Circulating Angiogenic Factors and the Risk of Preeclampsia
Richard J. Levine, M.D., M.P.H., Sharon E. Maynard, M.D., Cong Qian, M.S., Kee-Hak Lim, M.D., Lucinda J. England, M.D., M.S.P.H., Kai F. Yu, Ph.D., Enrique F. Schisterman, Ph.D., Ravi Thadhani, M.D., M.P.H., Benjamin P. Sachs, M.B., B.S., D.P.H., Franklin H. Epstein, M.D., Baha M. Sibai, M.D., Vikas P. Sukhatme, M.D., Ph.D., and S. Ananth Karumanchi, M.D.
Background The cause of preeclampsia remains unclear. Limiteddata suggest that excess circulating soluble fms-like tyrosinekinase 1 (sFlt-1), which binds placental growth factor (PlGF)and vascular endothelial growth factor (VEGF), may have a pathogenicrole.
Methods We performed a nested case–control study withinthe Calcium for Preeclampsia Prevention trial, which involvedhealthy nulliparous women. Each woman with preeclampsia wasmatched to one normotensive control. A total of 120 pairs ofwomen were randomly chosen. Serum concentrations of angiogenicfactors (total sFlt-1, free PlGF, and free VEGF) were measuredthroughout pregnancy; there were a total of 655 serum specimens.The data were analyzed cross-sectionally within intervals ofgestational age and according to the time before the onset ofpreeclampsia.
Results During the last two months of pregnancy in the normotensivecontrols, the level of sFlt-1 increased and the level of PlGFdecreased. These changes occurred earlier and were more pronouncedin the women in whom preeclampsia later developed. The sFlt-1level increased beginning approximately five weeks before theonset of preeclampsia. At the onset of clinical disease, themean serum level in the women with preeclampsia was 4382 pgper milliliter, as compared with 1643 pg per milliliter in controlswith fetuses of similar gestational age (P<0.001). The PlGFlevels were significantly lower in the women who later had preeclampsiathan in the controls beginning at 13 to 16 weeks of gestation(mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01),with the greatest difference occurring during the weeks beforethe onset of preeclampsia, coincident with the increase in thesFlt-1 level. Alterations in the levels of sFlt-1 and free PlGFwere greater in women with an earlier onset of preeclampsiaand in women in whom preeclampsia was associated with a small-for-gestational-ageinfant.
Conclusions Increased levels of sFlt-1 and reduced levels ofPlGF predict the subsequent development of preeclampsia.
Preeclampsia affects about 5 percent of pregnancies, resultingin substantial maternal and neonatal morbidity and mortality.1,2Although the cause remains unclear, the syndrome may be initiatedby placental factors that enter the maternal circulation andcause endothelial dysfunction resulting in hypertension andproteinuria.3,4,5,6
We and others have recently shown that soluble fms-like tyrosinekinase 1 (sFlt-1), a circulating antiangiogenic protein, isincreased in the placenta5,7 and serum5,8,9 of women with preeclampsia.This protein acts by adhering to the receptor-binding domainsof placental growth factor (PlGF) and vascular endothelial growthfactor (VEGF), preventing their interaction with endothelialreceptors on the cell surface and thereby inducing endothelialdysfunction. Decreased concentrations of circulating free PlGFand free VEGF have been noted during clinical preeclampsia5and even before its onset.10,11 We have recently demonstratedthat exogenous sFlt-1 administered to pregnant rats induceshypertension, proteinuria, and glomerular endotheliosis.5 Moreover,a 50 percent reduction in VEGF production in renal podocytesin mice with podocyte-specific heterozygosity for VEGF resultedin glomerular endotheliosis and massive proteinuria.12 Hypertensionand proteinuria have been reported in patients with cancer whowere treated with VEGF-signaling inhibitors.13,14 Taken together,these observations suggest that excess sFlt-1 may have a pathogenicrole in preeclampsia.5
In order to describe the gestational patterns of circulatingsFlt-1, free PlGF, and free VEGF in normotensive and preeclampticpregnancy, we performed a nested case–control study withinthe Calcium for Preeclampsia Prevention (CPEP) trial, usingarchived serum samples obtained before labor. Concentrationswere analyzed in a cross-sectional fashion within intervalsof gestational age and according to the time before the onsetof preeclampsia. We hypothesized that the sFlt-1 level wouldbe elevated before the onset of clinical disease, with reciprocaldecreases in the levels of free PlGF and VEGF.
