Prediction of Preeclampsia PDF

18 CME REVIEWARTICLE
Volume 59, Number 6 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright 2004 by Lippincott Williams & Wilkins
CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA/PRA category 1 credit hours can be earned in 2004. Instructions for how CME credits can be earned appear on the 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 Developmental Medicine, 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 of preeclampsia are described and evaluated. Placenta hormone markers do not predict future disease. They denounce the early placental changes that are part of the evolving disease and only predict the imminent of preeclamptic syndrome. This explains why tests are better predictors when preeclampsia supervenes shortly, and why screening in the first trimester is unlikely to work as well as in the second trimester. The use of multiple markers in the screening should reflect different aspects of the disease process and could increase the specificity and sensitivity of the screening and work on different etiologic factors. The possible use of second-trimester biochemical screening to predict the risk of preeclampsia remains to be investigated in the high-risk population. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning 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 of preeclampsia, and to describe the various screening tests for preeclampsia.
Preeclampsia is a common pregnancy-specific form of hypertension that complicates 5% to 8% of all pregnancies and increases both maternal and neonatal morbidity and mortality (1). Maternal mortality has been reduced in the United Kingdom (Fig. 1) (2), but in countries where prenatal care is not adequate, preeclampsia/eclampsia accounts for 40% to 80% of maternal deaths. Infants of women with preeclampsia have a 5-fold increase in mortality compared with infants of mothers without the disorder. Much of the neonatal mortality is attributable to iatrogenic prematurity. Approximately 10% of preeclampsia occurs before 34
Reprint requests to: William L. Ledger, PhD FRCOG, Professor, Head of Section of Reproductive and Developmental Medicine, Obstetrics and Gynaecology, University of Sheffield, The Jessop Wing, Tree Root Walk, Sheffield S10 2SF, U.K. E-mail: W.ledger@ sheffield.ac.uk The authors have disclosed no significant financial or other relationship with any commercial entity.
weeks gestational age, and iatrogenic premature delivery resulting from preeclampsia is responsible for 15% of preterm U.S. births (3). Care of the affected women and their premature babies places considerable demands on healthcare resources. PATHOGENESIS Preeclampsia has been called a disease of the theories illustrating the fact that the etiology of preeclampsia remains largely unexplained (Table 1). At present, the following 4 hypotheses are the subject of extensive investigation. Placental Ischemia This theory assumes that the increase in trophoblast deportation, as a result of placental ischemia, could inflict the endothelial cell dysfunction.
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Prediction of Preeclampsia: Can it Be Achieved? Y CME Review Article
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shallow nonvascular cytotrophoblast invasion of the spiral arteries and endothelial dysfunction. These lead to poor placental perfusion and placental ischemia, resulting in release of many factors that are capable of acting on peripheral sites around the body leading to a cascade of events, making preeclampsia a multisystem disorder syndrome. SCREENING FOR PREECLAMPSIA Much research has been done to identify unique screening tests that would predict the risk of developing preeclampsia before the classic symptoms appear and to distinguish preeclampsia from other hypertensive disorders. Table 2 summarizes the different suggested methods for screening. The reason for early screening for preeclampsia is to try to identify high-risk pregnancies allowing modification of antenatal care in this group and to allow preventive treatment regimens. Unfortunately, no simple tests are currently available to do this and the detection of preeclampsia continues to depend on increasingly frequent antenatal visits in late pregnancy for blood pressure measurement and urinalysis. Although this approach is both costly and not particularly sensitive or specific, modern antenatal care has little else to offer. Food supplementation, zinc, calcium and fish oil, and pharmacologic therapy, low-dose aspirin, low molecular-weight heparin, and antioxidants have been tried in a low-risk population as preventive methods for preeclampsia (4). Despite the controversy about the validity of these methods in prevention of preeclampsia in a low-risk population, these methods could have a role in prevention of the disease in high-risk groups, making screening important. CLINICAL ASSESSMENT Clinical History The first step in screening is to assess the risk of preeclampsia by taking a detailed history. Table 3 shows the maternal factors that could predispose to preeclampsia, with odds ratio (95% confidence interval [CI]) or relative risk.
Fig. 1 Maternal mortality has been reduced in the United Kingdom.
Very Low-Density Lipoprotein versus Toxicity-Preventing Activity In compensation for increased energy demand during pregnancy, nonesterified fatty acids are mobilized. In women with low albumin concentrations, transporting extra nonesterified fatty acids from adipose tissues to the liver is likely to reduce albumins antitoxic activity to a point at which very low-density lipoprotein toxicity is expressed. Immune Maladaptation Interaction between decidual leucocytes and invading cytotrophoblast cells is essential for normal trophoblast invasion and development. Immune maladaptation could cause shallow invasion of spiral arteries by endovascular cytotrophoblast cells and endothelial cell dysfunction mediated by an increased decidual release of cytokines, proteolytic enzymes, and free radical species. Genetic Imprinting Development of preeclampsia could be based on a single recessive gene or a dominant gene with incomplete penetrance. Penetrance could be dependent on fetal genotype. The possibility of genetic imprinting should be considered in further genetic investigations of preeclampsia. These hypotheses are not mutually exclusive and could interact. There seem to be 2 key features that underline the development of preeclampsia, namely
TABLE 1
Some modern hypotheses of the etiology of preeclampsia Redman, 19916 Roberts and Cooper, 20017 Smarason et al., 19938 Arbogast et al., 19949 Ness and Roberts, 199610 Redman et al., 199911
Immunologic maladaptation Genetic imprinting Placental ischemia, increased trophoblast deportation Very low-density lipoprotein-toxicity Distinct placental and maternal genesis, endothelial injury is the point of convergence Excessive maternal inflammatory response to pregnancy
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TABLE 2
Obstetrical and Gynecological Survey

