Introduction

Early prediction and prevention of pre-eclampsia remains elusive. Despite significant advances in our understanding of the complex pathogenesis of the condition, our ability to predict and prevent it lag far behind. Many recommended strategies for prediction are based on assessment of maternal risk factors; as an example, the National Institute of Clinical Excellence (NICE) in the UK recommends a screening strategy based on maternal history and characteristics, but this categorises more than 60% of pregnant women as ‘high-risk’, and predicts less than 30% of those destined to develop pre-eclampsia.

Worldwide, pre-eclampsia remains a leading cause of maternal mortality, with an estimated 10–15% of the 500,000 maternal deaths each year believed to be caused by hypertensive diseases of pregnancy. In developed countries, better antenatal care means that perinatal complications are arguably more important. Severe pre-eclamsia requiring delivery before 34 weeks is less common than term, and occurs in about 0.5% of pregnancies. However, this more severe end of the spectrum is the most common cause of iatrogenic prematurity and is associated with significant perinatal mortality and morbidity.

Our ability to identify pregnant women who are at highest risk of developing pre-eclampsia is important for several reasons. Firstly, it is highly likely that, in order for any preventative treatment to be successful, it will need to start early in pregnancy while there is still a window of opportunity to modify the process of placental development. Secondly, early risk stratification allows for more appropriate allocation of resources and increased surveillance and intervention in women at highest risk. In the developing world, early referral pathways for improved antenatal care based on adequate stratification may help reduce maternal mortality. In developed countries, the focus is on prediction of early onset pre-eclamsia in order to reduce the associated perinatal mortality and financial burden caused by extreme preterm delivery. Lastly, high-quality prediction would improve study designs for evaluating potential preventative treatments and investigating the pathogenesis of pre-eclamsia.

Researchers have been devising and evaluating tests to predict pre-eclamsia for over 50 years, but overall there has been little success. In 2004 Conde-Agudelo et al. conducted a large systematic review of predictive tests on behalf of the World Health Organization. They identified over 50 proposed screening tests in the published literature, of which many could be discounted because of low predictive values. They subjected the remainder to meta-analysis and found that only uterine artery Doppler, antiphospholipid antibodies and urinary kallikrein were of moderate predictive value in low-risk women. The authors concluded that, as of 2004, there was ‘no clinically useful screening test to predict pre-eclamsia’. They established desirable criteria for any future screening test ( Table 1 ) and advised that, because incidence rates for pre-eclamsia were low (1–3%) in developed countries, any screening test would need a high positive likelihood ratio to be of satisfactory predictive value.

More recently, the traditional approach to predicting pre-eclamsia with a single biomarker or test, which aims to identify only one maternal and placental factor, has been replaced by a multiple marker approach. Such a strategy of prediction may better parallel the complex pathophysiology of the disorder: both the placenta and the maternal predisposition are key factors in determining the severity and timing of onset for the disease, which can be highly variable. We aim to review the most promising predictive tests in recent published literature and explore their relationship to the underlying pathophysiology. We review markers in isolation but also the most promising models using panels of variables. In this review, predictive tests have been grouped according to their likely pathophysiological basis in Table 2 . Unsurprisingly, the most promising predictive models incorporate multiple components, and this approach may allow more robust prediction across the disease spectrum. Finally, we also review advances in available preventative treatments.

Uterine artery doppler

Normal placental development results in remodelling of the maternal spiral arteries from narrow, muscular and contractile vessels to wide, flaccid channels. This allows increased delivery of maternal blood through a low pressure placental bed. Where this remodelling is incomplete, there will be increased resistance to maternal blood flow. Assessment of impedance to uterine artery blood flow by Doppler ultrasound, as first described by Campbell et al. provides a proxy measure of the degree to which successful remodelling has occurred. Histological placental examination in pregnancies with pre-eclamsia and those with high resistance uterine artery Doppler has shown deficient spiral artery remodelling as early as the first trimester.

The use of uterine artery Doppler as a screening tool for pre-eclamsia and other pregnancy complications such as intrauterine growth restriction (IUGR) remains controversial. Criticism has tended to focus on the low positive predictive values for term disease reported in clinical trials in low-risk populations. However, it is important when evaluating the performance of uterine artery Doppler as a screening tool, that attention is focused on the diseases that matter most, such as early onset pre-eclampsia, which causes the highest burden of perinatal morbidity and mortality. In the prediction of pre-eclamsia requiring delivery before 34 weeks, Doppler at 20–23 weeks gestation performs well, with several large studies showing a detection rate of about 80%. Uterine artery Doppler also performs better at all gestations in predicting pre-eclamsia associated with IUGR (sensitivity 70%) than pre-eclamsia alone (25%), for a 5% false positive rate.

