CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 credit hours can be earned in 2004. Instructions for how CME credits can be earned appear onthe last page of the Table of Contents.

Prediction of Preeclampsia:Can It Be Achieved?

Khalid Farag, MRCOG,* Ismail Hassan, MSc, MRCOG,†and William L. Ledger, PhD, FRCOG‡

*Locum Consultant, Department of Obstetrics and Gynaecology, Barnsley District General Hospital, Barnsley,U.K., †Specialist Registrar, Department of Obstetrics and Gynaecology, University Hospital of North

Staffordshire, Stoke-on-Trent, U.K., and ‡Professor, Head of Section of Reproductive and DevelopmentalMedicine, Department of Obstetrics and Gynaecology, Jessop Wing Hospital for Women, Sheffield, U.K.

In this review, the various biochemical tests that have been proposed for the prediction ofpreeclampsia are described and evaluated. Placenta hormone markers do not predict futuredisease. They denounce the early placental changes that are part of the evolving disease and onlypredict the imminent of preeclamptic syndrome. This explains why tests are better predictors whenpreeclampsia supervenes shortly, and why screening in the first trimester is unlikely to work as wellas in the second trimester. The use of multiple markers in the screening should reflect differentaspects of the disease process and could increase the specificity and sensitivity of the screeningand work on different etiologic factors. The possible use of second-trimester biochemical screen-ing to predict the risk of preeclampsia remains to be investigated in the high-risk population.

Target Audience: Obstetricians & Gynecologists, Family PhysiciansLearning Objectives: After completion of this article, the reader should be able to list the various

theories on the etiology of preeclampsia, to relate the various risk factors for the development ofpreeclampsia, and to describe the various screening tests for preeclampsia.

Preeclampsia is a common pregnancy-specific formof hypertension that complicates 5% to 8% of all preg-nancies and increases both maternal and neonatal mor-bidity and mortality (1). Maternal mortality has beenreduced in the United Kingdom (Fig. 1) (2), but incountries where prenatal care is not adequate, pre-eclampsia/eclampsia accounts for 40% to 80% of ma-ternal deaths. Infants of women with preeclampsia havea 5-fold increase in mortality compared with infants ofmothers without the disorder. Much of the neonatalmortality is attributable to iatrogenic prematurity. Ap-proximately 10% of preeclampsia occurs before 34

weeks gestational age, and iatrogenic premature deliv-ery resulting from preeclampsia is responsible for 15%of preterm U.S. births (3). Care of the affected womenand their premature babies places considerable de-mands on healthcare resources.

PATHOGENESIS

Preeclampsia has been called “a disease of thetheories” illustrating the fact that the etiology ofpreeclampsia remains largely unexplained (Table 1).

At present, the following 4 hypotheses are thesubject of extensive investigation.

Placental Ischemia

This theory assumes that the increase in tropho-blast deportation, as a result of placental ischemia,could inflict the endothelial cell dysfunction.

Reprint requests to: William L. Ledger, PhD FRCOG, Professor,Head of Section of Reproductive and Developmental Medicine,Obstetrics and Gynaecology, University of Sheffield, The JessopWing, Tree Root Walk, Sheffield S10 2SF, U.K. E-mail: W.ledger@sheffield.ac.uk

The authors have disclosed no significant financial or otherrelationship with any commercial entity.

CME REVIEWARTICLE Volume 59, Number 6OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2004by Lippincott Williams & Wilkins18

464

Very Low-Density Lipoprotein versusToxicity-Preventing Activity

In compensation for increased energy demand dur-ing pregnancy, nonesterified fatty acids are mobi-lized. In women with low albumin concentrations,transporting extra nonesterified fatty acids from ad-ipose tissues to the liver is likely to reduce albumin’santitoxic activity to a point at which very low-densitylipoprotein toxicity is expressed.

Immune Maladaptation

Interaction between decidual leucocytes and invad-ing cytotrophoblast cells is essential for normal tro-phoblast invasion and development. Immune malad-aptation could cause shallow invasion of spiralarteries by endovascular cytotrophoblast cells andendothelial cell dysfunction mediated by an in-creased decidual release of cytokines, proteolytic en-zymes, and free radical species.

Genetic Imprinting

Development of preeclampsia could be based on asingle recessive gene or a dominant gene with in-complete penetrance. Penetrance could be dependenton fetal genotype. The possibility of genetic imprint-ing should be considered in further genetic investi-gations of preeclampsia.

These hypotheses are not mutually exclusive andcould interact. There seem to be 2 key features thatunderline the development of preeclampsia, namely

shallow nonvascular cytotrophoblast invasion of thespiral arteries and endothelial dysfunction. Theselead to poor placental perfusion and placental isch-emia, resulting in release of many factors that arecapable of acting on peripheral sites around the bodyleading to a cascade of events, making preeclampsiaa multisystem disorder syndrome.

SCREENING FOR PREECLAMPSIA

Much research has been done to identify uniquescreening tests that would predict the risk of devel-oping preeclampsia before the classic symptomsappear and to distinguish preeclampsia from otherhypertensive disorders. Table 2 summarizes thedifferent suggested methods for screening.

The reason for early screening for preeclampsia isto try to identify high-risk pregnancies allowingmodification of antenatal care in this group and toallow preventive treatment regimens. Unfortunately,no simple tests are currently available to do this andthe detection of preeclampsia continues to depend onincreasingly frequent antenatal visits in late preg-nancy for blood pressure measurement and urinaly-sis. Although this approach is both costly and notparticularly sensitive or specific, modern antenatalcare has little else to offer.

Food supplementation, zinc, calcium and fish oil, andpharmacologic therapy, low-dose aspirin, low molecu-lar-weight heparin, and antioxidants have been tried ina low-risk population as preventive methods for pre-eclampsia (4). Despite the controversy about the valid-ity of these methods in prevention of preeclampsia in alow-risk population, these methods could have a role inprevention of the disease in high-risk groups, makingscreening important.

CLINICAL ASSESSMENT

Clinical History

The first step in screening is to assess the risk ofpreeclampsia by taking a detailed history. Table 3shows the maternal factors that could predispose topreeclampsia, with odds ratio (95% confidence inter-val [CI]) or relative risk.

Fig. 1 Maternal mortality has been reduced in the UnitedKingdom.

