Maternal Administration of Sildenafil Citrate Alters Fetal and Placental Growth and Fetal–Placental Vascular Resistance in the Growth-Restricted Ovine Fetus

Oyston, Charlotte; Stanley, John C.; Oliver, Mark; Bloomfield, Frank H.; Baker, Philip N.

doi:10.1161/hypertensionaha.116.07662

Cited by 42 publications

(22 citation statements)

References 43 publications

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“…Furthermore, most nutritional interventions are associated with increased adiposity and not increased linear growth. More promising are interventions which increase uterine blood flow (Carr, et al 2016; David, et al 2008; Mehta, et al 2014; Oyston, et al 2016; Satterfield, et al 2010; von Dadelszen, et al 2011). Despite this progress, animal studies are required to evaluate the effect of these interventions on the fetal pathophysiological processes described in this review and to refine further the therapies to specific complications of placental insufficiency.…”

Section: Future Directionsmentioning

confidence: 99%

The impact of IUGR on pancreatic islet development and β-cell function

Boehmer

Limesand

Rozance

2017

Journal of Endocrinology

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Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.

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Section: Future Directionsmentioning

confidence: 99%

The impact of IUGR on pancreatic islet development and β-cell function

Boehmer

Limesand

Rozance

2017

Journal of Endocrinology

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“…Sildenafil is well tolerated in pregnancy . Animal models, ex vivo and in vivo human studies, and observational cohorts suggest that it augments uteroplacental circulation, enhances fetal growth and improves short‐term neonatal outcomes for infants affected by fetal growth restriction. High‐quality randomised placebo‐controlled trials designed to assess both safety and efficacy are required before the introduction of antenatal sildenafil therapy into clinical practice should be considered.…”

Section: Introductionmentioning

confidence: 99%

STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early‐onset fetal growth restriction

Groom

McCowan

Mackay

et al. 2019

BJOG

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Objective To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction.Design A randomised placebo-controlled trial.Setting Thirteen maternal-fetal medicine units across New Zealand and Australia.Population Women with singleton pregnancies affected by fetal growth restriction at 22 +0 to 29 +6 weeks.Methods Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32 +0 weeks, birth or fetal death (whichever occurred first). Main Outcome MeasuresThe primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia.Results Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and newonset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75).Conclusions Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing.Keywords Fetal growth restriction, intrauterine growth restriction, pre-eclampsia, sildenafil, small for gestational age, uterine artery Doppler.Tweetable abstract Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

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“…We used sildenafil as an intravenous infusion to the fetus. Studies on the use of sildenafil in placental insufficiency administer the drug to the mother over a period of days to weeks 13,29 as opposed to hours in the present study. Therefore, extrapolation of these results to human pregnancy should be done cautiously.…”

Section: Discussionmentioning

confidence: 99%

Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia

et al. 2019

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Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

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Maternal Administration of Sildenafil Citrate Alters Fetal and Placental Growth and Fetal–Placental Vascular Resistance in the Growth-Restricted Ovine Fetus

Cited by 42 publications

References 43 publications

The impact of IUGR on pancreatic islet development and β-cell function

The impact of IUGR on pancreatic islet development and β-cell function

STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early‐onset fetal growth restriction

Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia

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