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 5×10 ¹¹ particles Ad.VEGF-A ₁₆₅ ( 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.

Preventing in-breast recurrence is a primary goal for breast-conserving surgery (BCS), as local recurrence can lead to additional surgery, further systemic therapy, and poorer cosmetic outcomes. Prevention of local recurrence may also lead to improved overall survival, as suggested by a meta-analysis¹ of randomized clinical trials that showed 1 excess death for every 4 ipsilateral breast tumor recurrences. The strongest current predictor of local recurrence is the presence of tumor at the lumpectomy margins.^2-6 The site of local recurrence is often close to the original tumor site with histological characteristics similar to the primary tumor, suggesting that local recurrences can arise from residual tumor left at the time of lumpectomy.^7-9 Rates of residual carcinoma in reexcisions or mastectomies following initially negative lumpectomy margins have been shown to exceed 40% in some cohorts.^10-13

Poor placentation, which manifests as pre‐eclampsia and fetal growth restriction, is a major pregnancy complication. The underlying cause is a deficiency in normal trophoblast invasion of the spiral arteries, associated with placental inflammation, oxidative stress, and an antiangiogenic state. Peripartum therapies, such as prenatal maternal corticosteroids and magnesium sulphate, can prevent some of the adverse neonatal outcomes, but there is currently no treatment for poor placentation itself. Instead, management relies on identifying the consequences of poor placentation in the mother and fetus, with iatrogenic preterm delivery to minimise mortality and morbidity. Several promising therapies are currently under development to treat poor placentation, to improve fetal growth, and to prevent adverse neonatal outcomes. Interventions such as maternal nitric oxide donors, sildenafil citrate, vascular endothelial growth factor gene therapy, hydrogen sulphide donors, and statins address the underlying pathology, while maternal melatonin administration may provide fetal neuroprotection. In the future, these may provide a range of synergistic therapies for pre‐eclampsia and fetal growth restriction, depending on the severity and gestation of onset. © 2014 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

Uterine artery (UtA) adenovirus vector (Ad)-mediated over-expression of vascular endothelial growth factor (VEGF) enhances uterine blood flow in normal sheep pregnancy and increases fetal growth in the overnourished adolescent sheep model of fetal growth restriction (FGR). Herein we examined its impact on gestation length, neonatal survival, early postnatal growth and metabolism. Singleton-bearing ewes were evenly allocated to receive Ad.VEGF-A₁₆₅ (5 x 10¹⁰ particles/ml, 10 ml, n =17) or Saline (10 ml, n = 16) injected into each UtA at laparotomy (0.6 gestation). Fetal growth was serially monitored (blind) by ultrasound until delivery. Lambs were weighed and blood-sampled weekly and a glucose tolerance test performed (68d postnatal age). Hepatic DNA/RNA was extracted at necropsy (83d postnatal age) to examine methylation status of eight somatotropic axis genes. IGF1 mRNA and protein expression were measured by RT-PCR and radioimmunoassay, respectively. All pregnancies remained viable following Ad.VEGF-A₁₆₅ treatment. Fetal abdominal circumference and renal volume were greater in Ad.VEGF-A₁₆₅ versus Saline groups at 21/28 days (p ≤ 0.04) post-injection. At delivery, gestation length (p = 0.07), lamb birthweight (p = 0.08), umbilical girth (p = 0.06) and plasma glucose (p=0.09) tended to be greater in Ad.VEGF-A₁₆₅ treated lambs. Levels of neonatal intervention required to ensure survival was equivalent between groups. Absolute postnatal growth rate (p = 0.02), insulin area-under-the-curve (p = 0.04) and carcass weight at necropsy (p = 0.04) were increased by Ad.VEGF-A₁₆₅ treatment. There was no impact on markers of insulin sensitivity or methylation/expression of key genes involved in somatic growth. Ad.VEGF-A₁₆₅ gene therapy increased fetal growth in a sheep FGR model and lambs continued to thrive during the neonatal and early postnatal period.