Methods
Participants and Specimens
The CPEP trial was a randomized, double-blind clinical trialconducted from 1992 to 1995 to evaluate the effects of dailysupplementation with calcium or placebo on the incidence andseverity of preeclampsia.15,16 Healthy nulliparous women withsingleton pregnancies were enrolled between 13 and 21 weeksof gestation at five participating U.S. medical centers andwere followed until 24 hours after delivery, with the use ofa common protocol and identical data-collection forms. Writteninformed consent was obtained from all the participants. Gestationalage was determined by means of ultrasonographic examination.Serum specimens were requested from women before enrollmentin the trial, at 26 to 29 weeks of gestation, at 36 weeks ifthey were still pregnant, and when hypertension or proteinuriawas noted. "End-point specimens" were obtained at or after theonset of signs of preeclampsia but before labor and delivery.15,16
For the present study, we selected women with complete outcomeinformation, serum samples obtained at less than 22 weeks ofgestation, and a live-born male infant. This group had previouslybeen selected for a study of fetal DNA and preeclampsia, inwhich fetal and maternal DNA were differentiated through theamplification of a gene on the Y chromosome. Analysis of previouswork5 revealed no significant differences in the sFlt-1 or PlGFconcentrations between 10 women with preeclampsia who delivereda male infant and 8 women with preeclampsia who delivered afemale infant (sFlt-1 concentration, 6120 pg per millilitervs. 5404 pg per milliliter; P=0.78; PlGF concentration, 99 pgper milliliter vs. 125 pg per milliliter; P=0.42).
Of the 4589 women enrolled in the CPEP trial, we excluded 253who were lost to follow-up, 21 whose pregnancy ended before20 weeks, 13 who had missing data on maternal or perinatal outcome,4 who had no data on smoking history, 9 in whom the presenceof hypertension had not been verified by the team that reviewedeach chart, and 32 who had a stillbirth, leaving 4257 women.Of these women, 2156 had a male infant. After the exclusionof 1 woman whose infant had a chromosomal abnormality, 381 womenwith gestational hypertension, and 43 without a base-line serumspecimen, 1731 women remained. Preeclampsia developed in 175of these women, whereas 1556 remained normotensive throughoutpregnancy.
Calcium supplementation did not affect the serum concentrationsof angiogenic factors. Specimens collected at 8 to 20 weeksof gestation were considered the base-line specimens and wereobtained before the administration of calcium or placebo. At21 to 32 weeks, the mean serum sFlt-1 level in the controlswho were given placebo was 866 pg per milliliter, as comparedwith 889 pg per milliliter in the controls who were given calciumsupplements (P=0.57); the mean PlGF level was 765 pg per milliliterand 746 pg per milliliter, respectively (P=0.78); and the meanVEGF level was 13.0 pg per milliliter and 12.5 pg per milliliter,respectively (P=0.80). At 33 to 41 weeks, the concentrationsof these factors also did not differ significantly between thesetwo groups.
Since calcium supplementation had no effect on the risk or severityof preeclampsia16 or on the concentrations of angiogenic factors,the women with preeclampsia and the controls were chosen withoutregard to whether they had received calcium supplementationor placebo. For each woman with preeclampsia, one normotensivecontrol was selected, matched according to enrollment site,gestational age of the fetus at the collection of the firstserum specimen (within 1 week), and storage time of the samplesat –70°C (within 12 months). A total of 120 of 159matched pairs were randomly chosen for the analysis of all 655serum specimens that were obtained before labor. Of the 240women included in the study, 21 (8.8 percent) contributed oneserum specimen, 52 (21.7 percent) contributed two specimens,139 (57.9 percent) contributed three, 27 (11.2 percent) contributedfour, and 1 (0.4 percent) contributed five. The mean gestationalage of the fetus at the collection of the first serum specimenwas 112.8 days among the women with preeclampsia and 113.6 daysamong the controls; the mean duration of freezer storage was9.35 years and 9.39 years, respectively. Since most women hadthree or fewer serum specimens, we analyzed the data largelyin a cross-sectional manner. Among the few women with more thanone specimen per period, the earliest specimen was selectedfor analysis.
