Hypertensive disease is one of the most common medical disorders encountered in pregnancy. It remains a leading cause of maternal and foetal morbidity and mortality and is also the most frequent cause of iatrogenic prematurity. There have been several advances in the management of the condition; however, delivery still remains the only definite form of treatment.
Hypertension in pregnancy is defined as a diastolic blood pressure of ≥90mmHg taken on two occasions more than four hours apart or a single diastolic reading of ≥110mmHg. This can occur in women who are already hypertensive or as a new development after 20 weeks of gestation in women who were previously not known to be hypertensive. The latter is called pregnancy-induced hypertension or gestational hypertension.(1) Both groups are at an increased risk of developing pre-eclampsia.
Pre-eclampsia is a multi-system disorder in which hypertension is associated with proteinuria, defined as >300mg protein in a 24 hour urine collection or >30mg/mmol in a spot urinary protein:creatinine sample. The latter is now becoming the preferred method of quantifying urinary protein loss in view of its bed-side availability and rapidity in obtaining a result.
Pre-eclampsia typically manifests itself after twenty weeks of gestation and resolves postnatally. It occurs in 2–8% of all pregnancies whereas severe pre-eclampsia occurs in 1% of pregnancies.(2) The incidence ranges from 4.1% in a first pregnancy to 1.7% in a subsequent pregnancy. The risk rises to 14.7% in the second pregnancy following a previous pregnancy with pre-eclampsia and 31.9% in women who had pre-eclampsia in two previous pregnancies.(3)
Low-dose aspirin reduces the risk of developing pre-eclampsia in women who are at an increased risk. This was demonstrated by a Cochrane review of 59 trials including 37,560 women.(4) The risk reduction varies from 11 to 23% and is highest in women who have significant risk factors for developing the disease (previous pre-eclampsia, chronic hypertension, diabetes, renal disease, autoimmune disease). Therefore, women with these risk factors are recommended to start low-dose aspirin (75mg) from 12 weeks until the birth of the baby.(5) In addition, women with more than one of the following risk factors should be offered the same recommendation(5):
- first pregnancy
- age 40 years or older
- pregnancy interval of more than 10 years
- body mass index of >35kg/m2 at first visit
- family history of pre-eclampsia
- multiple pregnancy.
Other drugs and nutritional supplements have been studied to assess their efficacy in preventing pre-eclampsia, but none have shown any statistically significant effect. The only exception is the use of calcium supplementation in women who are deemed to be at high risk of developing pre-eclampsia and whose diet is low in dietary calcium. This risk reduction is not transferrable to communities with adequate dietary calcium intake.(6)
Investigations in suspected hypertension
Proteinuria has been linked to hypertension in pregnancy since the 19th century, and its severity has always been associated with adverse perinatal outcome leading to decisions to deliver on the basis of levels of proteinuria. However, recent evidence has suggested otherwise. In a systemic review of 16 articles involving 6749 patients with pre-eclampsia and proteinuria of varying severity, it was found that levels of proteinuria did not correlate with maternal or fetal outcomes.(7) Additionally, neonatal morbidity in babies delivered prematurely owing to high levels of proteinuria were related to the prematurity itself rather than the amount of protein in the maternal urine. Proteinuria estimation remains an important test to diagnose pre-eclampsia, but serial testing is not indicated as there does not seem to be a direct link between urinary protein levels and adverse outcome.(5) However, this needs to be confirmed further through well-designed prospective studies.
Pre-eclamptic toxaemia (PET) blood screen
This consists of a full blood count, particularly a platelet count, renal function tests, liver function tests and a coagulation screen in keeping with the multisystem nature of pre-eclampsia. There is no evidence of association between blood parameters and women suffering from gestational hypertension (without proteinuria); therefore, a PET blood screen in such cases is not indicated.(1)
There does not seem to be any clear evidence to suggest that high uric acid levels are associated with increased risks of pre-eclampsia complications. By contrast, platelet count, transaminases and serum creatinine are good predictors of disease progression, including adverse maternal and perinatal outcomes.(8) Coagulation tests are of no real value unless the platelet count falls below 100 x 109/l.
Anti-hypertensive treatment should be started with moderate hypertension (150/100–159/109mmHg), aiming to bring the diastolic blood pressure down to 80–100mmHg and the systolic blood pressure to a level <150mmHg. Similar levels should be aimed for with severe hypertension (≥160/110mmHg).
