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Obstetrics & Gynecology:
Original Research

Second‐Trimester Maternal Serum Placental Growth Factor and Vascular Endothelial Growth Factor for Predicting Severe, Early‐Onset Preeclampsia

Polliotti, Bruno M. PhD; Fry, A. Gordon MD; Saller, Devereux N. Jr MD; Mooney, Robert A. PhD; Cox, Christopher PhD; Miller, Richard K. PhD

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Author Information

Departments of Obstetrics and Gynecology, Pathology, and Biostatistics, University of Rochester Medical Center, Rochester, New York.

Address reprint requests to: Bruno M. Polliotti, PhD, New York University, School of Medicine, Department of Obstetrics and Gynecology, 1804 Wisteria Circle, Bellport, NY 11713; E-mail: bpolliotti@aol.com.

DNS is currently affiliated with the Department of Obstetrics and Gynecology, University of West Virginia, Robert C. Byrd Health Science Center, Morgantown, West Virginia.

Received July 11, 2002. Received in revised form October 31, 2002. Accepted November 13, 2002.

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Abstract

OBJECTIVE: To determine whether alterations in second-trimester maternal serum cytokine concentrations can identify women at risk for developing severe, early-onset preeclampsia.

METHODS: Patients with severe preeclampsia requiring delivery prior to 34 weeks (n = 20) were each matched by gestational age, gravidity, parity, and sample freezing time with three healthy controls who delivered at term (n = 60). By using second-trimester maternal sera originally collected for fetal aneuploidy screening, the concentrations of placental growth factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, endothelin-1, and human chorionic gonadotropin were compared between patients and controls. Logistic regression analysis was used to estimate odds ratios for high versus low (median split) cytokine concentrations with respect to the development of severe, early-onset preeclampsia. Receiver operating characteristic (ROC) curves based on a second logistic regression, using actual cytokine values, were plotted to illustrate reciprocal impact on sensitivity and specificity.

RESULTS: Placental growth factor and vascular endothelial growth factor levels were significantly lower in patients than in controls. No significant differences were observed for the other cytokines. The odds ratios (with 95% confidence intervals) were 15.54 (3.29, 73.40) for vascular endothelial growth factor and 4.20 (1.35, 13.06) for placental growth factor. Receiver operating characteristic analysis of placental growth factor and vascular endothelial growth factor confirmed that both were useful in discriminating between patients and controls. Models combining both vascular endothelial growth factor and placental growth factor provided the best performance for identifying patients at risk for developing severe, early-onset preeclampsia, according to both odds ratios and ROC analyses.

CONCLUSION: Combined analysis of placental growth factor and vascular endothelial growth factor is potentially useful as a tool for early identification of patients at risk for developing severe, early-onset preeclampsia.

Despite decades of research, the pathogenesis of preeclampsia remains poorly understood, and attempts to identify early markers of the disorder have been disappointing. Biochemical markers that could predict the subsequent onset of preeclampsia before maternal clinical manifestations become apparent would be advantageous because they may elucidate the pathophysiologic mechanisms of the disorder and identify specific patients early in pregnancy who are at high risk for developing preeclampsia. 1,2 Once identified, these women may benefit from targeted therapy that could prevent or diminish the effects of the disease. Because the preponderance of maternal and perinatal morbidity and mortality occurs when disease develops at an early gestational age, 3,4 early prediction of preeclampsia would have the greatest potential to favorably impact maternal and perinatal outcome if it can identify the subset of women destined to develop severe, early-onset disease.

The association between abnormal placentation and preeclampsia is well known and is thought to involve inadequate trophoblast invasion of maternal spiral arteries during early gestation. 5 Evidence of placental derangement may be reflected in maternal circulation by alterations in the concentration of biochemical markers involved in the process of normal placental development. Placental growth factor and vascular endothelial growth factor, members of the platelet-derived growth factor family, are both important local mediators of angiogenesis in the human placenta 6 and can be isolated from the maternal circulation. Changes in the circulating concentrations of these factors may represent abnormal placental development in pregnancies destined to develop preeclampsia. Recent publications present contradictory results for placental growth factor, showing decreased maternal serum levels early in the second trimester 7,8 or levels that are not significantly different from normal pregnancies at the same gestational age. 9 Livingston et al also have observed a decrease of placental growth factor at term 10 but not earlier in gestation. 9 The role of vascular endothelial growth factor is similarly unclear. Whereas some investigators report an increase in circulating maternal levels in patients with preeclampsia, as compared with patients with normal pregnancies, 11,12 others report a decrease. 10,13,14 However, most of these studies were performed after preeclampsia was clinically evident, and the pattern of circulating vascular endothelial growth factor levels earlier in pregnancy is not known.

