Pre-eclampsia is associated with increased maternal and perinatal mortality and morbidity. Early recognition of women at risk of pre-eclampsia will enable the identification of high-risk women who may benefit from enhanced surveillance and prophylaxis. In this chapter, we summarise the accuracy of various tests used to predict the onset of pre-eclampsia and the effectiveness of preventative treatment. The tests used to predict pre-eclampsia include clinical history, examination findings, laboratory and haemodynamic tests. In general, tests in early pregnancy for predicting later development of pre-eclampsia have better specificity than sensitivity, as Body Mass Index greater than 34, alpha-fetoprotein, fibronectin and uterine artery Doppler (bilateral notching) all have specificities above 90%. Only uterine artery Doppler resistance index and combinations of indices have a sensitivity of over 60%. Test such as kallikreinuria not used in clinical practice, has shown high sensitivity above 80%, without compromising specificity, and require further investigation. None of the tests are sufficiently accurate to recommend them for routine use in clinical practice. The various treatment options for preventing pre-eclampsia include pharmacological agents, dietary supplementation and lifestyle modification. Antiplatelet agents, primarily low-dose aspirin, reduce the risk of pre-eclampsia by 10% (RR 0.90, 95% CI 0.84 to 0.97). Calcium effectively prevents pre-eclampsia (RR 0.45, 95% CI 0.31 to 0.65); the beneficial effect being observed in the high-risk group (RR 0.22; 95% CI 0.12 to 0.42) and in the group with low nutritional calcium intake (RR 0.36, 95% CI 0.20 to 0.65). Pharmacological agents, such as low molecular weight heparin, progesterone, nitric oxide donors, anti-hypertensive medication and diuretics are not effective in preventing pre-eclampsia. Dietary supplements, such as magnesium, anti-oxidants, marine oils and folic acid, do not reduce the incidence of pre-eclampsia. Evidence is lacking to support lifestyle preventative interventions for pre-eclampsia, such as rest, exercise and reduced dietary salt intake.
Background
Pre-eclampsia is associated with adverse maternal and fetal outcomes. The incidence of pre-eclampsia varies, with the risk factor ranging from 2–8% of pregnancies. In unselected women, the incidence of pre-eclampsia is reported as 2.5% (95% CI 1.9 to 3.4%). The incidence is much higher in women at high risk for pre-eclampsia and estimated to be 10% (9.3–10.8%). Women at high risk of pre-eclampsia include those with chronic hypertension, chronic kidney disease, autoimmune disease (e.g.systemic lupus erythematosis, type 1 and 2 diabetes), and those with hypertension in a previous pregnancy. Pre-eclampsia can develop into severe pre-eclampsia, eclampsia, or both. Overall, 15–25% of women with gestational hypertension progress to pre-eclampsia.
Screening is undertaken in a healthy population. It identifies women more at risk from a disease. It assumes that early detection through confirmatory tests is possible and that treatment improves outcome. Typically, it involves a series of tests: initial (screening) test which, if positive, leads to a confirmatory or gold-standard test for disease. Only after confirmation of the second test would treatment be instituted. Hence, classical screening may be carried out by relatively poor initial tests. This is because the screening test guides confirmation and the confirmatory test guides treatment. In pre-eclampsia, this is not so ( Fig. 1 ). The intention here is to apply primary preventative treatment straight after initial screening. Therefore, in pre-eclampsia, we require screening performance to be far superior than expected for other screening tests.
Screening for pre-eclampsia is an important part of routine antenatal care. Identification of women at risk of pre-eclampsia will help to judiciously allocate resources for close monitoring and prophylactic treatment to minimise adverse maternal and fetal outcomes. This will depend on the accuracy of the tests carried out to predict the onset of pre-eclampsia. Ideally, a test should perform well in both sensitivity and specificity. Often, a trade-off can occur between sensitivity and specificity, and the preferred test performance depends on the prevalence and severity of the condition (i.e. pre-eclampsia and associated complications and the effectiveness, safety and cost of the prophylactic treatment).