No treatment is required for mild hypertension (140/90–149/99mmHg).(5) Patients with pre-eclampsia should be admitted to hospital for regular blood pressure readings, the frequency of which depends on the severity of the hypertension but should not be less than four times a day. They should also be tested for proteinuria and once established its quantification need not be repeated. A PET blood screen should be taken and repeated two or three times weekly.
Labetalol is a safe and effective anti-hypertensive which has been used widely in pregnancy and is considered to be the first-line agent.(5) It is contraindicated in patients suffering from asthma, and women of African–Caribbean origin can be resistant to it. Safe alternatives include methyl-dopa and nifedipine. The latter can be used safely in combination with methyl-dopa or labetalol.
In severe hypertension, the aim is to lower the blood pressure in a step-wise fashion and to avoid a sudden drop which can lead to placental perfusion insufficiency. The single most serious failing in the management of women with severe pre-eclampsia seems to be blood pressure control. This can lead to serious maternal complications including intracranial haemorrhage and aortic dissection.(9) There is insufficient evidence to establish any superiority amongst the anti-hypertensive agents used in severe pre-eclampsia, namely labetalol, nifedipine and hydrazine.(10) The latter can give rise to sudden severe hypotension, while labetalol is the only agent licensed for reducing blood pressure in pregnant women and has a very low side-effect profile.
The efficacy of magnesium sulphate in preventing eclampsia in women with pre-eclampsia has been demonstrated by the Magnesium Sulphate for Prevention of Eclampsia (MAGPIE) Trial Collaborative Group.(12) This study has shown that, in women with pre-eclampsia, magnesium sulphate reduces the risk of developing eclampsia by 58%. It is therefore recommended in patients with severe pre-eclampsia, defined as severe hypertension and proteinuria or mild or moderate hypertension and proteinuria with one or more of the following symptoms(5):
- symptoms of severe headache
- problems with vision, such as blurring or flashing before the eyes
- severe pain just below the ribs or vomiting
- signs of clonus (three or more beats)
- liver tenderness
- HELLP syndrome
- platelet count falling to <100 x 109/l
- abnormal liver enzymes (alanine transaminase or aspartate transaminase rising to above 70IU/l.
In addition, magnesium sulphate is the treatment of choice in women who develop eclampsia. It is superior to diazepam and phenytoin in controlling the convulsions associated with eclampsia and is associated with better perinatal outcomes. The regime for magnesium sulphate administration as per the Collaborative Eclampsia Trial is(13):
loading dose of 4g intravenously over 5 min followed by an infusion of 1g/hour maintained for 24hours
2–4g intravenously over 5min for recurrent seizures.
Fluid management is one of the main challenges in the treatment of severe pre-eclampsia. These patients are prone to develop adult respiratory distress syndrome which can be easily precipitated by a fluid overload. Volume expansion is to be avoided in pre-eclampsia even in the presence of oliguria. Fluid restriction is associated with a reduced incidence of fluid-related problems in the mother. Guidelines that restrict fluids to 80ml/hour and allow for low urine outputs (up to 8hours with an equivalent of <20ml/hour) have been associated with low rates of pulmonary oedema and renal complications requiring dialysis.(14)
Pre-eclampsia is associated with intra-uterine growth restriction necessitating growth scans and fetal biometry in these patients. The absence of end-diastolic velocities on umbilical artery Dopplers is associated with increased neonatal morbidity and mortality; therefore, the presence of end-diastolic flow is deemed to be reassuring. The use of umbilical artery Doppler velocimetry in patients with pre-eclampsia can reduce perinatal morbidity and mortality and helps in deciding timing of delivery, especially when there is absent end-diastolic blood flow.(11)
Use of the biophysical profile in pregnancies complicated by hypertension does not seem to have any impact on perinatal morbidity while the liquor volume is an important measure of foetal well-being. This can be assessed by measuring the equally effective amniotic fluid index or the single deepest vertical pocket.