TABLE 1 Some modern hypotheses of the etiology of preeclampsia

Immunologic maladaptation Redman, 19916

Genetic imprinting Roberts and Cooper, 20017

Placental ischemia, increased trophoblast deportation Smarason et al., 19938

Very low-density lipoprotein-toxicity Arbogast et al., 19949

Distinct placental and maternal genesis, endothelial injury is the point of convergence Ness and Roberts, 199610

Excessive maternal inflammatory response to pregnancy Redman et al., 199911

Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article 465

Women who have required early delivery in theprevious pregnancy for severe preeclampsia remain 1of the highest risk groups; approximately 1 in 5 ofthese women will develop preeclampsia in the sub-sequent pregnancy (5).

Measurement of Blood Pressure

Midtrimester blood pressure measurement has beenevaluated as a potential early screening test. The ma-jority of women who remain normotensive during preg-nancy have a diastolic blood pressure (DBP) of �75mm Hg before the 20th week of pregnancy, but thepredictive value of a DBP, taking �80 to 85 mm Hg asa cutoff point, was only 20% (23).

The mean arterial blood pressure (MAP) has also apoor predictive value. The positive predictive valueof MAP �90 mm Hg in the second trimester for the

later occurrence of preeclampsia was shown to beless than 10% (24). In a larger study (25), 2503women at high risk were recruited from 13 centersbetween their 13th and 26th weeks of pregnancy to arandomized, placebo-controlled trial comparing aspi-rin (60 mg) and placebo in preventing preeclampsia.Women participated in this study had diabetes mel-litus, chronic hypertension, multifetal gestation, orpreeclampsia in a previous pregnancy. The studyshowed that the risk of preeclampsia was 8% with amean arterial pressure at enrollment of �75 mm Hgversus 27% with a mean arterial pressure 85 mm Hgor above (relative risk, 3.3; 95% CI, 2.4–4.4).

Twenty-four-hour ambulatory blood pressure mea-surement has also been investigated as a predictor ofpreeclampsia in primigravidae. One study of 1048healthy primigravid women demonstrated that 24-hour ambulatory blood pressure measurement be-

TABLE 3 Maternal factors that may predispose to preeclampsia, with odds ratio (95% confidence interval) or relative risk

Family history of preeclampsia 2- to 5-fold Chesley and Cooper, 198612

Collagen vascular disease 3- to 4-fold Kaaja et al., 199013

Migraine 2.4 (1.4–4.2) Marcoux et al., 199214

Gestational diabetes mellitus 3-fold Suhonen and Teramo, 199315

Hyperthyroidism (uncontrolled) 4.7 (1.1–19.7) Millar et al., 199416

Chronic hypertension 9-fold Rey and Couturier, 199417

Primiparity 3.8 (2.8–5.2) Mittendorf et al., 199618

Elevated systolic blood pressure (during early pregnancy) 2.7 (1.7–4.3) Sibai et al., 19971

Elevated diastolic blood pressure (during early pregnancy) 1.7 (1.3–2.2) Sibai et al., 19971

Polycystic ovary syndrome 5- to 6-fold de Vries at al., 199819

Renal disease 7.2 (4.2–12.5) Fink et al., 199820

Insulin-dependent diabetes mellitus 5.6 (2.7–11.4) Ros et al., 199821

Obestiy 5.2 (2.4–11.5) Ros et al., 199821

Maternal low birth weight 5.2 (1.2–21.5) Innes et al., 199922

Maternal preterm birth 3.6 (1.3–10.3) Innes et al., 199922

TABLE 2 Different suggested methods for screening

Clinical assessment HistoryBlood pressure measurement

Angiotensin II sensitivity test and rollover testUrine test Urine human chorionic gonadotropin �-subunit core fragment

HypocalcuriaUrine kallikrein–creatinine ratioMicroalbuminuria

Maternal biochemistry and protein assay InhibinMaternal serum �-fetoprotein (MSAFP)Human chorionic gonadotrophin (hCG)Placental growth factor (PLGF)Biochemical markers associated with insulin resistanceFibronectinPlasma corticotrophin-releasing factorHomocysteineNeurokinin BAdhesion molecules

Fetal erythroblasts in maternal bloodGenomic screeningBiophysical screening

466 Obstetrical and Gynecological Survey

tween 18 and 24 weeks was not a useful clinicalpredictor (26). The absolute blood pressure differ-ences between the outcome groups were small andthe overlap between the groups was large.

ANGIOTENSIN II SENSITIVITY TEST ANDROLLOVER TEST

Women destined to develop preeclampsia dem-onstrate an increased sensitivity to vasoactive sub-stances such as angiotensin II (27). The resultsfrom an initial study that used this observation asa basis for s screening test were quite promising(sensitivity 90%, specificity 87%, positive predic-tive value 75%, negative predictive value 95%).These findings were replicated, with varying de-grees of success, in 5 subsequent studies (28).Despite these impressive results, angiotensin infu-sion tests have remained a research rather than aclinical tool for 2 reasons: the cumbersome andtime-consuming nature of the test and the fact thatit is only useful after 28 weeks gestation, when itis probably too late for any prophylactic therapy tobe effective. Also, in the largest study, involving495 nulliparous women, the reported positive(19%) and negative (87%) predictive values weredisappointing (29), raising doubts about the use ofthis test.

URINE TESTS

Urine Human Chorionic Gonadotropin�-Subunit Core Fragment

The hCG �-subunit core fragment (�-core frag-ment) is the end product of hCG metabolism, thefinal step of which occurs in the maternal kidney(30). It is a relatively small molecule with a molec-ular weight of 9000, which is less than one fourth thesize of intact hCG (molecular weight 36,700) (31). Ina study of 347 singleton pregnancies, of which 16(4.6%) developed preeclampsia, a significant linearassociation was found between urinary �-core frag-ment concentration and risk of developing pre-eclampsia (32). The relative risk (95% CI) of subse-quent preeclampsia increased from 2.07 (1.06–4.05)at �-core fragment levels of human chorionic gonad-otropin �2.0 multiples of the media to 5.17 (195–13.7) at �4.0 multiples of the media.