Other cytokines have also been implicated in the etiology of preeclampsia. Granulocyte colony stimulating factor may play a role in the development of preeclampsia by acting as a stimulus for vascular endothelial damage through the activation of granulocytes, and circulating granulocyte colony stimulating factor levels are reported to be elevated in maternal circulation in preeclampsia. 15 Endothelin-1 is a potent vasoconstrictor, and increased circulating levels serve as a marker for endothelial damage. Endothelin-1 in the placenta also stimulates trophoblast cell proliferation and invasion in vitro, implying a potential role in pathogenesis of preeclampsia at the placental level. 16 Whereas circulating maternal levels of endothelin-1 appear to be elevated, 17 placental production of endothelin-1 seems to be reduced in preeclamptic pregnancies. 16 In addition, granulocyte colony stimulating factor is also reported to stimulate endothelin-1, and this interaction has been associated with preeclamptic mechanisms. 18

Because increased maternal concentrations may be a marker for abnormal placentation in general, human chorionic gonadotropin (hCG) has also been studied as a potential tool for predicting the development of preeclampsia. Increased serum levels of β-hCG have been found during the second trimester in women who later developed preeclampsia. 19 Free α-hCG subunit levels have also been reported to be significantly higher among patients with severe preeclampsia. 20

The current data relating to the role of these cytokines in preeclampsia are inconsistent, explained in part by differing methodologies and experimental designs among the studies. It is also possible that the examination of multiple cytokines might be superior to the analysis of a single one. We therefore designed a study of multiple cytokines that, by focusing on a specific, narrowly defined subset of preeclamptic patients, addresses some of the discrepancies observed in previous studies. The purpose of this investigation was to determine whether the circulating concentrations of a combination of selected cytokines (placental growth factor, vascular endothelial growth factor, granulocyte colony stimulating factor, endothelin-1, and hCG) in second-trimester maternal serum could be used to predict the subsequent development of preeclampsia. Because most maternal and fetal morbidity and mortality occurs when preeclampsia presents at early gestational ages, we confined our analysis to women who were delivered before 34 weeks' gestation because of severe preeclampsia.

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MATERIALS AND METHODS

This was a case–control study comparing women who developed severe preeclampsia before 34 completed weeks' gestation and matched, healthy controls who delivered at term with respect to the concentration of cytokines that had been obtained in the second trimester. Maternal serum samples were originally collected for purposes of antenatal screening for fetal aneuploidy and neural tube defects. This screening program, which uses a triple marker assay of maternal serum for α-fetoprotein, estriol, and free β-hCG concentrations, is available to all pregnant women in the New York State Finger Lakes region through the Rochester Regional Genetics Program. Currently, approximately 60% of pregnant women in the Finger Lakes region elect to have second-trimester serum screening performed.

Candidates for inclusion in the study were identified through a computerized search of a perinatal database that included all deliveries occurring between January 1, 1999 and May 31, 2001 at Strong Memorial Hospital, University of Rochester Medical Center. The hospital records of study candidates were then carefully reviewed with regard to study criteria, described below. Stored serum samples of patients meeting these criteria were analyzed for cytokine concentration. The serum levels of placental growth factor, vascular endothelial growth factor, endothelin-1, and granulocyte colony stimulating factor were quantified with an enzyme-linked immunosorbent assay with a sensitivity of 7, 1, 1, and 20 pg/mL, a specificity nearly 100% (with various levels of cross-reactivity), a coefficient of variation interassay of 11.2, 7.3, 5.7, and 3.7% and a coefficient of variation intra-assay of 5.4, 5.4, 4.4, and 1.8%, respectively (R&D Systems Inc., Minneapolis, MN). A chemiluminescent enzyme immunoassay for hCG was used, with a sensitivity of 1 mIU/mL, a specificity of nearly 100% (with a cross-reactivity of 127% with hCG-β subunit), a coefficient of variation interassay of 6.5%, and a coefficient of variation intraassay of 3% (Immulite DPC, Los Angeles, CA). This research study protocol was reviewed and approved by the Research Subjects Review Board at the University of Rochester.

The study was designed to evaluate preeclamptic women whose disease was severe enough to mandate delivery at an early gestational age for either maternal or fetal indications. To be considered for inclusion in the study, all candidates must have shown an unequivocal history of both the following: 1) severe preeclampsia warranting delivery based on maternal or fetal indications, and 2) delivery before 34 completed weeks of gestation. Categorization of disease in study subjects was defined in accordance with the most recent consensus recommendations for classifying hypertensive disorders in pregnancy. 21,22 Specifically, preeclampsia was defined as newly detected hypertension (systolic blood pressure [BP] greater than or equal to 140 mm Hg, or diastolic BP greater than or equal to 90 mm Hg) with proteinuria (greater than or equal to 300 mg total urinary protein over a 24-hour collection period), both developing after 20 weeks' gestation. Severe preeclampsia was defined as preeclampsia complicated by either 1) severe hypertension (systolic BP greater than or equa1 to 160 mm Hg or diastolic BP greater than or equal to 110 mm Hg, measured on at least two separate occasions 6 hours apart), or 2) at least 5 g total urinary protein within a 24-hour collection period. Preeclampsia was also classified as severe in the presence of specific and otherwise unexplained abnormal laboratory or physical findings, regardless of elevated blood pressure or proteinuria. These findings included 1) elevated levels of aspartate aminotransferase (greater than 72 IU/L), 2) thrombocytopenia (platelet count less than 100,000/mm3), 3) pulmonary edema, 4) oliguria (less than 500 mL urine in 24 hours), and 5) abnormal neurologic findings (excluding headache occurring in an individual with a history of recurring or chronic headache).

