Usefulness of angiogenic factors in prenatal counseling of late-onset fetal growth-restricted and small-for-gestational-age gestations: a prospective observational study.

OBJECTIVES: To create a predictive model including biomarkers and evaluate its ability to predict adverse perinatal outcomes in late-onset small fetuses, ultimately helping to provide individualized counseling at the time of diagnosis. METHODS: This was a prospective observational study, including singleton pregnancies with an estimated fetal weight (EFW) below the 10th percentile, at a gestational age between 32 + 0 and 36 + 6 weeks of gestation (WG). Variables recorded at diagnosis to predict adverse pregnancy outcomes were: soluble fms-like tyrosine-kinase-1 to placental growth factor ratio (sFlt-1/PlGF), fetal Doppler (umbilical artery and middle cerebral artery), uterine artery pulsatility index (UtAPI), EFW percentile, gestational age, and the presence of maternal risk factors for placental insufficiency. Logistic regression models were developed for the prediction of three co-primary outcomes: composite adverse perinatal outcomes (APO), and the need for elective delivery before 35 or 37 WG. RESULTS: Sixty (52.2%) fetal growth restricted (FGR) and 55 (47.8%) small for gestational age (SGA) were enrolled. Thirteen (11.3%) women needed elective delivery before 35 WG and 27 (23.5%) women before 37 WG. At least one APO occurred in 43 (37.4%) pregnancies. The best marker in univariate analyses was the sFlt-1/PlGF ratio [AUC = 0.932 (95% CI, 0.864-0.999)]. The multivariate model including sFlt-1/PlGF showed a better predictive performance for APO than the multivariate model without sFlt-1/PlGF (P < 0.024). CONCLUSIONS: sFlt-1/PlGF is a good predictor of APO at the time of late-onset FGR/SGA diagnosis. Our predictive models may be useful to provide early individualized prenatal counseling in this group of women. Further studies are needed to validate these preliminary findings in a larger cohort.

The Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) Trial to Avoid Adverse Perinatal Outcomes: Protocol for a Multicenter, Open-Label, Randomized Controlled Trial.

BACKGROUND: Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. OBJECTIVE: The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. METHODS: This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. RESULTS: Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. CONCLUSIONS: The angiogenic factor-based protocol may reduce the number of pregnancies classified as having fetal growth restriction without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. TRIAL REGISTRATION: ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37452.

sFlt-1 to PlGF ratio cut-offs to predict adverse pregnancy outcomes in early-onset FGR and SGA: a prospective observational study.

This is a prospective, observational study, conducted in a tertiary referral hospital. We enrolled 175 singleton pregnancies with estimated foetal weight below the 10th centile between 20 + 0 and 31 + 6 weeks. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and fetoplacental circulation were assessed at the time of diagnosis. Receiver operating characteristic curves were used to assess the performance of sFlt-1/PlGF for predicting adverse perinatal outcomes (APO). The optimal cut-offs to predict each adverse outcome were calculated and the resulting areas under the curve (AUC) were compared to those calculated from the cut-off points of 38, 85 and 110. The need for delivery at <30 and <34 weeks and APO were the main outcome measures. The optimal cut-off points to predict APO, delivery <30 and <34 weeks were 24.9, 116.7 and 97.5, respectively. None of them proved to be superior to 38, 85 or 110 for predicting any adverse pregnancy outcome. Impact StatementWhat is already known on this subject? Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are biomarkers of placental dysfunction. High sFlt-1/PlGF values predict adverse perinatal outcomes in preeclampsia (PE).What do the results of this study add? No specific thresholds have been described to identify early-onset foetal growth restriction (FGR) and small for gestational age (SGA) foetuses at higher risk of adverse outcomes. This study describes these specific cut-offs and compares their predictive capacity to those described for PE.What are the implications of these findings for clinical practice and/or further research? The sFlt-1/PlGF cut-off points of 38, 85 and 110 might be useful for ruling out the occurrence of APO and the need for elective delivery at <30 and at <34 weeks from the moment of diagnosis in early-onset FGR and SGA. These cut-offs could aid Doppler studies in the distinction between FGR and SGA.

