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1.  Mid-pregnancy levels of angiogenic markers as indicators of pathways to preterm delivery 
Objective
To determine if midpregnancy levels of angiogenic markers were associated with increased risk of preterm delivery (PTD).
Methods
We studied a subcohort from the Pregnancy Outcomes and Community Health Study for whom midpregnancy angiogenic markers [(soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), and placental growth factor (PlGF)], and covariate data were available (N = 1301). Angiogenic marker levels were grouped as High/Not High (sFlt-1 & sEng), Low/Not Low (PlGF) and High/Intermediate/Low (sFlt-1). Associations between levels of angiogenic markers and PTD/PTD subtype were determined for women who were non-smokers during pregnancy (N=933).
Results
Low PlGF and High sEng were associated with medically-indicated PTD and PTD <35 weeks, largely due to preeclampsia. Excluding preeclampsia and small-for-gestational-age infants, Low sFlt-1 was positively associated with medically-indicated PTD.
Conclusions
Among non-smokers midpregnancy levels of angiogenic markers may mark multiple pathways leading to PTD, only one attributable to preeclampsia.
doi:10.3109/14767058.2011.625458
PMCID: PMC4151045  PMID: 21939291
endoglin; placental growth factor; preeclampsia; small-for-gestational age; soluble fms-like tyrosine kinase-1
2.  Cost and resource implications with serum angiogenic factor estimation in the triage of preeclampsia 
Objective
To analyze the economic and resource implications of using plasma soluble fms-like tyrosine kinase-1 (sFlt1) and placenta growth factor (PlGF) measurements in preeclampsia evaluation and management.
Design
Retrospective cost analysis of our prospective cohort study.
Setting
Boston, Massachusetts (USA).
Population
Women (n=176) presenting to the hospital at <34 weeks’ gestation for evaluation of possible preeclampsia during 2009–2010. Cases without complete cost or outcome data (n=9) and re-enrollments (n=18) were excluded.
Methods
Modeled comparisons between the standard approach (combination of blood pressure, urinary protein excretion, alanine aminotransferase, and platelet counts) and a novel approach (ratio of plasma sFlt1 and PlGF) using actual hospital data converted to 2012 US dollars in accordance with Centers for Medicare and Medicaid Services.
Main outcome measures
Direct two-week costs and resource utilization by groups having true or false positive and negative test results for adverse outcomes according to approach.
Results
The improved specificity of the novel approach decreased the proportion of women falsely labeled as test-positive from 42.3% (34.4% – 50.2%) to 4.0% (0.85% – 7.15%) and increased the proportion correctly labeled as test-negative from 23.5% (16.7% – 30.3%) to 61.7% (53.9% – 69.5%). This could potentially reduce average per-patient costs by $1,215. Substantial quantities of resources [47.2% (35.7% – 58.7%) of antenatal admissions and 72.5% (68.0% – 77.0%) of tests for fetal well-being] were unnecessarily used for women who were truly negative. A proportion of iatrogenic preterm deliveries among women with negative results was potentially avoidable representing further cost and resource savings.
Conclusions
Clinical use of the plasma sFlt1 and PlGF ratio improves risk stratification among women presenting for preeclampsia evaluation and has the potential to reduce costs and resource utilization.
doi:10.1111/1471-0528.12259
PMCID: PMC3744598  PMID: 23647884
angiogenic factors; preeclampsia; costs; resource utilization
3.  Preeclampsia and the risk of large for gestational age infants 
Objective
To compare the risk of giving birth to large for gestational age infants in women with and without preeclampsia, after adjustment for obesity and glucose intolerance.
Study Design
Prospective cohort study of pregnant women with and without preeclampsia who delivered infants between 1998 and 2006 at Massachusetts General Hospital.
Results
The risk of LGA was similar in women with and without preeclampsia (OR 0.81 95% CI 0.59–1.14). After adjustment for body mass index, glucose intolerance, and other factors, the risk of LGA was significantly lower in women with preeclampsia compared to those without preeclampsia (OR 0.69 95% CI 0.49–0.96). Stratified analysis in groups with a higher risk of LGA revealed that preeclampsia has a similar effect on the risk of LGA regardless of maternal obesity, glucose intolerance, parity, and race
Conclusion
Preeclampsia appears to be characterized by reduced, and not increased, fetal growth.
doi:10.1016/j.ajog.2010.12.030
PMCID: PMC4104476  PMID: 21371687
fetal growth; gestational diabetes; large for gestational age; preeclampsia
4.  Angiogenic factors in preeclampsia: potential for diagnosis and treatment 
Purpose of review
The review summarizes new observations of key roles for circulating angiogenic factors in diagnosing, managing, and treating preeclampsia.