Different suggested methods for screening History Blood pressure measurement Urine human chorionic gonadotropin -subunit core fragment Hypocalcuria Urine kallikrein creatinine ratio Microalbuminuria Inhibin Maternal serum -fetoprotein (MSAFP) Human chorionic gonadotrophin (hCG) Placental growth factor (PLGF) Biochemical markers associated with insulin resistance Fibronectin Plasma corticotrophin-releasing factor Homocysteine Neurokinin B Adhesion molecules
Clinical assessment Angiotensin II sensitivity test and rollover test Urine test
Maternal biochemistry and protein assay
Fetal erythroblasts in maternal blood Genomic screening Biophysical screening
Women who have required early delivery in the previous pregnancy for severe preeclampsia remain 1 of the highest risk groups; approximately 1 in 5 of these women will develop preeclampsia in the subsequent pregnancy (5). Measurement of Blood Pressure Midtrimester blood pressure measurement has been evaluated as a potential early screening test. The majority of women who remain normotensive during pregnancy have a diastolic blood pressure (DBP) of 75 mm Hg before the 20th week of pregnancy, but the predictive value of a DBP, taking 80 to 85 mm Hg as a cutoff point, was only 20% (23). The mean arterial blood pressure (MAP) has also a poor predictive value. The positive predictive value of MAP 90 mm Hg in the second trimester for the
TABLE 3
later occurrence of preeclampsia was shown to be less than 10% (24). In a larger study (25), 2503 women at high risk were recruited from 13 centers between their 13th and 26th weeks of pregnancy to a randomized, placebo-controlled trial comparing aspirin (60 mg) and placebo in preventing preeclampsia. Women participated in this study had diabetes mellitus, chronic hypertension, multifetal gestation, or preeclampsia in a previous pregnancy. The study showed that the risk of preeclampsia was 8% with a mean arterial pressure at enrollment of 75 mm Hg versus 27% with a mean arterial pressure 85 mm Hg or above (relative risk, 3.3; 95% CI, 2.44.4). Twenty-four-hour ambulatory blood pressure measurement has also been investigated as a predictor of preeclampsia in primigravidae. One study of 1048 healthy primigravid women demonstrated that 24hour ambulatory blood pressure measurement be-
Maternal factors that may predispose to preeclampsia, with odds ratio (95% confidence interval) or relative risk 2- to 5-fold 3- to 4-fold 2.4 (1.4 4.2) 3-fold 4.7 (1.119.7) 9-fold 3.8 (2.8 5.2) 2.7 (1.7 4.3) 1.7 (1.32.2) 5- to 6-fold 7.2 (4.212.5) 5.6 (2.711.4) 5.2 (2.4 11.5) 5.2 (1.221.5) 3.6 (1.310.3) Chesley and Cooper, 198612 Kaaja et al., 199013 Marcoux et al., 199214 Suhonen and Teramo, 199315 Millar et al., 199416 Rey and Couturier, 199417 Mittendorf et al., 199618 Sibai et al., 19971 Sibai et al., 19971 de Vries at al., 199819 Fink et al., 199820 Ros et al., 199821 Ros et al., 199821 Innes et al., 199922 Innes et al., 199922
Family history of preeclampsia Collagen vascular disease Migraine Gestational diabetes mellitus Hyperthyroidism (uncontrolled) Chronic hypertension Primiparity Elevated systolic blood pressure (during early pregnancy) Elevated diastolic blood pressure (during early pregnancy) Polycystic ovary syndrome Renal disease Insulin-dependent diabetes mellitus Obestiy Maternal low birth weight Maternal preterm birth
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tween 18 and 24 weeks was not a useful clinical predictor (26). The absolute blood pressure differences between the outcome groups were small and the overlap between the groups was large. ANGIOTENSIN II SENSITIVITY TEST AND ROLLOVER TEST Women destined to develop preeclampsia demonstrate an increased sensitivity to vasoactive substances such as angiotensin II (27). The results from an initial study that used this observation as a basis for s screening test were quite promising (sensitivity 90%, specificity 87%, positive predictive value 75%, negative predictive value 95%). These findings were replicated, with varying degrees of success, in 5 subsequent studies (28). Despite these impressive results, angiotensin infusion tests have remained a research rather than a clinical tool for 2 reasons: the cumbersome and time-consuming nature of the test and the fact that it is only useful after 28 weeks gestation, when it is probably too late for any prophylactic therapy to be effective. Also, in the largest study, involving 495 nulliparous women, the reported positive (19%) and negative (87%) predictive values were disappointing (29), raising doubts about the use of this test. URINE TESTS Urine Human Chorionic Gonadotropin -Subunit Core Fragment The hCG -subunit core fragment (-core fragment) is the end product of hCG metabolism, the final step of which occurs in the maternal kidney (30). It is a relatively small molecule with a molecular weight of 9000, which is less than one fourth the size of intact hCG (molecular weight 36,700) (31). In a study of 347 singleton pregnancies, of which 16 (4.6%) developed preeclampsia, a significant linear association was found between urinary -core fragment concentration and risk of developing preeclampsia (32). The relative risk (95% CI) of subsequent preeclampsia increased from 2.07 (1.064.05) at -core fragment levels of human chorionic gonadotropin 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 calcium absorption between patients with preeclampsia
and normotensive patients (33), hypocalciuria has been reported to be one of the most consistent findings in women with preeclampsia (34,35). In one study, a level of less than or equal to 195 mg elemental calcium in a 24-hour urine collection had an 87% positive predictive value (36). However, in a later study in which the 24-hour urinary excretion of calcium was evaluated in 69 primigravida at 17 to 20 weeks gestation, the sensitivity for prediction of preeclampsia was 80% (95% CI, 59.8100), specificity 64.8% (95% CI, 52.177.5), positive predictive value 38.7% (95% CI, 21.655.8), negative predictive value 92.1% (95% CI, 83.5100), and RR 4.9 (95% CI, 1.515.8) (34). This measurement does not have sufficient sensitivity to recommend its use as a screening test for the emergence of preeclampsia. Urinary albumin:creatinine and calcium:creatinine ratios have also been assessed with equally disappointing results (37,38). The low sensitivity of these tests does not support their use as screening tests for preeclampsia. Urinary KallikreinCreatinine Ratio(UK:Cr) Kallikreins are proteases with indirect vasomotor effects mediated by kinins and by the renninangiotensin system. Measurement of UK:Cr ratio in 307 normotensive women between 16 and 20 weeks gestation showed a sensitivity of 83% and a positive predictive value of 91% for the subsequent development of preeclampsia (39). The test is simple and easy to perform. However, the number of patients in this study was very small (only 12 women developed preeclampsia). In a larger study that compared urinary UK:Cr ratio with the angiotensin sensitivity test (AST) for the prediction of preeclampsia, the sensitivity and specificity for detecting preeclampsia were, respectively, 22% and 85% for the angiotensin sensitivity test and 67% and 75% for the UK:Cr ratio. The authors concluded that the UK:Cr ratio was a better screening test for preeclampsia than the AST, but overall neither test was a powerful predictor for the syndrome (40). Microalbuminuria Proteinuria is a common feature of various forms of hypertension and renal diseases and is regarded as a central feature of preeclampsia. The proteins excreted are predominantly albumin and transferrin (41). Microalbuminuria is defined as protein excretion of between 20 and 200 g/min of albumin (42,43). Persistent microalbuminuria indicates a high
