11.2Pre-eclampsia

Clinical question: What is the diagnostic value of different screening methods in identifying women at risk of developing pre-eclampsia?

StudyRef.PopulationInterventionOutcomesResultsCommentsStudy typeEL
Yaron, 1999857Sample size 60 040
Exclusion criteria: structural or chromosomal anomalies
Age not reported 14–22 weeks
Reference standard: SBP ≥ 140 mmHg or DBP ≥ 90 mmHg; presence of proteinuria
Index cut-off:
Competitive RIA (Sanofi Diagnostics)
2.5 MoM
Diagnostic value of AFP screening testIncidence of pre-eclampsia 3.2%
Sens: 4.3%
Spec: 97.4%
Multiple marker screening can be used for the detection of not only fetal anomalies and aneuploidy but also for detection of high-risk pregnancyProspective cohort studyII
Pouta, 1998858Sample size 637, Inclusion criteria: nulliparas
Exclusion criteria: multiple
pregnancies, fetal defects
27.7 ± 4.5 years
15–19 weeks
Reference standard: BP ≥ 140/90 mmHg 6 hours apart or rise 30/15 mmHg; Prot. ≥ 300 mg/24 hours

Index cut-off: time resolved FIA (Wallac)
2.0 MoM
Diagnostic value of AFP screening testIncidence of pre-eclampsia 5.3%
Sens: 3%
Spec: 98%
AFP not helpful in predicting pre-eclampsiaPopulation-based cohort studyII
Cotter, 2004859Sample size 264 (88 cases and 176 controls)
Inclusion criteria: Normotensive non-proteinuric women, male fetuses
Exclusion criteria: aneuploid fetuses
26.1 ± 5.9 years, 15.7 ± 3.6 weeks
Reference standard: BP ≥ 140/90 mmHg; Prot. ≥ 0.3 g/ 24 hours or 1+/2+ dipstick

Index cut-off: fDNA
Real-time PCR
TaqMan SRY

< 10,000 copies/ml
< 50,000
> 50,000
Diagnostic value of Fetal DNA screening testSRY copies/ml

< 10,000
Sens: 94.32%
Spec: 32.39%
LR+: 1.39

< 50,000
Sens: 81.82%
Spec: 64.77%
LR+: 2.32

> 50,000
Sens: 38.64%
Spec: 90.34%
LR+: 4.00
Increased fetal DNA is present in the maternal circulation in early pregnancy in women who subsequently develop pre-eclampsia and there appears to be a graded response between the quantity of fetal DNA and the risk of developing pre-eclampsia.Case control study (nested and matched)II
Leung, 2001860Sample size: 51 (18 cases and 33 controls), Inclusion criteria: singleton pregnancies, male fetuses
Age n.r. 11–22 weeks
Reference standard: DBP ≥ 90 mmHg 2x ≥ 4 hours apart or DBP ≥ 110 mmHg; Prot. ≥ 0.3 g/ 24 hours or 2+ dipstick 2x ≥ 4 hours apart, Incidence n.r. Index cut-off: fDNA
Real-time PCR
TaqMan SRY ≥ 33.5 Geq/ml
Diagnostic value of Fetal DNA screening testSRY ≥ 33.5 Geq/ml Sens: 67%
Spec: 82%
(cant calculate LRs)
Maternal plasma fetal DNA might be used as a marker for predicting pre-eclampsia.Case control study (nested and matched)II
Yaron, 1999857Sample size: 45 565, Exclusion criteria: structural or chromosomal anomalies
Age n.r. 14–22 weeks
Reference standard: SBP ≥ 140 mmHg or DBP ≥ 90 mmHg; presence of proteinuria
Index cut-off: β-hCG
IRMA
2.5 MoM
Diagnostic value of β-hCG screening testIncidence of pre-eclampsia 3.0%
Sens: 5.5%
Spec: 96%
Multiple marker screening can be used for the detection of not only fetal anomalies and aneuploidy but also for detection of high-risk pregnancyProspective cohort studyII
Lambert-Messerlian, 2000861Sample size: 359 (60 cases, 299 controls)
IN: singleton pregnancies
EX: chronic hypertension, diabetes; 26.9 ± 7.3 years 15–21 weeks
Reference standard: BP> 140/90 mmHg; Prot. > 300 mg/24 hours or ≥ 2+ dipstick, Index cut-off: Total hCG (Serono MAIO Clone)
2.3 MoM
Diagnostic value of β-hCG screening testIncidence of pre-eclampsia 16.7% With 95% specificity a modeled sensitivity of 15%