Preeclamptic patients were also required to have clear indications for delivery based on the severity of their disease before being included as study subjects. Maternal indications for delivery included severe hypertension despite maximal doses of oral antihypertensive agents, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, new onset of neurologic symptoms, thrombocytopenia or abnormal liver function tests without other evidence of HELLP, oliguria, pulmonary edema, new-onset coagulopathy, and epigastric pain. Fetal indications included repetitive late decelerations, bradycardia, and a persistent biophysical score of 4 or less.

Individuals with chronic hypertension, diabetes mellitus, and preexisting renal disease were eligible for inclusion if severe preeclampsia was unequivocally diagnosed after 20 weeks, based on new development of abnormal laboratory or physical findings described previously. Individuals with multiple gestations and with growth-restricted fetuses were also eligible for inclusion. The presence of severe blood pressure elevation or proteinuria alone, in the absence of concurrent clinical or laboratory abnormalities, was not sufficient to allow the inclusion of individuals with preexisting chronic hypertension or renal disease. Patients who were delivered because of nonreassuring fetal status were included if other clinical criteria were met.

Patients were excluded if delivery occurred after 34 weeks (even when severe preeclampsia developed before 34 weeks) or if delivery occurred because of factors related to conditions other than severe preeclampsia (eg, preterm labor, preterm premature rupture of membranes, chorioamnionitis, or nonreassuring fetal status clearly unrelated to preeclampsia [eg, umbilical cord prolapse]). Patients with preexisting hypertension or proteinuria were not included unless the new onset of abnormal physical or laboratory findings defining severe preeclampsia developed.

Stored samples from three control subjects were identified for each patient with preeclampsia and matched with preeclamptic patients based on maternal age, gestational age, gravidity, parity, and length of time of serum sample storage.

Differences between means of the two subject groups for clinical variables and for cytokine concentrations were assessed with unequal Student t test with unequal variance. Because some of the variables were highly skewed, parity and gravidity in particular, we also used a nonparametric test (Kruskal-Wallis test). A P value of less than .05 was considered to be significant. For cytokines found to have significantly different second-trimester concentrations between patients and controls, logistic regression analysis was used to model the probability of developing severe, early-onset preeclampsia. Two separate logistic regressions were performed. For the first analysis, the cytokine values were divided at the median and scored as low (below the median) or high (above the median). Odds ratios from this analysis are reported, together with 95% confidence intervals. The second analysis used the actual cytokine concentrations as predictor variables; this analysis was used to develop a receiver operating characteristic (ROC) curve for the combined set of cytokines. These analyses were performed by fitting linear logistic regression models for binary data by using the method of maximum likelihood. The maximum likelihood estimation was carried out with the Fisher scoring algorithm. 23

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RESULTS

Between January 1, 1999 and May 31, 2001, 129 patients were delivered preterm with severe preeclampsia at Strong Memorial Hospital. Of these, 20 patients fulfilling the clinical inclusion criteria for both diagnoses of severe preeclampsia and delivery before 34 weeks with a stored second-trimester serum sample suitable for cytokine analysis were identified. The clinical characteristics of these 20 women are summarized in Table 1, along with the indications for delivery. One patient had neither hypertension nor proteinuria. This individual was delivered after she developed HELLP syndrome. She also represented the only individual with a multiple gestation (twin pregnancy). Hemolysis, elevated liver enzymes, low platelets syndrome was the single most common indication for delivery, and the majority of patients were delivered for maternal rather than fetal indications. No patients developed a coagulopathy or epigastric pain.

Table 1
Table 1
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The 20 cases of preeclampsia were compared with 60 normal control patients (three per patient with preeclampsia). Comparison of the clinical characteristics of the two groups is summarized in Table 2. Maternal age, gravidity, parity, and gestational age refer to data at the time of sampling in the second trimester. Blood pressure, proteinuria, gestational age, and birth weight refer to data collected at or near the time of delivery. Blood pressure values are the mean of the first two readings that were separated by at least 6 hours, taken during the hospital admission in which delivery occurred. Some control subjects did not have blood pressure data recorded in such manner. In these instances, the last recorded blood pressure value, either before or after admission for delivery, was used. For preeclamptic patients, proteinuria was assessed during the hospital admission in which delivery occurred. For control subjects, the last recorded assessment of urine protein before delivery, either before or after admission for delivery, was used. Three preeclamptic patients did not have a complete 24-hour urine collection performed. For these patients, proteinuria was defined in accordance with consensus recommendations 22 as greater than or equal to a 1+ reading on qualitative dipstick analysis (corresponding to approximately 0.3 g/L), obtained in at least two random urine specimens. One preeclamptic patient did not have proteinuria. The two groups were perfectly matched for maternal age, gravidity and parity, and the gestational age at time of the sampling. The mean gestational age at the time of delivery was 30.7 weeks for patients with preeclampsia and 38.2 weeks for control subjects. As expected, blood pressure values were significantly higher in the preeclamptic patients as compared with the control subjects. No control subjects had proteinuria. Six cases of preeclampsia were also associated with intrauterine growth restriction, compared with none in the control group. No patients with diabetes or chorioamnionitis were found in either group.

Table 2
Table 2
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Maternal serum concentrations of placental growth factor and vascular endothelial growth factor were significantly reduced in cases of preeclampsia (Table 3). No significant differences in the concentrations of endothelin-1, granulocyte colony stimulating factor, and hCG were observed between the two groups. The raw data, including individual factor concentrations and gestational age at the time each sample was obtained, are shown for maternal serum placental growth factor (Figure 1, top) and vascular endothelial growth factor (Figure 1, bottom) levels. Both growth factors were decreased by 40–50% compared with the controls.