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probability of damage to the glomerular filtration capacity of the kidney. Results of studies of microalbuminuria as an early predictor of preeclampsia are conflicting (28,37,4147). Different studies report sensitivity between 50% and 68%, and specificity ranging from 58% to 92%, with positive predictive values between 26% and 61% (42,44,45,47). Given this controversy, it is not possible to recommend assessment of microalbuminuria as a screening test for development of preeclampsia, although further research could alter this position. MATERNAL SERUM MARKERS Inhibin in Pregnancies Subsequently Developing Preeclampsia Early work studying samples collected from women with preeclampsia compared with samples from gestation and age-matched normotensive pregnancies showed that levels of inhibin A and activin A were approximately 10-fold higher during established disease (48,49). Similar elevations were not seen in cases of pregnancy-induced (nonproteinuric) hypertension or essential hypertension. These findings have now been confirmed by a number of groups, all using the Groome assay for inhibin A (4952). Although sampled groups varied in size, parity, and severity of preeclampsia, it seems clear that the preeclamptic placenta is an important source of inhibin A and activin A. Although most studies agree that inhibin A and activin A concentrations in the circulation are elevated in established preeclampsia, the potential of these markers for identifying asymptomatic women at high risk of developing the disease is less clear. An initial study showed a statistically significant elevation in levels of inhibin A at approximately 16 weeks gestation in women who later developed severe preeclampsia (53). This finding has been confirmed in other cross-sectional studies of samples originally collected for Down syndrome screening at 13 to 18 weeks (54,55). However, other groups have not been able to identify early elevations in either inhibin A or activin A in women destined to develop preeclampsia (56,57). These studies can all be criticized; both had small numbers of patients with true preeclampsia and included both nulliparous and multiparous patients. The pathogenesis of preeclampsia in multipara could differ from that seen in nulliparae. To date, only 1 longitudinal study has been carried out using serial sampling of both women who remained normotensive and women who progressed to
preeclampsia (58). This study included 1496 nulliparous women, of whom 71 (4.8%) developed preeclampsia and 117 (7.8%) developed gestational hypertension. The longitudinal study of levels of inhibin A and activin A was accompanied by a nested casecontrol study of 70 preeclamptic patients and 240 randomly selected control subjects who were studied at 15 to 19 weeks and 21 to 25 weeks. The results confirmed the patterns of these analytes in normal pregnancy and further suggested the possibility that early elevation, particularly of activin A, might predict early-onset preeclampsia leading to delivery before 34 weeks. However, predictive sensitivities for later-onset preeclampsia were low. Maternal Serum -Fetoprotein (MSAFP) The association between elevated MSAFP in the second trimester (with a structurally normal fetus) and increased incidence of hypertension was first reported in 1978 (59). After the introduction of midtrimester biochemical screening for screening for spina bifida, this association was confirmed by several other studies (6064). The relative risk ratios for the subsequent development of preeclampsia in women with unexplained elevated MSAFP (2.0 multiples of the median) was modest, ranging from 1.75 to 3.8. However, recent studies observed that the concentration of maternal serum AFP at 22 to 24 weeks was not significantly different in cases that developed preeclampsia later from those who stayed normotensive, questioning the value of this test for screening (65,66). The sensitivity, specificity, positive predictive value, and negative predictive value have been reported as 4.8%, 98.6%, 6.7%, and 98%, respectively (67). Human Chorionic Gonadotrophin (hCG) The association between elevated hCG and established preeclampsia was first reported in 1939 (68) and subsequently confirmed by another study (69). These early studies focused on hCG levels in the presence of established preeclampsia. Human chorionic gonadotrophin production has been shown to increase when normal placental villi in organ cultures are maintained under conditions of low oxygen tension (70). Since the introduction of assay of serum hCG in screening for trisomy 21, a number of studies have show an association between elevation of second-trimester hCG and subsequent development of preeclampsia (7174). The majority of these studies
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observed only a modest correlation with preeclampsia, and the low predictive values would not justify the introduction of hCG as a screening test for this condition. Placenta Growth Factor (PLGF) The maternal serum concentration of PLGF is reduced significantly in clinically evident cases of preeclampsia. However, there were no differences between women who remained normotensive and those who developed severe preeclampsia when PLGF was measured in blood samples collected at 11 to 14 weeks, ruling out use as an early marker (75,76). However, another study used collected blood samples in the late second trimester (17 and 21 weeks of pregnancy) and showed a significantly lower concentration of PLGF in plasma of patients who later developed preeclampsia compared with control pregnancies (77). Biomarkers Associating Preeclampsia With Insulin Resistance Syndrome Insulin resistance is defined as an impaired ability of insulin to stimulate the uptake and disposal of glucose by muscle (78). An association between hyperinsulinemia and cardiovascular disease (CVD) in women was reported in 1998 (79) The mechanism(s) by which the insulin resistance syndrome and hyperinsulinemia could be related to endothelial dysfunction and disturbances in coagulation. Insulin resistance is associated with impaired fibrinolysis (80), blunted endothelium-dependent vasodilatation (81), reduced prostacyclin (PGI2) production, increased thromboxane (TxA2) production, increased coagulation, and platelet activation (82). Abnormalities in production of acute-phase cytokine such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-) could underlie the association of insulin resistance with coagulopathy, endothelial dysfunction, and cerebrovascular disease (83). The endothelial dysfunction and disturbances in coagulation appear to explain the link between insulin resistance and preeclampsia and gestational hypertension (84). A number of markers have been used to assess insulin resistance, including the glucose tolerance test and measurements of sex hormone-binding globulin (SHBG) (84). Also, the antiobesity hormone leptin and the cytokine tumor necrosis factor (TNF-) are new potential mediators of insulin resistance (85); they are produced in the placenta and therefore could play a vital role in insulin resistance in pregnancy (8688). TNF- as
a new paradigm explaining pregnancy-related insulin resistance challenges the long axiom that is the result of the production of placental reproductive hormone. However, this does not exclude the possibility that this hormone has a permissive role in insulin resistance in pregnancy by augmenting or attenuating the effects of the most direct mediators as TNF- (89). Impaired Glucose Tolerance Test as a Marker of Insulin Resistance Preeclampsia is associated with increased fasting insulin concentrations and higher glucose and insulin responses in the oral glucose tolerance test (OGTT), but the data on insulin sensitivity are contradictory. Both increased glucose response in the OGTT and elevated fasting insulin levels can identify a risk of preeclampsia (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 and could contribute to circulating leptin during pregnancy (87,96). The significant increase in maternal circulating leptin during the first and second trimesters of normal pregnancy is suggested to be in response to the marked changes in maternal weight, energy expenditure, and hormonal status. Also, increased maternal Leptin will increase circulating free fatty acids and glucose, providing nutritional support for the fetus (97). However, recent data demonstrate that the increase in circulating Leptin concentration begins in early pregnancy, before any changes in body fat or resting metabolic rate, suggesting that hormonal factors could be responsible (98). Preeclampsia has been reported to be associated with an increase in maternal plasma leptin concentrations (96,97,99). In cross-sectional and longitudinal study, plasma leptin concentrations were significantly greater in women with preeclampsia than in normal control subjects (P 0.001) Also, in question, concentrations of Leptin in women destined to develop preeclampsia were consistently higher from 20 weeks gestation (P 0.040.003) (99). However, in another contrasting study, concentrations of Leptin in serum did not differ between patients with different grades of preeclampsia and normotensive pregnant women (100). So, its clinical potential should be addressed in future research.
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TABLE 4

