre-eclampsia at less than 35 weeks' gestation those women who are likely to require delivery within the next 14 days (Chappell et al, 2008). These strategies could help direct hospital and outpatient management of pre-eclampsia in the future, but do not afford the opportunity to identify high-risk women at a time when pre-eclampsia could potentially be prevented.
Antenatal care of women with pre-eclampsia
Once pre-eclampsia has been diagnosed, subsequent management will be determined largely by gestation and severity. The cure for pre-eclampsia is simple—delivery of the placenta will ultimately lead to resolution of the disease. The challenges are in balancing the maternal risks of continuing pregnancy against the maternal risks of intervention and the fetal risks of preterm delivery (Tranquilli et al, 2014). While opting to continue pregnancy, the goals of treatment are to maintain a safe blood pressure, monitor the mother for deterioration and the fetus for signs of placental dysfunction and compromise (Steegers et al, 2010).
Following the diagnosis of pre-eclampsia, ultrasound assessment of fetal wellbeing and Doppler studies of the umbilical artery and middle cerebral artery should be performed (Milne et al, 2009; Tranquilli et al, 2014). All women should have a full blood count, and renal and liver function checked; a coagulation profile is necessary only if the platelet count is low (NICE, 2010).
Antihypertensive therapy
Antihypertensive therapy aims to control blood pressure, thereby reducing the risk of severe hypertension and cerebrovascular accidents (stroke), cardiovascular strain and renal injury. NICE guidance recommends commencing antihypertensive therapy when blood pressure exceeds 150/100 mmHg (NICE, 2010). The importance of treating systolic hypertension (not just diastolic hypertension) was stressed in the 2011 Centre for Maternal and Child Enquiries (CMACE) report (Cantwell et al, 2011). Failure to do so was a feature of several maternal deaths from cerebral haemorrhage and aortic dissection. The subsequent Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries (MBRRACE) report demonstrated that maternal deaths secondary to hypertensive disorders of pregnancy are now at the lowest level ever recorded. Only 10 women died in the triennium 2009–2011 (0.42 per 100 000 pregnancies) (Knight et al, 2014).
NICE recommends that the first-line antihypertensive should be labetalol; however, there is insufficient evidence as to which antihypertensive is most effective (Duley et al, 2013), and methyldopa and nifedipine are both acceptable and commonly used alternatives.
Severe hypertension (>160/100 mmHg) requires urgent treatment. However, this may be commenced orally in the absence of signs of impending eclampsia (Steegers et al, 2010; Tranquilli et al, 2014). It is important to avoid causing relative hypotension and compromising uteroplacental circulation but still reducing the blood pressure to a level not associated with cerebral adverse events. The target of treatment should be to maintain the blood pressure at <150/100 mmHg; aim for a diastolic blood pressure around 90 mmHg (NICE, 2010; Tranquilli et al, 2014).
Out-patient management
Women with stable blood pressure <150/100 mmHg (with or without treatment), normal laboratory studies, no concern about fetal wellbeing and a good understanding of their condition are candidates for out-patient management in a specialised day assessment unit (Milne et al, 2009; NICE 2010). There is no evidence to support bed rest in the hypertensive disorders of pregnancy, and there is a risk of harm from reduced mobility in terms of increased risk of thrombosis and psychosocial harm (ACOG, 2013). Women should have their diagnosis and the warning signs of progressive disease explained to them clearly, and the appropriate contact points documented in their maternity notes.
Severe pre-eclampsia
Women with severe pre-eclampsia should be managed as in-patients. It is common practice to continue pregnancy until the woman's condition can no longer be adequately stabilised (expectant management) (Churchill et al, 2013). Because delivery may become necessary, corticosteroids to improve fetal lung maturity should be considered at the time of the diagnosis of severe early-onset pre-eclampsia. Women who meet the criteria for the diagnosis of severe pre-eclampsia should be considered for treatment with magnesium sulphate for eclampsia prophylaxis. Magnesium sulphate is associated with a 50–67% reduction in the risk of seizures, a reduction in the risk of maternal death, and may have some benefit to the baby (Altman et al, 2002). The standard protocol is as described in the Collaborative Eclampsia Trial (The Eclampsia Trial Collaborative Group, 1995), i.e. a 4 g loading dose with a maintenance infusion of 1 g/hr.
Eclampsia
Eclampsia is an obstetric emergency and the first priority is to stabilise the mother. Most eclamptic seizures are self-limiting; however, magnesium sulphate should be commenced as soon as possible as it is the best treatment for managing seizures and for preventing repeat seizures (The Eclampsia Trial Collaborative Group, 1995), not only for preventing the first seizure in women with severe pre-eclampsia (Altman et al, 2002). If magnesium sulphate therapy has already been commenced, a further bolus may be given, and the maintenance infusion may be increased to 2 g/hr (The Eclampsia Trial Collaborative Group, 1995). Hypertension should be controlled; the intravenous route is preferable in this situation. Recurrent seizures may warrant intubation and paralysis in order to maintain adequate oxygenation. Fetal monitoring is not the main priority until the mother has been stabilised. Auscultation or CTG will inevitably show a fetal bradycardia during and immediately after a seizure, but the primary interventions are seizure and blood pressure control, not immediate delivery. Resuscitation and stabilisation of the mother will also resuscitate the baby.