Table 3
Table 3
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Figure 1
Figure 1
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To estimate odds ratios, logistic regression analysis was used to model the probability of developing severe preeclampsia based on second-trimester placental growth factor and vascular endothelial growth factor concentrations. Growth factor concentrations were dichotomized such that an individual value was considered either normal or decreased, based on whether it was above or below the respective median value of the sample distribution (80.8 pg/mL for placental growth factor, 4.20 pg/mL for vascular endothelial growth factor). Odds ratios were estimated by developing models based on the concentrations of placental growth factor and vascular endothelial growth factor alone, as well as a third model incorporating values of both factors (Table 4). The resulting odds ratios clearly demonstrate that, when considered individually, reduced levels of either placental growth factor or vascular endothelial growth factor are associated with an increased probability of developing severe, early-onset preeclampsia. However, when data from both factors are incorporated into a single model, the probability of developing severe, early-onset preeclampsia based on decreased second-trimester levels is even greater.

Table 4
Table 4
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Receiver operating characteristic analyses of placental growth factor and vascular endothelial growth factor as individual markers demonstrated convincing evidence for the use of these markers in identifying women at risk for developing severe, early-onset preeclampsia with areas under the curve equal to 0.799 and 0.773 for placental growth factor and vascular endothelial growth factor, respectively (Figure 2). Receiver operating characteristic curves based on a second logistic regression, using actual cytokine values, were plotted to illustrate the sensitivity–specificity trade off. Receiver operating characteristic curve analysis for the combination of placental growth factor and vascular endothelial growth factor present even greater value as a predictive method with an area under the curve equal to 0.923. The combination of endothelin-1 and granulocyte colony stimulating factor to placental growth factor and vascular endothelial growth factor did not significantly increase the area under the curve value (0.928).

Figure 2
Figure 2
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DISCUSSION

We determined that second-trimester serum levels of vascular endothelial growth factor and placental growth factor were significantly decreased when compared with normal control subjects at similar gestational ages. These results demonstrate that analysis of circulating vascular endothelial growth factor and placental growth factor levels appears to be a useful tool for the early identification of pregnant women at increased risk for developing severe, early-onset preeclampsia. Although both vascular endothelial growth factor and placental growth factor performed well individually, the logistic regression models and ROC analyses suggest that these factors perform better when both vascular endothelial growth factor and placental growth factor levels are combined as a single model than either does alone. The addition of granulocyte colony stimulating factor, endothelin-1, and hCG to the combined placental growth factor/vascular endothelial growth factor model did not improve the ability to identify these patients.

Because both may influence vascular development of the placental bed and regulate villus development and invasion, vascular endothelial growth factor and placental growth factor are attractive candidates for involvement in the etiology of preeclampsia. Because the placenta is reduced in its degree of invasion and size and is a major site of production for vascular endothelial growth factor and placental growth factor, we speculate that reduced maternal levels of vascular endothelial growth factor and placental growth factor reflect the impaired production of these factors by the placentae in women with severe preeclampsia.

Although second-trimester maternal serum vascular endothelial growth factor levels in preeclamptic pregnancies have not been examined as extensively, placental growth factor levels have received considerable attention recently. 7–9,24,25 The discrepant results of these studies make it difficult to clearly appreciate the role of these maternal and placental factors in the etiology of preeclampsia. A recent editorial published while our investigation was underway outlined potential areas of concern in studies of this type. 2 The methods employed in our study have addressed many factors that contribute to discrepant results. For example, our serum samples were preserved at a constant temperature of −20C, in a single freezer, and never left the storage facility at Strong Memorial Hospital. None of the specimens were thawed and refrozen before their use for this study. These specimens were carefully matched for the freezing time between preeclampsia patients and controls (three for each case of preeclampsia). Our cytokine assays were used in previous studies (R&D Systems Inc.). However, potential sources of discrepancy remain in our study. Although several vascular endothelial growth factor isoforms exist (vascular endothelial growth factor121, 165, 189, 206 AA residues), our assay was designed to detect only vascular endothelial growth factor165, and our results should be compared only with results that detect a similar isoform. This observation could also be generalized to placental growth factor, although its diversity seems confined to only two isoforms. The Quantikine immunoassay that we used for this study is designed to specifically measure the placental growth factor-1 isoform. However, the manufacturer (R&D Systems Inc.) reports up to 50% cross-reactivity with recombinant placental growth factor-2 isoform and 5% cross-reactivity with a recombinant placental growth factor heterodimer. Clearly, the potential effect of possible differential expression of various isoforms of these growth factors in preeclampsia is an area that requires further study. Finally, because we analyzed serum rather than plasma, the concentrations of some factors may have been spuriously elevated because some of these substances are released from platelets when blood coagulates.