Impaired glucose tolerance predicts the risk of preeclampsia Subjects Method 1-hour 50-g OGTT, 3-hour 100-g OGTT at 24 32 weeks gestation 2-hour 75-g OGTT at 28 32 weeks gestation Findings Elevation risk of preeclampsia associated with abnormal OGTT value vs. controls (OR, 2.81 [1.26 6.28]) Elevated risk (3-fold) for preeclampsia in women with GDM, but not in women with abnormal OGTT value A 1-hour 50-g OGTT value 7.8 mmol/L predicted preeclampsia, but not after adjustment for age, race, gestational age at OGTT, and pregravid BMI The 2-hour 100-g OGTT value was a significant predictor of preeclampsia after adjusting for BMI Fasting level of insulin 1.8-fold higher in women who developed preeclampsia The 1-hour 50-g OGTT value predicted preeclampsia, even in normoglycemic women Reference Lindsay et al., 198990
Women with 1 abnormal OGTT value
Women with gestational diabetes mellitus (GDM) and 1 abnormal OGTT value Preeclamptic women; women with gestational hypertension
Suhonen and Termo, 199315
1-hour 50-g, OGTT at 24 32 weeks gestation
Solomon et al., 199491
Women without GDM
1-hour 50-g OGTT, 3-hour 100-g OGTT at 26 28 weeks gestation Fasting levels of glucose and insulin at 18 22 weeks gestation 1-hour 50-g OGTT, 3-hour 100-g OGTT in the late second trimester
Sermer et al., 199592
Nulliparous women
Sowers et al., 199593
Nulliparous women with GDM
Joffe et al., 199894
Tumor Necrosis Factor (TNF-) Many cytokines expressed in adipose tissue such as TNF- has shown to reduce insulin-stimulated glucose uptake in adipocytes, suggesting that the increase in this cytokine contributes to insulin resistance (101). TNF also can induce the synthesis of other cytokines, which alone or in concert with others could alter endothelial function (102). The ischemic placenta is an important source of tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) (103,104). TNF also can induce the synthesis of other cytokines, which alone or in concert with others, could alter endothelial function (102). TNF- could as well be directly involved in endothelial dysfunction (105) and induce plasminogen activator inhibitor PAI-1 (106), which could be contributing to fibrin deposition and placental vascular lesion (107). Patients with preeclampsia have significantly elevated concentrations of TNF- and TNF- messenger ribonucleic acid in plasma, amniotic fluid, and placental tissue (108111), with plasma levels being elevated, by almost 2-fold, in women with preeclampsia (112). The mean serum concentration of sTNFp55, a marker of excessive TNF- release, was also found to be high in midpregnancy in patients who developed preeclampsia later (105).
However, TNF- and sTNFp55 are not ideal for use in screening tests. TNF- has a short half-life of approximately 15 minutes, so more than 1 blood sample could be needed. Also, TNF- is produced and acts locally in an autocrine or paracrine manner, and plasma concentrations might not actually reflect TNF- concentrations at the local level (113). Sex Hormone-Binding Globulin (SHBG) SHBG is a glycoprotein produced by the liver that mediates the balance between free and bound testosterone and estrogens (114). Hepatic SHBG synthesis is stimulated primarily by estradiol and thyroid hormone and is inhibited by insulin (115). The inhibitory effects of insulin prevail in circumstances when there are competing stimuli for hepatic SHBG production (115), such as pregnancy when both estradiol and insulin levels raise progressively (116). Unlike other markers of insulin resistance, SHBG has a minimal variability when comparing its fasting and postprandial levels (117). These properties appoint SHBG as a unique marker of insulin resistance that is particularly valuable in nonfasting status, including obstetric prenatal care (118). In a prospective, case control study, first-trimester SHBG levels were measured in 45 nulliparous women who subsequently developed preeclampsia and in 90 randomly selected normotensive nulliparous control subjects. Com-
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pared with control subjects, women who developed preeclampsia had significantly reduced first-trimester SHBG levels (302 130 vs. 396 186 nmol/L; P 0.01). Every 100-nmol/L increase in SHBG was associated with a 31% reduced risk of preeclampsia (odds ratio [OR], 0.69; 95% CI, 0.550.88; P 0.01]. In a multivariable analysis, there was a strong association between SHBG and preeclampsia among lean women, with every 100-nmol/L increase in serum SHBG associated with a 55% reduction in the risk of preeclampsia (OR, 0.45; 95% CI, 0.27 0.77; P 0.01), whereas in overweight women, the association was less (OR, 1.02; 95% CI, 0.621.69; P 0.9). They concluded that increased early-pregnancy insulin resistance is independently associated with subsequent preeclampsia. First-trimester SHBG concentration in serum might be a useful biomarker for preeclampsia, especially among lean women (119). Fibronectin (Fn) The fibronectins are a family of high molecularweight glycoproteins (440500 kD) that exist in nature as dimers or multimers of disulfide-linked subunits derived from a pool of similar but nonidentical peptides. The term plasma Fn refers to the total pool of soluble Fn in the circulation. The term cellular Fn (cFn) generally refers to isoforms of the Fn associated with endothelial cells and are found in soluble form within the extracellular matrix of tissues (120,121). The cellular type has a single exon, which is termed ED1, and can be measured in plasma. The cellular type is expressed more abundantly during tissue injury and remodeling (121,122). This might explain the high level of ED1Fn in preeclampsia (121,123,124). Several studies have identified high concentrations of Fn in women destined to develop preeclampsia (125127). In a recent longitudinal study, elevated fibronectin levels were detectable in women destined to develop preeclampsia significantly early, at 9 to 12 weeks gestation, with sensitivity, specificity, and positive and negative predictive values of 73%, 87%, 29%, and 98%, respectively; the odds ratio was 16.1 (95% CI, 8.630.2) at 22 to 26 weeks gestation in women destined to develop preeclampsia (128). These findings differ from those of another longitudinal study of 198 consecutive pregnant patients that demonstrated only significant differences between normotensive women and preeclamptics in the third trimester and concluded that cFn could not be used as a predictor of preeclampsia because the clinical symptoms of this pathology were already present at
the time of detection (129). More understanding of uteroplacental insufficiency and preeclampsia will be achieved if more of these longitudinal studies focus on the first trimester and larger numbers of patients are involved. Plasma Corticotrophin-Releasing Hormone (CRH) CRH is secreted in large amounts by placenta (130), and concentrations in the maternal circulation rise exponentially as term approaches, with significant elevation in preeclamptic women (67,130134). This elevation could represent a protective response to placental hypoperfusion seen in cases of preeclampsia (67). A rise in CRH concentration has been demonstrated at 11 weeks (131) and in midtrimester (67) before the development of signs and symptoms of the disease. However, in a large cohort study (67), both midtrimester CRH and maternal serum -fetoprotein (MSAFP) were assessed as predictive of preeclampsia. Both were significantly high in preeclamptic women but CRH and MSAFP when measured in midpregnancy did not have a strong predictive value. The sensitivity, specificity, positive predictive value, and negative predictive value for the midtrimester CRH test in prediction of preeclampsia were 38.1%, 79.9%, 3.8%, and 98.4%, respectively. Although the combination of both values improved the detection rate compared with CRH alone, there was still only a small increase in likelihood ratio (from 1.9 to 2.6) so that it is unlikely to be of great clinical value. Homocysteine Homocysteine is a demethylated metabolite of the essential amino acid methionine and is associated with increased oxidative stress and lipid peroxidation, smooth muscle proliferation, abnormalities of coagulation, and endothelial dysfunction (135138). In a casecontrol study, 56 patients who developed severe preeclampsia were found to have higher plasma homocysteine levels in early pregnancy when compared with women who remained normotensive throughout pregnancy (138). However, another study was unable to exhibit any difference in serum homocysteine levels at 16 weeks gestation between the 2 groups. They concluded that there were not major differences in homocysteine levels before the manifestation of preeclampsia (139). In addition to this uncertainty over validity of elevated homocysteine as a predictor of preeclamptic risk, its use is also compromised by many extrinsic factors that influence homocysteine metabolism in-