Timing of delivery
At any gestation, birth is indicated for life-threatening maternal disease, which may take the form of severe refractory hypertension, eclampsia, placental abruption or rapidly deteriorating HELLP syndrome or renal dysfunction. Birth may be achieved vaginally in selected cases, but is often by Caesarean section (Steegers et al, 2010; ACOG, 2013). After the age of viability, birth may also be indicated for serious fetal compromise. If this is the primary indication for delivery at 24–26 weeks, there should be a frank discussion with the parents regarding the poor prognosis for the baby, particularly in the setting of marked intrauterine growth restriction, and the potential complications of preterm surgery and classical uterine incision, before proceeding with delivery. In pregnancies before 34 weeks without immediate risk to mother or baby, expectant management with close monitoring is the best strategy (Churchill et al, 2013).
In all cases, the mother should be stabilised before proceeding to birth. Performing a category one caesarean section immediately after an eclamptic seizure without full assessment exposes the mother to severe risks. The risks of surgery in this situation include those related to anaesthesia including failed intubation, severe hypertension (triggered by intubation), aspiration or a further cerebral event. Surgical risks include bleeding secondary to an undetected coagulopathy, intra-operative damage to bladder and ureters due to rushed, potentially complex, surgery (Steegers et al, 2010). Once the woman has been stabilised, any necessary blood products ordered and the appropriate obstetric, anaesthetic and neonatal team assembled, birth can be accomplished safely, if indicated (NICE, 2010).
In the presence of stable hypertensive disease without severe features before 34 weeks, delivery is not indicated. Between 34 and 37 weeks, worsening disease should prompt a thorough review of the clinical scenario and consideration of birth (NICE, 2010).
After 37 weeks' gestation, any woman with gestational hypertension or mild-to-moderate pre-eclampsia should be offered delivery (NICE, 2010). The HYPITAT trial randomised women in this category to early induction (at 37 weeks) or expectant monitoring (Koopmans et al, 2009). The trial clearly demonstrated that induction of labour at this gestation reduces the risk of maternal complications and carries no additional risk to the baby. In addition, this strategy does not increase the risk of Caesarean section.
The HYPITAT study was conducted in a European population where common practice is not to initiate antihypertensive therapy until hypertension meets the criteria for severe hypertension and may not be directly applicable to a UK population, where it could be anticipated that a greater number of women would be on antihypertensive therapy. However, the findings that earlier induction did not increase the Caesarean section rate or neonatal morbidity are consistent with the DIGITAT study (Boers et al, 2010) and the results of a large retrospective Scottish study (Stock et al, 2012) and suggest that the risk–benefit profile is indeed in favour of induction after 37 weeks even in women with mild disease.
Intrapartum care
Women with gestational hypertension and pre-eclampsia of any severity have a higher risk of placental insufficiency and subsequent fetal hypoxic stress during labour. For this reason, they should be recommended continuous fetal monitoring in labour. Blood pressure should be measured at least hourly and any antihypertensive medication continued. There is no indication to limit the length of the second stage of labour if the blood pressure is well-controlled. However, in the event of severe uncontrolled hypertension or neurological symptoms, elective instrumental delivery should be recommended.
In the third stage, ergometrine should be avoided for women with known hypertensive disease of any kind, even if the blood pressure is normal at the time of birth. Several maternal deaths have been provoked by the hypertension associated with the use of ergometrine (Cantwell et al, 2011).
Postnatal care
Although delivery is the cure for pre-eclampsia and related disorders, resolution is often not immediate and many women may initially deteriorate after birth, or re-present some days later with worsening disease.
Postpartum hypertension
In normal pregnancy, blood pressure falls immediately after birth and peaks 3–6 days later. In hypertensive women, this is also the case, and women frequently experience a further spike in their blood pressure several days postpartum. In fact, 32-44% of all eclampsia occurs postpartum, so continued vigilance is essential (Bramham et al, 2013).
Other factors that can cause or exacerbate hypertension postpartum are pain, anxiety, the use of certain drugs (such as ergometrine) and fluid overload in labour. These factors should be assessed, and analgesia and fluid management adjusted as necessary before altering antihypertensive therapy.
Post-pregnancy debriefing and planning for future health
It is important that women clearly understand their diagnosis and the rationale for any interventions during pregnancy. Ideally, the senior clinician involved would have the opportunity to debrief the woman postnatally, but in reality this task often falls to the midwives and junior doctors on the postnatal wards. For more complicated cases a formal postnatal debriefing appointment should be arranged.
It is important to convey the following three messages:
Future developments in management of the hypertensive disorders of pregnancy
A growing body of research has demonstrated that increased antenatal surveillance and monitoring in women known to be at high risk produces better maternal and fetal outcomes in women affected by pre-eclampsia. A current research priority is identifying accurately those women at high risk and appropriately targeting care while avoiding over-medicalisation of otherwise normal women.
Conclusion
Pre-eclampsia remains a potentially serious complication of pregnancy. Faced with a likely rising incidence and armed with a growing understanding of the complex factors that underlie the disease, we are challenged with identifying high-risk women in new ways and developing an individualised approach to management, involving the woman in the management and monitoring of her condition.