Experimental results from various studies of this design are also subject to inconsistent results based on whether preeclampsia is mild versus severe, occurs at term versus preterm, is complicated by maternal medical conditions, or involves abnormalities of fetal growth. Investigators from different studies may in fact be comparing “different diseases,” thus arriving at different results. Given that early-onset preeclampsia and preeclampsia at term have distinctly different clinical implications, they may also have distinctly different pathophysiologic mechanisms. For this reason, we sought to carefully define the subtype of preeclampsia to be studied and restrict our study to the subtype responsible for the largest proportion of morbidity and mortality. Most other published studies have not restricted analysis of preeclamptic patients to those with severe disease, although the study by Tidwell et al 8 is a notable exception. This group found no difference in second-trimester placental growth factor concentrations in women who ultimately developed severe preeclampsia. However, in contrast to our investigation, the mean gestational age at delivery in that study was at term (38.3 weeks).

We also did not exclude women with preexisting risk factors for developing preeclampsia (maternal hypertension, renal disease, diabetes, etc), which is commonly done in investigations of similar design. One reason for excluding these patients was to eliminate potential confounding variables in the diagnosis of preeclampsia when such high-risk factors are present. To address this concern, we relied on strict, widely accepted clinical diagnostic criteria and indications for delivery, 21,22 to ensure that only patients delivered because of severe preeclampsia, rather than other complications relating to these preexisting medical conditions, were included. Furthermore, women already at increased risk for developing severe preeclampsia because of certain medical complications are precisely those who may benefit the most, in terms of additional counseling and possible intervention, by further defining their risk early in pregnancy.

Finally, because abnormal placentation can also affect fetal growth, the presence of intrauterine growth restriction was a major concern in this study. A recent study published while our investigation was underway found decreased levels of maternal placental growth factor during first trimester in pregnancies complicated by intrauterine growth restriction, but not in those destined to develop preeclampsia. 25 This suggests that the relationship of growth factors levels with preeclampsia may be confounded by the presence of a growth-restricted fetus. In our data set, only six cases of preeclampsia were accompanied by intrauterine growth restriction, and these revealed no significant differences in maternal growth factor levels when compared with other cases of preeclampsia without intrauterine growth restriction. Nonetheless, the sample size of our study does not permit us to fully assess the possible relationship between vascular endothelial growth factor and placental growth factor levels patterns and the coexistence of intrauterine growth restriction with preeclampsia.

In conclusion, this case–control study demonstrates that a combined analysis of second-trimester maternal placental growth factor and vascular endothelial growth factor levels is a potentially useful tool for identifying women at increased risk for the development of severe, early-onset preeclampsia. However, this preliminary study must be confirmed by a prospective study to assess the importance of the disease severity in the process of diagnosis and to allow separation of cause from effect. Mild preeclampsia and preeclampsia occurring at later gestational ages could respond differently or less specifically and warrant further investigation.

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Early onset preeclampsia and second trimester serum markers
Lambert-Messerlian, GM; Palomaki, GE; Neveux, LM; Chien, E; Friedman, A; Rosene-Montella, K; Hayes, M; Canick, JA
Prenatal Diagnosis, 29(): 1109-1117.
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Placenta
Human placental explants in culture: Approaches and assessments
Miller, RK; Genbacev, O; Turner, MA; Aplin, JD; Caniggia, I; Huppertz, B
Placenta, 26(6): 439-448.
10.1016/j.placenta.2004.10.002
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Hypertension in Pregnancy
Circulating angiogenic factors and abnormal uterine artery Doppler velocimetry in the second trimester
Muller, PR; James, AH; Murtha, AP; Yonish, B; Jamison, MG; Dekker, G
Hypertension in Pregnancy, 25(3): 183-192.
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Ultrasound in Obstetrics & Gynecology
Maternal serum placental growth factor at 11+0 to 13+6 weeks of gestation in the prediction of pre-eclampsia
Akolekar, R; Zaragoza, E; Poon, LCY; Pepes, S; Nicolaides, KH
Ultrasound in Obstetrics & Gynecology, 32(6): 732-739.
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American Journal of Obstetrics and Gynecology
Circulating angiogenic factors in gestational proteinuria without hypertension
Holston, AM; Qian, C; Yu, KF; Epstein, FH; Karumanchi, A; Levine, RJ
American Journal of Obstetrics and Gynecology, 200(4): -.
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Kidney International
Placental ischemia and soluble fms-like tyrosine kinase 1: Cause or consequence of preeclampsia?
Karumanchi, SA; Epstein, FH
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Hypertension in Pregnancy
Placental growth factor (PlGF) is a surrogate marker in preeclamptic hypertension
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Hypertension in Pregnancy, 27(1): 65-73.
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Endocrine Journal
Circulating leptin and angiogenic factors in preeclampsia patients
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New England Journal of Medicine
Soluble endoglin and other circulating antiangiogenic factors in preeclampsia
Levine, RJ; Lam, C; Qian, C; Yu, KF; Maynard, SE; Sachs, BP; Sibai, BM; Epstein, FH; Romero, R; Thadhani, R; Karumanchi, SA
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Prenatal Diagnosis
Gene expression in chorionic villous samples at 11 weeks' gestation from women destined to develop preeclampsia
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Thrombosis Research
Angiogenic factors and preeclampsia
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Journal of Maternal-Fetal & Neonatal Medicine
A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia
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Journal of Maternal-Fetal & Neonatal Medicine, 22(): 1021-1038.
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Molecular Human Reproduction
Vascular endothelial growth factor gene polymorphisms and pre-eclampsia
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Journal of the American Society of Nephrology
New aspects in the pathophysiology of Preeclampsia
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Journal of Maternal-Fetal & Neonatal Medicine
Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia
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European Journal of Obstetrics Gynecology and Reproductive Biology
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European Journal of Obstetrics Gynecology and Reproductive Biology, 122(1): 33-39.
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Labmedicine
Assessing the pregnant patient: A review of new potential screening tests
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Labmedicine, 37(6): 371-374.
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Frontiers in Bioscience
Placental cytokines and preeclampsia
Keelan, JA; Mitchell, MD
Frontiers in Bioscience, 12(): 2706-2727.