Angiogenic factors for planning fetal surveillance in fetal growth restriction and small-for-gestational-age fetuses: A prospective observational study.

OBJECTIVE: The aim of this study was to assess the added value of the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio for adjusting the periodicity of ultrasound examinations in early-onset fetal growth restriction (FGR) and small for gestational age (SGA). DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. POPULATION: One hundred and thirty-four single pregnancies with ultrasonographic estimated fetal weight (EFW) below the 10th centile between 20+0 and 31+6  weeks of gestation with antegrade umbilical artery flow. METHODS: The time from Doppler and sFlt-1/PlGF assessment to delivery was recorded and classified into four ranges: <1, <2, <3 and <4 weeks. MAIN OUTCOME MEASURES: Sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of sFlt-1/PlGF values to predict the time to delivery. RESULTS: In the SGA cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 3 weeks, and 98% for delivery before 4 weeks after diagnosis (95% CI 0.89-1.00). In the FGR cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 2 weeks after diagnosis (95% CI 0.92-1.00). By contrast, more than 50% of cases with an sFlt-1/PlGF value of >85 required an elective delivery before 1 week. CONCLUSIONS: sFlt-1/PlGF values in early-onset SGA and FGR are predictive of the time to delivery and could be used for planning fetal surveillance, by reducing the frequency of ultrasound in cases with sFlt-1/PlGF < 38 and by providing closer follow-up in cases with sFlt-1/PlGF >85. TWEETABLE ABSTRACT: sFlt-1/PlGF values in early-onset SGA/FGR could be used in addition to Doppler for planning fetal surveillance.

Individual risk assessment for prenatal counseling in early-onset growth-restricted and small-for-gestational-age fetuses.

INTRODUCTION: Early-onset fetal growth restriction and small-for-gestational age of fetuses lead to an increased risk of adverse pregnancy outcomes. Doppler abnormalities can predict the occurrence of complications in the short term, but normal fetal Doppler values at the time of diagnosis do not exclude their occurrence in the long term. The objective of this study was to investigate the capacity of a predictive model to assess individual risks for prenatal counseling at the time of diagnosis. MATERIAL AND METHODS: This was a prospective observational study of singleton pregnancies with estimated fetal weight below the 10th centile between 20+0 and 31+6  weeks of gestational age. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) levels, estimated fetal weight centile, uterine artery pulsatility index, fetal Doppler and maternal risk factors for placental disease were assessed at the time of enrollment. The occurrence of adverse perinatal outcomes or the need for elective delivery at <30, <34 or <37 weeks was considered an adverse pregnancy outcomes. Univariable logistic regression analysis was used to examine the association between each predictive variable and the adverse outcomes. A multivariable logistic regression-based model was constructed with the combination of all variables. An additional model without sFlt-1/PlGF was also created. Both models, and the sFlt-1/PlGF alone, were used to develop the different formulas to assess individual risks. Receiver operating characteristic curves were constructed to assess and compare their performance of screening. RESULTS: Forty-nine small-for-gestational-age fetuses and 124 with fetal growth restriction were enrolled at a median gestational age of 23.6 weeks. Elective delivery was needed in 77 (44.5%) women at <37 weeks, 53 (30.6%) women at <34 weeks and 30 (17.3%) at <30 weeks. Adverse perinatal outcomes occurred in 81 (55.9%) pregnancies. When areas under the curve were compared among models, no statistically significant differences were observed between the model with sFlt-1/PlGF and sFlt-1/PlGF alone; however, the model without sFlt-1/PlGF yielded an overall poorer performance. CONCLUSIONS: Individual risk assessment can be made at the time of early-onset fetal growth restriction/small-for-gestational-age diagnosis, which permits accurate counseling of parents with an affected fetus. Two formulas could be used: one combining maternal characteristics and ultrasound findings and the other with a single sFlt-1/PlGF measurement.

Cut-off values for Gaussian first-trimester screening for early-onset preeclampsia with maternal history, biochemical markers and uterine artery Doppler.