Preeclampsia was defined as a diastolic blood pressure of atleast 90 mm Hg and proteinuria of at least 1+ (30 mg per deciliter)on dipstick testing, each on two occasions 4 to 168 hours apart.Severe preeclampsia was defined as the HELLP syndrome (hemolysis,elevated liver-enzyme levels, and a low platelet count), eclampsia,or preeclampsia with either severe hypertension (diastolic bloodpressure 110 mm Hg) or severe proteinuria (urinaryprotein excretion 3.5 g per 24 hours or findingsof 3+ [300 mg per deciliter] on dipstick testing).Detailed definitions have been published previously.15,16 Thetime of onset of preeclampsia (the end point) was defined asthe time of the first elevated blood-pressure or urinary proteinmeasurement leading to the diagnosis of preeclampsia. A small-for-gestational-ageinfant was defined as an infant whose birth weight was belowthe 10th percentile according to U.S. tables of birth weightfor gestational age that accounted for race, parity, and thesex of the infant.17 Because the study used data and specimensthat were collected as part of the CPEP trial and could notbe linked to identifiable women, the Office of Human SubjectsResearch of the National Institutes of Health granted it anexemption from the requirement for review and approval by theinstitutional review board.
Procedures
Assays were performed by personnel who were unaware of the outcomeof the pregnancy. Specimens were randomly ordered for analysis.Enzyme-linked immunosorbent assays (ELISAs) for human sFlt-1(also called soluble VEGF receptor 1), free PlGF, and free VEGFwere performed in duplicate, as previously described, with theuse of commercial kits (R&D Systems).5 The minimal detectabledoses in the assays for sFlt-1, PlGF, and VEGF were 5, 7, and5 pg per milliliter, respectively, with interassay and intra-assaycoefficients of variation of 7.6 and 3.3 percent, respectively,for sFlt-1; 10.9 and 5.6 percent, respectively, for PlGF; and7.3 and 5.4 percent, respectively, for VEGF.
Statistical Analysis
Chi-square tests were used for the comparison of categoricalvariables, and t-tests were used for the comparison of continuousvariables. Although the arithmetic mean concentrations are reportedin the text and figures, statistical testing was conducted afterlogarithmic transformation. All P values are two-tailed. TheWilcoxon rank-sum test was also applied to the comparisons withinthe gestational-age intervals and provided P values indicatingsimilar significance. Odds ratios were adjusted with the useof logistic-regression analysis.
Results
Characteristics of the Women
Of the 120 women with preeclampsia, 80 had mild preeclampsiaand 40 had severe preeclampsia, including 3 with the HELLP syndromeand 3 with eclampsia. As compared with the controls, the womenwith preeclampsia had greater body-mass index (the weight inkilograms divided by the square of the height in meters) andhigher blood pressure at the time of enrollment in the CPEPtrial; a larger proportion of their current pregnancies werecomplicated by preterm delivery or resulted in small-for-gestational-ageinfants (Table 1).
Table 1. Characteristics of Women Who Later Had Preeclampsia and Controls at Enrollment in the CPEP Trial and Characteristics of Their Infants.
Differences in sFlt-1, PlGF, and VEGF Levels
We first confirmed that the serum levels of sFlt-1, free PlGF,and free VEGF were altered in women with clinical preeclampsia.5,8Among 23 pairs of women with preeclampsia and controls withfetuses of similar gestational age, specimens drawn after theonset of preeclampsia ("end-point specimens") had higher levelsof sFlt-1 and lower levels of PlGF and VEGF than specimens fromcontrols (mean sFlt-1 level, 4382 pg per milliliter vs. 1643pg per milliliter; P<0.001; mean PlGF level, 137 pg per millilitervs. 669 pg per milliliter; P<0.001; and mean VEGF level,6.4 pg per milliliter vs. 13.9 pg per milliliter; P=0.07).