Hypocalcuria

Despite there being no difference in intestinal cal-cium absorption between patients with preeclampsia

and normotensive patients (33), hypocalciuria hasbeen reported to be one of the most consistent find-ings in women with preeclampsia (34,35). In onestudy, a level of less than or equal to 195 mg ele-mental calcium in a 24-hour urine collection had an87% positive predictive value (36). However, in alater study in which the 24-hour urinary excretion ofcalcium was evaluated in 69 primigravida at 17 to 20weeks gestation, the sensitivity for prediction of pre-eclampsia was 80% (95% CI, 59.8–100), specificity64.8% (95% CI, 52.1–77.5), positive predictive value38.7% (95% CI, 21.6–55.8), negative predictivevalue 92.1% (95% CI, 83.5–100), and RR 4.9 (95%CI, 1.5–15.8) (34). This measurement does not havesufficient sensitivity to recommend its use as ascreening test for the emergence of preeclampsia.

Urinary albumin:creatinine and calcium:creatinineratios have also been assessed with equally disap-pointing results (37,38). The low sensitivity of thesetests does not support their use as screening tests forpreeclampsia.

Urinary Kallikrein–Creatinine Ratio(UK:Cr)

Kallikreins are proteases with indirect vasomotoreffects mediated by kinins and by the rennin–angio-tensin system. Measurement of UK:Cr ratio in 307normotensive women between 16 and 20 weeks ges-tation showed a sensitivity of 83% and a positivepredictive value of 91% for the subsequent develop-ment of preeclampsia (39). The test is simple andeasy to perform. However, the number of patients inthis study was very small (only 12 women developedpreeclampsia). In a larger study that compared uri-nary UK:Cr ratio with the angiotensin sensitivity test(AST) for the prediction of preeclampsia, the sensi-tivity and specificity for detecting preeclampsiawere, respectively, 22% and 85% for the angiotensinsensitivity test and 67% and 75% for the UK:Cr ratio.The authors concluded that the UK:Cr ratio was abetter screening test for preeclampsia than the AST,but overall neither test was a powerful predictor forthe syndrome (40).

Microalbuminuria

Proteinuria is a common feature of various formsof hypertension and renal diseases and is regarded asa central feature of preeclampsia. The proteins ex-creted are predominantly albumin and transferrin(41). Microalbuminuria is defined as protein excre-tion of between 20 and 200 �g/min of albumin(42,43). Persistent microalbuminuria indicates a high

Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article 467

probability of damage to the glomerular filtrationcapacity of the kidney. Results of studies of mi-croalbuminuria as an early predictor of preeclampsiaare conflicting (28,37,41–47). Different studies re-port sensitivity between 50% and 68%, and specific-ity ranging from 58% to 92%, with positive predic-tive values between 26% and 61% (42,44,45,47).Given this controversy, it is not possible to recom-mend assessment of microalbuminuria as a screeningtest for development of preeclampsia, although fur-ther research could alter this position.

MATERNAL SERUM MARKERS

Inhibin in Pregnancies Subsequently DevelopingPreeclampsia

Early work studying samples collected fromwomen with preeclampsia compared with samplesfrom gestation and age-matched normotensive preg-nancies showed that levels of inhibin A and activin Awere approximately 10-fold higher during estab-lished disease (48,49). Similar elevations were notseen in cases of pregnancy-induced (nonproteinuric)hypertension or essential hypertension.

These findings have now been confirmed by anumber of groups, all using the “Groome” assay forinhibin A (49–52). Although sampled groups variedin size, parity, and severity of preeclampsia, it seemsclear that the preeclamptic placenta is an importantsource of inhibin A and activin A.

Although most studies agree that inhibin A andactivin A concentrations in the circulation are ele-vated in established preeclampsia, the potential ofthese markers for identifying asymptomatic womenat high risk of developing the disease is less clear. Aninitial study showed a statistically significant eleva-tion in levels of inhibin A at approximately 16 weeksgestation in women who later developed severe pre-eclampsia (53). This finding has been confirmed inother cross-sectional studies of samples originallycollected for Down syndrome screening at 13 to 18weeks (54,55). However, other groups have not beenable to identify early elevations in either inhibin A oractivin A in women destined to develop preeclampsia(56,57). These studies can all be criticized; both hadsmall numbers of patients with true preeclampsia andincluded both nulliparous and multiparous patients.The pathogenesis of preeclampsia in multipara coulddiffer from that seen in nulliparae.

To date, only 1 longitudinal study has been carriedout using serial sampling of both women who re-mained normotensive and women who progressed to

preeclampsia (58). This study included 1496 nullip-arous women, of whom 71 (4.8%) developed pre-eclampsia and 117 (7.8%) developed gestational hy-pertension. The longitudinal study of levels ofinhibin A and activin A was accompanied by a nestedcase–control study of 70 preeclamptic patients and240 randomly selected control subjects who werestudied at 15 to 19 weeks and 21 to 25 weeks. Theresults confirmed the patterns of these analytes innormal pregnancy and further suggested the possibil-ity that early elevation, particularly of activin A,might predict early-onset preeclampsia leading todelivery before 34 weeks. However, predictive sen-sitivities for later-onset preeclampsia were low.

Maternal Serum �-Fetoprotein (MSAFP)

The association between elevated MSAFP in thesecond trimester (with a structurally normal fetus)and increased incidence of hypertension was firstreported in 1978 (59). After the introduction ofmidtrimester biochemical screening for screening forspina bifida, this association was confirmed by sev-eral other studies (60–64). The relative risk ratios forthe subsequent development of preeclampsia inwomen with unexplained elevated MSAFP (�2.0multiples of the median) was modest, ranging from1.75 to 3.8.

However, recent studies observed that the concen-tration of maternal serum AFP at 22 to 24 weeks wasnot significantly different in cases that developedpreeclampsia later from those who stayed normoten-sive, questioning the value of this test for screening(65,66). The sensitivity, specificity, positive predic-tive value, and negative predictive value have beenreported as 4.8%, 98.6%, 6.7%, and 98%, respec-tively (67).

Human Chorionic Gonadotrophin (hCG)

The association between elevated hCG and estab-lished preeclampsia was first reported in 1939 (68)and subsequently confirmed by another study (69).These early studies focused on hCG levels in thepresence of established preeclampsia. Human chori-onic gonadotrophin production has been shown toincrease when normal placental villi in organ culturesare maintained under conditions of low oxygen ten-sion (70). Since the introduction of assay of serumhCG in screening for trisomy 21, a number of studieshave show an association between elevation of sec-ond-trimester hCG and subsequent development ofpreeclampsia (71–74). The majority of these studies

468 Obstetrical and Gynecological Survey

observed only a modest correlation with preeclamp-sia, and the low predictive values would not justifythe introduction of hCG as a screening test for thiscondition.