On one hand, the consequences of false–positive results include the costs of intensive monitoring and treatment associated with morbidity among normal women who would not develop pre-eclampsia. It is, therefore, important that test specificity is suitably high. On the other hand, falsely negative results miss women who develop pre-eclampsia at a later stage, leading to additional costs and morbidity of cases left untreated, necessitating a test with high sensitivity. Presence of effective, cheap and safe interventions favours a test with high sensitivity than specificity.
The risk status of pregnant women who may develop pre-eclampsia is currently assessed at the first antenatal booking visit through clinical history and examination. Routine screening for pre-eclampsia is based on measurement of blood pressure and urinalysis for proteinuria.
Sources of information
The evidence for accuracy of tests and effectiveness of treatment for the prediction and prevention of pre-eclampsia has been obtained by meta-analyses, including Cochrane reviews, Health Technology Assessment reports, relevant guidelines, and primary studies in Medline (1966 to date). The tests evaluated in the prediction of pre-eclampsia and the preventative treatment methods used are provided in Table 1 .
| Prediction of pre-eclampsia | Clinical history | Clinical examination | Laboratory tests | Other tests | Haemodynamic investigations |
|---|---|---|---|---|---|
| Maternal age | BMI ≥ 25 | Uric acid | Alpha-foetoprotein | Uterine artery Doppler Pulsatility index Unilateral/bilateral notching Resistance index systolic–diastolic ratio Albumin–creatinine ratio Notch index | |
| Parity | BMI ≥ 30 | Proteinuria Total 24 h proteinuria Microalbuminuria Spot albumin–creatinine ratio Spot protein–creatinine ratio Urinary kallikrein | Human chorionic gonadotrophin | ||
| Family history of pre-eclampsia | BMI ≥ 35 | Plasma fibronectin Cellular fibronectin Total fibronectin | |||
| Multiple pregnancy | Blood pressure in the first trimester and second trimester Mean arterial pressure Systolic blood pressure Diastolic blood pressure | Angiogenic biomarkers Placental growth factor Soluble fms-like tyrosine kinase 1 Soluble Endoglin | |||
| Pre-eclampsia in previous pregnancy | |||||
| History of autoimmunie disease, thrombophilia, diabetes, chronic hypertension | |||||
| Molar pregnancy |
Sources of information
The evidence for accuracy of tests and effectiveness of treatment for the prediction and prevention of pre-eclampsia has been obtained by meta-analyses, including Cochrane reviews, Health Technology Assessment reports, relevant guidelines, and primary studies in Medline (1966 to date). The tests evaluated in the prediction of pre-eclampsia and the preventative treatment methods used are provided in Table 1 .
| Prediction of pre-eclampsia | Clinical history | Clinical examination | Laboratory tests | Other tests | Haemodynamic investigations |
|---|---|---|---|---|---|
| Maternal age | BMI ≥ 25 | Uric acid | Alpha-foetoprotein | Uterine artery Doppler Pulsatility index Unilateral/bilateral notching Resistance index systolic–diastolic ratio Albumin–creatinine ratio Notch index | |
| Parity | BMI ≥ 30 | Proteinuria Total 24 h proteinuria Microalbuminuria Spot albumin–creatinine ratio Spot protein–creatinine ratio Urinary kallikrein | Human chorionic gonadotrophin | ||
| Family history of pre-eclampsia | BMI ≥ 35 | Plasma fibronectin Cellular fibronectin Total fibronectin | |||
| Multiple pregnancy | Blood pressure in the first trimester and second trimester Mean arterial pressure Systolic blood pressure Diastolic blood pressure | Angiogenic biomarkers Placental growth factor Soluble fms-like tyrosine kinase 1 Soluble Endoglin | |||
| Pre-eclampsia in previous pregnancy | |||||
| History of autoimmunie disease, thrombophilia, diabetes, chronic hypertension | |||||
| Molar pregnancy |
Predictors of onset of pre-eclampsia
Clinical history