(cant calculate LRs)
second-trimester serum levels of hCG is a modest predictor of later onset pre-eclampsia.Case–control studyII
Ashour, 1997862Sample size: 6138, IN: singleton pregnancies
EX: fetal/ chromosomal abnormalities, diabetes, chronic hypertension
28.1 ± 5.3 years
15–22 weeks
Reference standard:
SBP ≥ 140 mmHg or DBP ≥ 90 mmHg 2x 6 hours apart; Prot. > 300 mg/24 hours or ≥ 1+ dipstick 2x 6 hours apart Index cut-off: β-hCG (IMx Abbott)
2.0 MoM
Diagnostic value of β-hCG screening testIncidence of pre-eclampsia 3.2%The utility of an elevated second-trimester β-hCG level as a screening test for pre-eclampsia is limited.Prospective cohort studyII
Sanchez-Ramos, 1991863Sample size: 99, Inclusion criteria: Normotensive nulliparas
Exclusion criteria: diabetes mellitus, renal disease, chronic hypertension, other chronic medical illnesses
18.7 ± 0.5 years, 10–24 weeks
Reference standard: BP ≥ 140/90 mmHg twice ≥ 6 hours apart or rise SBP ≥ 30 mmHg or DBP ≥ 15 mmHg
Prot. ≥ 0.3 g/ 24 hours or ≥ 1+ dipstick
Index cut-off: Colorimetric/ colorimetric autoanalyser ≤ 195 mg/24 hours
Diagnostic value of urinary calcium excretion screening testIncidence of pre-eclampsia 8.1%
Sens: 86%
Spec: 84%
PPV: 46%
NPV: 98%
The study suggests a pathophysiologic role for altered urinary calcium excretion in women with pre-eclampsia that may contribute to early identification of patients at risk for the disease.Prospective longitudinal studyII
Baker, 1994864Sample size: 500, Inclusion criteria: Normotensive nulliparas
Exclusion criteria: renal disease, chronic hypertension
Median 27 years (range 24–31), 18–19 weeks
Reference standard: DBP ≥ 90 mmHg twice ≥ 4 hours apart
Prot. ≥ 0.3 g/ 24 hours
Index cut-off:
Perspective analyser (colorimetric)/Monarch centrifugal analyser (kinetic)
n.r.
Diagnostic value of urinary calcium excretion screening testIncidence of pre-eclampsia: 2.6%
Sens: 31%
Spec: 72%

(correctly predicted 71%)
Prospective, non-interventional studyII
Rogers, 1994865Sample size: 199, Inclusion criteria: normotensive primigravidas, singleton pregnancies
Exclusion criteria: congenital malformations
27.1 ± 3.8 years, 18–26 weeks
Reference standard: BP ≥ 140/90 mmHg ≥ twice
Prot. ≥ 0.3 g/l
Index cut-off: Cresolphtalein method (American Monitor)/ Beckman Astra-8 analyser 0.3
Diagnostic value of calcium creatinine ratio screening testIncidence of pre-eclampsia 4.0%
Sens: 49%
Spec: 90%
Cohort studyII
Conde, 1994866Sample size: 387 women, Inclusion criteria: normotensive nulliparas, singleton pregnancies
Exlcusion criteria: diabetes mellitus, renal disease, proteinuria, chronic hypertension, other chronic medical illnesses
23.8 ± 5.7 years, 20 weeks
Reference standard: SBP ≥ 140 or DBP ≥ 90 mmHg twice ≥ 6 hours apart
Prot. ≥ 0.3 g/l
Index cut-off: Colorimetric (direct)/ picrato alcalino method
0.07
Diagnostic value of calcium creatinine ratio screening testIncidence of pre-eclampsia 3.4%

