Antenatal therapy with sildenafil: don't throw the baby out with the bathwater

Russo, Francesca Maria; Hooper, Stuart B.; Tibboel, Dick; DeKoninck, Philip; Benachi, Alexandra; Tréluyer, Jean‐Marc; Allegaert, Karel; Kumar, Sailesh; Deprest, Jan

doi:10.1002/uog.20201

Cited by 14 publications

(13 citation statements)

References 7 publications

(13 reference statements)

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“… 32 While this effect was not confirmed in other trial arms, prenatal use of sildenafil was since banned from further application despite our appeal to keep its indication for CDH. 33 , 34 Similarly, we conclude that based on our findings any investigation of prenatal treprostinil in conditions with normal lung development should be avoided, at least until the pathophysiologic mechanism is better understood.…”

Section: Discussionmentioning

confidence: 60%

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

et al. 2022

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Section: Discussionmentioning

confidence: 60%

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

et al. 2022

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“…The findings of the aforementioned studies might therefore not be applicable to fetuses without growth restriction. We have previously argued that prenatal sildenafil therapy should remain considered in CDH, primarily due to the different pulmonary pathophysiology between CDH and IUGR [40]. We and others have previously demonstrated in rat and rabbit models of CDH that the effect of antenatal sildenafil on hypoplastic versus control lungs is different [14, 15].…”

Section: Discussionmentioning

confidence: 99%

Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model

et al. 2021

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Background: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects. Methods: Twelve fetal lambs (127–133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored. Results: The transplacental sildenafil transfer was 2.9% (range: 1.4–7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38–78%) and increased both pulmonary blood flow (32–132%) and heart rate (13–49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion. Conclusion: In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe.

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“…When sildenafil was given to rodents and rabbits without DH, it decreased the number of distal vessels and decreased total vascular volume. Given the recent safety concerns regarding the use of antenatal sildenafil to treat intrauterine growth restriction (STRIDER), these worrying findings in rodents and rabbits may require further investigation in the lamb DH model before antenatal sildenafil treatment is considered for mild and moderate CDH cases that may not have significantly abnormal pulmonary vascular development.…”

Section: Discussionmentioning

confidence: 99%

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

Kashyap

DeKoninck

Rodgers

et al. 2019

Ultrasound in Obstet & Gyne

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Objectives Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). Methods DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH‐sildenafil lambs and six DH‐saline control lambs. Results Lung‐to‐body‐weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2O; P = 0.72) were similar in DH‐sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH‐sildenafil lambs, and was 4‐fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH‐sildenafil than in DH‐saline lambs at 120 min. Throughout the 120‐min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH‐sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. Conclusions Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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Antenatal therapy with sildenafil: don't throw the baby out with the bathwater

Cited by 14 publications

References 7 publications

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia

Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

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