INTRODUCTION: Several algorithms for first-trimester screening for preeclampsia are available; however, the Gaussian model algorithm is more likely to match the characteristics of different populations. It is recommended to validate a screening strategy before being implemented in clinical practice; unfortunately, the validation process might not be feasible in all settings. Thus, the aim of this study was to provide cut-off values for the Gaussian model for its use in clinical practice. MATERIAL AND METHODS: This prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) from October 2015 to September 2017. A total of 2641 women with singleton pregnancies were recruited. Recorded at the first-trimester scan were demographic characteristics, maternal obstetric history, maternal history, uterine artery Doppler and arterial blood pressure. Serum concentrations of pregnancy-associated plasma protein-A and placental growth factor were assessed from the first-trimester blood test. Detection rates and cut-off values for fixed 5%, 10 %, 15 %, 20 %, 25 % and 30 % false-positive rates were calculated for all combinations of markers. RESULTS: Ninety (3.41 %) of the 2641 women developed preeclampsia, which was early-onset in 11 (0.42 %). The cut-off values and their respective detection rates, for the screening of early-onset PE by all possible combinations of markers involved in this model, are provided. DISCUSSION: When external validation of first-trimester screening for preeclampsia before its clinical implementation is not feasible, the cut-off values from the Gaussian model algorithm provided in this study could be used and median values corrected prospectively if necessary.

NGF-Enhanced Vasculogenic Properties of Epithelial Ovarian Cancer Cells Is Reduced by Inhibition of the COX-2/PGE2 Signaling Axis.

Epithelial ovarian cancer (EOC) is a lethal gynecological neoplasia characterized by extensive angiogenesis and overexpression of nerve growth factor (NGF). Here, we investigated the mechanism by which NGF increases vascular endothelial growth factor (VEGF) expression and the vasculogenic potential of EOC cells, as well as the contribution of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) signaling axis to these events. EOC biopsies and ovarian cell lines were used to determine COX-2 and PGE2 levels, as well as those of the potentially pro-angiogenic proteins c-MYC (a member of the Myc transcription factors family), survivin, and ß-catenin. We observed that COX-2 and survivin protein levels increased during EOC progression. In the EOC cell lines, NGF increased the COX-2 and PGE2 levels. In addition, NGF increased survivin, c-MYC, and VEGF protein levels, as well as the transcriptional activity of c-MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef) in a Tropomyosin receptor kinase A (TRKA)-dependent manner. Also, COX-2 inhibition prevented the NGF-induced increases in these proteins and reduced the angiogenic score of endothelial cells stimulated with conditioned media from EOC cells. In summary, we show here that the pro-angiogenic effect of NGF in EOC depends on the COX-2/PGE2 signaling axis. Thus, inhibition COX-2/PGE2 signaling will likely be beneficial in the treatment of EOC.

Describing the growth curve of local turkey using non-linear models / Descripción de la curva de crecimiento de pavos locales usando modelos no lineales

ABSTRACT Objective. Determine the best non-linear model to fit the growth curve of local turkeys managed under confinement in Michoacan, Mexico. Material and methods. Twenty-four and 43 female and male turkeys, reared under commercial conditions were given commercial feed. Birds were weighed weekly from hatch to 29 weeks of age. The Gompertz, Brody, Richards, von Bertalanffy and Logistic models were chosen to describe the age-weight relationship. Results. The best fitting model was selected based on the multiple determination coefficient (R2), the Akaike information criterion (AIC) and visual analysis of the observed and predicted curves. In both female and male, von Bertalanffy was the best model. The highest estimates of parameter A (mature weight) for both females and males were obtained with the von Bertalanffy model followed by the Gompertz and Logistic. The estimates of A were higher for males than for females. The highest estimates of parameter k (rate of maturity) for both females and males were, in decreasing order, for the Logistic, Gompertz, and von Bertalanffy models. k values for female turkeys was higher than for males. The age at the point of inflection (ti) and body weight at the age of point of inflection (WI) varied with the model used. The largest values of TI and WI corresponded to the Logistic model. Between sexes, the largest TI and WI values corresponded to males. Conclusions. The best models to describe turkey growth was the von Bertalanffy because it present the highest R2 and lowest AIC values.