Placenta Growth Factor (PLGF)

The maternal serum concentration of PLGF is re-duced significantly in clinically evident cases of pre-eclampsia. However, there were no differences be-tween women who remained normotensive and thosewho developed severe preeclampsia when PLGF wasmeasured in blood samples collected at 11 to 14weeks, ruling out use as an early marker (75,76).However, another study used collected blood sam-ples in the late second trimester (17 and 21 weeks ofpregnancy) and showed a significantly lower concen-tration of PLGF in plasma of patients who laterdeveloped preeclampsia compared with control preg-nancies (77).

Biomarkers Associating Preeclampsia WithInsulin Resistance Syndrome

Insulin resistance is defined as an impaired abilityof insulin to stimulate the uptake and disposal ofglucose by muscle (78).

An association between hyperinsulinemia andcardiovascular disease (CVD) in women was re-ported in 1998 (79) The mechanism(s) by whichthe insulin resistance syndrome and hyperinsulin-emia could be related to endothelial dysfunctionand disturbances in coagulation. Insulin resistanceis associated with impaired fibrinolysis (80),blunted endothelium-dependent vasodilatation(81), reduced prostacyclin (PGI2) production, in-creased thromboxane (TxA2) production, increasedcoagulation, and platelet activation (82). Abnor-malities in production of acute-phase cytokinesuch as interleukin-6 (IL-6) and tumor necrosisfactor-alpha (TNF-�) could underlie the associa-tion of insulin resistance with coagulopathy, endo-thelial dysfunction, and cerebrovascular disease(83). The endothelial dysfunction and disturbancesin coagulation appear to explain the link betweeninsulin resistance and preeclampsia and gestationalhypertension (84). A number of markers have beenused to assess insulin resistance, including theglucose tolerance test and measurements of sexhormone-binding globulin (SHBG) (84). Also, theantiobesity hormone leptin and the cytokine tumornecrosis factor (TNF-�) are new potential media-tors of insulin resistance (85); they are produced inthe placenta and therefore could play a vital role ininsulin resistance in pregnancy (86–88). TNF-� as

a new paradigm explaining pregnancy-related in-sulin resistance challenges the long axiom that isthe result of the production of placental reproduc-tive hormone. However, this does not exclude thepossibility that this hormone has a permissive rolein insulin resistance in pregnancy by augmentingor attenuating the effects of the most direct medi-ators as TNF-� (89).

Impaired Glucose Tolerance Test as a Marker ofInsulin Resistance

Preeclampsia is associated with increased fastinginsulin concentrations and higher glucose and insulinresponses in the oral glucose tolerance test (OGTT),but the data on insulin sensitivity are contradictory.Both increased glucose response in the OGTT andelevated fasting insulin levels can identify a risk ofpreeclampsia (Table 4).

Leptin

Leptin, a protein product of the obesity (Lepob)gene, is synthesized and secreted by adipocytes(87,95). It is also synthesized by the placenta andcould contribute to circulating leptin during preg-nancy (87,96). The significant increase in maternalcirculating leptin during the first and second trimes-ters of normal pregnancy is suggested to be in re-sponse to the marked changes in maternal weight,energy expenditure, and hormonal status. Also, in-creased maternal Leptin will increase circulating freefatty acids and glucose, providing nutritional supportfor the fetus (97).

However, recent data demonstrate that the increasein circulating Leptin concentration begins in earlypregnancy, before any changes in body fat or restingmetabolic rate, suggesting that hormonal factorscould be responsible (98).

Preeclampsia has been reported to be associatedwith an increase in maternal plasma leptin concen-trations (96,97,99). In cross-sectional and longitudi-nal study, plasma leptin concentrations were signif-icantly greater in women with preeclampsia than innormal control subjects (P � 0.001) Also, in ques-tion, concentrations of Leptin in women destined todevelop preeclampsia were consistently higher from20 weeks gestation (P � 0.04–0.003) (99).

However, in another contrasting study, concentra-tions of Leptin in serum did not differ between pa-tients with different grades of preeclampsia and nor-motensive pregnant women (100). So, its clinicalpotential should be addressed in future research.

Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article 469

Tumor Necrosis Factor (TNF-�)

Many cytokines expressed in adipose tissue such asTNF-� has shown to reduce insulin-stimulated glu-cose uptake in adipocytes, suggesting that the in-crease in this cytokine contributes to insulin resis-tance (101).

TNF also can induce the synthesis of other cyto-kines, which alone or in concert with others couldalter endothelial function (102).

The ischemic placenta is an important source oftumor necrosis factor-� (TNF-�) and interleukin-1(IL-1) (103,104). TNF also can induce the synthesisof other cytokines, which alone or in concert withothers, could alter endothelial function (102). TNF-�could as well be directly involved in endothelialdysfunction (105) and induce plasminogen activatorinhibitor PAI-1 (106), which could be contributing tofibrin deposition and placental vascular lesion (107).

Patients with preeclampsia have significantly ele-vated concentrations of TNF-� and TNF-� messen-ger ribonucleic acid in plasma, amniotic fluid, andplacental tissue (108–111), with plasma levels beingelevated, by almost 2-fold, in women with pre-eclampsia (112).

The mean serum concentration of sTNFp55, amarker of excessive TNF-� release, was also foundto be high in midpregnancy in patients who devel-oped preeclampsia later (105).

However, TNF-� and sTNFp55 are not ideal foruse in screening tests. TNF-� has a short half-life ofapproximately 15 minutes, so more than 1 bloodsample could be needed. Also, TNF-� is producedand acts locally in an autocrine or paracrine manner,and plasma concentrations might not actually reflectTNF-� concentrations at the local level (113).

