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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1076
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 180-184
Copyright © 2006 by The Endocrine Society

Maternal Serum-Soluble Vascular Endothelial Growth Factor Receptor-1 in Early Pregnancy Ending in Preeclampsia or Intrauterine Growth Retardation

Katja-Anneli Wathén1, Eija Tuutti1, Ulf-Håkan Stenman, Henrik Alfthan, Erja Halmesmäki, Patrik Finne, Olavi Ylikorkala and Piia Vuorela

Departments of Obstetrics and Gynecology (K.-A.W., E.T., E.H., O.Y., P.V.) and Clinical Chemistry (U.-H.S., H.A., P.F.), Helsinki University Central Hospital, Biomedicum Helsinki, 00029 HUS, Helsinki, Finland

Address all correspondence and requests for reprints to: Professor Olavi Ylikorkala, Helsinki University Central Hospital, P.O. Box 140, 00029 HUS, Finland.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Vascular endothelial growth factor (VEGF) promotes placental vascularization, which is inadequate in preeclampsia and intrauterine growth retardation (IUGR). The soluble receptor of VEGF (sVEGFR-1), also known as soluble fms-like tyrosine kinase-1, is produced in the placenta and reduces VEGF activity. Therefore, elevated sVEGFR-1 could contribute to the development of preeclampsia and IUGR.

Objective: The objective of this study was to study maternal serum sVEGFR-1 concentration in early pregnancy ending in preeclampsia and IUGR.

Design: This was a case-control study.

Setting: This study was conducted at Helsinki University Central Hospital (Helsinki, Finland), a tertiary referral center.

Patients: Patients included 124 pregnant women, of whom 49 developed preeclampsia, 16 gave birth to IUGR infants without preeclampsia, and 59 remained normotensive and gave birth to normal-sized infants. Serum samples were collected at 12–15 and 16–20 gestational weeks.

Main Outcome Measures: Serum sVEGFR-1 concentrations were determined by ELISA.

Results: Women with subsequent preeclampsia had higher [median; interquartile range (IQR)] concentrations of sVEGFR-1 at 16–20 wk gestation (436 and 282–699 ng/liter; P = 0.005) than the controls (296 and 184–508 ng/liter). The conclusion was the same if women with mild (340 and 285–750 ng/liter; P = 0.043) or severe (497 and 235–699 ng/liter; P = 0.022) preeclampsia were analyzed separately. An elevated sVEGFR-1 concentration at 16–20 wk gestation is associated with an increased risk of preeclampsia but not of isolated IUGR. Soluble VEGFR-1 concentration decreased by 15% from the first to the second sampling in the controls but not in women with preeclampsia or IUGR.

Conclusion: Elevated sVEGFR-1 concentrations at 16–20 wk gestation precede the clinical manifestations of preeclampsia. By neutralizing VEGF, sVEGFR-1 may contribute to inadequate placental vascularization.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
AFFECTING ABOUT 5% of all pregnancies, preeclampsia is the most common cause of maternal and perinatal mortality and morbidity. Although the etiology of preeclampsia is still unknown, it has been shown to be associated with placental factors that are present, insufficiently or excessively, already in the early placenta. Poor placental and decidual vascularization precedes the clinical manifestations of preeclampsia by several weeks (1, 2). Similar vascular defects also occur in mothers whose pregnancies end in the birth of infants with intrauterine growth retardation (IUGR) without preeclampsia; this may imply a common vascular etiology for IUGR and preeclampsia (3).

Vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-1), also known as soluble fms-like tyrosine kinase-1, are potent vasoactive factors, which are produced by the placenta (4, 5). VEGF promotes neovascularization, reduces blood pressure, and is crucial in the formation and maintenance of the glomerular filtration barrier (6, 7, 8). Therefore, its deficiency could well explain the main clinical manifestations of preeclampsia (hypertension, proteinuria, and edema). Soluble VEGFR-1 binds VEGF and is the most potent regulator of VEGF activity in vivo (9). It is known that sVEGFR-1 leaks from early trophoblasts into the maternal circulation as early as 30 d after conception (10). Increased concentrations of sVEGFR-1 have been detected in the placenta, amniotic fluid, and blood of women with clinically manifested preeclampsia (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). These data imply that elevated placental production and release of sVEGFR-1 and the subsequent rise of its concentration in maternal circulation may contribute to the development of clinical preeclampsia by inhibiting the function of VEGF (21).