RESUMEN Objetivo. Determinar el modelo no lineal que mejor ajuste la curva de crecimiento de pavos locales criados en confinamiento. Material y métodos. Veinticuatro y 43 pavos hembras y machos, respectivamente, criados en confinamiento fueron alimentados con dietas comerciales. Cada animal se pesó desde el nacimiento hasta la semana 29 de edad. Los modelos de Gompertz, Brody, Richards, von Bertalanffy y Logístico fueron elegidos para describir la relación edad-peso. El mejor modelo se seleccionó con base en el coeficiente de determinación (R2), el criterio de información de Akaike (AIC) y el análisis visual de las curvas observadas y predichas. Resultados. El mejor ajuste (machos y hembras) correspondió al modelo von Bertalanffy. El más alto valor del parámetro A (edad a la madurez), para hembras y machos correspondió al modelo von Bertalanffy, seguido de Gompertz y Logístico. El estimador A fue mayor para machos que hembras. El mayor valor del parámetro k (tasa de madurez), para hembras y machos, variaron según el modelo utilizado. Los valores de k fueron más altos para hembras que para machos. La edad al punto de inflexión (T:) y peso vivo al punto de inflexión (W:) también variaron de un modelo a otro. Los valores más altos de T, y Wj correspondieron al modelo Logístico. Entre sexos, los valores mayores de T: y WI correspondieron a los machos. Conclusiones. El mejor modelo que describió la curva de crecimiento de los pavos locales fue el de von Bertalanffy.

Screening for Sex Chromosome Aneuploidy by Cell-Free DNA Testing: Patient Choice and Performance.

OBJECTIVE: To study patient choice regarding testing for sex chromosome aneuploidy (SCA) and the performance of cell-free DNA (cfDNA) screening for SCA. METHODS: Patient choice regarding screening for SCA and factors influencing this choice were evaluated in a single center. In a subsequent two-center study, cases that screened positive for SCA were analyzed to determine the positive predictive value (PPV) for each SCA. RESULTS: In all, 1,957 (61.9%) of the 3,162 patients undergoing cfDNA testing opted for SCA screening. Regression analysis demonstrated that independent predictors of a patient's decision for SCA were earlier gestational age, spontaneous conception, and cfDNA chosen as a primary method of screening. A total of 161 cases screened positive for SCA and follow-up data were available for 118 (73.3%). Forty-six of the 61 cases of 45,X were false-positive results and 15 were concordant with the fetal karyotype (PPV = 24.6%). Seventeen of the 22 cases of 47,XXX were false positive and 5 concordant (PPV = 22.7%). Eleven of the 30 cases of 47,XXY were false positive and 19 concordant (PPV = 63.3%). All 5 cases of 47,XYY were correctly identified, thus yielding a PPV of 100%. CONCLUSION: More than half of the patients undergoing cfDNA aneuploidy screening also opted for SCA testing, but they were less likely to do so in the presence of an increased risk of trisomy. SCAs involving the X chromosome had a lower PPV than those involving the Y chromosome.

Comparison of conventional 2D ultrasound to magnetic resonance imaging for prenatal estimation of birthweight in twin pregnancy.