Sex Hormone-Binding Globulin (SHBG)

SHBG is a glycoprotein produced by the liver thatmediates the balance between free and bound testos-terone and estrogens (114). Hepatic SHBG synthesisis stimulated primarily by estradiol and thyroid hor-mone and is inhibited by insulin (115). The inhibi-tory effects of insulin prevail in circumstances whenthere are competing stimuli for hepatic SHBG pro-duction (115), such as pregnancy when both estradioland insulin levels raise progressively (116). Unlikeother markers of insulin resistance, SHBG has aminimal variability when comparing its fasting andpostprandial levels (117). These properties appointSHBG as a unique marker of insulin resistance that isparticularly valuable in nonfasting status, includingobstetric prenatal care (118). In a prospective, case–control study, first-trimester SHBG levels were mea-sured in 45 nulliparous women who subsequentlydeveloped preeclampsia and in 90 randomly selectednormotensive nulliparous control subjects. Com-

TABLE 4 Impaired glucose tolerance predicts the risk of preeclampsia

Subjects Method Findings Reference

Women with 1 abnormal OGTTvalue

1-hour 50-g OGTT, 3-hour100-g OGTT at 24–32weeks gestation

Elevation risk of preeclampsiaassociated with abnormalOGTT value vs. controls (OR,2.81 [1.26–6.28])

Lindsay et al., 198990

Women with gestational diabetesmellitus (GDM) and 1 abnormalOGTT value

2-hour 75-g OGTT at28–32 weeks gestation

Elevated risk (3-fold) for pre-eclampsia in women withGDM, but not in women withabnormal OGTT value

Suhonen and Termo,199315

Preeclamptic women; women withgestational hypertension

1-hour 50-g, OGTT at24–32 weeks gestation

A 1-hour 50-g OGTT value�7.8 mmol/L predicted pre-eclampsia, but not after ad-justment for age, race, ges-tational age at OGTT, andpregravid BMI

Solomon et al., 199491

Women without GDM 1-hour 50-g OGTT, 3-hour100-g OGTT at 26–28weeks gestation

The 2-hour 100-g OGTT valuewas a significant predictor ofpreeclampsia after adjustingfor BMI

Sermer et al., 199592

Nulliparous women Fasting levels of glucoseand insulin at 18–22weeks gestation

Fasting level of insulin 1.8-foldhigher in women who devel-oped preeclampsia

Sowers et al., 199593

Nulliparous women with GDM 1-hour 50-g OGTT, 3-hour100-g OGTT in the latesecond trimester

The 1-hour 50-g OGTT valuepredicted preeclampsia, evenin normoglycemic women

Joffe et al., 199894

470 Obstetrical and Gynecological Survey

pared with control subjects, women who developedpreeclampsia had significantly reduced first-trimesterSHBG levels (302 � 130 vs. 396 � 186 nmol/L; P�0.01). Every 100-nmol/L increase in SHBG wasassociated with a 31% reduced risk of preeclampsia(odds ratio [OR], 0.69; 95% CI, 0.55–0.88; P�0.01]. In a multivariable analysis, there was astrong association between SHBG and preeclampsiaamong lean women, with every 100-nmol/L increasein serum SHBG associated with a 55% reduction inthe risk of preeclampsia (OR, 0.45; 95% CI, 0.27–0.77; P �0.01), whereas in overweight women, theassociation was less (OR, 1.02; 95% CI, 0.62–1.69; P� 0.9). They concluded that increased early-preg-nancy insulin resistance is independently associatedwith subsequent preeclampsia. First-trimester SHBGconcentration in serum might be a useful biomarkerfor preeclampsia, especially among lean women(119).

Fibronectin (Fn)

The fibronectins are a family of high molecular-weight glycoproteins (440–500 kD) that exist in na-ture as dimers or multimers of disulfide-linked sub-units derived from a pool of similar but nonidenticalpeptides. The term plasma Fn refers to the total poolof soluble Fn in the circulation. The term cellular Fn(cFn) generally refers to isoforms of the Fn associ-ated with endothelial cells and are found in solubleform within the extracellular matrix of tissues(120,121). The cellular type has a single exon, whichis termed ED1, and can be measured in plasma. Thecellular type is expressed more abundantly duringtissue injury and remodeling (121,122). This mightexplain the high level of ED1�Fn in preeclampsia(121,123,124).

Several studies have identified high concentrationsof Fn in women destined to develop preeclampsia(125–127). In a recent longitudinal study, elevatedfibronectin levels were detectable in women destinedto develop preeclampsia significantly early, at 9 to 12weeks gestation, with sensitivity, specificity, andpositive and negative predictive values of 73%, 87%,29%, and 98%, respectively; the odds ratio was 16.1(95% CI, 8.6–30.2) at 22 to 26 weeks gestation inwomen destined to develop preeclampsia (128).These findings differ from those of another longitu-dinal study of 198 consecutive pregnant patients thatdemonstrated only significant differences betweennormotensive women and preeclamptics in the thirdtrimester and concluded that cFn could not be used asa predictor of preeclampsia because the clinicalsymptoms of this pathology were already present at

the time of detection (129). More understanding ofuteroplacental insufficiency and preeclampsia will beachieved if more of these longitudinal studies focuson the first trimester and larger numbers of patientsare involved.

Plasma Corticotrophin-Releasing Hormone(CRH)

CRH is secreted in large amounts by placenta(130), and concentrations in the maternal circulationrise exponentially as term approaches, with signifi-cant elevation in preeclamptic women (67,130–134).This elevation could represent a protective responseto placental hypoperfusion seen in cases of pre-eclampsia (67). A rise in CRH concentration hasbeen demonstrated at 11 weeks (131) and in midtri-mester (67) before the development of signs andsymptoms of the disease. However, in a large cohortstudy (67), both midtrimester CRH and maternalserum �-fetoprotein (MSAFP) were assessed as pre-dictive of preeclampsia. Both were significantly highin preeclamptic women but CRH and MSAFP whenmeasured in midpregnancy did not have a strongpredictive value. The sensitivity, specificity, positivepredictive value, and negative predictive value forthe midtrimester CRH test in prediction of pre-eclampsia were 38.1%, 79.9%, 3.8%, and 98.4%,respectively. Although the combination of both val-ues improved the detection rate compared with CRHalone, there was still only a small increase in likeli-hood ratio (from 1.9 to 2.6) so that it is unlikely to beof great clinical value.

Homocysteine

Homocysteine is a demethylated metabolite of theessential amino acid methionine and is associatedwith increased oxidative stress and lipid peroxida-tion, smooth muscle proliferation, abnormalities ofcoagulation, and endothelial dysfunction (135–138).