Recent findings
Alterations in circulating angiogenic factors (soluble fms-like tyrosine kinase-1 and placental growth factor) in preeclampsia correlate with the diagnosis and adverse outcomes, particularly when the disease presents prematurely (<34 weeks). Measurement of these angiogenic biomarkers further helps differentiate preeclampsia and its complications from other disorders that present with similar clinical profiles. A ratio of soluble fms-like tyrosine kinase-1/placental growth factor greater than 85 appears ideal as the cut-off for both diagnosis and prognosis. There is also evidence that modulating these factors has therapeutic effects, suggesting a future role for angiogenic factors in treatment and prevention of preeclampsia.
Summary
Circulating angiogenic biomarkers help in diagnostic and prognostic profiling of preeclampsia and may facilitate better management of these patients.
doi:10.1097/MNH.0b013e328365ad98
PMCID: PMC3932709  PMID: 24076553
adverse outcomes; angiogenic factors; placental growth factor (PIGF); preeclampsia; soluble fms-like tyrosine kinase-1 (sFlt1)
5.  The course of angiogenic factors in early- vs. late-onset preeclampsia and HELLP syndrome 
Journal of perinatal medicine  2013;41(5):511-516.
Aims
Preeclampsia (PE) is considered a uniformly progressive disease, however, it shows a different pattern of clinical progression in patients with early (<34 weeks) or late (≥34 weeks) onset of the disease. Angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) are closely related to the clinical course of PE. We evaluated sFlt-1 and PlGF levels in the clinical course of PE in women admitted with a diagnosis of PE at different gestational ages.
Methods
This retrospective study included 34 patients with PE, of which 11 patients had HELLP syndrome (over a period of 3 years). Serial measurements of sFlt-1 and PlGF were completed from admission until delivery. Values are presented as mean±standard deviation.
Results
Mean gestational age of admission among women with early onset PE was significantly lower, at 29±3 weeks compared to 37±1 weeks among patients with late onset disease. Mean prolongation of pregnancy was 6 days, which was similar within the two groups. Compared to women with late onset PE, women with early-onset PE had a greater increase in sFlt-1 (11% vs. 3% per day, P<0.05), greater decrease in PlGF levels (21% vs. 10% per day, P=0.30), resulting in a much higher increase in sFlt-1/PlGF ratio (23% vs. 8% per day, P<0.05). Patients with HELLP syndrome showed comparable progression patterns.
Conclusion
In a similar way to the progressively worsening clinical course observed in women with early onset PE, there were changes in the angiogenic profile that leads to a more anti-angiogenic state in these women with each passing day. These findings may have implications in identification of the women for appropriate patient management and possible future therapies based on the reduction of sFlt-1 levels.
doi:10.1515/jpm-2012-0248
PMCID: PMC3928646  PMID: 23612628
Angiogenic factors; biomarker; HELLP syndrome; preeclampsia; sFlt-1/PlGF ratio
6.  Subclinical Left Ventricular Dysfunction in Preeclamptic Women with Preserved Left Ventricular Ejection Fraction: A 2D Speckle Tracking Imaging Study 
Circulation. Cardiovascular imaging  2012;5(6):10.1161/CIRCIMAGING.112.973818.
Background
Patients with preeclampsia are at risk for cardiovascular disease. Changes in cardiac function are subtle in preeclampsia and are difficult to quantify with conventional imaging. Strain measurements using speckle-tracking echocardiography have been used to sensitively quantify abnormalities in other disease settings.
Methods and Results
We evaluated the feasibility and sensitivity of strain imaging using speckle-tracking echocardiography in women with preeclampsia. Forty-seven women were enrolled in this pilot study and 39 were analyzed: 11 with preeclampsia, 17 without a hypertensive disorder and 11 with nonproteinuric hypertension. Echocardiographic ejection fraction and global peak longitudinal, radial and circumferential strain were measured.
Longitudinal strain was significantly worsened in women with preeclampsia compared to women without a hypertensive disorder (P=0.0009). Similar results were observed for radial strain (P=0.007) and circumferential strain (P=0.04). Women with preeclampsia also had significantly worsened longitudinal (P=0.04), radial (P=0.01) and circumferential (P=0.002) strain compared with women with nonproteinuric hypertension. Women with preeclampsia did not have a significantly different ejection fraction compared with women without a hypertensive disorder (P=0.52) and women with nonproteinuric hypertension (P=0.44).