BACKGROUND: During prenatal follow-up of twin pregnancies, accurate identification of birthweight and birthweight discordance is important to identify the high-risk group and plan perinatal care. Unfortunately, prenatal evaluation of birthweight discordance by 2-dimensional ultrasound has been far from optimal. OBJECTIVE: The objective of the study was to prospectively compare estimates of fetal weight based on 2-dimensional ultrasound (ultrasound-estimated fetal weight) and magnetic resonance imaging (magnetic resonance-estimated fetal weight) with actual birthweight in women carrying twin pregnancies. STUDY DESIGN: Written informed consent was obtained for this ethics committee-approved study. Between September 2011 and December 2015 and within 48 hours before delivery, ultrasound-estimated fetal weight and magnetic resonance-estimated fetal weight were conducted in 66 fetuses deriving from twin pregnancies at 34.3-39.0 weeks; gestation. Magnetic resonance-estimated fetal weight derived from manual measurement of fetal body volume. Comparison of magnetic resonance-estimated fetal weight and ultrasound-estimated fetal weight measurements vs birthweight was performed by calculating parameters as described by Bland and Altman. Receiver-operating characteristic curves were constructed for the prediction of small-for-gestational-age neonates using magnetic resonance-estimated fetal weight and ultrasound-estimated fetal weight. For twins 1 and 2 separately, the relative error or percentage error was calculated as follows: (birthweight - ultrasound-estimated fetal weight (or magnetic resonance-estimated fetal weight)/birthweight) × 100 (percentage). Furthermore, ultrasound-estimated fetal weight, magnetic resonance-estimated fetal weight, and birthweight discordance were calculated as 100 × (larger estimated fetal weight-smaller estimated fetal weight)/larger estimated fetal weight. The ultrasound-estimated fetal weight discordance and the birthweight discordance were correlated using linear regression analysis and Pearson's correlation coefficient. The same was done between the magnetic resonance-estimated fetal weight and birthweight discordance. To compare data, the χ2, McNemar test, Student t test, and Wilcoxon signed rank test were used as appropriate. We used the Fisher r-to-z transformation to compare correlation coefficients. RESULTS: The bias and the 95% limits of agreement of ultrasound-estimated fetal weight are 2.99 (-19.17% to 25.15%) and magnetic resonance-estimated fetal weight 0.63 (-9.41% to 10.67%). Limits of agreement were better between magnetic resonance-estimated fetal weight and actual birthweight as compared with the ultrasound-estimated fetal weight. Of the 66 newborns, 27 (40.9%) were of weight of the 10th centile or less and 21 (31.8%) of the fifth centile or less. The area under the receiver-operating characteristic curve for prediction of birthweight the 10th centile or less by prenatal ultrasound was 0.895 (P < .001; SE, 0.049), and by magnetic resonance imaging it was 0.946 (P < .001; SE, 0.024). Pairwise comparison of receiver-operating characteristic curves showed a significant difference between the areas under the receiver-operating characteristic curves (difference, 0.087, P = .049; SE, 0.044). The relative error for ultrasound-estimated fetal weight was 6.8% and by magnetic resonance-estimated fetal weight, 3.2% (P < .001). When using ultrasound-estimated fetal weight, 37.9% of fetuses (25 of 66) were estimated outside the range of ±10% of the actual birthweight, whereas this dropped to 6.1% (4 of 66) with magnetic resonance-estimated fetal weight (P < .001). The ultrasound-estimated fetal weight discordance and the birthweight discordance correlated significantly following the linear equation: ultrasound-estimated fetal weight discordance = 0.03 + 0.91 × birthweight (r = 0.75; P < .001); however, the correlation was better with magnetic resonance imaging: magnetic resonance-estimated fetal weight discordance = 0.02 + 0.81 × birthweight (r = 0.87; P < .001). CONCLUSION: In twin pregnancies, magnetic resonance-estimated fetal weight performed immediately prior to delivery is more accurate and predicts small-for-gestational-age neonates significantly better than ultrasound-estimated fetal weight. Prediction of birthweight discordance is better with magnetic resonance imaging as compared with ultrasound.

Role of Nerve Growth Factor (NGF) and miRNAs in Epithelial Ovarian Cancer.

Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3'-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression.

Prophylactic use of the Arabin cervical pessary in fetuses with severe congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion (FETO): preliminary experience.

OBJECTIVE: The aim of this study was to describe whether the prophylactic use of a cervical pessary decreases the rate of premature birth in congenital diaphragmatic hernia (CDH) fetuses treated with fetoscopic tracheal occlusion (FETO). METHODS: The study concerns a consecutive series of cases with CDH and FETO and a group of CDH without FETO. In a subgroup of the FETO group, a prophylactic cervical pessary was inserted the day following the procedure. Gestational age (GA) at birth was the primary outcome. RESULTS: Fifty-nine fetuses with FETO and 47 expectantly managed were included. The last 15 FETO had a cervical pessary inserted. The median GA at delivery in the FETO group with pessary was 35.1 weeks and was not different from that in the FETO group without a pessary (34.3 weeks; p = 0.28) but was below that in the expectantly managed group (38.3 weeks; p < 0.001). CONCLUSION: Early results suggest that prophylactic use of an Arabin cervical pessary does not prolong gestation of CDH fetuses treated with FETO. © 2015 John Wiley & Sons, Ltd.