In a case–control study, 56 patients who developedsevere preeclampsia were found to have higherplasma homocysteine levels in early pregnancy whencompared with women who remained normotensivethroughout pregnancy (138). However, another studywas unable to exhibit any difference in serum homo-cysteine levels at 16 weeks gestation between the 2groups. They concluded that there were not majordifferences in homocysteine levels before the mani-festation of preeclampsia (139).

In addition to this uncertainty over validity ofelevated homocysteine as a predictor of preeclampticrisk, its use is also compromised by many extrinsicfactors that influence homocysteine metabolism in-

Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article 471

tensely: genetic, environmental, or nutritional factorsas well as renal function (140). Also, an inadequateintake of vitamin B12, B6, or folic acid has been seenin cases of hyperhomocystinemia. This could createdifficulties in reliability of homocysteine as a markerfor preeclampsia.

Neurokinin B (NKB)

NKB belongs to a family of neuropeptides calledthe tachykinins. NKB was identified in human pla-cental tissue (141). Their biologic actions includesmooth muscle contraction, vasodilatation, paintransmission, neurogenic inflammation, and activa-tion of the immune system (142). It has been sug-gested that NKB secretion from the placenta in nor-mal pregnancy plays a role in some hemodynamicadaptations by shunting the blood from the liver andmesenteric area to the uterus and placenta (141).NKB could also cause dilatation of the spiral arteriesby stimulating NK3 receptors, which act as media-tors to relax smooth muscle through the nitric oxidepathway (143).

Initial studies indicate that NKB is present in highconcentration in the plasma of preeclamptic women,whereas it is low or not detected in most normoten-sive women. The expression of neurokinin B wasconfined to the outer syncytiotrophoblast of the pla-centa, and significant concentration of NBK could bedetected in plasma as early as 9 weeks gestation.NKB remains a potential candidate for developmentof an early predictive test for preeclampsia (141), butlonger longitudinal studies are needed.

Adhesion Molecules

Adhesion molecules are receptors that modulateinflammatory responses by permitting leukocyteadhesion to the inflammatory site. Some adhesionmolecules are considered to be important for leu-kocyte extravasation in the placental bed duringtrophoblast invasion. Intercellular adhesion mole-cule 1 (1CAM-1) and vascular cell adhesion molecule(VCAM-1) are largely expressed by the vascular endo-thelium of human deciduus (144).

Because the soluble forms of 1CAM-1 (sICAM-1)and VACM-1 (sVCAM-1) are markers of arterialwall inflammation and endothelial dysfunction, theyshould be elevated in preeclamptic patients. How-ever, the level of sICAM-1 is reported to be un-changed in cases of preeclampsia (145,146).

Also, the level of sVCAM-1 was reported to behigh in cases of preeclampsia (147); however, itshowed no change in the second trimester, which

discourages the possibility of using sVCAM-1 as apredictor (147).

FETAL ERYTHROBLASTS INMATERNAL BLOOD

A century ago, Schmoral noticed that trophoblasticcells could be detected in the lungs of patients whohad preeclampsia (148). This is thought to resultfrom placental damage and subsequent increased de-portation across the placenta (66). Several studieshave demonstrated increased fetal cell trafficking(�6-fold) (66,149), and cell free DNA (�3-fold)(150–152), from 20 weeks onward in the maternalcirculation of women who developed preeclampsialater. The cell-free DNAs could be apoptotic DNAfragments from uterine wall placental cytotropho-blasts through the breakdown of these cells and arenot the results of fetal cell trafficking. These particlescould contribute to a cytotoxic effect on endothelialcells characteristic of preeclampsia (65,153).

At present, results overlap between preeclamptic andcontrol groups, with low sensitivity and specificity(152). The most likely clinical application for detectionof fetal erythroblasts in maternal blood is as a latesecond-trimester marker of preeclampsia. This testcould be used to reduce the false-positive rate of otherearly second-trimester markers of preeclampsia.

GENOMIC STUDIES OFPREECLAMPTIC RISK

A familial tendency in preeclampsia is well estab-lished. This information dates back to a classic studyby Chesley and Copper, who found preeclampsia in26% of the daughters and 16% of the granddaughtersof eclamptic mothers (12). There is growing evi-dence, which indicates genetic or immunologic con-flicts between the mother and fetus as etiologic fac-tors in preeclampsia. Preeclamptic risk is increasedin pregnancy after oocyte donation (154–156), whenthe fetus differs genetically from the mother, and inpregnancies in which the male partner has previouslyfathered a preeclamptic pregnancy (157). A familyhistory of preeclampsia predisposes to a 2- to 3-foldincreased risk for development of the condition com-pared with women with no family history (158,159).

Several studies that searched the genome for re-gions associated with preeclampsia have been re-ported. Two studies found evidence for a maternalsusceptibility locus for preeclampsia on the short armof the chromosome 2 (160,161), whereas anotherreported a LOD on the long arm of chromosome 4

472 Obstetrical and Gynecological Survey

(162). The roles of other genes or polymorphismshave been investigated, including those for factor VLeiden mutation (163–165), endothelial nitric oxidesynthetase (166–169), angiotensin genes (170,171),methylenetetrafolate reductase mutations (172,173),epoxide hydrolase polymorphism (174), and poly-morphism related to tumor necrosis factor (175,176).Preeclampsia has a complex inheritance pattern in-volving multiple disease susceptibility loci, environ-mental gene interaction, and paternal (fetal) interac-tions, which complicate elucidation of theinheritance mode of the condition.

BIOPHYSICAL SCREENING

Doppler ultrasound is a noninvasive procedure thatis regularly used to assess maternal and fetal hemo-dynamics. This test is based on the principle that adeficient uterine, placental, or fetal circulation canlead to an adverse pregnancy outcome and that theseabnormalities could be detected with the use ofDoppler velocimetry. Doppler techniques have beenused in obstetrics since the first report of successfulrecording of blood flow signals from the umbilicalartery by Fitzgerald and Drumm in 1977 (177).

