Eleazar Soto

Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia

Objective: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. Study design: Patients presenting with the diagnosis “rule out PE” to the obstetrical triage area of our hospital at <37 weeks of gestation (n=87) were included in this study. Delivery outcomes were used to classify patients into four groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n = 19); II): mild PE who delivered at term (n = 15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n = 26); and IV): diagnosis of severe PE (n = 27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory (n = 180; 1046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis. Results: The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p < 0.05). A plasma concentration of PlGF/sVEGFR-1 ≤ 0.05 MoM or PlGF/sEng ≤0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8–25 and 8.6, 95% CI 2.9–25, respectively), while that of PlGF ≤0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03–0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (≤0.05 MoM) as well as that of PlGF/sEng (≤0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [adjusted odds ratio (OR) = 27 (95% CI 6.4–109) and adjusted OR 30 (95% CI 6.9–126), respectively]. Among patients who presented <34 weeks gestation (n = 59), a plasma concentration of PlGF/sVEGFR-1 < 0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval-to-delivery due to PE [hazard ratio = 6 (95% CI 2.5–14.6)]. Conclusions: Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery.

Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia

OBJECTIVE To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) at 30-34 weeks of gestation can identify patients at risk for stillbirth, late preeclampsia, and delivery of small-for-gestational-age (SGA) neonates. STUDY DESIGN A prospective cohort study included 1269 singleton pregnant women from whom blood samples were obtained at 30-34 weeks of gestation and who delivered at >34 weeks of gestation. Plasma concentrations of PlGF, sEng, and sVEGFR-1 were determined by enzyme-linked immunosorbent assay. RESULTS The prevalence of late (>34 weeks of gestation) preeclampsia, severe late preeclampsia, stillbirth, and SGA was 3.2% (n = 40), 1.8% (n = 23), 0.4% (n = 5), and 8.5% (n = 108), respectively. A plasma concentration of PlGF/sEng <0.3 MoM was associated with severe late preeclampsia (adjusted odds ratio, 16); the addition of PlGF/sEng to clinical risk factors increased the area under the receiver-operating characteristic curve from 0.76 to 0.88 (P = .03). The ratio of PlGF/sEng or PlGF/sVEGFR-1 in the third trimester outperformed those obtained in the first or second trimester and uterine artery Doppler velocimetry at 20-25 weeks of gestation for the prediction of severe late preeclampsia (comparison of areas under the receiver-operating characteristic curve; each P ≤ .02). Both PlGF/sEng and PlGF/sVEGFR-1 ratios achieved a sensitivity of 74% with a fixed false-positive rate of 15% for the identification of severe late preeclampsia. A plasma concentration of PlGF/sVEGFR-1 <0.12 MoM at 30-34 weeks of gestation had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the identification of subsequent stillbirth. Similar findings (sensitivity 80%; specificity 93%) were observed in a separate case-control study. CONCLUSION Risk assessment for stillbirth and severe late preeclampsia in the third trimester is possible with the determination of maternal plasma concentrations of angiogenic and antiangiogenic factors at 30-34 weeks of gestation.

Clinical significance of the presence of amniotic fluid 'sludge' in asymptomatic patients at high risk for spontaneous preterm delivery.

To determine the clinical significance of the presence of amniotic fluid (AF) ‘sludge’ among asymptomatic patients at high risk for spontaneous preterm delivery.

Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion

Objective: An imbalance between maternal angiogenic/anti-angiogenic factors concentrations has been observed in preeclampsia (PE) and other obstetrical syndromes. However, the frequency of pathologic findings in the placenta and the changes in maternal plasma angiogenic/anti-angiogenic factor concentrations differ between late- and early-onset PE. The aim of this study was to determine if the maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 and 2 (sVEGFR-1 and sVEGFR-2) are different in late-onset PE with and without placental pathologic findings consistent with maternal underperfusion. Study design: A cross-sectional study was conducted including 64 uncomplicated women and 66 women with late-onset PE (>34 weeks) who had blood samples and placenta available for pathologic examination. Patients with late-onset PE were divided into those with and without placental histologic findings consistent with maternal underperfusion as proposed by the Society for Pediatric Pathology. Maternal plasma concentrations of PlGF, sEng, sVEGFR-1 and sVEGRF-2 were determined by ELISA. Non-parametric statistics were used for analysis. Results: 1) the prevalence of placental histological findings consistent with maternal underperfusion among women with late-onset PE was higher than that of those with an uncomplicated pregnancy (47% (31/66) vs. 7.8% (5/64), respectively; p < 0.01); 2) patients with late-onset PE and histological findings consistent with maternal underperfusion had a significantly lower median plasma concentration of PlGF, plasma PlGF/sVEGFR-1 ratio and plasma PlGF/sEng ratio than those with late-onset PE without placental underperfusion lesions (each p < 0.05); 3) the most common pathological findings in the placenta of patient with PE were lesions consistent with villous changes (77%, 24/31); and 4) isolated vascular lesions in the placenta were found only in 2 cases (6.5%), and the rest had a combination of villous and vascular lesions. Conclusions: Nearly half of the patients with late-onset PE have placental lesions consistent with maternal underperfusion. These lesions are associated with an imbalance in the maternal concentration of angiogenic/anti-angiogenic factors. We propose that there is a link between maternal underperfusion and an anti-angiogenic state characterized by the changes in the concentrations of angiogenic and anti-angiogenic factors in women with late onset PE.

Resistin: a hormone which induces insulin resistance is increased in normal pregnancy.

Abstract Aims: Resistin, a newly discovered adipokine, is thought to play a key role in the regulation of insulin resistance. The objectives of this study were to develop a nomogram of maternal plasma concentrations of resistin from 11 weeks of gestation to term and to determine whether resistin concentrations differ between normal and overweight pregnant women. Methods: In this cross-sectional study, plasma concentrations of resistin were determined in normal pregnant women of normal body mass index (BMI 18.5–24.9; n=261), overweight pregnant women (BMI ≥25; n=140), and non-pregnant women of normal BMI (n=40). Blood samples were collected once from each woman between the first trimester and term. Percentiles for resistin concentration were determined for five pre-specified windows of gestational age. Plasma resistin concentration was determined by immunoassay. Non-parametric statistics were used for analysis. Results: The median maternal plasma concentration of resistin between 11 to 14 weeks of gestation in women of normal weight was significantly higher than non-pregnant women; the plasma concentration of resistin increased with gestational age. Conclusions: Normal pregnant women have a higher median plasma concentration of resistin than non-pregnant women and the concentration of this adipokine increases with advancing gestation. Alterations in the maternal plasma concentration of resistin during pregnancy could contribute to metabolic changes of pregnancy.

Human β-defensin-2: A natural antimicrobial peptide present in amniotic fluid participates in the host response to microbial invasion of the amniotic cavity

Objective. Human β-defensin-2 (HBD-2) is a potent antimicrobial peptide that is part of the innate immune response. The purpose of this study was to determine whether HBD-2 is present in amniotic fluid and if its concentration changes with microbial invasion of the amniotic cavity (MIAC) and labor. Study design. Amniotic fluid was retrieved by amniocentesis from 318 patients in the following groups: (1) mid-trimester (n = 75); (2) term not in labor (n = 28) and in labor (n = 51); (3) preterm labor and intact membranes without MIAC who delivered at term (n = 36), who delivered preterm without MIAC (n = 52), and preterm labor with MIAC who delivered preterm (n = 25); and (4) preterm premature rupture of membranes (preterm PROM) with (n = 25) and without MIAC (n = 26). MIAC was defined as a positive amniotic fluid culture for microorganisms. Amniotic fluid HBD-2 concentrations were determined using a sensitive and specific ELISA. Non-parametric statistics were used for analysis. Results. (1) HBD-2 was detected in all amniotic fluid samples; (2) the concentration of HBD-2 did not change with gestational age from mid-trimester to term (p = 0.8); (3) intra-amniotic infection was associated with a significant increase in amniotic fluid concentrations of HBD-2 in both women with preterm labor and intact membranes, and women with preterm PROM (p < 0.05 for each comparison); (4) patients with preterm labor and a negative amniotic fluid culture who delivered preterm had a higher median amniotic fluid HBD-2 concentration than those with preterm labor who delivered at term (p=0.001); and (5) among patients with preterm labor without MIAC, those who had intra-amniotic inflammation (amniotic fluid white blood cell count >100 cells per mL) had a higher median amniotic fluid concentration of HBD-2 than those without this condition (p < 0.002). Conclusion. (1) Amniotic fluid contains HBD-2, a natural antimicrobial peptide, and this may account for some of the antimicrobial activity of amniotic fluid; (2) amniotic fluid HBD-2 concentrations are increased in women with MIAC, regardless of the membrane status (intact membranes or PROM); and (3) we propose that amniotic fluid HBD-2 is part of the innate immune system within the amniotic cavity.