Sens: 33%
Spec: 78%
PPV:5%
NPV: 97%
Poor predictive values suggest that changes in the biochemical and hematologic tests occur only when pre-eclampsia has been established.Prospective cohort studyII
Kazerooni, 2003867Sample size: 102, Inclusion criteria: nulliparas (18–35 years)
Exclusion criteria: renal disease, diabetes mellitus, proteinuria, chronic hypertension, other chronic medical illnesses
22.8 ± 4.5 years, 20–24 weeks
Reference standard: BP ≥ 140/90 mmHg or rise SBP ≥ 30 mmHg or DBP ≥ 15 mmHg twice ≥ 6 hours apart
Prot. ≥ 0.3 g/ 24 hours or ≥ 1+ dipstick
Index cut-off: n.r. ≤ 0.01 mmol/litre:mmol/litre (0.229 (mg/100 ml:mg/100 ml)
Diagnostic value of calcium creatinine ratio screening testIncidence of pre-eclampsia 7.8%
Sens: 75%
Spec: 77.7%
PPV: 20.7%
NPV: 97%
Single urine calcium to creatinine ratio may be an effective method for screening women at the greatest risk of pre-eclampsia.Prospective cross-sectional studyII
Baker, 1994864Sample size: 500, Inclusion criteria: Normotensive nulliparas
Exclusion criteria: renal disease, chronic hypertension
Median 27 years (range 24–31), 18–19 weeks
Reference standard: DBP ≥ 90 mmHg twice ≥ 4 hours apart Prot. ≥ 0.3 g/ 24 hours
Index cut-off Perspective analyser (colorimetric)/Monarch centrifugal analyser (kinetic)
n.r.
Diagnostic value of calcium creatinine ratio screening testIncidence of pre-eclampsia 2.6%
Sens: 31%
Spec: 55%

(correctly predicted 71%)
Prospective, non-interventional studyII
Papageorghiou, 2001868Sample size: 7851, Inclusion criteria: singleton pregnancies, routine antenatal care. Exclusion criteria: fetal abnormalities
29.7 (16–47) yrs, 22–24 weeks
Reference standard: DBP ≥ 90 mmHg twice > 4 hours apart, prot. ≥ 0.3 g/24 hours or ≥ 2+ dipstick twice if no 24 hour collection available
Index cut-off: CD+PW, transvaginal
Acuson SP-10, Aloka 5000, Aloka 17000, ATL HDI 3000, ATL Hdi 3500, Hitachi, Toshiba, Siemens
Diagnostic value of bilateral notches screening testIncidence of pre-eclampsia 1.4%
Sens: 25.4%
Spec: 90.9%
PPV: 2.5%
NPV: 99.3%
LR+: 8.87
LR−: 0.62
Cohort studyII
Harrington, 1997869Sample size: 626, Inclusion criteria: Singleton pregnancies, unselected
15–49 years, 12–16 weeks
Reference standard: SBP≥ 140 or DBP≥ 90 mmHg, prot > 0.3 g/24 hours
Index cut-off: CD+PW, transvaginal
Acuson 128
Diagnostic value of bilateral notches screening testIncidence of pre-eclampsia 4.8%
Sens: 92.9%
Spec: 85.1% PPV: 23.6%
NPV: 99.5%
Cohort studyII
Marchesoni, 2003870895 (177 cases and 718 controls) Unselected women
31.7 ± 5.3 years, 20 weeks, 24 weeks
Reference standard: BP> 140/90 mmHg, prot. > 0.3 g/24 hours
Index cut-off: CD
Acuson Sequoia
Diagnostic value of bilateral notches screening testIncidence of pre-eclampsia 2.9%
Sens: 72%
Spec: 94%
PPV: 26%
NPV: 99%
Case control studyII
Schwarze, 2005871Sample size: 346 women (19–22 weeks: 215 women) (23–26 weeks-131 women), Exclusion criteria: essential hypertension, DM, autoimmune disorders, history of PE, FGR, IUD, placental abruption; multiple pregnancies, fetal abnormalities
31.4 (17–46) yrs, 19–22 weeks, 23–26 weeks
Reference standard: RR≥ 140/90 mmHg, prot. ≥ 0.3 g/24 hours, no UTI
Index cut-off: CD
Elegra (Siemens), Acuson 128 XP10
Diagnostic value of bilateral notches screening testIncidence of pre-eclampsia 4.9% 19–22 weeks vs 23–26 weeks