Trophoblast invasion into the myometrial segmentof spiral arteries occurs early in the second trimesterand is associated with remarkable hemodynamicchanges in the placental circulation (178). Thesechanges are demonstrated by the shape of the uterineartery velocity waveform, which is unique. It is char-acterized by high end-diastolic velocities with con-tinuous forward blood flow throughout diastole. Typ-ically, as gestational age advances, the degree ofend-diastolic flow increases, so the high-resistanceprofile of early pregnancy transforms to a low-resis-tance profile by 24 weeks (179–181). Defective pla-centation results in increased vascular resistance ofthe uterine artery and decreased perfusion of theplacenta (181–184). This causes a persistent highresistance to uteroplacental blood flow. The changein the pattern of uteroplacental blood flow can bedetected by Doppler ultrasound of the maternal uter-ine arteries (185–187). A pathologic waveform isdescribed as the presence of either high impedance inform of a high pulsatility index (PI), resistance index(RI), or A/B ratio, presence of a notch in the wave-form from one or both uterine arteries (188–192), orcombinations of both (193–196). This “notch” ispresent in most waveforms in nonpregnant womenand early pregnancy but disappears in the secondtrimester in normal pregnancy (180). The diastolicnotch is probably not related to increased resistance

but to arterial wall compliance, indicating that theappearance—or failure of disappearance—of the di-astolic notch could denote an abnormal maternalartery wall status (197).

Uterine artery Doppler waveform analysis offers abiophysical marker of inadequate placental perfu-sion. Several studies have examined use of Dopplerwaveform analysis to predict preeclampsia (Table 5).

Twenty-seven published and unpublished observa-tional studies involving 12,994 pregnancies havebeen metaanalyzed. These pregnancies were strati-fied into low- or high-risk categories for developingpreeclampsia. The metaanalysis suggested that in thelow-risk population, a positive test result could pre-dict risk of preeclampsia with a likelihood ratio of60.4 (95% CI, 50.7–7.1), whereas a negative testresult had a likelihood ratio of 0 0.7 (95% CI, 0.6–0.8). In the high-risk population, a positive test resultcould predict risk of preeclampsia with a likelihoodratio of 2.8 (95% CI, 20.3–30.4), whereas a negativetest had a likelihood ratio of 0.8 (95% CI, 0.7–0.9).Based on these results, the authors concluded thatuterine artery Doppler flow velocimetry had limiteddiagnostic accuracy in predicting preeclampsia (198).

DISCUSSION

To screen for a certain disease, the disease shouldhave well-understood biology, and early detectionand treatment should lead to an increase in long-termimprovement of the condition, should not create un-due anxiety, and be acceptable to patients. Despitethe fact that screening for preeclampsia does notmeet all of these criteria, early detection of hyper-tension during pregnancy permits clinical monitoringand prompt therapeutic intervention for severe pre-eclampsia or eclampsia, and clinical experience sug-gests that early detection and treatment of preeclamp-sia is beneficial to the patient and fetus. This view isbased, in part, on the apparent effectiveness of reg-ular antenatal care in reducing the complications ofpreeclampsia/eclampsia, and it could as well, in thefuture, allow treating these patients early in preg-nancy, which could lead to a better outcome.

Generally, the validity of the available tests isdifficult to evaluate as a result of the absence of a“gold standard” to confirm the diagnosis, and moststudies of potential screening tests for preeclampsiahave relied on clinical criteria to confirm thediagnosis.

Clinical assessment is not useful in the predictionof preeclampsia. Selection of pregnancies at risk onthe basis of maternal risk factors predisposing to

Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article 473

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474 Obstetrical and Gynecological Survey

preeclampsia would not provide us with an effectivescreening test for the general obstetric population.Also, blood pressure measurement alone (midtrimes-ter, mean arterial pressure, or ambulatory blood pres-sure) has failed to provide a useful predictor forpreeclampsia.

The rapid expansion in the application of biochem-ical markers in recent years has been largely theresult of the development of sensitive immunoassaysusing monoclonal antibodies, which yield reproduc-ible results.

Urine and serum biochemical assays have providedevidence that there are differences in the metabolismof women who subsequently develop preeclampsiacompared with women who remain normotensiveduring their pregnancy. However, the main problemsare:

1. The majority of these markers do not fulfill thecriteria for useful screening test because thesensitivity is too low or the false-positive rate istoo high.

2. None of the biochemical markers have beenassessed in prospective studies with adequatepower to demonstrate efficacy.

3. Some of the markers are relatively expensiveand complex to measure.

4. Placental hormone markers do not predict fu-ture disease. They denounce the early placentalchanges that are part of the evolving diseaseand only predict the imminent development ofthe preeclampsia syndrome. This explains whyscreening in the first trimester is unlikely towork as well as in the second or third trimester.

Urinary assay of creatinine and kallikrein could yetoffer useful and practical screening tests. However,there are only 12 women with preeclampsia who have,as yet, been studied and further work is required.

Among the maternal protein markers, inhibin A isthe most studied. All 5 studies were essentially cross-sectional, using samples collected and frozen in earlypregnancy for other purposes. The prospective lon-gitudinal study on inhibin, which involved 1496 par-ticipants (58), tried to clarify the ability of inhibin Aand activin A measurement to predict risk of pre-eclampsia. This study showed that the value of in-hibin/activin is low in predicting late-onset pre-eclampsia (after 34 weeks). Although the ligandswere better predictors of early overt preeclampsia,the early form of preeclampsia is relatively uncom-mon (0.74% of this cohort); it represents the mostsevere end of the spectrum, and early intervention

might allow prolongation of these pregnancies, im-proving the chances of fetal survival.

Research is continuing. The identification of thevasodilator-stimulated phosphoprotein (VASP) in thehuman placenta from the first trimester suggests thatthis protein could be associated with trophoblasticcell motility and could have a role in implantationand trophoblastic cell invasion. A marker of thisprotein could have a place in screening for pre-eclampsia syndrome (213).

The increased prevalence of preeclampsia indaughters born to eclamptic mothers could indicatean influence of the fetal genotype (paternal genome)on susceptibility to preeclampsia. The genetic con-flict theory assumes, in general, mother and fetus donot carry identical gene sets (in other words, mater-nal and fetal interests are not always in harmony). Sointeractions between the fetus and the mother and theinvolvement of imprinting in the control of cell be-havior within fetomaternal interfaces of the placentawith paternal genome function is working to depletematernal resources for the advantage of the fetus,whereas the maternal genome is counteracting thisdrain for the benefit of the mother and her subsequentpregnancies (214). This mechanism could be opera-tive in gestational hypertension, in which fetal prog-nosis is known to be good. In contrast, in preeclamp-sia, the hypertension results from vasoconstrictionrather than increased cardiac output. In addition tothe problem concerning the mode of inheritance, it isunclear whether nonproteinuric hypertension repre-sents the same disease as proteinuric preeclampsia.At present, several groups conducting linkage studiesand complete maternal genomewide scans to dis-cover preeclampsia genes. However, so far, no suchgenes have been identified. The hunt for genes forpreeclampsia will yield many that operate as riskfactors (11). Whether this will lead to a clinicallyuseful predictor of risk remains to be seen.

