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Uteroplacental adenovirus vascular endothelial growth factor gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies.

ABSTRACT: Fetal growth restriction (FGR) occurs in ?8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestation correlates with reduced lamb birthweight near term. Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently offered a high intake (n=45) or control intake (n=12) of a complete diet to generate FGR or normal fetoplacental growth, respectively. High-intake ewes were randomized midgestation to receive bilateral UtA injections of 5×10¹¹ particles Ad.VEGF-A165 (n=18), control vector Ad.LacZ (n=14), or control saline (n=13). Fetal growth/well-being were evaluated using serial ultrasound. UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularization within the perivascular adventitia, and placental mRNA expression of angiogenic factors/receptors were examined using organ bath analysis, anti-vWF immunohistochemistry, and qRT-PCR, respectively. Ad.VEGF significantly increased ultrasonographic fetal growth velocity at 3-4 weeks postinjection (p=0.016-0.047). At 0.9 gestation fewer fetuses were markedly growth-restricted (birthweight >2SD below contemporaneous control-intake mean) after Ad.VEGF therapy. There was also evidence of mitigated fetal brain sparing (lower biparietal diameter-to-abdominal circumference and brain-to-liver weight ratios). No effects were observed on UBF or neovascularization; however, Ad.VEGF-transduced vessels demonstrated strikingly enhanced vasorelaxation. Placental efficiency (fetal-to-placental weight ratio) and FLT1/KDR mRNA expression were increased in the maternal but not fetal placental compartments, suggesting downstream effects on placental function. Ad.VEGF gene therapy improves fetal growth in a sheep model of FGR, although the precise mechanism of action remains unclear.

SUBMITTER: Carr DJ

PROVIDER: S-EPMC3997090 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Uteroplacental adenovirus vascular endothelial growth factor gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies.

Carr David J DJ Wallace Jacqueline M JM Aitken Raymond P RP Milne John S JS Mehta Vedanta V Martin John F JF Zachary Ian C IC Peebles Donald M DM David Anna L AL

Human gene therapy 20140407 4

Fetal growth restriction (FGR) occurs in ∼8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestati ...[more]

PMID: 24593228

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Project description:BackgroundAccurately identifying pregnancies with accelerated or diminished fetal growth is challenging and generally based on cross-sectional percentile estimates of fetal weight. Longitudinal growth velocity might improve identification of abnormally grown fetuses.ObjectiveWe sought to complement fetal size standards with fetal growth velocity, develop a model to compute fetal growth velocity percentiles for any given set of gestational week intervals, and determine association between fetal growth velocity and birthweight.Study designThis was a prospective cohort study with data collected at 12 US sites (2009 through 2013) from 1733 nonobese, low-risk pregnancies included in the singleton standard. Following a standardized sonogram at 10w0d-13w6d, each woman was randomized to 1 of 4 follow-up visit schedules with 5 additional study sonograms (targeted ranges: 16-22, 24-29, 30-33, 34-37, and 38-41 weeks). Study visits could occur ± 1 week from the targeted GA. Ultrasound biometric measurements included biparietal diameter, head circumference, abdominal circumference, and femur length, and estimated fetal weight was calculated. We used linear mixed models with cubic splines for the fixed effects and random effects to flexibly model ultrasound trajectories. We computed velocity percentiles in 2 ways: (1) difference between 2 consecutive weekly measurements (ie, weekly velocity), and (2) difference between any 2 ultrasounds at a clinically reasonable difference between 2 gestational ages (ie, velocity calculator). We compared correlation between fetal growth velocity percentiles and estimated fetal weight percentiles at 4-week intervals, with 32 (±1) weeks' gestation for illustration. Growth velocity was computed as estimated fetal growth rate (g/wk) between ultrasound at that gestational age and from prior visit [ie, for 28-32 weeks' gestational age: velocity = (estimated fetal weight 32-28)/(gestational age 32-28)]. We examined differences in birthweight by whether or not estimated fetal weight and estimated fetal weight velocity were <5th or ≥5th percentiles using χ2.ResultsFetal growth velocity was nonmonotonic, with acceleration early in pregnancy, peaking at 13, 14, 15, and 16 weeks for biparietal diameter, head circumference, femur length, and abdominal circumference, respectively. Biparietal diameter, head circumference, and abdominal circumference had a second acceleration at 19-22, 19-21, and 27-31 weeks, respectively. Estimated fetal weight velocity peaked around 35 weeks. Fetal growth velocity varied slightly by race/ethnicity although comparisons reflected differences for parameters at various gestational ages. Estimated fetal weight velocity percentiles were not highly correlated with fetal size percentiles (Pearson r = 0.40-0.41, P < .001), suggesting that these measurements reflect different aspects of fetal growth and velocity may add additional information to a single measure of estimated fetal weight. At 32 (SD ± 1) weeks, if both estimated fetal weight velocity and size were <5th percentile, mean birthweight was 2550 g; however, even when size remained <5th percentile but velocity was ≥5th percentile, birthweight increased to 2867 g, reflecting the important contribution of higher growth velocities. For estimated fetal weight ≥5th percentile, but growth velocity <5th, birthweight was smaller (3208 vs 3357 g, respectively, P < .001).ConclusionWe provide fetal growth velocity data to complement our previous work on fetal growth size standards, and have developed a calculator to compute fetal growth velocity. Preliminary findings suggest that growth velocity adds additional information over knowing fetal size alone.