Sens: 40% vs 67%
Spec: 82% vs 84%
PPV: 10% vs 17%
NPV: 97% vs 98%
The predictive value of uterine artery Doppler for adverse pregnancy outcome in a low-risk population is of limited diagnostic value. Performing uterine artery Doppler studies at 23–26 weeks of gestation increases the predictive value for adverse pregnancy outcomes.Prospective studyII
Emine, 2005872Sample size: 178, Exclusion criteria: multiple pregnancies, hypertension before 26 weeks, diabetes or pregnancy with prenatal and postnatal diagnosis of a chromosomal/ structural abnormality, previous pregnancy complicated by pre-eclampsia, 28.8 ± 5.1
30.6 ± 4.3, 16–18 weeks
24–26 weeks
Reference standard: BP≥ 140/90 mmHg and first DX after 20 weeks, proteinuria ≥ 300 mg/24 hour
Index cut-off: Two site enzyme immunoassays, immunometric assays, two site chemiluminescent immunometric assay, ultrasound machines
Diagnostic value of integrated Doppler screening testIncidence of pre-eclampsia 7.9%
Bilateral notch
Sens: 85.7%
Spec: 97.6%

Bilateral notch + serum activin
Sens: 78.6%
Spec: 100%

Bilateral notch+ serum inhibin A
Sens: 71.4%
Spec: 100%

Bilateral notch OR serum activin
Sens: 100%
Spec: 86%
Maternal serum inhibin A and activin A levels and uterine artery Doppler appear to be uselful screening tests during the second trimester for pre-eclampsia. However the addition of these hormonal markers to Doppler velocimetry only slightly improves the predictive efficacy.Prospective studyII
Audibert, 2005873Sample size: 2615, EX: multiple pregnancies, without ultrasound between 10–14 weeks, women refered for nuchal translucency, structural anomalies, chromosomal abnormalities, 30.9 ± 4.5 years, 14–18 weeks
18–26 weeks
Reference standard: SBP ≥ 140 mmHg or a DBP ≥ 90 mmHg twice, proteinuria > 0.3 g/24 hour or at least 2+ protein on urine dipstick
Index cut-off: Amerlite kit
Diagnostic value of integrated Doppler screening testPrevalence of PE 1.95%
Bilateral notch
Sens: 21.56%
Spec: 95.94%