Gestational Changes in the sFlt-1 Level
To evaluate gestational patterns, we performed a cross-sectionalanalysis of serum obtained within gestational-age intervalsof four to five weeks (Figure 1A). The sFlt-1 concentrationsin controls remained constant until 33 to 36 weeks of gestation,when they increased by approximately 145 pg per milliliter perweek until labor and delivery. In the women in whom preeclampsialater developed, but before the onset of preeclampsia, the concentrationsbegan to increase at 21 to 24 weeks of gestation, with a steeperincrease at 29 to 32 weeks. When we compared the sFlt-1 concentrationsat different stages of pregnancy in specimens from women inwhom preeclampsia developed, we found that among women withspecimens drawn when their fetuses were in the same gestational-ageinterval, those who already had clinical preeclampsia had significantlyhigher concentrations than those who did not.
Figure 1. Concentrations of Soluble fms-like Tyrosine Kinase 1 (sFlt-1).
Panel A shows the mean sFlt-1 concentrations before and after the onset of clinical preeclampsia according to the gestational age of the fetus. I bars represent standard errors. The P values given are for the comparisons, after logarithmic transformation, with specimens from controls obtained during the same gestational-age interval; the differences, after logarithmic transformation, between the specimens obtained at 33 to 41 weeks from women who already had clinical preeclampsia and those obtained at 33 to 41 weeks from women in whom preeclampsia later developed were also significant (P=0.004 for the comparison at 33 to 36 weeks and P=0.02 for the comparison at 37 to 41 weeks). Panel B shows the mean sFlt-1 concentration according to the number of weeks before the onset of preeclampsia. I bars represent standard errors. Panel C shows longitudinal plots of the mean sFlt-1 concentrations within individual women according to the gestational age of the fetus. A total of 24 controls and 19 women with preeclampsia (in whom end-point specimens were obtained at 38 weeks) are included. The controls included were those who had a specimen collected at the latest points in pregnancy; among women in whom specimens were obtained on the same day of gestation, the controls were selected randomly. Because all but one control had specimens obtained at 38 weeks of gestation or earlier, only women with preeclampsia who had end-point specimens obtained at 38 weeks or less were included. Of the two controls with sFlt-1 levels above 3000 pg per milliliter, one had 2+ (100 mg per deciliter) proteinuria on two occasions without hypertension, and the other had one measurement of diastolic hypertension without proteinuria.
The concentrations of sFlt-1 were increased in women who laterhad preeclampsia beginning 11 to 9 weeks before the onset ofpreeclampsia (Figure 1B). Samples drawn within five weeks beforethe onset of preeclampsia revealed a more rapid increase inthe sFlt-1 levels. By one week before the onset of clinicalsigns, the concentrations approached those observed in end-pointspecimens. The increases in the sFlt-1 concentration at fourweeks, three weeks, two weeks, and one week before the onsetof preeclampsia occurred with little change in the mean gestationalage of the fetus, and the increase observed between eight weeksand five weeks before the onset of preeclampsia appeared tobe about one and a half times the increase that would be expectedon the basis of advancing gestational age alone. Five weeksbefore the onset of preeclampsia, the average concentrationin women in whom preeclampsia developed was similar to the concentrationsin controls at term, but after this point the sFlt-1 concentrationin the women with preeclampsia was higher. More than five weeksbefore the onset of preeclampsia, no substantial differenceswere observed between controls and women in whom preeclampsialater developed (Figure 1A). An increase in the sFlt-1 concentrationalso occurred in normal pregnancies, but it occurred later duringgestation and was less pronounced. Figure 1C depicts longitudinallythe increase in the sFlt-1 concentration for individual women;the increase occurred during late gestation in the controlsbut earlier and to a greater extent in the women with preeclampsia.