Project description:ObjectivesTo determine whether decreased fetal growth velocity precedes antepartum fetal death and to evaluate whether fetal growth velocity is a better predictor of antepartum fetal death compared to a single fetal biometric measurement at the last available ultrasound scan prior to diagnosis of demise.MethodsThis was a retrospective, longitudinal study of 4285 singleton pregnancies in African-American women who underwent at least two fetal ultrasound examinations between 14 and 32 weeks of gestation and delivered a liveborn neonate (controls; n = 4262) or experienced antepartum fetal death (cases; n = 23). Fetal death was defined as death diagnosed at ≥ 20 weeks of gestation and confirmed by ultrasound examination. Exclusion criteria included congenital anomaly, birth at < 20 weeks of gestation, multiple gestation and intrapartum fetal death. The ultrasound examination performed at the time of fetal demise was not included in the analysis. Percentiles for estimated fetal weight (EFW) and individual biometric parameters were determined according to the Hadlock and Perinatology Research Branch/Eunice Kennedy Shriver National Institute of Child Health and Human Development (PRB/NICHD) fetal growth standards. Fetal growth velocity was defined as the slope of the regression line of the measurement percentiles as a function of gestational age based on two or more measurements in each pregnancy.ResultsCases had significantly lower growth velocities of EFW (P < 0.001) and of fetal head circumference, biparietal diameter, abdominal circumference and femur length (all P < 0.05) compared to controls, according to the PRB/NICHD and Hadlock growth standards. Fetuses with EFW growth velocity < 10th percentile of the controls had a 9.4-fold and an 11.2-fold increased risk of antepartum death, based on the Hadlock and customized PRB/NICHD standards, respectively. At a 10% false-positive rate, the sensitivity of EFW growth velocity for predicting antepartum fetal death was 56.5%, compared to 26.1% for a single EFW percentile evaluation at the last available ultrasound examination, according to the customized PRB/NICHD standard.ConclusionsGiven that 74% of antepartum fetal death cases were not diagnosed as small-for-gestational age (EFW < 10th percentile) at the last ultrasound examination when the fetuses were alive, alternative approaches are needed to improve detection of fetuses at risk of fetal death. Longitudinal sonographic evaluation to determine growth velocity doubles the sensitivity for prediction of antepartum fetal death compared to a single EFW measurement at the last available ultrasound examination, yet the performance is still suboptimal. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Project description:BackgroundThe common use of singleton fetal growth standard to access twin growth might lead to over-monitoring and treatment. We aimed to develop fetal growth standards for Chinese twins based on ultrasound measurements, and compare it with Zhang's and other twin fetal growth charts.MethodsA cohort of uncomplicated twin pregnancies were prospectively followed in 2014-2017. Smoothed estimates of fetal growth percentiles for both monochorionic (MC) and dichorionic (DC) twins were obtained using a linear mixed model. We also created growth charts for twins using a model-based approach proposed by Zhang et al. Our twin standards were compared with Hadlock's (singleton) in predicting adverse perinatal outcomes.ResultsA total of 398 twin pregnancies were included, with 214 MC and 582 DC live-born twins. The MC twins were slightly lighter than the DC twins, with small differences throughout the gestation. Our ultrasound-based fetal weight standards were comparable to that using Zhang's method. Compared with previous references/standards from the US, Brazil, Italy and UK, our twins had very similar 50th percentiles, but narrower ranges between the 5th and 95th or 10th and 90th percentiles. Compared with the Hadlock's standard, the risks of neonatal death and adverse perinatal outcomes for small for gestational age (SGA) versus non-SGA were substantially elevated using our standards.ConclusionsA normal fetal growth standard for Chinese twins was created. The differences between MC and DC twins were clinically insignificant. The 50th weight percentiles of the Chinese twins were identical to those in other races/ethnicities but the ranges were markedly narrower. Our standard performed much better than the Hadlock's in predicting low birth weight infants associated with adverse perinatal outcomes in twin pregnancies. The present study also indicated that Zhang's method is applicable to Chinese twins, and other areas may use Zhang's method to generate their own curves for twins if deemed necessary.

Dataset Information

Uteroplacental adenovirus vascular endothelial growth factor gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies.

Publications

Uteroplacental adenovirus vascular endothelial growth factor gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies.

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