The risk factors assessed in screening for pre-eclampsia include the following: age; parity; history of pre-eclampsia in a previous pregnancy, especially if severe or early onset ; a family history of pre-eclampsia ; multiple pregnancy ; duration between pregnancies and pre-existing medical conditions such as diabetes ; chronic hypertension ; renal disease ; thrombophilias and autoimmune disease. Obstetric factors associated with high risk include a current hydropic or molar pregnancy. A systematic review of studies showed that the risk of pre-eclampsia is almost doubled in women over 40 years of age (RR 1.7, 95% CI 1.2 to 2.3 in primiparous women and RR 2, 95% CI 1.3 to 2.9 in multiparous women). The risk of pre-eclampsia is tripled in nulliparous women (RR 2.9, 95% CI 1.3 to 6.6), women with a family history of pre-eclampsia (RR 2.9, 95% CI 1.7 to 4.9) and in women with multiple pregnancies (RR 2.9, 95% CI 2.0 to 4.2 in twins and RR 2.8, 95% CI 1.3 to 6.4 in triplet pregnancy). The risk is even increased seven-fold in women who have had pre-eclampsia in a previous pregnancy (RR 7.2; 95% CI 5.9, 8.8). In women with insulin-dependent diabetes, the risk of developing pre-eclampsia is quadrupled (RR 3.6; 95% CI 2.5 to 5). Women with a history of autoimmune disease and thrombophilia are at significantly increased risk of developing pre-eclampsia with RR of 6.9 (95% CI 1.1 to 42.3) and 9.7 (95% CI 4.3 to 21.8), respectively.
Clinical examination
Body mass index
Obesity in pregnancy is considered to be a risk factor for developing pre-eclampsia. The body mass index (BMI) is a standard for obesity measurement adjusting bodyweight for height (weight [kg]/height squared [m2]). BMI is categorised as underweight (BMI < 20), normal weight (BMI 20–25), overweight (BMI > 25) and obese (BMI > 30). A systematic review of 36 studies involving 1,699,073 women evaluated the accuracy of BMI in predicting pre-clampsia. Pooled estimates for all studies with overweight and obese women (18 studies) were 47% (33–61) for sensitivity and 73% (64–83) for specificity. For a BMI ≥ 30 (19 studies), these estimates were 19% (19–20) and 90% (88–93), and for a BMI ≥ 35 (four studies), the estimates were 21% (12–31) and 92% (89–95). The corresponding likelihood ratios were 1.7 (95% CI 0.3 to 12) for BMI ≥ 25 and 0.73 (95% CI 0.22 to 2.5) for BMI < 25, 1.9 (95% CI 0.3 to 12) for BMI ≥ 29 and 0.88 (95% CI 0.61 to 1.3) for BMI < 29, and 2.7 (95% CI 1.0 to 7.3) for BMI ≥ 35 and 0.86 (95% CI 0.68 to 1.07) for BMI < 35. BMI (at any cut-off), pre-pregnancy or at booking, was a fairly weak predictor for pre-eclampsia.
Blood pressure
Blood-pressure measurement is routinely carried out in antenatal care to diagnose or predict hypertensive disease. A systematic review of 34 studies with 60,599 women evaluated the role of blood pressure as a predictor of pre-eclampsia. The areas under the summary receiver operating characteristic curves for blood pressure measurement in the second trimester were 0.76 (95% CI 0.70 to 0.82) for mean arterial pressure, 0.68 (95% CI 0.64 to 0.72) for systolic blood pressure and 0.66 (95% CI 0.59 to 0.72) for diastolic blood pressure. A similar trend was noticed for blood pressure measurements in the first trimester.
A mean arterial pressure of 90 mm Hg or more showed a pooled sensitivity of 62% (95% CI 35 to 89%) and a pooled specificity of 82% (95% CI 72 to 92%), which corresponds with derived likelihood ratio of a positive test 3.5 (95% CI 2 to 5) and likelihood ratio of a negative test of 0.46 (95% CI 0.16 to 0.75). For a specificity of 90%, the sensitivities of diastolic blood pressure and systolic blood pressure were 35% and 24%, respectively. In high-risk populations, a diastolic blood pressure of 75 mm Hg or more at 13–20 weeks’ gestation best predicted pre-eclampsia, although the accuracy of prediction was modest (likelihood ratio of positive and negative test of 2.8 and 0.39, respectively). Mean arterial pressure seems to be a better predictor for pre-eclampsia than systolic blood pressure, diastolic blood pressure, or increased blood pressure. Blood-pressure measurements in the first and second trimester at the first antenatal visit for healthy normotensive women do not help predict pre-eclampsia.