In view of pre-eclampsia being associated with a disturbance in utero–placental blood flow, assessment of uterine blood flow in the second trimester can help predict the development of the disease. However, this test has a relatively low predictive ability and sensitivity, and a positive result would probably not alter the management of patients who are at a high risk of developing pre-eclampsia. Additionally, these women would already be on low-dose aspirin and would have their blood pressure and urine closely monitored.(1)
Timing of delivery
Delivery remains the ultimate treatment of pre-eclampsia. There does not seem to be any benefit in prolonging pregnancy beyond 34 weeks in women with severe pre-eclampsia. Clear maternal or fetal compromise would necessitate earlier delivery. In addition, timing of delivery should not be made solely on biochemical and haematological parameters (including level of proteinuria) but by taking the clinical picture as a whole.(1)
In women with non-severe pre-eclampsia, delivery should be planned for after 37 weeks, as there does not seem to be any benefit in prolonging the pregnancy further.(5) The mode of delivery depends on the clinical circumstances, the patient’s parity and her wishes.
Apart from eclampsia, pre-eclampsia is associated with other complications including placental abruption, intra-uterine death and haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. The latter complicates
10–20% of cases with severe pre-eclampsia. The severity of the syndrome seems to be linked to the platelet drop with severe HELLP syndrome defined as a platelet nadir ≤50,000cells/mm.(3,15) Delivery is the ultimate treatment for this syndrome. Patients with HELLP syndrome are at an increased risk of eclampsia, intracerebral bleeding and death; therefore, preterm delivery is unavoidable in such situations.
Up to 44% of eclamptic fits occur postnatally, necessitating close vigilance in the postnatal period especially in women who had severe pre-eclampsia or one of its complications antenatally. Antihypertensive treatment will need to be continued postnatally and reduced when the blood pressure falls below 130/80mmHg. Methyl-dopa is contraindicated in the postnatal period as it is associated with postnatal depression. The patient can be transferred to community care when she is asymptomatic, her blood pressure is <149/99mmHg and the blood tests are stable or improving.(5)
Although pre-eclampsia has been known to us since the ancient civilisations of India, China and Egypt, delivery still remains the ultimate treatment. We are now able to understand the pathophysiology and disease process better as well as identifying the patients at greater risk of developing the disease. We are able to provide targeted investigations and management strategies which have resulted in improved maternal and neonatal outcomes. The future lies in effectively predicting and preventing the disease and improving our management strategies further to reduce the complications on the mother and the incidence of iatrogenic premature delivery.
- Ciantar E, Walker JJ. Pre-eclampsia, severe pre-eclampsia and haemolysis, elevated liver enzymes and low platelets syndrome: what is new? Women’s Health 2011;7(5):555–69.
- Steegers EA et al. Pre-eclampsia. Lancet 2010;376(9741):631–44.
- Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study. BMJ 2009;339:b2225.
- Duley L et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2;CD004659. 2007.
- National Collaborating Centre for Women’s and Children’s Health. Hypertension in pregnancy: the management of hypertensive disorders during pregnancy 2010. Royal College of Obstetricians and Gynaecologists, London.
- Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. (Cochrane Review). Cochrane Database Syst Rev Cochrane Database Syst Rev;CD001059. 2006.
- Thangaratinam S et al. Estimation of proteinuria as a predictor of complications of pre-eclampsia: a systematic review. BMC Med 7;2009:10.
- Menzies J et al. Current CHS and NHBPEP criteria for severe pre-eclampsia do not uniformly predict adverse maternal or perinatal outcomes. Hypertens Pregnancy 2007;26(4):447–62.
- Draycott T, Lewis G, Stephens I. Centre for Maternal and Child Enquiries (CMACE) executive summary. BJOG 2011;118(Suppl. 1):E12–21.
- Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Sys Rev 3;CD001449. 2006.
- Westergaard HB et al. A critical appraisal of the use of umbilical artery Doppler ultrasound in high-risk pregnancies: use of meta-analyses in evidence-based obstetrics. Ultrasound Obstet Gynecol 2001;17(6):466–76.
- Altman D 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(9321):1877–90.
- Duley L. Which anticonvulsant for women with eclampsia? Evidence from the collaborative eclampsia trial. Lancet 1995;345(8963):1455–63.
- Tuffnell DJ et al. Outcomes of severe pre-eclampsia/eclampsia in Yorkshire. BJOG 2005;112(7):875–80.
- Martin JN et al. The spectrum of severe preeclampsia: comparative analysis by HELLP syndrome classification. Am J Obstet Gynecol 1999;180(6 Pt 1):1373–84.