Biochemical Journal
Vascular endothelial growth factor acts through novel, pregnancy-enhanced receptor signalling pathways to stimulate endothelial nitric oxide synthase activity in uterine artery endothelial cells
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Bjog-An International Journal of Obstetrics and Gynaecology
Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia
Masuyama, H; Segawa, T; Sumida, Y; Masumoto, A; Inoue, S; Akahori, Y; Hiramatsu, Y
Bjog-An International Journal of Obstetrics and Gynaecology, 117(3): 314-320.
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Acta Obstetricia Et Gynecologica Scandinavica
Maternal serum placental growth factor and soluble fms-like tyrosine kinase 1 as early predictors of preeclampsia
Shokry, M; Bedaiwy, MA; Fathalla, MMF; Alsemary, A; Elwakil, S; Murphy, A
Acta Obstetricia Et Gynecologica Scandinavica, 89(1): 143-146.
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American Journal of Obstetrics and Gynecology
Angiogenic imbalances: the obstetric perspective
Espinoza, J; Uckele, JE; Starr, RA; Seubert, DE; Espinoza, AF; Berry, SM
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Journal of Clinical Endocrinology & Metabolism
First trimester placental growth factor and soluble Fms-like tyrosine kinase 1 and risk for preeclampsia
Thadhani, R; Mutter, WP; Wolf, M; Levine, RJ; Taylor, RN; Sukhatme, VP; Ecker, J; Karumanchi, SA
Journal of Clinical Endocrinology & Metabolism, 89(2): 770-775.
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New England Journal of Medicine
Circulating angiogenic factors and the risk of preeclampsia
Levine, RJ; Maynard, SE; Qian, C; Lim, KH; England, LJ; Yu, KF; Schisterman, EF; Thadhani, R; Sachs, BP; Epstein, FH; Sibai, BM; Sukhatme, VP; Karumanchi, SA
New England Journal of Medicine, 350(7): 672-683.

Journal of Maternal-Fetal & Neonatal Medicine
Preeclampsia and small-for-gestational age are associated with decreased concentrations of a factor involved in angiogenesis: Soluble Tie-2
Gotsch, F; Romero, R; Kusanovic, JP; Chaiworapongsa, T; Dombrowski, M; Erez, O; Than, NG; Mazaki-Tovi, S; Mittal, P; Espinoza, J; Hassan, SS
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Nutrition Reviews
Role of nutrition in the risk of preeclampsia
Xu, HR; Shatenstein, B; Luo, ZC; Wei, SQ; Fraser, W
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Prenatal Diagnosis
Maternal plasma soluble fins-like tyrosine kinase-1 and free vascular endothelial growth factor at 11 to 13 weeks of gestation in preeclampsia
Akolekar, R; de Cruz, J; Foidart, JM; Munaut, C; Nicolaides, KH
Prenatal Diagnosis, 30(3): 191-197.
10.1002/pd.2433
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Maternal and Child Health Journal
Racial disparity in infant and maternal mortality: Confluence of infection, and microvascular dysfunction
Fiscella, K
Maternal and Child Health Journal, 8(2): 45-54.

Clinical Science
The endogenous anti-angiogenic family of splice variants of VEGF, VEGF(xxx)b, are down-regulated in pre-eclamptic placentae at term
Bates, DO; MacMillan, PP; Manjaly, JG; Qiu, Y; Hudson, SJ; Bevan, HS; Hunter, AJ; Soothill, PW; Read, M; Donaldson, LF; Harper, SJ
Clinical Science, 110(5): 575-585.
10.1042/CS20050292
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Journal of Korean Medical Science
Increased sFlt-1 to PIGF ratio in women who subsequently develop Preeclampsia
Kim, SY; Ryu, HM; Yang, JH; Kim, MY; Han, JY; Kim, JO; Chung, JH; Park, SY; Lee, MH; Kim, DJ
Journal of Korean Medical Science, 22(5): 873-877.

