Effect of sildenafil on maternal hemodynamics in pregnancies complicated by severe early-onset fetal growth restriction: planned subgroup analysis from a multicenter randomized placebo-controlled double-blind trial

OBJECTIVES: Fetal growth restriction (FGR) is associated with maternal cardiovascular changes. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide and has been proposed to alter maternal hemodynamics, potentially improving placental perfusion. Recently, the Dutch trial was stopped prematurely due to excess neonatal mortality secondary to pulmonary hypertension. The main aim of this study was to investigate the effect of sildenafil on maternal hemodynamics in pregnancies with severe early-onset FGR.

METHODS: In this UK multicenter, placebo-controlled trial, we randomly assigned 135 women with singleton pregnancies and severe early-onset FGR (defined as a combination of estimated fetal weight or abdominal circumference below the 10th centile and absent/reversed end diastolic flow in the umbilical artery on Doppler velocimetry diagnosed between 22+0 -29+6 weeks' gestation), to receive either sildenafil 25mg three times daily or placebo until 32+0 weeks' gestation or delivery. The maternal blood pressure (BP), heart rate (HR), augmentation index, pulse wave velocity (PWV), cardiac output, stroke volume (SV) and total peripheral resistance were recorded before, 1-2 hours after, and 48-72 hours post-randomization, and 24-48 hours postnatally. For continuous data, the analysis was performed using repeated measures ANOVA methods including terms for time, treatment allocation and their interaction.

RESULTS: Sildenafil increased maternal HR by 4bpm when compared to placebo [5bpm (95%CI: 1, 12) vs 1 (-5, 8); P=0.004] and reduced systolic BP by 1mmHg more than placebo [-4mmHg (-9, 1) vs -3mmHg (-8, 5); P=0.048]. Even after adjusting for maternal BP, sildenafil reduced aortic PWV by 0.6 m/sec more than placebo did [-0.90m/sec (-1.31, -0.51) vs -0.26 (-0.75, 0.59); P=0.001]. Sildenafil was associated with a non-significant decrease in the SV index [-5.5m/m2 /beat (-11, -0.5) vs 0 (-0.5, 4); P=0.056].

CONCLUSIONS: Sildenafil in a dose of 25 mg three times daily increases HR, reduces BP and reduces arterial stiffness in pregnancies complicated by FGR. These changes are modest, consistent with the anticipated vasodilatory effect and their clinical impact on the mother and baby, in both the short- and long-term, remains uncertain. This article is protected by copyright. All rights reserved.