A reliable biochemical marker for early prediction of preeclampsia has been sought for a long time. Due to its vascular potency and early appearance in the maternal circulation, sVEGFR-1 holds promise for this purpose. Elevated maternal serum sVEGFR-1 concentrations have been detected approximately 5–6 wk before the clinical onset of preeclampsia (17, 20). Also, IUGR has been reported to be associated with an increase in placental and circulating sVEGFR-1 concentrations during the 3rd trimester in some, although not in all, studies (11, 13). However, only limited data, mainly from mid- and late gestation, are available on serial concentrations of sVEGFR-1 (17, 18, 19, 20). The aim of the present study was to measure sVEGFR-1 concentrations in maternal sera collected in the 1st and 2nd trimesters in women whose pregnancies ended in preeclampsia, IUGR, or proceeded normally to term.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
With the approval of the local Ethics Committee and with a written informed consent from each woman, blood samples were collected from 3240 pregnant women during a routine two-phase ultrasound screening visit at 12–15 and 16–20 wk gestation between January 1, 2001 and December 31, 2002. The first blood sample was collected at 13.7 ± 0.5 (mean ± SD) weeks and the second one at 19.2 ± 0.6 wk gestation. All women were monitored in prenatal clinics of the Helsinki Health Region and were delivered in the Helsinki University Central Hospital.

At the time of sampling, all women included into the study were judged to be healthy and their pregnancies normal. Excluded were women with a history of hypertension, renal disease, diabetes, or any other chronic or preexisting disease. Smoking more than five cigarettes per day, race other than Caucasian, and multiple pregnancy also caused exclusion.

Seventy-one women developed preeclampsia, the criteria of which were elevation of blood pressure over 140/90 mm Hg (measured at least twice 24 h apart) and proteinuria (>0.3 g/24 h). Using the above exclusion criteria, a total of 22 women were excluded. Thus, 49 women with preeclampsia were included in the study (Table 1Go). Preeclampsia was mild in 29 women and severe in 20 women, the criteria for the latter being blood pressure more than 160/110 mm Hg and/or proteinuria >5 g/24 h.


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  		TABLE 1. Clinical characteristics of study population

 
Fetal growth was followed by palpation and symphysis-fundus height measurements at routine prenatal visits. Seventy-three women were admitted to the outpatient department for closer growth estimation by ultrasound examination. Sixteen of these women finally gave birth to infants with a birth weight at least two SD values below the national average at the particular gestational age (IUGR). Their histories and the clinical course of their pregnancies were entirely normal except for the early onset IUGR.

The control group included 59 women who had no history of hypertension, diabetes, other chronic disease, or smoking more than five cigarettes per day, and who remained normotensive, nonproteinuric, and who gave birth to infants of normal weight (± 1 SD of national average at term). The serum samples in the control group were collected at the same gestational weeks as the samples in the patient groups, and they were followed in the same prenatal clinics and delivered in the same hospital.

Blood samples were allowed to clot at room temperature, and aliquots of serum, separated by centrifugation, were stored at –80 C until analyses. Soluble VEGFR-1 was determined in duplicate by ELISA according to the manufacturer’s instructions (R&D Systems, Inc., Minneapolis, MN). Intra- and interassay coefficients of variation were <5.0% and <8.2%, respectively. The detection limit of the assay was 5 ng/liter. To reduce the impact of interassay variation, all measurements were done in five batches, each containing samples from both patient and control groups. When available, serial samples from a given individual were analyzed in the same batch.