Reproductive Biology and Endocrinology
Potential markers of preeclampsia - a review
Grill, S; Rusterholz, C; Zanetti-Dallenbach, R; Tercanli, S; Holzgreve, W; Hahn, S; Lapaire, O
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Journal of Pediatrics
Maternal Preeclampsia Predicts the Development of Bronchopulmonary Dysplasia
Hansen, AR; Barnes, CM; Folkman, J; McElrath, TF
Journal of Pediatrics, 156(4): 532-536.
10.1016/j.jpeds.2009.10.018
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Seminars in Thrombosis and Hemostasis
Placental Vasculature in Health and Disease
Khankin, EV; Royle, C; Karumanchi, SA
Seminars in Thrombosis and Hemostasis, 36(3): 309-320.
10.1055/s-0030-1253453
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Hypertension
Insulin resistance and alterations in angiogenesis - Additive insults that may lead to preeclampsia
Thadhani, R; Ecker, JL; Mutter, WP; Wolf, M; Smirnakis, KV; Sukhatme, VP; Levine, RJ; Karumanchi, SA
Hypertension, 43(5): 988-992.
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American Journal of Obstetrics and Gynecology
Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies
Wolf, M; Shah, A; Lam, C; Martinez, A; Smirnakis, KV; Epstein, FH; Taylor, RN; Ecker, JL; Karumanchi, SA; Thadhani, R
American Journal of Obstetrics and Gynecology, 193(1): 16-22.
10.1016/j.ajog.2005.03.016
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American Journal of Obstetrics and Gynecology
Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia
Powers, RW; Roberts, JM; Cooper, KM; Gallaher, MJ; Frank, MP; Harger, GF; Ness, RB
American Journal of Obstetrics and Gynecology, 193(1): 185-191.
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Journal of Thrombosis and Haemostasis
Is vascular biology in preeclampsia better?
Myatt, L; Webster, RP
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10.1111/j.1538-7836.2008.03259.x
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Journal of Maternal-Fetal & Neonatal Medicine
The use of angiogenic biomarkers to differentiate non-HELLP related thrombocytopenia from HELLP syndrome
Young, B; Levine, RJ; Salahuddin, S; Qian, C; Lim, KH; Karumanchi, SA; Rana, S
Journal of Maternal-Fetal & Neonatal Medicine, 23(5): 366-370.
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Frontiers in Bioscience
Smoking and risk of preeclampsia: a systematic review
England, L; Zhang, J
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Geburtshilfe Und Frauenheilkunde
Angiogenic factors during pregnancy: Indicators of preeclampsia
Schmidt, M; Gellhaus, A; Kasimir-Bauer, S; Winterhager, E; Kimmig, R
Geburtshilfe Und Frauenheilkunde, 67(3): 228-235.
10.1055/s-2007-964944
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Seminars in Nephrology
Angiogenic imbalance in the pathophysiology of preeclampsia: Newer insights
Bdolah, Y; Sukhatme, VP; Karumanchi, SA
Seminars in Nephrology, 24(6): 548-556.

Thrombosis and Haemostasis
Plasma markers of angiogenesis in pregnancy induced hypertension
Nadar, SK; Karalis, I; Al Yemeni, E; Blann, AD; Lip, GYH
Thrombosis and Haemostasis, 94(5): 1071-1076.
10.1160/TH05-03-0167
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Proceedings of the 7th World Congress of Perinatal Medicine
Fetal and maternal placental growth factor in normal and preeclamptic pregnancy
Catarino, C; Rebelo, I; Rocha, S; Belo, L; Castro, E; Patricio, B; Quintanilha, A; Santos-Silva, A
Proceedings of the 7th World Congress of Perinatal Medicine, (): 247-251.

Molecular Aspects of Medicine
Serum markers for predicting pre-eclampsia
Baumann, MU; Bersinger, NA; Surbek, DV
Molecular Aspects of Medicine, 28(2): 227-244.
10.1016/j.mam.2007.04.002
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Journal of Maternal-Fetal & Neonatal Medicine
Vascular endothelial growth factor gene polymorphisms and pregnancy
Galazios, G; Papazoglou, D; Tsikouras, P; Kolios, G
Journal of Maternal-Fetal & Neonatal Medicine, 22(5): 371-378.
10.1080/14767050802645035
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American Journal of Obstetrics and Gynecology
Plasma level of soluble c-Met is tightly associated with the clinical risk of preeclampsia
Zeng, X; Sun, Y; Yang, HX; Li, D; Li, YX; Liao, QP; Wang, YL
American Journal of Obstetrics and Gynecology, 201(6): -.
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Annual Review of Pathology-Mechanisms of Disease
Pathogenesis of Preeclampsia
Young, BC; Levine, RJ; Karumanchi, SA
Annual Review of Pathology-Mechanisms of Disease, 5(): 173-192.
10.1146/annurev-pathol-121808-102149
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Prenatal Diagnosis
First-trimester placental growth factor as a marker for hypertensive disorders and SGA
Cowans, NJ; Stamatopoulou, A; Matwejew, E; von Kaisenberg, CS; Spencer, K
Prenatal Diagnosis, 30(6): 565-570.
10.1002/pd.2525
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Kidney International
Preeclampsia: A renal perspective
Karumanchi, SA; Maynard, SE; Stillman, IE; Epstein, FH; Sukhatme, VP
Kidney International, 67(6): 2101-2113.