Laboratory tests
Uric acid
The association between high blood uric acid levels and pre-eclampsia was reported in 1917. Renal impairment and an increased breakdown of purines in the ischaemic placenta leading to overproduction of uric acid may explain increased serum uric acid levels in pregnant women destined to develop pre-eclampsia. The role of uric acid as a predictor of pre-eclampsia was evaluated in a systematic review that included five studies with 514 women. The sensitivity ranged from 0.0% to 55.6% and the specificity from 76.9% to 94.9%. Significant clinical heterogeneity and poor reporting in the included studies was observed. The accuracy of the available evidence is insufficient to recommend uric acid as a predictor of pre-eclampsia.
Proteinuria
Routine proteinuria urinalysis is conducted in antenatal clinics from first booking for pre-eclampsia prediction. Early detection of proteinuria in women with new-onset hypertension helps to differentiate those women with pre-eclampsia from gestational hypertension, thereby influencing further management. Proteinuria is usually evaluated by dipstick (visual or automated) or by 24-h urinary total protein excretion. The use of spot protein: creatinine ratio and spot albumin: creatinine ratio has been recently used in clinical practice. A review of diagnostic accuracy of proteinuria in predicting pre-eclampsia onset included 11 studies (4,388 women). The pooled estimates of sensitivity and specificity were for total proteinuria 35% (95% CI 13 to 68%) and 89% (95% CI 79 to 94%); for microalbuminuria 62% (95% CI 23 to 90%) and 68% (95% CI 57 to 77%); albumin–creatinine ratio 19% (95% CI 12 to 28%) and 75% (95% CI 73 to 77%). The excretion of urinary kallikrein is lower than in normotensive pregnancy, with sensitivity greater than 80% and specificity greater than 90%.
Cellular and total fibronectin
Women who develop pre-eclampsia are reported to have higher plasma fibronectin concentrations than pregnant controls. Fibronectin is a glycoprotein of which several subtypes exist. Inflammation, vascular injury and malignancy are generally associated with increased expression of the ED-A (also called ED-1+ or oncofetal fibronectin) and ED-B (also called ED-2+) forms of fibronectin, particularly in the blood vessel walls. ED-A and ED-B are both called cellular fibronectin, and represent only 5% of all fibronectin in plasma, whereas total fibronectin contains all subtypes of fibronectin. A review on the accuracy of fibronectin as a predictor of pre-eclampsia onset included three studies. For cellular fibronectin, the highest specificity of 96% (95% CI 79 to 99%) was achieved in the second trimester at a cut-off value of 5.0 μg/ml with a sensitivity of 50% (95% CI 29.9 to 70.1%). For total fibronectin, the highest specificity was 94% (95% CI 86 to 98%) with a sensitivity of 65% (95% CI 44 to 83%) at a cut-off value of 293 μg/m.
Angiogenic biomarkers
Vascular endothelial growth factor (VEGF) is crucial for vascular development, angiogenesis, maintenance of the vasculature, and normal kidney function. Pathogenesis of pre-eclampsia is considered to be related to an imbalance between proangiogenic factors, such as VEGF or placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1, a splice variant of VEGF receptor-1) and the soluble form of endoglin. Circulating levels of VEGF and maternal serum concentrations of PlGF are significantly lower in women with pre-eclampsia compared with healthy control participants. sFlt-1 and soluble endoglin have been shown to be increased in the maternal circulation in pre-eclampsia even before the onset of disease. Although sFlt-1 and PlGF provide a degree of discrimination between normal pregnancies and those destined to develop pre-eclampsia, their combination (ratio of sFlt-1 to PlGF) may provide superior performance. For a diagnostic cut-off of 38.46 for sFlt-1/PlGF ratio, the positive and negative predictive values were 88.5%, positive likelihood ratio was 7.7 and negative likelihood ratio was 0.13. For a cut-off value of 85 for sFlt-1/PlGF ratio, the highest sensitivity was 82% and specificity was 95%.