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tensely: genetic, environmental, or nutritional factors as well as renal function (140). Also, an inadequate intake of vitamin B12, B6, or folic acid has been seen in cases of hyperhomocystinemia. This could create difficulties in reliability of homocysteine as a marker for preeclampsia. Neurokinin B (NKB) NKB belongs to a family of neuropeptides called the tachykinins. NKB was identified in human placental tissue (141). Their biologic actions include smooth muscle contraction, vasodilatation, pain transmission, neurogenic inflammation, and activation of the immune system (142). It has been suggested that NKB secretion from the placenta in normal pregnancy plays a role in some hemodynamic adaptations by shunting the blood from the liver and mesenteric area to the uterus and placenta (141). NKB could also cause dilatation of the spiral arteries by stimulating NK3 receptors, which act as mediators to relax smooth muscle through the nitric oxide pathway (143). Initial studies indicate that NKB is present in high concentration in the plasma of preeclamptic women, whereas it is low or not detected in most normotensive women. The expression of neurokinin B was confined to the outer syncytiotrophoblast of the placenta, and significant concentration of NBK could be detected in plasma as early as 9 weeks gestation. NKB remains a potential candidate for development of an early predictive test for preeclampsia (141), but longer longitudinal studies are needed. Adhesion Molecules Adhesion molecules are receptors that modulate inflammatory responses by permitting leukocyte adhesion to the inflammatory site. Some adhesion molecules are considered to be important for leukocyte extravasation in the placental bed during trophoblast invasion. Intercellular adhesion molecule 1 (1CAM-1) and vascular cell adhesion molecule (VCAM-1) are largely expressed by the vascular endothelium of human deciduus (144). Because the soluble forms of 1CAM-1 (sICAM-1) and VACM-1 (sVCAM-1) are markers of arterial wall inflammation and endothelial dysfunction, they should be elevated in preeclamptic patients. However, the level of sICAM-1 is reported to be unchanged in cases of preeclampsia (145,146). Also, the level of sVCAM-1 was reported to be high in cases of preeclampsia (147); however, it showed no change in the second trimester, which
discourages the possibility of using sVCAM-1 as a predictor (147). FETAL ERYTHROBLASTS IN MATERNAL BLOOD A century ago, Schmoral noticed that trophoblastic cells could be detected in the lungs of patients who had preeclampsia (148). This is thought to result from placental damage and subsequent increased deportation across the placenta (66). Several studies have demonstrated increased fetal cell trafficking (6-fold) (66,149), and cell free DNA (3-fold) (150152), from 20 weeks onward in the maternal circulation of women who developed preeclampsia later. The cell-free DNAs could be apoptotic DNA fragments from uterine wall placental cytotrophoblasts through the breakdown of these cells and are not the results of fetal cell trafficking. These particles could contribute to a cytotoxic effect on endothelial cells characteristic of preeclampsia (65,153). At present, results overlap between preeclamptic and control groups, with low sensitivity and specificity (152). The most likely clinical application for detection of fetal erythroblasts in maternal blood is as a late second-trimester marker of preeclampsia. This test could be used to reduce the false-positive rate of other early second-trimester markers of preeclampsia. GENOMIC STUDIES OF PREECLAMPTIC RISK A familial tendency in preeclampsia is well established. This information dates back to a classic study by Chesley and Copper, who found preeclampsia in 26% of the daughters and 16% of the granddaughters of eclamptic mothers (12). There is growing evidence, which indicates genetic or immunologic conflicts between the mother and fetus as etiologic factors in preeclampsia. Preeclamptic risk is increased in pregnancy after oocyte donation (154156), when the fetus differs genetically from the mother, and in pregnancies in which the male partner has previously fathered a preeclamptic pregnancy (157). A family history of preeclampsia predisposes to a 2- to 3-fold increased risk for development of the condition compared with women with no family history (158,159). Several studies that searched the genome for regions associated with preeclampsia have been reported. Two studies found evidence for a maternal susceptibility locus for preeclampsia on the short arm of the chromosome 2 (160,161), whereas another reported a LOD on the long arm of chromosome 4
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(162). The roles of other genes or polymorphisms have been investigated, including those for factor V Leiden mutation (163165), endothelial nitric oxide synthetase (166169), angiotensin genes (170,171), methylenetetrafolate reductase mutations (172,173), epoxide hydrolase polymorphism (174), and polymorphism related to tumor necrosis factor (175,176). Preeclampsia has a complex inheritance pattern involving multiple disease susceptibility loci, environmental gene interaction, and paternal (fetal) interactions, which complicate elucidation of the inheritance mode of the condition. BIOPHYSICAL SCREENING Doppler ultrasound is a noninvasive procedure that is regularly used to assess maternal and fetal hemodynamics. This test is based on the principle that a deficient uterine, placental, or fetal circulation can lead to an adverse pregnancy outcome and that these abnormalities could be detected with the use of Doppler velocimetry. Doppler techniques have been used in obstetrics since the first report of successful recording of blood flow signals from the umbilical artery by Fitzgerald and Drumm in 1977 (177). Trophoblast invasion into the myometrial segment of spiral arteries occurs early in the second trimester and is associated with remarkable hemodynamic changes in the placental circulation (178). These changes are demonstrated by the shape of the uterine artery velocity waveform, which is unique. It is characterized by high end-diastolic velocities with continuous forward blood flow throughout diastole. Typically, as gestational age advances, the degree of end-diastolic flow increases, so the high-resistance profile of early pregnancy transforms to a low-resistance profile by 24 weeks (179181). Defective placentation results in increased vascular resistance of the uterine artery and decreased perfusion of the placenta (181184). This causes a persistent high resistance to uteroplacental blood flow. The change in the pattern of uteroplacental blood flow can be detected by Doppler ultrasound of the maternal uterine arteries (185187). A pathologic waveform is described as the presence of either high impedance in form of a high pulsatility index (PI), resistance index (RI), or A/B ratio, presence of a notch in the waveform from one or both uterine arteries (188192), or combinations of both (193196). This notch is present in most waveforms in nonpregnant women and early pregnancy but disappears in the second trimester in normal pregnancy (180). The diastolic notch is probably not related to increased resistance