The prediction of term pre-eclamsia is poor with Doppler, and this may reflect fundamental differences in the underlying pathophysiology. It is has been suggested that term pre-eclamsia may be caused by ageing of an initially normal placenta or as a result of increased maternal predisposition. Pre-eclampsia represents a heterogenous spectrum of disease resulting from both placental factors (defective remodelling or placental mass effect as in multiple pregnancy) and maternal factors. It is, therefore, not surprising that a single screening modality may not adequately predict all presentations.

Over the past 5–10 years, the focus has moved from second-trimester screening to the first trimester. The search to date for preventative treatments has been disappointing, and it is likely that, to be effective, any future interventions will need to begin early in the disease pathology. As routine antenatal care commences in the first trimester in the developed world, this offers the opportunity to screen for diseases associated with poor placentation in addition to current programmes. The largest study to date of uterine artery Doppler in 6015 women at 11–13 ⁺⁶ weeks had a sensitivity of 82% for pre-eclamsia requiring delivery before 34 weeks for a 10% false positive rate. Another prospective study of 3058 singleton pregnancies found that abnormal uterine artery Doppler at 11–14 weeks was significantly associated with preterm but not term pre-eclamsia, again supporting the theory that early pre-eclamsia is related to poor placentation, whereas late onset pre-eclampsia may have different causal mechanisms.

The intriguing unanswered question is what factors regulate the defective placentation underlying the development of pre-eclamsia? Research into this area has been hampered by the inability to distinguish between first-trimester pregnancies that are developing normally and those which have defective placentation. The ability to obtain first-trimester samples from pregnancies undergoing elective pregnancy termination that have previously been screened by uterine artery Doppler and stratified according to risk represents a significant advance. Inherent biological differences between first-trimester pregnancies at lowest and highest risk of developing pre-eclamsia have been defined, and work in this promising area may produce new insights into the early causal events of poor placentation.

Uterine artery doppler

Normal placental development results in remodelling of the maternal spiral arteries from narrow, muscular and contractile vessels to wide, flaccid channels. This allows increased delivery of maternal blood through a low pressure placental bed. Where this remodelling is incomplete, there will be increased resistance to maternal blood flow. Assessment of impedance to uterine artery blood flow by Doppler ultrasound, as first described by Campbell et al. provides a proxy measure of the degree to which successful remodelling has occurred. Histological placental examination in pregnancies with pre-eclamsia and those with high resistance uterine artery Doppler has shown deficient spiral artery remodelling as early as the first trimester.

The use of uterine artery Doppler as a screening tool for pre-eclamsia and other pregnancy complications such as intrauterine growth restriction (IUGR) remains controversial. Criticism has tended to focus on the low positive predictive values for term disease reported in clinical trials in low-risk populations. However, it is important when evaluating the performance of uterine artery Doppler as a screening tool, that attention is focused on the diseases that matter most, such as early onset pre-eclampsia, which causes the highest burden of perinatal morbidity and mortality. In the prediction of pre-eclamsia requiring delivery before 34 weeks, Doppler at 20–23 weeks gestation performs well, with several large studies showing a detection rate of about 80%. Uterine artery Doppler also performs better at all gestations in predicting pre-eclamsia associated with IUGR (sensitivity 70%) than pre-eclamsia alone (25%), for a 5% false positive rate.

The prediction of term pre-eclamsia is poor with Doppler, and this may reflect fundamental differences in the underlying pathophysiology. It is has been suggested that term pre-eclamsia may be caused by ageing of an initially normal placenta or as a result of increased maternal predisposition. Pre-eclampsia represents a heterogenous spectrum of disease resulting from both placental factors (defective remodelling or placental mass effect as in multiple pregnancy) and maternal factors. It is, therefore, not surprising that a single screening modality may not adequately predict all presentations.

Over the past 5–10 years, the focus has moved from second-trimester screening to the first trimester. The search to date for preventative treatments has been disappointing, and it is likely that, to be effective, any future interventions will need to begin early in the disease pathology. As routine antenatal care commences in the first trimester in the developed world, this offers the opportunity to screen for diseases associated with poor placentation in addition to current programmes. The largest study to date of uterine artery Doppler in 6015 women at 11–13 ⁺⁶ weeks had a sensitivity of 82% for pre-eclamsia requiring delivery before 34 weeks for a 10% false positive rate. Another prospective study of 3058 singleton pregnancies found that abnormal uterine artery Doppler at 11–14 weeks was significantly associated with preterm but not term pre-eclamsia, again supporting the theory that early pre-eclamsia is related to poor placentation, whereas late onset pre-eclampsia may have different causal mechanisms.