Gestational Changes in PlGF and VEGF Levels
The gestational pattern in the PlGF level is shown in Figure 2A.The PlGF concentrations in the controls increased duringthe first two trimesters, peaked at 29 to 32 weeks, and decreasedthereafter. The PlGF concentrations in the women with preeclampsiafollowed a similar pattern but were significantly lower thanthose in the controls from 13 to 16 weeks onward; at 13 to 16weeks, the mean level was 90 pg per milliliter in the womenwho later had preeclampsia and 142 pg per milliliter in thecontrols (P=0.01). Figure 2B shows the PlGF concentrations inthe women in whom preeclampsia developed according to the numberof weeks before the onset of preeclampsia. The PlGF concentrationsbegan to decrease 11 to 9 weeks before the onset of preeclampsia,with substantial reductions during the 5 weeks before the onsetof hypertension or proteinuria. At about five weeks before theonset of preeclampsia, the average PlGF concentration in womenwho later had preeclampsia was similar to the average PlGF concentrationin controls at term, but after this point, the PlGF concentrationin the women with preeclampsia was lower. By one week beforethe onset of preeclampsia, the concentrations approached thosefound in women with established preeclampsia (Figure 2B). Whenspecimens obtained within 5 weeks before the onset of preeclampsiawere excluded, the differences between the controls and thewomen who later had preeclampsia were less pronounced at 25to 28 weeks and 29 to 32 weeks of gestation; no differenceswere observed at 33 to 36 weeks (Figure 2A).
Figure 2. Concentrations of Placental Growth Factor (PlGF).
Panel A shows the mean free PlGF concentrations before and after the onset of preeclampsia according to the gestational age of the fetus. I bars represent standard errors. The P values given are for the comparisons, after logarithmic transformation, with specimens from controls obtained during the same gestational-age interval; the differences, after logarithmic transformation, between the specimens obtained at 29 to 36 weeks from women who already had clinical preeclampsia and those obtained at 29 to 36 weeks from women in whom preeclampsia later developed were also significant (P=0.05 for the comparison at 29 to 32 weeks and P=0.003 for the comparison at 33 to 36 weeks). Panel B shows the mean PlGF concentration according to the number of weeks before the onset of preeclampsia. I bars represent standard errors.
The VEGF concentrations were low throughout pregnancy and didnot differ between controls and women who later had preeclampsia,with two exceptions. In specimens obtained at 37 to 41 weeksof gestation, the VEGF levels were lower in the women with preeclampsia(6.7 pg per milliliter, vs. 9.9 pg per milliliter in the controls;P=0.02). In specimens obtained at 21 to 32 weeks, the VEGF levelswere lower only if the specimen was obtained within 5 weeksbefore the onset of preeclampsia (5.1 pg per milliliter, vs.12.8 pg per milliliter in the controls; P=0.002).
Relationship to Body-Mass Index and Severity of Preeclampsia
Since obesity is an important risk factor for preeclampsia,we examined whether alterations in the body-mass index couldaccount for the elevated sFlt-1 levels and diminished free PlGFlevels observed in preeclamptic pregnancy. We performed linearregression analyses of log-transformed sFlt-1 levels and log-transformedfree PlGF levels in relation to the body-mass index in controlwomen. Body-mass index was not related to the free PlGF levelsat 8 to 20 weeks, 21 to 32 weeks, or 33 to 41 weeks, nor tothe sFlt-1 levels at 8 to 20 weeks or 33 to 41 weeks (data notshown); it was inversely related to the sFlt-1 levels at 21to 32 weeks (estimated beta coefficient for the associationwith the log-transformed sFlt-1 level, –0.02; P=0.02).Higher sFlt-1 levels and lower PlGF levels in preeclamptic pregnancy,therefore, cannot be explained by greater body-mass index inwomen in whom preeclampsia develops.