but to arterial wall compliance, indicating that the appearanceor failure of disappearanceof the diastolic notch could denote an abnormal maternal artery wall status (197). Uterine artery Doppler waveform analysis offers a biophysical marker of inadequate placental perfusion. Several studies have examined use of Doppler waveform analysis to predict preeclampsia (Table 5). Twenty-seven published and unpublished observational studies involving 12,994 pregnancies have been metaanalyzed. These pregnancies were stratified into low- or high-risk categories for developing preeclampsia. The metaanalysis suggested that in the low-risk population, a positive test result could predict risk of preeclampsia with a likelihood ratio of 60.4 (95% CI, 50.77.1), whereas a negative test result had a likelihood ratio of 0 0.7 (95% CI, 0.6 0.8). In the high-risk population, a positive test result could predict risk of preeclampsia with a likelihood ratio of 2.8 (95% CI, 20.330.4), whereas a negative test had a likelihood ratio of 0.8 (95% CI, 0.70.9). Based on these results, the authors concluded that uterine artery Doppler flow velocimetry had limited diagnostic accuracy in predicting preeclampsia (198). DISCUSSION To screen for a certain disease, the disease should have well-understood biology, and early detection and treatment should lead to an increase in long-term improvement of the condition, should not create undue anxiety, and be acceptable to patients. Despite the fact that screening for preeclampsia does not meet all of these criteria, early detection of hypertension during pregnancy permits clinical monitoring and prompt therapeutic intervention for severe preeclampsia or eclampsia, and clinical experience suggests that early detection and treatment of preeclampsia is beneficial to the patient and fetus. This view is based, in part, on the apparent effectiveness of regular antenatal care in reducing the complications of preeclampsia/eclampsia, and it could as well, in the future, allow treating these patients early in pregnancy, which could lead to a better outcome. Generally, the validity of the available tests is difficult to evaluate as a result of the absence of a gold standard to confirm the diagnosis, and most studies of potential screening tests for preeclampsia have relied on clinical criteria to confirm the diagnosis. Clinical assessment is not useful in the prediction of preeclampsia. Selection of pregnancies at risk on the basis of maternal risk factors predisposing to
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TABLE 5
Prev. PET CW/PW PW PW CW CW PW PW CW CW 18 22 and 24 RI95th centile notches 46% 86% 16 24 RI95th centile 24 95 20 19 20 and 24 RI95th centile notches 76 97 44 96 16 18 18 20 26 34 34 36 16 18 and 24 20 and 24 RI0.58 RI0.57 RI 0.52 RI0.58 RI0.57 67 64 7 63 44 64 84 94 89 73 42 70 26 10 33 87 80 76 99 80 Doppler analysis test Sen. (%) Spec. (%) PPV (%) NPV (%) 24.6% 36.6% 24% 7% 29% 2.4% 4.6% 2.2% Gestational age
Summary of Doppler studies examined the use of Doppler waveform analysis to predict preeclampsia
Abnormal outcome
No.
Population
Campbell199 (1986) Arduini200 (1987) Hanretty201 (1989) Steel202 (1991) Jacobson203 (1990)
126 60 543 1014 93
Unselected High-risk Unselected Nulliparas High-risk
Harrington204 (1991)
2437
Unselected
Bewley205 (1991)
977
Unselected
Bower188 (1993)
2058
Unselected
North206 (1994) Chan190 (1995) Harrington194 (1996) Frusca207 (1997) Kurdi193 (1998) Mires208 (1998) 3.3% 6.9% 3.6% 1.9% 2.2% 5.5% 2.1% 0.9% 5% 0.68 Color & PW PW 19 20 TV 20 23 Color & PW 2224 TV PW PI90th centile Color CW CW/Color CW/Color Color color 19 24 20 19 21 and 24 20 and 24 19 21 18 20 2224 1114 83 27 22 77 50 37 5.5 17 27
457 334 1326 419 946 6579
Nulliparas Selected Unselected Nulliparas Unselected Unselected
RI0.57 AC ratio RI90th centile notches RI 95th centile notches RI0.58 RI 0.55 Bilataral notches notches
Martin209 (2001)
3045
Unselected
90 97 94 92 89 98 98 95 86
29% 88% 79% 8 36 31 11 18 13 9.5 11 4
84% 85% 85% 97 94 99 99 95 96 99 98 99
Papageorghiou210 (2001)
7,851
Unselected
BP140/90 mm Hg BP 140/90 on 2 occasions BP 140/90 Bp 140/90 and Prot. 300 mg/L Diastolic rise 25 mm Hg and Prot. 500 mg/24 hrs Diastolic rise of 25 mm Hg and Prot. 500 mg/24 hrs Diasolic 90 and Prot. 150-mg/ 24hrs Mild PET; rise 30/25, pr Moderate PET; rise 30/ severe PET; rise 110. BP 140/90 and Prot. 300 mg/L BP 140/90 and Prot. 300 mg/L BP 30/25, Prot. 500 mg/24 hrs BP 140/90 and Prot. 300 mg/L Diastolic 25 mm Hg Prot. Mild PET (ICD-9 642.6) Severe PET ICD-9 642.7 BP/90 and Prot. 300 mg/24 hrs or Prot. BP 140/90 and Prot. 30 mg/24 hrs or Prot. 60 26 38 93 94 91 33 21 19 98 95.6 96 BP 140/90 and Prot. 300 mg/24 hrs
Aquilina211 (2001) Becker212 (2002)
689 7502
Unselected Unselected
PI95th percentile Bilateral notches RI 0.56 notches Uni or bilateral notches PI90th centile
Prev. previous; CW Continuous Wave Doppler; PW Pulsed wave Doppler; TV Transvaginal; PET pre-eclampsia; PI Pulsatility Index; RI resistance index; BP blood Pressure; Sen. sensitivity; Spec specifity; PPV positive predictive value; NPV negative predictive value.
475
preeclampsia would not provide us with an effective screening test for the general obstetric population. Also, blood pressure measurement alone (midtrimester, mean arterial pressure, or ambulatory blood pressure) has failed to provide a useful predictor for preeclampsia. The rapid expansion in the application of biochemical markers in recent years has been largely the result of the development of sensitive immunoassays using monoclonal antibodies, which yield reproducible results. Urine and serum biochemical assays have provided evidence that there are differences in the metabolism of women who subsequently develop preeclampsia compared with women who remain normotensive during their pregnancy. However, the main problems are: 1. The majority of these markers do not fulfill the criteria for useful screening test because the sensitivity is too low or the false-positive rate is too high. 2. None of the biochemical markers have been assessed in prospective studies with adequate power to demonstrate efficacy. 3. Some of the markers are relatively expensive and complex to measure. 4. Placental hormone markers do not predict future disease. They denounce the early placental changes that are part of the evolving disease and only predict the imminent development of the preeclampsia syndrome. This explains why screening in the first trimester is unlikely to work as well as in the second or third trimester. Urinary assay of creatinine and kallikrein could yet offer 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 is the most studied. All 5 studies were essentially crosssectional, using samples collected and frozen in early pregnancy for other purposes. The prospective longitudinal study on inhibin, which involved 1496 participants (58), tried to clarify the ability of inhibin A and activin A measurement to predict risk of preeclampsia. This study showed that the value of inhibin/activin is low in predicting late-onset preeclampsia (after 34 weeks). Although the ligands were better predictors of early overt preeclampsia, the early form of preeclampsia is relatively uncommon (0.74% of this cohort); it represents the most severe end of the spectrum, and early intervention