History of pre-eclampsia or bilateral notch or hCG> 2.5 MoM
Sens: 41.17%
Spec: 91.61%
Combination of serum markers and abnormal uterine Doppler ultrasound improves the identification of women at risk for subsequent pregnancy complications. The care providers should be encouraged to perform a uterine Doppler ultrasound when serum markers are abnormal. However, the sensitivity of these tests is too low to provide an efficient generalised screening.Cohort studyII
Skjaerven et al., 2002531Sample size: 551,478 women who had 2 or more singleton deliveries and 209,423 women who had 3 or more singleton deliveries were studiedA large registry used in Norway to evaluate the effects on the risk of pre-eclampsia of both the interbirth interval and a change of partnerTime interval between pregnanciesRisk in a second or third pregnancy was directly related to the time elapsed since the previous delivery. The association between risk of pre-eclampsia and interval was more significant than the association between risk and change of partner. When the interval was 10 years or more the risk of pre-eclampsia was about the same as that in nulliparous women. After adjustment for the presence or absence of a change of partner, maternal age, and year of delivery, the probability of pre-eclampsia was increased by 1.12 for each year increase in the interval (odds ratio 1.12, 1.11 to 1.13).The protective effect of previous pregnancy against pre-eclampsia is transient.Prospective study2+
Conde-Agudelo et al., 2000874456,889 parous women delivering singleton infantsImpact of interpregnancy intervalMaternal morbidity and mortalitywomen with more than 59 months between pregnancies had significantly increased risks of pre-eclampsia (RR 1.83, 1.72 to 1.94) compared with women with intervals of 18–23 monthsinterpregnancy intervals < 6 months and > 59 months are associated with an increased risk of adverse maternal outcomes.Retrospective cross-sectional study3
Basso et al., 2001875Danish women with pre-eclampsia in the previous birth (8,401 women)
all women with pre-eclampsia in second (but not first) birth together with a sample of women with two births (26,596 women)
Interpregnancy intervalInterpregnancy interval may confound or modify the paternal effect on pre-eclampsiaa long interval between pregnancies was associated with a significantly higher risk of pre-eclampsia in a second pregnancy when pre-eclampsia had not been present in the first pregnancy and paternity had not changedThe interval between births should be taken into consideration when studying the effect of changing partner on pre-eclampsia.cohort study2+
Reiss et al., 198787630 patients met their criteria for pre-eclampsia and were matched for age, race, and parity with normotensive control subjectsReviewed the outpatient charts of all patients with pre-eclampsia who received prenatal care at their clinics during the past 3 yearsBlood pressure at bookingBoth systolic and diastolic blood pressures were significantly higher (P < 0.05) in the first trimester for women with pre-eclampsia than for normal control subjects beginning in the first trimester.This difference persisted throughout pregnancy and was also present at the 6 week postpartum visit (P < 0.025).Retrospective study2−
Sibai et al., 19958772947 healthy women with a single fetus were prospectively followed up from randomisation at 13 to 27 weeks of gestation to the end of pregnancyDetermine whether any maternal demographic or clinical characteristics are predictive of pre-eclampsiaBlood pressure at bookingHigher systolic and diastolic blood pressures at the first visit were associated with an increased incidence of pre-eclampsia (3.8% in women with diastolic blood pressure of < 55 mmHg, 7.4% in those with diastolic blood pressure 70–84 mmHg). However, their recruitment was limited to women with a first blood pressure reading of ≤ 135/85 mmHg.Risk factors should be of value to practitioners counselling women regarding pre-eclampsia.Clinical trial1+
Odegard et al., 2000878323 cases of pre-eclampsia and 650 healthy controls were selectedStudied the associations between established risk factors for pre-eclampsia and different clinical manifestations of the diseaseClinical manifestations of diseasea systolic blood pressure ≥ 130 mmHg compared with < 110 mmHg at the first visit before 18 weeks was significantly associated with the development of pre-eclampsia later in pregnancy (adjusted OR 3.6 [2.0 to 6.6]). The association with a diastolic pressure ≥ 80 mmHg compared with < 60 mmHg was similar but not significant (adjusted OR 1.8 [0.7 to 4.6]).Nulliparity and hypertension increased the risk for each subgroup of pre-eclampsia, but high maternal weight, previous pre-eclampsia and smoking were not consistently associated with each clinical subtypePopulation based nested case– control2+
Stamilio et al., 2000530Cases with severe pre-eclampsia were compared with control subjects with respect to clinical data and multiple-marker screening test results. Patients were assigned a predictive score according to the presence or absence of predictive factorsTo develop a clinical prediction rule for severe pre-eclampsia that was based on clinical risk factors and biochemical factors.The only variables that remained significantly associated with severe pre-eclampsia were nulliparity (RR 3.8, 95% CI, 1.7–8.3), history of pre-eclampsia (RR 5.0, 95% CI, 1.7–17.2), elevated screening mean arterial pressure (RR 3.5, 95% CI, 1.7–7.2), and low unconjugated estriol concentration (RR 1.7, 95% CI, 0.9–3.4). This predictive model for severe pre-eclampsia, which included only these 4 variables, had a sensitivity of 76% and a specificity of 46%.Even after incorporation of the strongest risk factors, the predictive model had only modest sensitivity and specificity for discrimination of patients at risk for development of severe pre-eclampsia.Retrospective cohort study2−
Stettler et al., 199287965 pregnancies in 53 women with the following criteria: proteinuria exceeding 500 mg per day, no previously known renal disease, no reversible renal dysfunction, and no evidence for pre-eclampsia at discovery were studied.Evaluated varying degrees of chronic proteinuria as a predictor of pregnancy outcome. Determined the significance of otherwise ‘asymptomaticproteinuria identified during pregnancyPerinatal outcomes58% of the women with proteinuria combined with renal insufficiency developed pre-eclampsia. 100% of women with preteinuria combined with chronic hypertension developed pre-eclampsia whereas 77% of women with with all three together developed pre-eclampsiaAsymptomaticproteinuria is associated with a number of adverse pregnancy outcomes and serious long-term maternal morbidity.Retrospective study2−

From: Evidence tables

Cover of Antenatal Care
Antenatal Care: Routine Care for the Healthy Pregnant Woman.
NICE Clinical Guidelines, No. 62.
National Collaborating Centre for Women's and Children's Health (UK).
London: RCOG Press; 2008 Mar.
Copyright © 2008, National Collaborating Centre for Women’s and Children’s Health.

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