Because the distribution of sVEGFR-1 concentrations was skewed, logarithmic transformation was performed. Normally distributed variables were compared between groups using Student’s t test. Changes in the concentration of sVEGFR-1 in serial samples were analyzed using paired-samples Student’s t test. Correlation between sVEGFR-1 concentrations and continuous variables was assessed using Spearman rank correlation. Differences in distributions between categorical variables were assessed by the {chi}2 test. The concentrations of sVEGFR-1 were classified as below the median (low) and above the median (high), and odds ratios (ORs) between concentrations and the diagnosed diseases were calculated. The sVEGFR-1 concentrations were also divided into quartiles, and P values for the trend of changing prevalence of preeclampsia and IUGR were calculated by the {chi}2 test. A two-tailed P value < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The study groups were comparable in regard to pregnancy variables, such as age, parity, and blood pressure. Preeclampsia was clinically diagnosed at 33 wk gestation (mean), which was 19 wk after the first and 13 wk after the second blood sampling. Three women fulfilled the criteria of the hemolysis, elevated liver enzymes, and low platelet count syndrome. Twelve preeclamptic patients gave birth to infants with IUGR, but their infants, as well as all the others, were born in good condition (Apgar score > 8 at 5 min, normal umbilical artery pH) (Table 1Go).

Soluble VEGFR-1 was detectable in each sample. At the first sampling, the concentration of sVEGFR-1 showed no difference between the three study groups. However, when divided into mild and severe preeclampsia, the sVEGFR-1 concentrations tended to be higher in women with subsequent severe preeclampsia or IUGR, although no statistically significant differences in the median sVEGFR-1 concentrations between the groups were found (Table 2Go and Fig. 1Go).


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  		TABLE 2. sVEGFr-1 concentrations (ng/liter) in maternal serum at 13.7 ± 0.5 (mean ± SD) and 19.2 ± 0.6 wk gestation in women who stayed normotensive or developed preeclampsia or IUGR

 


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  		FIG. 1. Maternal sVEGFR-1 concentrations at 12–15 and 16–20 gestational weeks in healthy controls and in women with later mild preeclampsia, severe preeclampsia, or isolated IUGR. Box plot demonstrates 10th, 25th, 50th, 75th, and 90th percentiles. *, P = 0.043; **, P = 0.022 compared with controls.

 
At the second sampling, sVEGFR-1 concentrations in women with subsequent preeclampsia were higher than among the controls when analyzed as a whole group (P = 0.005), or in subgroups of either severe (P = 0.022) or mild (P = 0.043) preeclampsia. However, sVEGFR-1 concentrations in women with isolated IUGR were normal (Table 2Go and Fig. 1Go). In the subgroup of women with subsequent preeclampsia and concomitant IUGR, the sVEGFR-1 concentrations were similar to those in healthy controls (Table 2Go).

Paired samples were available from 26 of 49 women with subsequent preeclampsia, five of 16 women with subsequent IUGR, and 28 of 59 healthy controls. From the first to the second sampling, median sVEGFR-1 decreased (P = 0.003) by 15% in the controls, whereas in women with subsequent preeclampsia or IUGR, no significant change was seen. Yet, sVEGFR-1 in serial samples showed no statistically significant difference between the groups (Table 2Go).

Women with sVEGFR-1 concentrations above the median were characterized by an elevated risk of preeclampsia [OR, 2.1; 95% confidence interval (CI), 0.8–5.6] or severe preeclampsia (OR, 4.1; CI, 1.1–15.6). The quartile analysis also demonstrated the association between high sVEGFR-1 and risk of subsequent preeclampsia (P = 0.033) and especially severe preeclampsia (P = 0.018, data not shown) (Tables 2Go and 3Go).


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  		TABLE 3. ORs and 95% CI for preeclampsia (PE) according to quartiles of sVEGFR-1 concentrations with the lowest quartile as the reference category

 
The serum sVEGFR-1 concentrations did not correlate with the degree of hypertension or proteinuria, maternal age, gestational age at delivery, or fetal or placental weight. Moreover, sVEGFR-1 concentrations or the change in serial samples did not correlate with the time of onset of preeclampsia (P = 0.39, Spearman rank correlation).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
A large number of biochemical markers, e.g. atrial natriuretic peptide, hCG, {alpha}-fetoprotein, IGF binding protein-1, homocysteine, and corticotropin-releasing factor, have been tested for prediction of preeclampsia (22, 23, 24, 25), but none of them has proven to be clinically useful. In view of the vasoactive role of VEGF and the inhibitory effect of sVEGFR-1 on this capacity, it is possible that an elevated sVEGFR-1 concentration contributes to the development of preeclampsia. We evaluated the pattern of sVEGFR-1 in early pregnancy proceeding normally or ending in preeclampsia or IUGR because this factor appears in maternal circulation already 30 d after conception (10) and because it is elevated in various compartments in women diagnosed with preeclampsia (12, 13, 14, 15, 16, 17). A role of sVEGFR-1 in preeclampsia is strongly supported by studies in rats in which exogenous administration of sVEGFR-1 induces preeclampsia (15).