Conclusions
Myocardial strain imaging using speckle tracking is more sensitive than left ventricular ejection fraction to detect differences in left ventricular systolic function in women with and without preeclampsia.
doi:10.1161/CIRCIMAGING.112.973818
PMCID: PMC3871635  PMID: 22891044
preeclampsia; echocardiography; speckle tracking
7.  Clinical Characterization and Outcomes of Preeclampsia with Normal Angiogenic Profile 
Objective
The objective of this study was to compare the clinical characteristics and outcomes of preeclamptic women presenting with a normal plasma angiogenic profile with those subjects that are characterized by an abnormal angiogenic profile.
Methods
This was a secondary analysis of a prospective cohort study in women presenting to obstetrical triage at <37 weeks of gestation and diagnosed with preeclampsia within 2 weeks of enrollment and in whom angiogenic factors (sFlt1 and PlGF) measurements were available. Patients were divided into two groups based on their circulating levels of these factors described as a ratio the sFlt1/PlGF ratio, non-angiogenic preeclampsia (sFlt1/PlGF ratio <85) and angiogenic preeclampsia (sFlt1/PlGF ratio ≥85). The data are presented by sFlt1/PlGF category using median and quartile 1-quartile 3 for continuous variables and by frequency and sample sizes for categorical variables.
Results
In our cohort the patients with non-angiogenic preeclampsia (N=46) were more obese {BMI - 35.2 (31.6,38.7) vs. 31.1(28.0,39.0), p=0.04}, more likely to have preexisting diabetes (21.7% vs. 2.0%, p=0.002) and presented at a later gestational age {35 (32,37) vs. 32 (29,34) weeks, p<0.0001} as compared to women with angiogenic preeclampsia (N=51). Women with non-angiogenic preeclampsia had no serious adverse outcomes {Elevated LFT's/Low platelets: 0% vs. 23.5%, abruption: 0% vs. 9.8%, pulmonary edema: 0% vs. 3.9%, eclampsia: 0% vs. 2.0 %, small for gestational age: 0% vs. 17.7% and fetal/neonatal death: 0% vs. 5.9%} as compared to women with angiogenic preeclampsia. The rate of preterm delivery <34 weeks was 8.7% in non-angiogenic preeclampsia compared to 64.7% in angiogenic preeclampsia (p<0.0001). Interestingly, delivery between 34-37 weeks and resource utilization (hospital admission days) were similar in the two groups.
Conclusion
In contrast to the angiogenic form, the non-angiogenic form of preeclampsia is characterized by little to no risk of preeclampsia related adverse outcomes, other than iatrogenic prematurity. Incorporation of angiogenic biomarkers in the evaluation of preeclampsia may allow accurate and early identification of severe disease.
doi:10.3109/10641955.2013.784788
PMCID: PMC3744824  PMID: 23725084
non-angiogenic preeclampsia; angiogenic factors; adverse outcomes
8.  First Trimester Vitamin D, Vitamin D Binding Protein, and Subsequent Preeclampsia 
Hypertension  2010;56(4):758-763.
Prior studies report an association between vitamin D deficiency and hypertension, including the pregnancy-specific disorder, preeclampsia. Circulating vitamin D is almost entirely bound to vitamin D binding protein, which increases 2-fold during pregnancy, but previous studies have not examined vitamin D binding protein or free vitamin D levels. We performed a nested case-control study within the Massachusetts General Hospital Obstetrical Maternal Study (MOMS), measuring first trimester total 25-hydroxyvitamin D and vitamin D binding protein, and calculating free 25-hydroxyvitamin D levels. We compared these levels from pregnancies complicated by subsequent preeclampsia (cases, n=39) with those from normotensive pregnancies (controls, n=131). First trimester total 25-hydroxyvitamin D levels were similar in cases and controls (27.4 ±1.9 ng/ml vs. 28.8±0.80 ng/ml, p=0.435). Despite an association between higher first trimester blood pressures and subsequent preeclampsia, first trimester total 25-hydroxyvitamin D was not associated with first trimester systolic (r=0.11, p=0.16) or diastolic blood pressures (r=0.03, p=0.72). Although there was a trend toward increased risk of preeclampsia with 25-hydroxyvitamin D levels less than 15 ng/ml (OR 2.5, 95% CI 0.89-6.9), this was attenuated after adjustment for body mass index and other covariates (OR 1.35 95% CI 0.40-4.5). First trimester vitamin D binding protein and free 25-hydroxyvitamin D levels were similar in cases and controls and were not associated with first trimester blood pressures. These data suggest that first trimester total and free 25-hydroxyvitamin D levels are not independently associated with first trimester blood pressure or subsequent preeclampsia.
doi:10.1161/HYPERTENSIONAHA.110.158238
PMCID: PMC3775612  PMID: 20733087
vitamin D; vitamin D Binding Protein; preeclampsia; pregnancy
9.  Circulating Lymphangiogenic Factors in Preeclampsia 
Background
Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state due to high levels of circulating soluble vascular endothelial growth factor 1 (sVEGFR-1). However, the role of lymphangiogenesis in preeclampsia has not been investigated. Recently, impaired VEGF-C (factor that regulates lymphangiogenesis) signalling has been implicated in the pathogenesis of interstitial edema and salt-sensitive hypertension. Therefore, we hypothesized that circulating VEGF-C and its circulating receptors (sVEGFR-2 and sVEGFR-3) may also be altered in preeclampsia and correlate with the severity of the phenotype.