might allow prolongation of these pregnancies, improving the chances of fetal survival. Research is continuing. The identification of the vasodilator-stimulated phosphoprotein (VASP) in the human placenta from the first trimester suggests that this protein could be associated with trophoblastic cell motility and could have a role in implantation and trophoblastic cell invasion. A marker of this protein could have a place in screening for preeclampsia syndrome (213). The increased prevalence of preeclampsia in daughters born to eclamptic mothers could indicate an influence of the fetal genotype (paternal genome) on susceptibility to preeclampsia. The genetic conflict theory assumes, in general, mother and fetus do not carry identical gene sets (in other words, maternal and fetal interests are not always in harmony). So interactions between the fetus and the mother and the involvement of imprinting in the control of cell behavior within fetomaternal interfaces of the placenta with paternal genome function is working to deplete maternal resources for the advantage of the fetus, whereas the maternal genome is counteracting this drain for the benefit of the mother and her subsequent pregnancies (214). This mechanism could be operative in gestational hypertension, in which fetal prognosis is known to be good. In contrast, in preeclampsia, the hypertension results from vasoconstriction rather than increased cardiac output. In addition to the problem concerning the mode of inheritance, it is unclear whether nonproteinuric hypertension represents the same disease as proteinuric preeclampsia. At present, several groups conducting linkage studies and complete maternal genomewide scans to discover preeclampsia genes. However, so far, no such genes have been identified. The hunt for genes for preeclampsia will yield many that operate as risk factors (11). Whether this will lead to a clinically useful predictor of risk remains to be seen. The variations in results of studies on Doppler as a predictor for preeclampsia are the result of many factors. Uteroplacental waveforms can be affected by the location of the placenta, the presence of Braxton Hicks contraction, sample site (uterine or arcuate artery), and Doppler technique. The uterine artery is reported to be the best sample site to obtain consistent information about the uteroplacental circulation; it is easy to locate on real-time imaging, provides good reproducibility, and reflects the resistance in the entire distal placental bed. Comparing continuous-wave Doppler with the pulsed-wave Doppler, the pulsed-wave Doppler has the ability to determine the exact location of the sample site; therefore, it is
476
the preferred method in determining uteroplacental blood flow profiles. The prevalence of preeclampsia in the studies of Doppler in preeclampsia varies between 2.2% and 24%. This could reflect differences in hospital population, environmental factors, and differences in the definition of hypertensive disorders. The gestational age at the time of Doppler assessment is an important factor. Screening before 20 weeks might be associated with more false-positive test results because the spiral artery adaptation is still in progress but not yet finished. Most of studies were performed between 16 and 24 weeks. Other studies performed measurements at or even beyond 26 weeks. Good predictive values are reported in 2-stage studies in which an initial scan at 18 to 20 weeks is followed, if abnormal, by a repeat scan at 24 weeks to reduce the high rate of false-positive results. There is as-yet no agreement about the definition of pathologic waveforms. Initially, only high impedance was thought to be important. Later, bilateral notching was included in the assessment. Further studies described pathologic waveform as the presence of high impedance in the form of high PI, RI, or A/B ratio, the presence of a notch in one or both uterine arteries, or combination of both. It is not completely clear in many studies whether impedance was evaluated on only one side 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, with concurrence in detection of notching by 2 operators being only 85% with disagreement of unilateral notching being 9.8% and bilateral notching 6.8%. Overall, there is a lack of randomized, controlled trials of the use of uterine artery Doppler studies in the screening of pregnancy complications such as preeclampsia. Use of Multiple Markers Prevention of any disease process requires knowledge of its etiology and pathogenesis, as well as the
TABLE 6 Risk factors of preeclampsia
availability of methods for prediction of those at high risk for this disorder. At the present time, there is a consensus that the etiology of preeclampsia is multifactorial. The use of multiple markers in the screening should reflect different aspects of the disease process and increase the specificity and sensitivity of the screening. Combinations of maternal biochemical markers, serum inhibin A, free -human chorionic gonadotropin (free -hCG), unconjugated estriol (uE3), and alpha-fetoprotein (AFP) have been investigated in prediction of preeclampsia. Stored serum samples were used. Nineteen women who developed preeclampsia had sequential blood samples taken from 8 weeks gestation. For each sample, 3 control samples were collected from women with unaffected pregnancies matched for gestation age and maternal age. In pregnancies that developed preeclampsia, the median inhibin A value was raised (1.7 multiples of the media [MoM] for unaffected pregnancies) (95% CI, 1.12.7 MOM), the median free -hCG was raised (2.1, 1.43.3 MoM), and the median uE3 was lowered (0.8, 0.60.98 MoM) after 19 completed weeks of gestation and at least 2 weeks before the onset of proteinuria. Values of AEP were similar in affected and unaffected pregnancies. Combining the values of inhibin A, free hCG, and uE3 to form a screening test would detect an estimated 55% of affected pregnancies with a false-positive rate of 5%. Combining second-trimester maternal serum inhibin-A and uterine artery Doppler improves the screening efficacy for prediction of preeclampsia. Inhibin A levels were measured between 15 and 19 weeks gestation and color flow pulsed Doppler of both uterine arteries was carried out between 18 and 22 weeks gestation. The improvement in sensitivity for the combined method, compared with either inhibin-A or uterine artery Doppler alone, was statistically significant for preeclampsia (211) (P 0.05).
Genetic factors Obstetric history
Medical factors
Women whose mothers had preeclampsia (have a 20 25% risk) Women with sisters with a history of preeclampsia (have a 35 40% risk) Primiparity Multiple pregnancy Hydrops with a large placenta Preexciting hypertension Renal disease (even without Function renal impairment) Diabetes (preexisting or gestational) Antiphospholipid antibodies
477
Screening of Low-Risk versus High-Risk Population A multicenter, randomized, controlled trial involving 3317 subjects was carried out to assess whether systemic screening with an uterine Doppler in lowrisk pregnant women followed by the prescription of low-dose aspirin in cases with abnormal results reduce the incidence of intrauterine growth restriction and preeclampsia. This study showed that there is no justification for screening with uterine artery Doppler in a low-risk population, even if abnormal results are followed by aspirin treatment (215). Clinical Recommendation The 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 all pregnant women indiscriminately, any test should combine a high sensitivity, to justify the costs, with a high positive predictive value, to avoid unnecessary interventions. None of the available tests fulfill these requirements. A second objective could be to identify among high-risk pregnant women (Table 6) those with a very low probability of developing preeclampsia in their present pregnancy. In this case, a hormonal test that achieves optimal negative predictor value could be used to reduce anxiety in the patient and to prevent unnecessary intervention and hospitalization. The possible use of second-trimester markers such as hCG, inhibin A, and AFP to predict the risk of preeclampsia remains to be investigated in high-risk populations. REFERENCES
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18 CME REVIEWARTICLE

