Abstract
ABSTRACTPoor 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.
Highlights
In normal pregnancy, trophoblast invasion of the maternal spiral arteries produces a low-resistance, high-flow maternal uterine circulation
Recent evidence from a study of placental bed biopsies in pregnancies affected by fetal growth restriction (FGR) and pre-eclampsia confirms that there is a major defect in myometrial spiral artery remodelling that is linked to clinical parameters.[3]
The sequence and relative contributions of the defects are unclear, the result is a relative reduction in uterine artery blood flow,[3,4] an increase in the soluble vascular endothelial growth factor (VEGF) receptor soluble fms-like tyrosine kinase 1, and a reduction in the available maternal VEGF and placental growth factor (PlGF).[1,2,5,6]
Summary
Trophoblast invasion of the maternal spiral arteries produces a low-resistance, high-flow maternal uterine circulation. The catechol-O-methyltransferase (COMT-/-) knockout mouse model of poor placentation results in increased umbilical artery pulsatility index (UAPI) and smaller and lighter pups compared with controlled mice.[25] COMT-/- mice given sildenafil from 12.5 to 18.5 days postconception (dpc) had significantly higher pup weight, crown-rump length, and abdominal circumference (AC) than untreated COMT-/- mice and significantly lower UAPI This effect of sildenafil on fetal growth was not replicated in a study using the rat reduction of uteroplacental perfusion pressure (RUPP) model, which involves clipping the maternal aorta and ovarian arteries at 14 dpc (term = 22 dpc), resulting in maternal hypertension, an increase in sFlt-1 and oxidative stress, and a reduction in free VEGF and fetal weight.[26] RUPP dams receiving sildenafil did have a significantly lower mean arterial pressure than untreated RUPP dams. In mice administered Ad.sFlt-1 at 8 dpc, which produces a pre-eclampsia-like phenotype and increased vascular
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