Andrew Shennan
MB BS FRCOG MD
Professor of Obstetrics
Anja Wilton
MB BS
Honorary Clinical Fellow
King’s College
London, UK
More than one in 10 women will become hypertensive in pregnancy, although the syndrome of pre-eclampsia – characterised by hypertension and proteinuria with its associated maternal and fetal morbidity and mortality – affects less than 5%. However, even in developed countries it is a major cause of maternal death.(1) About 15% of all preterm births can be attributed to pre-eclampsia. One in four of babies born under 1500g are from pre-eclamptic mothers. An eclamptic fit complicates only one in 2,000 pregnancies and therefore about 1% of women with pre-eclampsia. Most women who die from this disease will not suffer an eclamptic fit. However, 2% of women who have an eclamptic fit will die, but this represents a particularly severe form of the disease.(2)
Women in their first pregnancy are twice as likely to develop pre-eclampsia, while women with a risk factor, such as an underlying cardiovascular problem (eg, hypertension, diabetes or anti-phospholipid syndrome), have approximately a one in five chance of developing the disease. Multiple pregnancy and obesity are also important risk factors. Table 1 shows the risk factors for developing pre-eclampsia in the pregnancy at antenatal booking.
[[HHE06_table1_C51]]
Clinical features
Inadequate trophoblast invasion results in widespread endothelial dysfunction that is possibly related to an abnormal maternal inflammatory response and oxidative stress. The consequent vasoconstriction results in hypertension (diastolic blood pressure =90mmHg on two occasion more than four hours apart), while glomerular damage causes proteinuria (>300mg/24 hours). These two signs have become key diagnostic features but the maternal renal, hepatic, cardiovascular, central nervous or haematological systems can all be affected. Placental insufficiency results in growth restriction usually with early onset pre-eclampsia where it affects about one in four fetuses. Fetal morbidity is also related to iatrogenic prematurity. The course and onset of the disease is highly unpredictable and often asymptomatic. Headache, epigastric pain, nausea, vomiting and visual disturbance – although clinical symptoms of pre-eclampsia – are far from uniform even in serious disease. Eclampsia can occur in women with relatively normal blood pressures. The unpredictability of the disease results in extensive inpatient care. Long-term problems can face the very premature infant. Therefore, improved prediction and prevention of the disease would have a major impact on healthcare.
Identifying those at risk
Taking a careful history can help to assess those at risk and this is recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK.(4) Screening for pre-eclampsia can involve either chemical or haemodynamic parameters. The disease is diagnosed only when end-organ damage, such as hypertension and proteinuria, has occurred. Biochemical markers of placental and endothelial origin are raised before the clinical manifestations of the disease. These may not give perfect results, but recent research shows that combinations of these markers do provide clinically important means of prediction. Doppler ultrasound of the uteroplacental vessels is probably the best predictor although positive predictive values remain modest (~20%). This test is based on defective physiological conversion of the spiral arteries to accommodate the growing uterus. Bilateral arterial notching in the waveform from the second trimester is associated with severe early onset of the disease.
[[HHE06_fig1_C50]]
Prophylactic measures
Low dose aspirin can be used to prevent pre-eclampsia but only in a minority of women. These cyclooxygenase inhibitors improve the prostacyclin/thromboxane imbalance. Trials on more than 30,000 women show approximately a 15% reduction in the risk of pre-eclampsia with associated benefits in reduced fetal death.(5) Routine Doppler screening has not been recommended although it may become a way of targeting prophylactic measures in the future. Other preventative measures that have been investigated include fish oils, calcium and antioxidants. Prophylactic calcium (1.5g/day) has not been shown to reduce pre-eclampsia but may improve outcomes including maternal morbidity and neonatal mortality in a developing world setting.(6) Recently the early promise of high-dose vitamin C and E to reduce pre-eclampsia has been refuted; indeed, it may even increase the risks to the pregnancy.(7)
Diagnosis and management
Assessment of risk, close antenatal surveillance, and early recognition and intervention therapy are the mainstays of management. Booking blood pressure should be measured accurately and secondary causes of hypertension investigated in early pregnancy if hypertension is new.(8) Risk factors should be carefully evaluated to plan a schedule of antenatal visits. Urine dipsticks must always be performed with regular blood pressure assessments.(3)
Because there are many false positives and negatives with urinalysis, the NICE guidelines recommend automated urinalysis readers and that point-of-care tests be confirmed with 24-hour urine collections. Proteinuria levels over 300mg in a 24-hour collection should be considered significant. Korotkoff sound IV should be used to determine diastolic blood pressure.(9) Women with symptoms indicating disease progression, such as headache, visual disturbance and epigastric pain, should be closely monitored. They can be assessed in an obstetric day unit if diagnosis is uncertain.
Once the diagnosis of pre-eclampsia is established, admission to hospital is required for surveillance of blood pressure and biochemical parameters including liver, clotting and renal functions. Regular growth scans, Doppler ultrasound of the umbilical arteries as well as cardiotocography are also vital to ensure fetal wellbeing. Delivery is usually required within two to three weeks of admission because the disease is progressive. This can be for either fetal or maternal reasons. Inducing labour is possible but an elective caesarean section is often required if the fetus is compromised.
Severe hypertension should be avoided. Antihypertensive treatment itself does not alter disease progression but it is worthwhile since cerebral haemorrhage is an important cause of death. When diastolic blood pressure is 100mmHg or more then alpha-methyldopa is often instigated. Alternatively beta-blockers and calcium channel-blockers are equally efficacious. ACE inhibitors should be avoided because they are toxic to the fetal kidney.
Magnesium sulfate (MgSO(4)) should be used to prevent further fits after eclampsia. It is also beneficial when given as a prophylactic agent to prevent fits in pre-eclamptic women requiring delivery.(10) Given the large numbers of women needing treatment, only severe cases should be treated with MgSO(4) to prevent a fit. Post- pregnancy counselling should be offered to all women, particularly those with severe pre-eclampsia, because they are affected by a recognised risk factor for future cardiovascular events. Previous pre- eclampsia presents a risk for future pre- eclampsia. However, the majority of women will not develop the disease again and it will be less severe for those who do.
Conclusion
Care in targeting high-risk populations and establishing diagnosis is likely to improve the management of pre-eclampsia. There remains room for improvement with prophylactic therapies, such as aspirin, as well as acute phase treatment like anticonvulsant and antihypertensive treatment. MgSO(4) is indicated to prevent fits in women with eclampsia.
References
- Department of Health. Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom. London: ROCG Press; 2001. p. 1197-99.
- Douglas KA, Redman CW. Eclampsia in the United Kingdom. BMJ 1994;309:1395-1400.
- Shennan AH, Waugh J. Pre-eclampsia. London: RCOG Press; 2003.
- National Institute for Clinical Excellence. NICE Guideline CG6: antenatal care – routine care for the healthy pregnant woman. London: NICE; 2003.
- Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2004;(1):CD004659.
- Villar J, Abdel-Aleem H, Merialdi M, et al. WHO randomised trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol 2006;194:639-9.
- 7. Poston L, Briley AL, Seed PT, et al. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367: 1145-54.
- Penny JA, Shennan AH, Halligan AW, et al. Blood pressure measurement in severe pre-eclampsia. Lancet 1997;349:1518.
- Shennan AH, Gupta M, Halligan A, et al. Lack of reproducibility in pregnancy of Korotkoff phase IV as measured by mercury sphygmomanometry. Lancet 1996;347:139-42
- Altman D, Carroli G, Duley L, et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002;359:1877-90.
