Sildenafil Applications in Fetal Growth Restriction

Sildenafil, a selective phosphodiesterase-5 inhibitor originally licensed for pulmonary arterial hypertension, has emerged as a candidate therapy for fetal growth restriction (FGR), a condition in which the placenta fails to supply sufficient nutrients and oxygen to the developing fetus. By enhancing nitric oxide–mediated vasodilatation, sildenafil can improve uteroplacental blood flow, potentially supporting fetal weight gain and prolonging gestation. Preclinical studies in rodent models have demonstrated that maternal sildenafil administration increases placental perfusion, raises birth weights and, in some cases, confers neuroprotective effects by mitigating intrauterine hypoxia. Early clinical trials and systematic evaluations have explored dosing strategies, maternal safety and neonatal outcomes. These investigations reveal that while sildenafil may increase birth weight and extend pregnancy duration, there is a concurrent elevation in the risk of neonatal pulmonary hypertension. Optimising the balance between efficacy and safety remains the principal challenge. Ongoing efforts include refined pharmacokinetic modelling to predict maternal–fetal drug exposure and careful monitoring of maternal side-effects. The global burden of FGR, particularly in low-resource settings, underscores the need for accessible interventions; sildenafil offers a promising, repurposed approach that could benefit diverse populations once its risk profile is fully characterised.

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Sildenafil Applications in Fetal Growth Restriction publication trend

The graph below shows the total number of articles in sildenafil applications in fetal growth restriction across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphodiesterase-5 (PDE-5) inhibitor: A compound that blocks the enzyme responsible for breaking down cyclic guanosine monophosphate (cGMP), thereby enhancing nitric oxide–mediated vasodilatation in blood vessels.

Uteroplacental blood flow: The circulation of maternal blood through the uterine and placental vessels that delivers oxygen and nutrients to the fetus.

Physiologically based pharmacokinetic (PBPK) modelling: A computational approach that uses mathematical descriptions of drug absorption, distribution, metabolism and excretion in maternal and fetal compartments to predict concentration–time profiles.

Pulmonary hypertension: A condition characterised by elevated blood pressure within the pulmonary arteries; in neonates, it may arise from altered vascular tone and lead to respiratory compromise.

Umbilical artery pulsatility index: A Doppler ultrasound measurement reflecting placental resistance; higher values indicate increased vascular impedance and are often associated with FGR.

References

1. PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia. Frontiers in Pharmacology (2023).
2. Safety and efficacy of phosphodiesterase-5 (PDE-5) inhibitors in fetal growth restriction: a systematic literature review and meta-analysis. Journal of Pharmacy & Pharmaceutical Sciences (2024).
3. Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction. JAMA Network Open (2020).
4. Sildenafil Citrate Increases Fetal Weight in a Mouse Model of Fetal Growth Restriction with a Normal Vascular Phenotype. PLOS ONE (2013).
5. Effects and mechanisms of action of sildenafil citrate in human chorionic arteries. Reproductive Biology and Endocrinology (2009).