The variations in results of studies on Doppler as apredictor for preeclampsia are the result of manyfactors. Uteroplacental waveforms can be affected bythe location of the placenta, the presence of BraxtonHicks contraction, sample site (uterine or arcuateartery), and Doppler technique. The uterine artery isreported to be the best sample site to obtain consis-tent information about the uteroplacental circulation;it is easy to locate on real-time imaging, providesgood reproducibility, and reflects the resistance inthe entire distal placental bed. Comparing continu-ous-wave Doppler with the pulsed-wave Doppler, thepulsed-wave Doppler has the ability to determinethe exact location of the sample site; therefore, it is

Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article 475

the preferred method in determining uteroplacentalblood flow profiles.

The prevalence of preeclampsia in the studies ofDoppler in preeclampsia varies between 2.2% and24%. This could reflect differences in hospital pop-ulation, environmental factors, and differences in thedefinition of hypertensive disorders.

The gestational age at the time of Doppler assessmentis an important factor. Screening before 20 weeks mightbe associated with more false-positive test results be-cause the spiral artery adaptation is still in progress butnot yet finished. Most of studies were performed be-tween 16 and 24 weeks. Other studies performed mea-surements at or even beyond 26 weeks. Good predictivevalues are reported in 2-stage studies in which an initialscan at 18 to 20 weeks is followed, if abnormal, by arepeat scan at 24 weeks to reduce the high rate offalse-positive results.

There is as-yet no agreement about the definition ofpathologic waveforms. Initially, only high impedancewas thought to be important. Later, bilateral notchingwas included in the assessment. Further studies de-scribed pathologic waveform as the presence of highimpedance in the form of high PI, RI, or A/B ratio, thepresence of a notch in one or both uterine arteries, orcombination of both. It is not completely clear in manystudies whether impedance was evaluated on only oneside or if the mean for both sides was taken.

In addition to this, personal variation has a role.The reproducibility of notch detection is low, withconcurrence in detection of notching by 2 operatorsbeing only 85% with disagreement of unilateralnotching being 9.8% and bilateral notching 6.8%.

Overall, there is a lack of randomized, controlledtrials of the use of uterine artery Doppler studies inthe screening of pregnancy complications such aspreeclampsia.

Use of Multiple Markers

Prevention of any disease process requires knowl-edge of its etiology and pathogenesis, as well as the

availability of methods for prediction of those at highrisk for this disorder. At the present time, there is aconsensus that the etiology of preeclampsia is mul-tifactorial. The use of multiple markers in the screen-ing should reflect different aspects of the diseaseprocess and increase the specificity and sensitivity ofthe screening.

Combinations of maternal biochemical markers,serum inhibin A, free �-human chorionic gonado-tropin (free �-hCG), unconjugated estriol (uE3),and alpha-fetoprotein (AFP) have been investi-gated in prediction of preeclampsia. Stored serumsamples were used. Nineteen women who devel-oped preeclampsia had sequential blood samplestaken from 8 weeks gestation. For each sample, 3control samples were collected from women withunaffected pregnancies matched for gestation ageand maternal age. In pregnancies that developedpreeclampsia, the median inhibin A value wasraised (1.7 multiples of the media [MoM] for un-affected pregnancies) (95% CI, 1.1–2.7 MOM), themedian free �-hCG was raised (2.1, 1.4–3.3MoM), and the median uE3 was lowered (0.8,0.6–0.98 MoM) after 19 completed weeks of ges-tation and at least 2 weeks before the onset ofproteinuria. Values of AEP were similar in af-fected and unaffected pregnancies. Combining thevalues of inhibin A, free �–hCG, and uE3 to forma screening test would detect an estimated 55% ofaffected pregnancies with a false-positive rate of 5%.

Combining second-trimester maternal serum in-hibin-A and uterine artery Doppler improves thescreening efficacy for prediction of preeclampsia.

Inhibin A levels were measured between 15 and19 weeks gestation and color flow pulsed Dopplerof both uterine arteries was carried out between 18and 22 weeks gestation. The improvement in sen-sitivity for the combined method, compared witheither inhibin-A or uterine artery Doppler alone,was statistically significant for preeclampsia (211)(P �0.05).

TABLE 6 Risk factors of preeclampsia

Genetic factors Women whose mothers had preeclampsia (have a 20–25% risk)Women with sisters with a history of preeclampsia (have a 35–40% risk)

Obstetric history PrimiparityMultiple pregnancyHydrops with a large placenta

Medical factors Preexciting hypertensionRenal disease (even without Function renal impairment)Diabetes (preexisting or gestational)Antiphospholipid antibodies

476 Obstetrical and Gynecological Survey

Screening of Low-Risk versus High-Risk Population

A multicenter, randomized, controlled trial involv-ing 3317 subjects was carried out to assess whethersystemic screening with an uterine Doppler in low-risk pregnant women followed by the prescription oflow-dose aspirin in cases with abnormal results re-duce the incidence of intrauterine growth restrictionand preeclampsia. This study showed that there is nojustification for screening with uterine artery Dopplerin a low-risk population, even if abnormal results arefollowed by aspirin treatment (215).

Clinical RecommendationThe use of hormone markers to predict the risk of

preeclampsia could serve more than one objective.First, to be used in a screening program covering allpregnant women indiscriminately, any test shouldcombine a high sensitivity, to justify the costs, with ahigh positive predictive value, to avoid unnecessaryinterventions. None of the available tests fulfill theserequirements.

A second objective could be to identify amonghigh-risk pregnant women (Table 6) those with avery low probability of developing preeclampsia intheir present pregnancy. In this case, a hormonal testthat achieves optimal negative predictor value couldbe used to reduce anxiety in the patient and to pre-vent unnecessary intervention and hospitalization.

The possible use of second-trimester markers suchas hCG, inhibin A, and AFP to predict the risk ofpreeclampsia remains to be investigated in high-riskpopulations.

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