Methods
We analyzed plasma levels of VEGF-C, sVEGFR-1, sVEGFR-2 and sVEGFR-3 in women with gestational hypertension (GHTN, n=20), preeclampsia (PE, n=20) and normotensive pregnancies (NP, n=20) in the third trimester and values reported as mean ± SD in pg/ml.
Results
As previously reported, sVEGFR-1 levels were significantly higher in subjects with PE (19938 ± 12973) than in GHTN (7156 ± 5432), p<0.01 or NP (7760 ± 6018), p<0.01. VEGF-C levels were lower in subjects with GHTN (676 ± 323) than in PE (1335 ± 625), p<0.01, but not statistically different than in NP (971 ± 556), p=0.11. There was a trend towards lower sVEGFR-2 in PE as compared to GHTN or NP. Interestingly sVEGFR-3 was significantly lower in PE (54371 ± 21107) as compared to NP (83709 ± 24983), p<0.01, but not different as compared to GHTN (54642 ± 26947). The ratio of sVEGFR-2+sVEGFR-3/VEGF-C was dramatically lower during PE (57 ± 38) as compared to GHTN (113 ± 72), p<0.01 or NP (133 ± 91), p<0.01.
Conclusion
Preeclampsia is characterized by circulating pro-lymphangiogenic state as evidenced by decreased sVEGFR-3, slightly decreased sVEGFR-2, increased VEGF-C and a dramatically lower ratio of sVEGFR-2+sVEGFR-3/VEGF-C. Our data suggests that the circulating pro-lymphoangiogenic state during preeclampsia may be a compensatory response to edema and hypertension. Additional studies are needed to evaluate the clinical relevance of the altered lymphangiogenic signalling pathway during preeclampsia.
doi:10.3109/10641955.2012.697953
PMCID: PMC3570685  PMID: 22957504
Preeclampsia; VEGF-C; sVEGFR-2; sVEGFR-3; Lymphangiogenesis
10.  Management of abnormal serum markers in the absence of aneuploidy or neural tube defects 
Objective
Few guidelines address the management of pregnancies complicated by abnormal maternal serum analytes (MSAs) in the absence of aneuploidy or neural tube defects (NTDs). Our objective was to gather preliminary data regarding current opinions and management strategies among perinatologists in the US.
Methods
This survey of Maternal Fetal Medicine (MFM) physicians and fellows used a secure electronic web-based data capture tool.
Results
A total of 545 potential participants were contacted, and 136 (25%) responded. The majority were experienced academic physicians with robust practices. Nearly all (97.7%) respondents reported a belief in an association between abnormal MSAs and adverse pregnancy outcomes other than aneuploidy or NTDs. Plasma protein A (PAPP-A) and α-fetoprotein (AFP) were most often chosen as markers demonstrating a strong association with adverse outcomes. Most (86.9%) respondents acknowledged that abnormal MSAs influenced their counseling approach, and the majority (80.1%) offered additional ultrasound examinations. Nearly half started at 28 weeks and almost one-third at 32 weeks. Respondents acknowledging a relevant protocol in their hospital or practice were more likely to offer additional antenatal testing (p = 0.01).
Conclusions
Although most perinatologists were in agreement regarding the association of MSAs with adverse pregnancy outcomes, a lack of consensus exists regarding management strategies.
doi:10.3109/14767058.2012.668583
PMCID: PMC3686267  PMID: 22372385
Adverse; analytes; maternal; outcomes; pregnancy
11.  Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia 
Hypertension  2012;60(2):10.1161/HYPERTENSIONAHA.112.195065.
