Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

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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.

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Neurologic and developmental disability at six years of age after extremely preterm birth.

Neil Marlow, Dieter Wolke, Melanie A Bracewell … (2005)

Birth before 26 weeks of gestation is associated with a high prevalence of neurologic and developmental disabilities in the infant during the first two years of life. We studied at the time of early school age children who had been born at 25 or fewer completed weeks of gestation in the United Kingdom and Ireland in 1995. Each child had been evaluated at 30 months of age. The children underwent standardized cognitive and neurologic assessments at six years of age. Disability was defined as severe (indicating dependence on caregivers), moderate, or mild according to predetermined criteria. Of 308 surviving children, 241 (78 percent) were assessed at a median age of six years and four months; 160 classmates delivered at full term served as a comparison group. Although the use of test reference norms showed that cognitive impairment (defined as results more than 2 SD below the mean) was present in 21 percent of the children born extremely preterm (as compared with 1 percent in the standardized data), this value rose to 41 percent when the results were compared with those for their classmates. The rates of severe, moderate, and mild disability were 22 percent, 24 percent, and 34 percent, respectively; disabling cerebral palsy was present in 30 children (12 percent). Among children with severe disability at 30 months of age, 86 percent still had moderate-to-severe disability at 6 years of age. In contrast, other disabilities at the age of 30 months were poorly predictive of developmental problems at 6 years of age. Among extremely preterm children, cognitive and neurologic impairment is common at school age. A comparison with their classroom peers indicates a level of impairment that is greater than is recognized with the use of standardized norms. Copyright 2005 Massachusetts Medical Society.

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Adult consequences of fetal growth restriction.

DAVID BARKER (2006)

Low birthweight in relation to the length of gestation, is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and type 2 diabetes. These associations extend across the whole range of birthweight, which implies that normal variations in nutrient delivery to the fetus have profound long-term effects. The associations are thought to reflect the body's plasticity during development, by which its structure and function can be permanently changed by the intra uterine and early post natal environment. Slow growth during infancy and rapid weight gain after the age of two years exacerbate the effect of slow fetal growth. Cardiovascular disease and type 2 diabetes arise through a series of interactions between environmental influences and the pathways of development that precede them.