The intriguing unanswered question is what factors regulate the defective placentation underlying the development of pre-eclamsia? Research into this area has been hampered by the inability to distinguish between first-trimester pregnancies that are developing normally and those which have defective placentation. The ability to obtain first-trimester samples from pregnancies undergoing elective pregnancy termination that have previously been screened by uterine artery Doppler and stratified according to risk represents a significant advance. Inherent biological differences between first-trimester pregnancies at lowest and highest risk of developing pre-eclamsia have been defined, and work in this promising area may produce new insights into the early causal events of poor placentation.

Mean arterial blood pressure

Traditionally, routine antenatal blood pressure measurement has been the mainstay of pre-eclamsia diagnosis. However, women who subsequently develop pre-eclamsia are known to have higher systolic blood pressure and mean arterial pressure (MAP) readings before the onset of clinical disease, at 18 and 28 weeks. Various approaches to blood-pressure measurement have been evaluated as predictive tests for pre-eclamsia, including diastolic blood pressure, systolic blood pressure, 24 h ambulatory blood pressure and MAP. Cnossen et al. subjected these methods to a systematic review and found that MAP was a better predictor for pre-eclamsia than systolic blood pressure, diastolic blood pressure or an increase of blood pressure. The reviewers assessed 34 studies involving 60,599 women, with the incidence of pre-eclamsia varying between 0.8% and 40.8%, reflecting significant study variation in entry and diagnostic criteria. Second trimester MAP of 90 mm Hg or above showed a positive likelihood ratio of 3.5 (95% confidence interval [CI] 2 to 5) and a negative likelihood ratio of 0.46 (0.16 to 0.75); falling far short of the desirable likelihood ratios for a predictive test of over 10 and less than 0.1, respectively. As with other predictive tests, the focus has increasingly moved to evaluating blood pressure in the first trimester. MAP in the first trimester can be used as a predictive test for pre-eclamsia, and is most likely a proxy for increased maternal vascular susceptibility to pre-eclamsia or as a marker for underlying undiagnosed hypertension. Maternal MAP is an easy, cheap and non-invasive measurement that can be taken in all women at their first routine antenatal visit and as such is an attractive test.

Traditionally, the use of a mercury sphygmomanometer has been the gold standard for non-invasive blood-pressure monitoring in pregnancy, and the use of Korotcoff phase V sound is recommended. However, this method is dependent on the observer. The use of automated machines can overcome these problems, but altered haemodynamics in pregnancy and, particularly the reduced vascular compliance in pre-eclampsia, can lead to systematic underestimation of blood pressure by these machines. Hence, automated devices should be validated for pregnancy and carefully calibrated and maintained. Furthermore, the reported techniques for blood-pressure measurement are highly variable in the published literature. In pregnancy, blood pressure is known to be altered by maternal position (lower in left lateral and higher on sitting), time of day and anxiety. It has been advised that an average of several readings in either arm following a period of quiet rest is appropriate. In the UK, the National Institute for Clinical Excellence (NICE) limit themselves to recommending a single reading, using the correct cuff size at heart level and Korotkoff phase V. The National Heart Foundation of Australia recommend the following standardised approach: measure blood pressure in both arms simultaneously after a period of 5 min rest, carry out a series of readings each minute until variations between consecutive readings fall to less than 10 mm Hg in systolic blood pressure and 6 mm Hg diastolic blood pressure in both arms. When this ‘point of stability’ is reached, the MAP can be calculated as an average of the last two measurements for each arm; the highest final MAP reading should be used. It remains unclear whether this complex method using the ‘point of stability’ has advantages over other simpler methods.

Poon et al. evaluated the performance of MAP at 11–13 ⁺⁶ weeks in combination with maternal variables in the prediction of pre-eclamsia. This was a prospective study of 5193 women with singleton pregnancies attending for routine care. A validated, automated device was used with the standardised method suggested by the National Heart Foundation of Australia as detailed above. Interestingly, 87% of women reached the ‘point of stability’ after only two readings and less than 3% required four or more readings. They found that MAP in combination with maternal variables (e.g. ethnic origin, body mass index, personal history of pre-eclamsia) had a better predictive accuracy than MAP alone. Combination testing could, for a 10% false positive rate, identify 62.5% of those who would develop pre-eclamsia and 40% of those who would develop gestational hypertension. Unlike uterine artery Doppler, no difference was found in the ability of MAP to predict early onset pre-eclamsia over term disease.