To evaluate whether angiogenic factor levels correlate with preeclampsia-related adverse maternal and perinatal outcomes in women with twin pregnancy, we studied 79 women with suspected preeclampsia in the 3rd trimester. Anti-angiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and pro-angiogenic placental growth factor (PlGF) were measured at presentation on an automated platform. An adverse outcome was defined as hemolysis elevated liver enzymes and low platelets syndrome; disseminated intravascular coagulation; abruption; pulmonary edema; cerebral hemorrhage; maternal, fetal and neonatal death; eclampsia; acute renal failure; small for gestational age; and indicated delivery. All outcomes were ascertained 2 weeks after initial evaluation. Comparing the 52 (65.8%) women who experienced an adverse outcome to the 27 (34.2%) women without an adverse outcome, the median sFlt1 was elevated [11461.5 pg/ml (8794.0–14847.5) versus 7495.0 pg/ml (3498.0–10482.0, P=0.0004], PlGF was reduced [162.5 pg/ml (98.0–226.5) versus 224.0 pg/ml (156.0–449.0), P=0.005] and sFlt1/PlGF ratio was elevated [74.2 (43.5–110.5) versus 36.2 (7.1–71.3), P=0.0005]. Among those presenting <34 weeks (n=40), the difference in sFlt1/PlGF ratio was more striking [97.7 (76.6–178.1) versus 31.7 (6.5–48.7); P=0.001]. Addition of sFlt1/PlGF to the highest systolic blood pressure and proteinuria improved prediction of adverse outcomes. We conclude that in women with twin pregnancy and suspected preeclampsia, the sFlt1/PlGF ratio at the time of initial evaluation is associated with subsequent adverse maternal and perinatal outcomes. These findings are similar to singleton pregnancies and may implicate common pathogenic pathways.
doi:10.1161/HYPERTENSIONAHA.112.195065
PMCID: PMC3432569  PMID: 22753210
angiogenic factors; twin pregnancy; preeclampsia; adverse outcomes
12.  PHYSICIANS’ KNOWLEDGE OF FUTURE VASCULAR DISEASE IN WOMEN WITH PREECLAMPSIA 
Preeclampsia, a hypertensive disorder of pregnancy, affects 5–8% of women. Large studies demonstrate a strong association between preeclampsia and future cardiovascular disease. Despite cardiovascular disease being the leading cause of mortality for women, there has been little education for internal medicine physicians or obstetrician-gynecologists about this association, and published guidelines do not include preeclampsia as a risk factor for future cardiovascular disease. Therefore, women with a history of preeclampsia may not receive adequate risk reduction counseling for cardiovascular disease. It is unclear whether primary care physicians are aware of the association; thus, we sought to determine whether primary care providers at our institution were aware of preeclampsia’s association with future cardiovascular disease and whether they were providing appropriate counseling.
An anonymous on-line survey was sent to all internists and obstetrician-gynecologists at our hospital. Although most internists (95%) and obstetrician-gynecologists (70%) provide routine cardiovascular risk reduction counseling, a substantial proportion of them were unaware of any health risk associated with a history of preeclampsia. Many internists were unsure or did not know if preeclampsia is associated with ischemic heart disease (56%), stroke (48%) and decreased life expectancy (79%). The corresponding proportions for obstetrician-gynecologists were 23%, 38% and 77%. A majority of internists (88%) and obstetrician-gynecologists (79%) were incorrect about or unaware whether preeclampsia was included as a risk factor in the American Heart Association guidelines for prevention of ischemic heart disease. Only 9% of internists and 38% of obstetrician-gynecologists were providing cardiovascular risk reduction counseling to women with a history of preeclampsia.
doi:10.3109/10641955.2010.544955
PMCID: PMC3227747  PMID: 21332326
preeclampsia; cardiovascular disease; ischemic heart disease; stroke; primary prevention
13.  The Impact of Magnesium Sulfate Therapy on Angiogenic Factors in Preeclampsia 
Pregnancy hypertension  2012;2(1):16-21.
Objective
The objective was to evaluate whether intravenous magnesium sulfate (magnesium) alters levels of angiogenic factors in women with preeclampsia.
Study Design
This was a prospective cohort study comparing women with preeclampsia treated with magnesium for seizure prophylaxis to those who were not. Serum levels of angiogenic factors, soluble fms-like tyrosine kinase 1, soluble endoglin and placental growth factor, were measured at the time of diagnosis and approximately 24 hours later. Secondary analysis compared women receiving magnesium for preeclampsia to women receiving magnesium for preterm labor. Analysis of covariance was used to compare levels at 24 hours, adjusting for levels at enrollment and potential confounders.
Results
Angiogenic factor levels did not differ between preeclampsia groups with and without magnesium or between preeclampsia and preterm labor groups treated with magnesium (all P > 0.05).
Conclusion
Magnesium likely decreases seizure risk in preeclampsia by a mechanism other than altering angiogenic factor levels.
doi:10.1016/j.preghy.2011.08.118
PMCID: PMC3254114  PMID: 22247820
angiogenic factors; magnesium sulfate; preeclampsia; pregnancy; toxemia
14.  Cardiac Angiogenic Imbalance Leads to Peri-partum Cardiomyopathy 
Nature  2012;485(7398):333-338.
Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.
doi:10.1038/nature11040
PMCID: PMC3356917  PMID: 22596155
15.  Plasma Concentrations of Soluble Endoglin versus Standard Evaluation in Patients with Suspected Preeclampsia 
PLoS ONE  2012;7(10):e48259.
Background
The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks.
Methods and Findings
Data from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009−October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25−75th centile}. Thirty-three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73−25.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = −0.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74).
Conclusions
In women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia.
doi:10.1371/journal.pone.0048259
PMCID: PMC3482204  PMID: 23110221
16.  Intravital high-frequency ultrasonography to evaluate cardiovascular and uteroplacental blood flow in mouse pregnancy 
Pregnancy hypertension  2011;2(2):84-92.
Objective
The objective of this study is to define the ultrasonographic changes in the cardiovascular and uteroplacental circulation of normal pregnant mice compared to non-pregnant mice using high-frequency, high-resolution ultrasonography.
Methods
Ten to twelve-week-old CD-1 mice (six non-pregnant and six pregnant animals) were used for all experiments. Vevo® 2100 (VisualSonics) was used to evaluate the cardiovascular and uteroplacental circulation physiology. Cardiac echocardiogram and uterine artery Doppler studies were performed on all animals. Pregnant animals were evaluated on embryonic day seven (E7), thirteen (E13) and eighteen (E18). Fetal heart rate and umbilical artery Doppler flows were obtained on pregnant animals. Three-dimensional ultrasonography imaging was utilized for quantification of placental volumes. All data are presented as median {10th–90th percentiles}.
Results
In pregnant mice on E7 compared to non-pregnant mice, there was an increase in cardiac output (p=0.008), stroke volume (p=0.002), ejection fraction, (p=0.02) and fractional shortening (p=0.02). The maternal heart rate increased throughout gestation (p= 0.009). During pregnancy, a gestational sac was clearly visible on E7. Between E13 and E18, the fetal size and fetal heart rate increased (p=0.001) and the umbilical artery peak systolic velocity increased (p <0.001). Minimal diastolic blood flow was observed in the umbilical artery on E13, which increased slightly on day E18 (p=0.01). There was also no change in the uterine artery resistance index between non-pregnant and pregnant mice. The placental volume increased between E13 and E18 (p=0.03).
Conclusion
Several changes noted in cardiovascular and uteroplacental systems occurring during normal murine pregnancy have striking similarities to humans and can be accurately measured using newer ultrasonographic techniques. Further studies are needed to evaluate changes in these vascular beds in mouse models of diseases such as preeclampsia and intrauterine growth restriction.
PMCID: PMC3337859  PMID: 22544045
high-frequency ultrasonography; mouse pregnancy; echocardiography; uteroplacental Doppler flow
17.  Angiogenic Factors and the Risk of Adverse Outcomes in Women with Suspected Preeclampsia 
Circulation  2012;125(7):911-919.
Background
An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia.
Methods and Results
We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation, and examined for an association between sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks.
The median [25th–75th centile] sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared to those who did not (47.0 [15.5–112.2] versus 10.8 [4.1–28.6], p<0.0001). Among those presenting <34 weeks (N=167), the results were more striking (226.6 [50.4–547.3] versus 4.5 [2.0–13.5], p<0.0001), and the risk was markedly elevated when the highest sFlt1/PlGF ratio tertile was compared to the lowest (OR 47.8, 95% CI 14.6–156.6). Among participants presenting at <34 weeks, the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (AUC=0.93 for hypertension, proteinuria, and sFlt1/PlGF versus AUC=0.84 for hypertension and proteinuria alone; P=0.001). Delivery occurred within two weeks of presentation in 86.0% of women with sFlt1/PlGF ratio ≥ 85 compared with 15.8% of women with sFlt1/PlGF ratio <85 (HR 15.2, 95% CI 8.0–28.7).
Conclusions
In women with suspected preeclampsia presenting at <34 weeks, circulating sFlt1/PlGF ratio predicts adverse outcomes occurring within two weeks. The accuracy of this test is substantially better than current approaches and may be useful in risk stratification and management. Additional studies are warranted to validate these findings.
doi:10.1161/CIRCULATIONAHA.111.054361
PMCID: PMC3319742  PMID: 22261192
Preeclampsia; adverse maternal and perinatal outcomes; angiogenic factors; triage; hypertension; proteinuria
18.  Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating sFlt1 in preeclampsia 
Hypertension  2012;59(2):256-264.