Before the onset of preeclampsia, there were particularly largedifferences between the concentrations of sFlt-1 and PlGF incontrols and those in women who later had early-onset preeclampsiaor who had preeclampsia and a small-for-gestational-age infant.Figure 3 shows the concentrations between 21 and 32 weeks ofgestation (Figure 3A) and 33 to 41 weeks of gestation (Figure 3B).Alterations in the sFlt-1 and PlGF levels were also morepronounced before the onset of preeclampsia in women who hadpreeclampsia before term (<37 weeks of gestation) than inwomen who had an onset of preeclampsia at term (37weeks) (at 21 to 32 weeks: sFlt-1 level, 1672 pg per milliliterin women with preeclampsia before term vs. 935 pg per milliliterin women with preeclampsia at term; P<0.001; PlGF level,297 vs. 676 pg per milliliter; P<0.001; at 33 to 41 weeks:sFlt-1 level, 8150 vs. 2467 pg per milliliter; P<0.001; PlGFlevel, 73 vs. 370 pg per milliliter; P=0.05). Furthermore, thesFlt-1 and PlGF levels in specimens obtained before the onsetof preeclampsia from women who later had preeclampsia and asmall-for-gestational-age infant were significantly differentfrom the concentrations in the women who later had preeclampsiabut whose infants were not small for gestational age (at 21to 32 weeks: sFlt-1 level, 1993 vs. 985 pg per milliliter; P<0.001;PlGF level, 229 vs. 634 pg per milliliter; P<0.001; at 33to 41 weeks: sFlt-1 level, 4329 vs. 2442 pg per milliliter;P=0.003; PlGF level, 120 vs. 388 pg per milliliter; P=0.009).
Figure 3. Mean Concentrations of Soluble fms-like Tyrosine Kinase 1 (sFlt-1) and Placental Growth Factor (PlGF) According to Preeclampsia Status and Severity.
Panel A shows the concentrations at 21 to 32 weeks of gestation, and Panel B the concentrations at 33 to 41 weeks of gestation, in controls and in women who later had clinical preeclampsia (PE) according to whether they had mild preeclampsia, severe preeclampsia, preeclampsia with an onset at less than 37 weeks of gestation, preeclampsia and a small-for-gestational-age infant (SGA), or preeclampsia with an onset at less than 34 weeks of gestation. Specimens from women in whom preeclampsia developed were obtained before the onset of clinical disease. The P values given are for the comparisons with the specimens from the controls. I bars represent SEs.
Odds Ratios for Preeclampsia Associated with Angiogenic Factors
To determine whether the concentrations of sFlt-1 or PlGF inspecimens obtained before the onset of clinical signs of preeclampsiawere associated with the risk of this condition, we calculatedodds ratios for preeclampsia in each quartile of values forsFlt-1 and PlGF in the controls, as compared with the lowestor highest quartile, respectively (Table 2). We also examinedthe risk of preeclampsia in the extreme quartiles with respectto all the other quartiles, as follows. For specimens obtainedduring the second trimester or the early part of the third trimester,the lowest quartile of PlGF was associated with an increasedrisk of preterm preeclampsia (at <37 weeks' gestation; oddsratio for specimens from weeks 13 to 20, 7.4; 95 percent confidenceinterval, 1.8 to 30.2; odds ratio for specimens from weeks 21to 32, 7.9; 95 percent confidence interval, 2.9 to 21.5). APlGF level in the lowest quartile, however, was not a significantpredictor of preeclampsia with an onset at term (37weeks). Associations between the sFlt-1 level and preeclampsiawere observed only closer to the onset of disease. An sFlt-1level in the highest quartile from 21 to 32 weeks of gestation(but not earlier) predicted preterm preeclampsia (odds ratio,5.1; 95 percent confidence interval, 2.0 to 13.0), and a levelin the highest quartile between 33 and 41 weeks (but not earlier)predicted preeclampsia at term (odds ratio, 6.0; 95 percentconfidence interval, 2.9 to 12.5). These findings are consistentwith the results presented in Figure 1B, which shows that theelevation in the sFlt-1 level occurs largely within the fiveweeks before the onset of clinical disease. The lowest quartileof VEGF was not predictive of preeclampsia.
Table 2. Odds Ratios for Preeclampsia at Less Than 37 Weeks of Gestation and at 37 Weeks or More of Gestation According to Quartile of Total sFlt-1 and Quartile of Free PlGF.