The placenta produces sVEGFR-1; therefore, we measured maternal serum sVEGFR-1 concentrations around 14 wk gestation, when early placentation has taken place and steroid production has shifted from corpus luteum to placenta. It is possible that a placental defect causing preeclampsia is operating already in this phase of pregnancy. The second sampling took place at 19 wk, when preeclampsia on the placental level should be present. Our data show that sVEGFR-1 concentrations around 14 wk of pregnancy were not elevated in women who later developed preeclampsia, and this finding is in line with one previous study (26). However, at the second sampling around 19 wk of pregnancy, concentrations of sVEGFR-1 were elevated in women developing preeclampsia, either mild or severe. It has been reported that sVEGFR-1 concentrations may increase approximately 5 wk before the clinical onset of preeclampsia (17, 20). Our data show that elevated concentrations of sVEGFR-1 may precede the clinical onset of preeclampsia even by 13 wk.

We screened a large number of women and included only those who remained entirely healthy or who developed preeclampsia or IUGR without any preexisting risk factor. This can be seen as a strength of our study. On the other hand, it limited the sample sizes, which hampered reliable statistical calculation of the value of sVEGFR-1 concentrations in the early prediction of preeclampsia. However, our data are encouraging for further large-scale clinical studies on this topic.

IUGR, especially if starting early in gestation and not being secondary to any other pregnancy complication, has been suggested to be a form of preeclampsia only affecting the myometrium, placenta, and fetus (3). Therefore, we evaluated the pattern of sVEGFR-1 in women with subsequent early onset IUGR. Our data show that this complication is not associated with changes in maternal serum sVEGFR-1 concentrations in early gestation. This may suggest that if an excess of sVEGFR-1 is a causative factor in IUGR, it is limited only to the placenta but is not detectable in maternal serum. In contrast, IUGR appearing in preeclamptic pregnancy was accompanied by high sVEGFR-1 concentrations, but the levels were not significantly higher than those in all women developing preeclampsia.

No previous data exist on serial sVEGFR-1 concentrations in early pregnancy, although it is known that the concentration of sVEGFR-1 rises in late gestation (15). Therefore, we did not expect to see a fall of 15% in the concentration of sVEGFR-1 in women with uncomplicated pregnancies. The reason for this phenomenon is not known, and it is possible that it is a random finding. However, a fall in sVEGFR-1 soon after early placentation can be physiologically meaningful because it leaves vasoactive VEGF uninhibited and thus enhances placental vascularization. The absence of the fall of sVEGFR-1 concentrations in women with subsequent preeclampsia or IUGR may support this notion, although the limited number of women does not allow us to draw any definitive conclusions. Thus, more data are needed before a judgment of sVEGFR-1 behavior in early gestation can be made.

In summary, sVEGFR-1 is elevated in maternal serum at 16–20 wk gestation in women with subsequent preeclampsia but not IUGR. However, larger patient series must be studied before this test can be applied clinically for prediction of preeclampsia.


   Acknowledgments
 
We thank the Helsinki University Central Hospital Research Funds and The Medical Society of Finland for funding this study.


   Footnotes
 
First Published Online November 1, 2005

1 K.-A.W. and E.T. contributed equally to this work and should be considered equal first authors. Back

Abbreviations: CI, Confidence interval; IQR, interquartile range; IUGR, intrauterine growth retardation; OR, odd ratio; sVEGFR, soluble receptor of VEGF; VEGF, vascular endothelial growth factor.

Received May 16, 2005.

Accepted October 20, 2005.


   References
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 Introduction
 Patients and Methods
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Soluble vascular endothelial growth factor receptor-1 in intrauterine growth retardation
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