Prediction of Preeclampsia: Can It Be Achieved?

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

Fig. 1 Maternal mortality has been reduced in the United Kingdom.

Obstetrical and Gynecological Survey

Maternal biochemistry and protein assay

Fetal erythroblasts in maternal blood Genomic screening Biophysical screening

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

Obstetrical and Gynecological Survey

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

Obstetrical and Gynecological Survey

Women with 1 abnormal OGTT value

Suhonen and Termo, 199315

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

Solomon et al., 199491

Women without GDM

Sermer et al., 199592

Sowers et al., 199593

Nulliparous women with GDM

Joffe et al., 199894

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

Obstetrical and Gynecological Survey

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

126 60 543 1014 93

Unselected High-risk Unselected Nulliparas High-risk

457 334 1326 419 946 6579

Nulliparas Selected Unselected Nulliparas Unselected Unselected

Obstetrical and Gynecological Survey

29% 88% 79% 8 36 31 11 18 13 9.5 11 4

84% 85% 85% 97 94 99 99 95 96 99 98 99

Aquilina211 (2001) Becker212 (2002)

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

Obstetrical and Gynecological Survey

Genetic factors Obstetric history

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

Obstetrical and Gynecological Survey

53. 54. 55. 56. 57.

34. 35. 36. 37.

58. 59. 60.

42. 43. 44. 45. 46. 47. 48. 49.

65. 66. 67.

68. 69. 70. 71.

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

82. 83. 84. 85. 86.

87. 88. 89. 90. 91.

Obstetrical and Gynecological Survey

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

155. 156. 157. 158. 159. 160.

Obstetrical and Gynecological Survey

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