Discussion
The experimental production of a preeclampsia-like phenotypein rats with the induction of high circulating levels of sFlt-1raised the possibility that this antiangiogenic factor mighthave a pathogenic role in preeclampsia.5 Our findings suggestthat concentrations of sFlt-1, which were previously reportedto be increased in women with established preeclampsia,5,8 beginto increase steeply about five weeks before the onset of clinicaldisease. Parallel with the increase in the sFlt-1 level, thereare decreases in the free PlGF and free VEGF levels, suggestingthat the decrease in these factors may be attributable in partto binding by sFlt-1. Women with preterm preeclampsia or preeclampsiaand a small-for-gestational-age infant had higher sFlt-1 levelsand lower PlGF levels at 21 to 32 weeks and at 33 to 41 weeksthan those with an onset of preeclampsia at term or preeclampsiawithout a small-for-gestational-age infant, respectively.
We have also demonstrated that there is a moderate but significantdecrease in the PlGF level beginning early in the second trimesteramong women in whom preeclampsia later develops, which is consistentwith previous observations.11,18,19,20,21 Finally, we have shownthat women with low concentrations of PlGF during early gestationhave a much greater risk of early-onset preeclampsia.
In normotensive pregnancy, the sFlt-1 levels are stable duringthe early and middle stages of gestation, and there is a steadyincrease beginning at 33 to 36 weeks. This increase correspondsto the late-gestational decrease in the free PlGF level in normalpregnancy that is reported here and has been observed by others.11,22During the second trimester, the PlGF concentrations are highand the sFlt-1 concentrations low, creating a proangiogenicstate. We speculate that in later gestation, placental vasculargrowth may be tempered by the increase in the levels of antiangiogenicsFlt-1 and the decrease in the levels of proangiogenic VEGFand PlGF. In women with preeclampsia, sFlt-1 appears to increaseearlier in gestation and to reach a higher concentration thanit does in controls. Thus, in preeclampsia, the antiangiogenic"brakes" may be applied too soon and too hard — an exaggerationof a normal process governing placental growth and function.A study involving renal biopsies that demonstrated mild glomerularendotheliosis in normal term pregnancy and severe lesions inpreeclampsia23 is consistent with the hypothesis that preeclampsiais an exacerbation of the antiangiogenic state of normotensivepregnancy at term.
Since they are not accompanied by reciprocal increases in systemicsFlt-1 levels, diminished PlGF levels early in the pregnanciesof women in whom preeclampsia later develops might reflect eitherless placental production or increased binding to local circulatingand membrane-bound receptors. Diminished levels of placentalPlGF could play a role in the aberrant cytotrophoblast invasion("pseudovasculogenesis") that is characteristic of preeclampsia.24,25Alterations of the sFlt-1 and PlGF levels appeared to be greaterin women who had early-onset preeclampsia and in women withpreeclampsia who delivered a small-for-gestational-age infant,suggesting that defective angiogenesis may be especially importantin these cases. The VEGF levels were decreased during and withinfive weeks before established preeclampsia, but low levels werenot a significant predictor of future preeclampsia.
Our study has limitations. The data are primarily cross-sectionaland do not permit the distinction of subgroups in which thesFlt-1 and PlGF concentrations might be altered even more ornot at all. Nevertheless, longitudinal plots of sFlt-1 concentrationsin individual women according to the gestational age of thefetus have confirmed the third-trimester increase in the sFlt-1level in controls and the greater increase in women with preeclampsia.We found the sFlt-1 levels in women with established preeclampsiato be lower than others have reported them to be.5,8 Longerfreezer-storage times may have resulted in decreased sFlt-1levels in our study. A more likely explanation is that the womenin our study may have had milder preeclampsia. The mean gestationalage of the fetus at the time when specimens were obtained fromwomen with clinical preeclampsia was 38 weeks in this study,as compared with 34 weeks or less in other studies. Finally,we did not examine other complications of pregnancy, such asintrauterine growth restriction in the absence of hypertensionor gestational hypertension without proteinuria.
In summary, we have demonstrated a marked increase in the circulatingsFlt-1 concentration beginning five weeks before the onset ofpreeclampsia, accompanied by decreases in the circulating freePlGF and VEGF levels. These findings lend support to the hypothesisthat circulating angiogenic proteins may have an important biologicrole in preeclampsia. Data from prospective, longitudinal studiesin which serial concentrations of sFlt-1 and free PlGF are measuredthroughout pregnancy are needed to better assess the relevanceof these markers to the early identification of preeclampsiaand the prediction of its severity.