Other tests
Maternal serum alpha-fetoprotein and human chorionic gonadotrophin are routinely used to screen for fetal aneuploidy and anomalies. A review of diagnostic accuracy of alpha-fetoprotein in predicting pre-eclampsia included 12 studies (137,097 women) with pooled estimates of sensitivity and specificity of 9% (95% CI 5 to 16%) and 96% (95% CI 94 to 98%). The evidence for diagnostic accuracy of maternal human chorionic gonadotrophin included 16 studies (72,732 women), with pooled estimates of sensitivity and specificity of 24% (16–35%) and 89% (86–92%), respectively.
Haemodynamic investigations
Pre-eclampsia is characterised by abnormal placentation, resulting in inadequate uteroplacental blood flow. Uterine artery Doppler ultrasound has been shown to be a reliable, non-invasive method of examining uteroplacental perfusion. The velocity of uterine artery blood flow assessed by the Doppler ultrasound has been evaluated as part of routine ultrasound screening for pre-eclampsia. Uterine artery Doppler findings may report unilateral or bilateral notching, single ratios, such as systolic–diastolic ratio, albumin–creatinine ratio and Notch Index, pulsatility index or resistance index.
A systematic review included 74 studies ( n = 79,547) in which uterine artery Doppler ultrasonography was used to predict pre-eclampsia. In low-risk women, an increased pulsatility index with diastolic notching in the second trimester (>16 weeks) was the best predictor of pre-eclampsia (likelihood ratio of a positive test LR + 7.5, 95% CI 5.4 to 10.2; likelihood ratio of a negative test LR− 0.59, 95% CI 0.47 to 0.71). A second-trimester finding of increased pulsatility index (LR+ 15.6, 95% CI 13.3 to 17.3; LR− 0.23, 95% CI 0.15 to 0.35) and bilateral notching (LR+ 13.4, 95% CI 8.5 to 17.4); LR− 0.4 (95% CI 0.2 to 0.6) in the second trimester also predicted the onset of severe pre-eclampsia in low-risk women. In high-risk women, the best predictor of pre-eclampsia was unilateral notching (LR+ 20.2, 95% CI 7.5 to 29.5; LR− 0.17, 95% CI 0.03 to 0.56) and an increased pulsatility index with notching (LR+ 21.0, 95% CI 5.5 to 80.5; LR− 0.82, 95% CI 0.72 to 0.93) in the second trimester. Use of Doppler to predict severe pre-eclampsia in high-risk patients had low diagnostic accuracy (LR+ 3.7). Pulsatility index and bilateral notching in the second trimester seem to be the most promising Doppler indices for prediction of pre-eclampsia.
Placental profile, including uterine artery doppler imaging and placental morphology in the second trimester and maternal serum screening in the first trimester, have been evaluated as predictors of pre-eclampsia. Abnormal placental morphological condition included shape, texture or both. The odds ratio of developing pre-eclampsia or haemolysis, elevated liver enzymes and low platelet count syndrome in the group with normal placental profile compared with women with one or more abnormal profile test results was 0.2 (95% CI 0.1 to 0.4).
Pharmacological treatment for the prevention of pre-eclampsia
Current strategies for prevention focus on pharmacological therapy, dietary interventions and modification of lifestyle ( Table 2 ).
| Pharmacological treatment |
| Antiplatelet agents Nitric oxide agents Low molecular weight heparin Anti hypertensives for mild and moderate hypertension Progesterone Diuretics |
| Nutritional supplementation |
| Calcium Anti oxidants Folic acid Magnesium Marine oil and prostaglandin precursors |
| Lifestyle intervention and diet |
| Rest Exercise Altered dietary salt Energy and protein intake Garlic |
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