The cardinal manifestations of the pregnancy-specific disorder preeclampsia, new-onset hypertension and proteinuria that resolve with placental delivery, have been linked to an extracellular protein made by the placenta, sFlt1 (soluble fms-like tyrosine kinase 1), that injures the maternal vasculature. However, the mechanisms by which sFlt1, which is heavily matrix-bound, gains access to the systemic circulation remain unclear. Here we report that the preeclamptic placenta’s outermost layer, the syncytiotrophoblast, forms abundant “knots” that are enriched with sFlt1 protein. These syncytial knots easily detach from the syncytiotrophoblast, resulting in free, multinucleated aggregates (50–150 μm diameter) that are loaded with sFlt1 protein and mRNA, are metabolically active, and are capable of de novo gene transcription and translation. At least 25% of the measurable sFlt1 in 3rd trimester maternal plasma is bound to circulating placental microparticles. We conclude that detachment of syncytial knots from the placenta results in free, transcriptionally active syncytial aggregates that represent an autonomous source of sFlt1 delivery into the maternal circulation. The process of syncytial knot formation, shedding of syncytial aggregates, and appearance of placental microparticles in the maternal circulation appears to be greatly accelerated in preeclampsia and may contribute to the maternal vascular injury that characterizes this disorder.
doi:10.1161/HYPERTENSIONAHA.111.182170
PMCID: PMC3319764  PMID: 22215706
Syncytial knots; syncytial aggregates; microparticles; sFlt1; soluble VEGFR1; preeclampsia
19.  Mid-pregnancy levels of angiogenic markers in relation to maternal characteristics 
Objective
To describe relations among maternal demographic and lifestyle characteristics and mid-pregnancy levels of angiogenic markers (soluble Fms-like tyrosine kinase-1 (sFlt-1); placental growth factor (PlGF); soluble endoglin (sEng)).
Study Design
In a large pregnancy cohort, linear models were used to evaluate relations among maternal characteristics and mid-pregnancy angiogenic markers with and without covariate adjustment. Associations were examined in a sub-cohort including term and preterm deliveries (N = 1302) and among “normal” term pregnancies (N = 668).
Results
Concentrations of all factors declined with increasing maternal BMI. Multiparous women had lower sFlt-1 levels than primiparas. Higher PlGF and slightly lower sEng were observed among women who smoked at enrollment, but not among those who quit before enrollment. African-American women had higher levels of all markers.
Conclusions
Understanding relations among maternal characteristics and levels of angiogenic factors may improve studies utilizing these markers to examine etiologies and/or to predict adverse pregnancy outcome.
doi:10.1016/j.ajog.2010.10.001
PMCID: PMC3079927  PMID: 21145529
preeclampsia; angiogenic factors; soluble endoglin; placental growth factor; soluble Fms-like tyrosine kinase-1
20.  Angiogenic Factors and Renal Disease in Pregnancy 
Background. Preeclampsia is difficult to diagnose in patients with underlying renal disease and proteinuria. Prior studies show that there is an angiogenic factor imbalance with elevated levels of antiangiogenic proteins soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) and reduced levels of the proangiogenic protein, placental growth factor (PlGF) in women with preeclampsia. These angiogenic biomarkers may be useful in distinguishing preeclampsia from other conditions of pregnancy, which may present with overlapping clinical characteristics. Cases. Case 1: A multiparous woman at 18 weeks gestation with nephrotic syndrome presented with hypertensive emergency and worsening renal insufficiency. She underwent induction of labor for severe preeclampsia. Her sFlt1 and sEng levels were at the 97 percentile while her PlGF level was undetectable (less than the 1st percentile). Case 2: A nulliparous woman with lupus nephritis at 22 weeks gestation presented with fetal demise and heart failure. Three weeks previously, the patient had developed thrombocytopenia and hypertensive urgency. She underwent dilation and evacuation. Her angiogenic profile was consistent with severe preeclampsia. Conclusion. Angiogenic factors may provide evidence to support a diagnosis of preeclampsia in patients with preexisting renal disease and proteinuria, conditions in which the classical definition of hypertension and proteinuria cannot be used.
doi:10.1155/2011/281391
PMCID: PMC3335608  PMID: 22567501
21.  The use of angiogenic biomarkers to differentiate non-HELLP related thrombocytopenia from HELLP syndrome 
Objective
Preeclampsia is diagnosed using clinical criteria and in atypical cases the diagnosis may be inaccurate as there are no specific tests to confirm or exclude preeclampsia. This study sought to evaluate the utility of angiogenic biomarkers, sFlt1, sEng and PlGF to distinguish patients with gestational thrombocytopenia and immune thrombocytopenic purpura (ITP) from patients with thrombocytopenia resulting from the HELLP syndrome, a complication of severe preeclampsia.
Methods
Serum was collected and the angiogenic biomarkers of patients with ITP and gestational thrombocytopenia (N=9) were compared to patients with HELLP (N=11) and preeclampsia (N=11). Circulating levels of these angiogenic biomarkers were also compared by gestational age to 1564 randomly selected normotensive women from the Calcium for Preeclampsia Prevention study.