Supported by funds from the Beth Israel Deaconess Medical CenterObstetrics Department Research Foundation and by grants (DK64255 and DK 02825, to Dr. Karumanchi) from the National Institutesof Health. The CPEP trial was supported by contracts (N01-HD-1-3121,N01-HD-1-3122, N01-HD-1-3123, N01-HD-1-3124, N01-HD-1-3125,N01-HD-1-3126, N01-HD-3154, and N01-HD-5-3246) with the NationalInstitute of Child Health and Human Development, with cofundingfrom the National Heart, Lung, and Blood Institute.
Drs. Maynard, Sukhatme, and Karumanchi report being named ascoinventors on a pending patent filed by Beth Israel DeaconessMedical Center for the use of angiogenesis-related proteinsfor the diagnosis and treatment of preeclampsia.
We are indebted to Patricia Moyer for assistance with figures;to Dr. Harold Dvorak, Department of Pathology, Beth Israel DeaconessMedical Center, for helpful suggestions and for his pioneeringwork in angiogenesis; to the patients who participated in thestudy; and to the following members of the CPEP Study Group,who assembled the data base and specimen repository: J.C. Hauth,R. Goldenberg, B.S. Stofan (University of Alabama at Birmingham);L.B. Curet, G.M. Joffe, V. Dorato (University of New Mexicoat Albuquerque); B.M. Sibai, S.A. Friedman, B.M. Mercer, T.Carr (University of Tennessee at Memphis); P.M. Catalano, A.S.Petrulis, L. Barabach (Case Western Reserve University at MetroHealthMedical Center, Cleveland); C. Morris, S.-L. Jacobson, K. McCracken(Oregon Health Sciences University, Portland); J.R. Esterlitz,M.G. Ewell, D.M. Brown (the Emmes Corporation, Rockville, Md.);R.J. Levine, R. DerSimonian, J.D. Clemens, M.A. Klebanoff, E.G.Raymond, J.G. Rigau-Perez, H. Shifrin (National Institute ofChild Health and Human Development); J.A. Cutler, D.E. Bild(National Heart, Lung, and Blood Institute); M. Lindheimer,C. Begg, T. Chalmers, M. Druzin, R. Sokol (Data and Safety MonitoringBoard).
Source Information
From the Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Department of Health and Human Services, Bethesda, Md. (R.J.L., L.J.E., K.F.Y., E.F.S.); the Departments of Medicine (S.E.M., F.H.E., V.P.S., S.A.K.) and Obstetrics and Gynecology (K.-H.L., B.P.S., S.A.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; Allied Technology Group, Rockville, Md. (C.Q.); the Harvard School of Public Health, Boston (B.P.S.); the Departments of Medicine and Obstetrics, Massachusetts General Hospital and Harvard Medical School, Boston (R.T.); and the Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati (B.M.S.). Drs. Levine and Karumanchi contributed equally to the article.
Address reprint requests to Dr. Levine at the National Institute of Child Health and Human Development, Bldg. 6100, Rm. 7B03, Bethesda, MD 20892, or at levinerj{at}mail.nih.gov, or to Dr. Karumanchi at Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 517, Boston, MA 02215, or at sananth{at}bidmc.harvard.edu.
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Cindrova-Davies, T., Yung, H.-W., Johns, J., Spasic-Boskovic, O., Korolchuk, S., Jauniaux, E., Burton, G. J., Charnock-Jones, D. S.
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110 mm Hg) or severe proteinuria (urinary protein excretion 
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38 weeks) are included. The controls included were those who had a specimen collected at the latest points in pregnancy; among women in whom specimens were obtained on the same day of gestation, the controls were selected randomly. Because all but one control had specimens obtained at 38 weeks of gestation or earlier, only women with preeclampsia who had end-point specimens obtained at 38 weeks or less were included. Of the two controls with sFlt-1 levels above 3000 pg per milliliter, one had 2+ (100 mg per deciliter) proteinuria on two occasions without hypertension, and the other had one measurement of diastolic hypertension without proteinuria.