Hypertension
Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia
Lam, C; Lim, KH; Karumanchi, SA
Hypertension, 46(5): 1077-1085.
10.1161/01.HYP.0000187899.34379.b0
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Journal of Clinical Endocrinology & Metabolism
Correlation between soluble endoglin, vascular endothelial growth factor receptor-1, and adipocytokines in preeclampsia
Masuyama, H; Nakatsukasa, H; Takamoto, N; Hiramatsu, Y
Journal of Clinical Endocrinology & Metabolism, 92(7): 2672-2679.
10.1210/jc.2006-2349
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Laboratory Investigation
Elevated vasoinhibins may contribute to endothelial cell dysfunction and low birth weight in preeclampsia
Gonzalez, C; Parra, A; Ramirez-Peredo, J; Garcia, C; Rivera, JC; Macotela, Y; Aranda, J; Lemini, M; Arias, J; Ibargungoitia, F; De la Escalera, GM; Clapp, C
Laboratory Investigation, 87(): 1009-1017.
10.1038/labinvest.3700662
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Pediatrics
Excess soluble fms-like tyrosine kinase 1 and low platelet counts in premature neonates of preeclamptic mothers
Tsao, PN; Wei, SC; Su, YN; Chou, HC; Chen, CY; Hsieh, WS
Pediatrics, 116(2): 468-472.

Current Topics in Developmental Biology, Vol 71
Angiogenic factors in the pathogenesis of preeclampsia
Yuan, HT; Haig, D; Karumanchi, SA
Current Topics in Developmental Biology, Vol 71, 71(): 297-+.
10.1016/S0070-2153(05)71009-7
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Ultrasound in Obstetrics & Gynecology
First-trimester maternal serum PP-13, PAPP-A and second-trimester uterine artery Doppler pulsatility index as markers of pre-eclampsia
Spencer, K; Cowans, NJ; Chefetz, I; Tal, J; Meiri, H
Ultrasound in Obstetrics & Gynecology, 29(2): 128-134.
10.1002/uog.3876
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Journal of Korean Medical Science
The levels of circulating vascular endothelial growth factor and soluble Flt-1 in pregnancies complicated by preeclampsia
Lee, ES; Oh, MJ; Jung, JW; Lim, JE; Seol, HJ; Lee, KJ; Kim, HJ
Journal of Korean Medical Science, 22(1): 94-98.

Molecular and Cellular Endocrinology
The gonadotropins: Tissue-specific angiogenic factors?
Reisinger, K; Baal, N; McKinnon, T; Minstedt, K; Zygmunt, M
Molecular and Cellular Endocrinology, 269(): 65-80.
10.1016/j.mce.2006.11.015
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Clinical Chemistry and Laboratory Medicine
Altered angiogenesis in preeclampsia: evaluation of a new test system for measuring placental growth factor
Schmidt, M; Dogan, C; Birdir, C; Callies, R; Kuhn, U; Gellhaus, A; Janetzko, A; Kimmig, R; Kasimir-Bauer, S
Clinical Chemistry and Laboratory Medicine, 45(): 1504-1510.
10.1515/CCLM.2007.316
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American Journal of Reproductive Immunology
Serum levels of macrophage colony stimulating, vascular endothelial, and placenta growth factor in relation to later clinical onset of pre-eclampsia and a small-for-gestational age birth
Bersinger, NA; Odegard, RA
American Journal of Reproductive Immunology, 54(2): 77-83.
10.1111/j.1600-0897.2005.00290.x
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Prenatal Diagnosis
Second-trimester uterine artery Doppler pulsatility index and maternal serum PP13 as markers of pre-eclampsia
Spencer, K; Cowans, NJ; Chefetz, I; Tal, J; Kuhnreich, I; Meiri, H
Prenatal Diagnosis, 27(3): 258-263.
10.1002/pd.1664
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Journal of the Chemical Society of Pakistan
Role of Cytokines in the Pathophysiology of Hypertension during Preeclampsia
Saeed, SA; Khan, NS; Saleem, A; Qureshi, ZUR; Saeed, TZ; Quadri, J; Tasneem, S; Waqar, MA
Journal of the Chemical Society of Pakistan, 31(1): 175-185.

Thrombosis and Haemostasis
Tissue pathway factor inhibitor (TFPI) activity is elevated in pregnant patients at 20 weeks gestation who subsequently develop preeclampsia
Hillman, S; Chant, I; Gu, M; Rose, P; Vatish, M
Thrombosis and Haemostasis, 101(4): 778-780.
10.1160/TH08-10-0633
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Anesthesiology
Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture
Fernando, R
Anesthesiology, 106(3): 615-621.

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Cardiology in Review
Hypertension in Pregnancy: A Comprehensive Update
Jim, B; Sharma, S; Kebede, T; Acharya, A
Cardiology in Review, 18(4): 178-189.
10.1097/CRD.0b013e3181c60ca6
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Clinical Obstetrics and Gynecology
Circulating Angiogenic Factors in Preeclampsia
Levine, RJ; Karumanchi, SA
Clinical Obstetrics and Gynecology, 48(2): 372-386.
10.1097/01.grf.0000160313.82606.d7
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Obstetrics & Gynecology
Placental Growth Factor and Soluble FMS-Like Tyrosine Kinase-1 in Early-Onset and Late-Onset Preeclampsia
Wikström, A; Larsson, A; Eriksson, UJ; Nash, P; Nordén-Lindeberg, S; Olovsson, M
Obstetrics & Gynecology, 109(6): 1368-1374.
10.1097/01.AOG.0000264552.85436.a1
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Obstetrics & Gynecology
Circulating Angiogenic Factors and Placental Abruption
Signore, C; Mills, JL; Qian, C; Yu, K; Lam, C; Epstein, FH; Karumanchi, SA; Levine, RJ
Obstetrics & Gynecology, 108(2): 338-344.
10.1097/01.AOG.0000216014.72503.09
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