Results
Patients with non-HELLP thrombocytopenia had lower sFlt1 (7.3 +/- 3.8 ng/mL vs 15.5 +/- 5 ng/mL, p<0.001), lower sEng (8.7 +/- 3.6 vs 34 +/- 17, p <0.001) and higher PlGF (484 +/- 412 vs 66.3 +/- 44, p= 0.003) than patients with HELLP syndrome. Angiogenic factor abnormalities in patients with preeclampsia were similar to patients with HELLP syndrome, suggesting a common pathogenesis. Patients with non-HELLP thrombocytopenia had angiogenic profiles similar to normotensive controls, whereas patients with HELLP syndrome had levels higher than the 90th percentile for sFlt1 and sEng and lower than the 10th percentile for PLGF.
Conclusion
Angiogenic biomarkers may be useful in excluding conditions, which mimic preeclampsia.
doi:10.1080/14767050903184207
PMCID: PMC3132879  PMID: 19701867
preeclampsia; angiogenic factors; thrombocytopenia
22.  CIRCULATING SOLUBLE ENDOGLIN AND PLACENTAL ABRUPTION 
Prenatal diagnosis  2008;28(9):852-858.
Objective
Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption.
Methods
In a nested case control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (<20 weeks), mid- (21–32 weeks), and late (≥33 weeks) pregnancy.
Results
There was no significant difference in sEng between abruption cases and controls in early pregnancy. sEng was significantly elevated among abruption cases at 21–32 weeks (10.7 versus 5.9 ng/mL, P<0.01). Subgroup analyses revealed no differences in sEng concentrations at any gestational age interval between cases with abruption without hypertension and healthy controls. Among women who developed hypertension and placental abruption, sEng was not significantly increased in early pregnancy, but was in mid-pregnancy (19.3 versus 5.5 ng/mL, P=0.002) and in late pregnancy (15.6 versus 9.5 ng/mL, P=0.04).
Conclusion
Serum levels of the anti-angiogenic factor sEng are elevated prior to the development of hypertension and placental abruption. These elevations are not apparent until the late second trimester (26 – 27 weeks, on average), but they persist from this time in gestation onward. sEng may be useful for identifying pregnant women at risk for abruption and hypertension.
doi:10.1002/pd.2065
PMCID: PMC2574843  PMID: 18702104
Abruptio placentae; preeclampsia; gestational hypertension; endoglin; angiogenic factors
23.  The association of circulating angiogenic factors and HbA1c with the risk of preeclampsia in women with preexisting diabetes 
Hypertension in Pregnancy  2013;33(1):81-92.
Objective:
To assess whether glycemic control, soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) were associated with the development of preeclampsia (PE) or gestational hypertension (GHTN) in women with preexisting diabetes.
Methods:
Maternal circulating angiogenic factors (sFlt1 and PlGF) measured on automated platform were studied at four time points during pregnancy in women with diabetes (N = 159) and reported as multiples of the median (MOM) of sFlt1/PlGF ratio (median, 25th–75th percentile) noted in non-diabetic non-hypertensive control pregnant population (N = 139). Diagnosis of PE or GHTN was determined by review of de-identified clinical data.
Results:
PE developed in 12% (N = 19) and GHTN developed in 23% (N = 37) of the women with diabetes. Among diabetic women without PE or GHTN, median sFlt1/PlGF levels at 35–40 weeks was threefold higher than in non-diabetic controls [MOM 3.21(1.19–7.24), p = 0.0001]. Diabetic women who subsequently developed PE had even greater alterations in sFlt1/PlGF ratio during the third trimester [MOM for PE at 27–34 weeks 15.18 (2.37–26.86), at 35–40 weeks 8.61(1.20–18.27), p ≤ 0.01 for both windows compared to non-diabetic controls]. Women with diabetes who subsequently developed GHTN also had significant alterations in angiogenic factors during third trimester; however, these findings were less striking. Among women with diabetes, glycosylated hemoglobin (HbA1c) during the first trimester was higher in subjects who subsequently developed PE (7.7 vs 6.7%, p = 0.0001 for diabetic PE vs diabetic non-PE).
Conclusions:
Women with diabetes had a markedly altered anti-angiogenic state late in pregnancy that was further exacerbated in subjects who developed PE. Altered angiogenic factors may be one mechanism for the increased risk of PE in this population. Increased HbA1c in the first trimester of pregnancies in women with diabetes was strongly associated with subsequent PE.
doi:10.3109/10641955.2013.837175
PMCID: PMC3894714  PMID: 24354578
Angiogenesis; Diabetes; HbA1C; PlGF; Preeclampsia; sFlt1.

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