Twin-to-twin transfusion syndrome: an antiangiogenic state?

OBJECTIVE An imbalanced chronic blood flow between the donor and recipient twin through placental vascular anastomoses is the accepted pathophysiology of twin-to-twin transfusion syndrome (TTTS). Vascular endothelial growth factor receptor-1 (VEGFR-1) mRNA is overexpressed only in the syncytiotrophoblast of the donor twin in some cases of TTTS. This study was conducted to determine maternal plasma concentrations of placental growth factor (PlGF), soluble VEGFR-1, and soluble endoglin (s-Eng) in monochorionic-diamniotic pregnancies with and without TTTS. STUDY DESIGN This case-control study included monochorionic-diamniotic pregnancies between 16-26 weeks with and without TTTS. Maternal plasma concentrations of PlGF, sVEGFR-1, and s-Eng were determined with ELISA. A P value < .05 was considered statistically significant. RESULTS Patients with TTTS had higher median plasma concentrations of s-Eng (14.8 ng/mL vs 7.8 ng/mL; P < .001) and sVEGFR-1 (6383.1 pg/mL vs 3220.1 pg/mL; P < .001]; and lower median plasma concentrations of PlGF (115.5 pg/mL vs 359.3 pg/mL; P = .002) than those without TTTS. CONCLUSION We propose that an antiangiogenic state may be present in some cases of TTTS.

Four-dimensional ultrasonography of the fetal heart using a novel Tomographic Ultrasound Imaging display

Abstract Objective: The objective of this study was to investigate the feasibility of examining the fetal heart with Tomographic Ultrasound Imaging (TUI) using four-dimensional (4D) volume datasets acquired with spatiotemporal image correlation (STIC). Material and methods: One hundred and ninety-five fetuses underwent 4D ultrasonography (US) of the fetal heart with STIC. Volume datasets were acquired with B-mode (n=195) and color Doppler imaging (CDI) (n=168), and were reviewed offline using TUI, a new display modality that automatically slices 3D/4D volume datasets, providing simultaneous visualization of up to eight parallel planes in a single screen. Visualization rates for standard transverse planes used to examine the fetal heart were calculated and compared for volumes acquired with B-mode or CDI. Diagnoses by TUI were compared to postnatal diagnoses. Results: (1) The four- and five-chamber views and the three-vessel and trachea view were visualized in 97.4% (190/195), 88.2% (172/195), and 79.5% (142/195), respectively, of the volume datasets acquired with B-mode; (2) these views were visualized in 98.2% (165/168), 97.0% (163/168), and 83.6% (145/168), respectively, of the volume datasets acquired with CDI; (3) CDI contributed additional diagnostic information to 12.5% (21/168), 14.2% (24/168) and 10.1% (17/168) of the four- and five-chamber and the three-vessel and trachea views; (4) cardiac anomalies other than isolated ventricular septal defects were identified by TUI in 16 of 195 fetuses (8.2%) and, among these, CDI provided additional diagnostic information in 5 (31.3%); (5) the sensitivity, specificity, positive- and negative-predictive values of TUI to diagnose congenital heart disease in cases where both B-mode and CDI volume datasets were acquired prenatally were 92.9%, 98.8%, 92.9% and 98.8%, respectively. Conclusion: Standard transverse planes commonly used to examine the fetal heart can be automatically displayed with TUI in the majority of fetuses undergoing 4D US with STIC. Due to the retrospective nature of this study, the results should be interpreted with caution and independently confirmed before this methodology is introduced into clinical practice.

Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection

Objective. The complement system plays an important role in host defense against infection. Concentrations of complement split products or anaphylatoxins (C3a, C4a, and C5a) in biological fluids are considered to reflect complement activation. The purpose of this study was to determine if term and preterm parturition are associated with evidence of complement activation in the amniotic fluid. Study design. Amniotic fluid (AF) samples were collected from 270 women in the following groups: (1) normal pregnant women in midtrimester (n = 70), (2) term not in labor (n = 23), (3) term in labor (n = 48), and (4) preterm labor (PTL) (n = 129). PTL was categorized into: (a) PTL without microbial invasion of the amniotic cavity (MIAC) who delivered at term (n = 42), (b) PTL who delivered preterm without MIAC (n = 57), and (c) PTL with MIAC (n = 30). C5a, C4a, and C3a concentrations in amniotic fluid were determined by ELISA. Nonparametric tests were used for statistical analysis. Results. (1) The median AF C5a concentration was higher in women at term than that of those in the midtrimester (p = 0.02); (2) Spontaneous labor at term was not associated with changes in AF concentrations of anaphylatoxins C3a, C4a, and C5a (all p > 0.05); (3) Among patients with PTL who delivered preterm, those with MIAC had higher AF C4a and C5a concentrations than those without infection (p < 0.01); and (4) AF C3a, C4a, and C5a concentrations were higher in patients with PTL with MIAC than in those with PTL without MIAC who delivered at term. Conclusion. Patients with spontaneous preterm labor and intact membranes with microbial invasion of the amniotic cavity had higher median amniotic fluid concentration of complement split products C3a, C4a, and C5a than patients without intra-amniotic infection. These findings suggest that preterm labor in the context of infection is associated with activation of the complement system.

What does 2-dimensional imaging add to 3- and 4-dimensional obstetric ultrasonography?

Objective. The purpose of this study was to determine whether 2‐dimensional (2D) ultrasonography adds diagnostic information to that provided by the examination of 3‐dimensional/4‐dimensional (3D/4D) volume data sets alone. Methods. Ninety‐nine fetuses were examined by 3D/4D volume ultrasonography. Volume data sets were evaluated by a blinded independent examiner who, after establishing an initial diagnostic impression by 3D/4D ultrasonography, performed a 2D ultrasonographic examination. The frequency of agreement and diagnostic accuracy of each modality to detect congenital anomalies were calculated and compared. Results. Fifty‐four fetuses with no abnormalities and 45 fetuses with 82 anomalies diagnosed by 2D ultrasonography were examined. Agreement between 3D/4D and 2D ultrasonography occurred for 90.4% of the findings (123/136; intraclass correlation coefficient, 0.834; 95% confidence interval, 0.774–0.879). Six anomalies were missed by 3D/4D ultrasonography when compared to 2D ultrasonography (ventricular septal defect [n = 2], interrupted inferior vena cava with azygous continuation [n = 1], tetralogy of Fallot [n = 1], horseshoe kidney [n = 1], and cystic adenomatoid malformation [n = 1]). There were 2 discordant diagnoses: transposition of the great arteries diagnosed as a double‐outlet right ventricle and pulmonary atresia misinterpreted as tricuspid atresia on 3D/4D ultrasonography. One case of occult spinal dysraphism was suspected on 3D ultrasonography but not confirmed by 2D ultrasonography. When compared to diagnoses performed after delivery (n = 106), the sensitivity and specificity of 3D/4D ultrasonography (92.2% [47/51] and 76.4% [42/55], respectively) and 2D ultrasonography (96.1% [49/51] and 72.7% [40/55]) were not significantly different (P = .233). Conclusions. Information provided by 2D ultrasonography is consistent, in most cases, with information provided by the examination of 3D/4D volume data sets alone.