Prenatal Use of Sildenafil in Fetal Growth Restriction and Its Effect on Neonatal Tissue Oxygenation—A Retrospective Analysis of Hemodynamic Data From Participants of the Dutch STRIDER Trial

Abstract

Objective: Sildenafil is under investigation as a potential agent to improve uteroplacental perfusion in fetal growth restriction (FGR). However, the STRIDER RCT was halted after interim analysis due to futility and higher rates of persistent pulmonary hypertension and mortality in sildenafil-exposed neonates. This hypothesis-generating study within the Dutch STRIDER trial sought to understand what happened to these neonates by studying their regional tissue oxygen saturation (rSO2) within the first 72 h after birth.Methods: Pregnant women with FGR received 25 mg placebo or sildenafil thrice daily within the Dutch STRIDER trial. We retrospectively analyzed the cerebral and renal rSO2 monitored with near-infrared spectroscopy (NIRS) in a subset of neonates admitted to two participating neonatal intensive care units, in which NIRS is part of standard care. Secondarily, blood pressure and heart rate were analyzed to aid interpretation. Differences in oxygenation levels and interaction with time (slope) between placebo- and sildenafil-exposed groups were tested using mixed effects analyses with multiple comparisons tests.Results: Cerebral rSO2 levels were not different between treatment groups (79 vs. 77%; both n = 14) with comparable slopes. Sildenafil-exposed infants (n = 5) showed lower renal rSO2 than placebo-exposed infants (n = 6) during several time intervals on day one and two. At 69–72 h, however, the sildenafil group showed higher renal rSO2 than the placebo group. Initially, diastolic blood pressure was higher and heart rate lower in the sildenafil than the placebo group, which changed during day two.Conclusions: Although limited by sample size, our data suggest that prenatal sildenafil alters renal but not cerebral oxygenation in FGR neonates during the first 72 post-natal hours. The observed changes in renal oxygenation could reflect a vasoconstrictive rebound from sildenafil. Similar changes observed in accompanying vital parameters support this hypothesis.

Tadalafil for Treatment of Fetal Growth Restriction: A Review of Experimental and Clinical Studies

“…Based on the findings from these small clinical studies, the Sildenafil TheRapy in Dismal prognosis Early-onset intrauterine growth Restriction (STRIDER) consortium was launched. The study group evaluated sildenafil for the treatment of FGR with a prospective Individual Participant Data (IPD) and aggregate data systematic review with a meta-analysis and trial sequential analysis [34][35][36][37][38][39][40]. The STRIDER consortium, including the United Kingdom (UK), the Netherlands, New Zealand/Australia, and Canada, conducted randomized controlled trials examining the effects of sildenafil for the treatment of FGR [34].…”

“…Based on the above, the benefits of sildenafil for the treatment of FGR are considered negative, and even harmful [11,41]. Subsequent data from neonates born to the Dutch STRIDER participants have been evaluated for causes of PPHN [40]. In that study, the authors speculated that sildenafil may have had a "rebound effect" on neonates due to sudden withdrawal of the drug at birth.…”

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

“…The trial’s authors recently reported in more detail on the patients with pulmonary hypertension (PH) and deceased neonates, describing a higher incidence of early PH in sildenafil-exposed cases, yet without difference in late-onset PH or PH-related mortality [ 89 ]. Finally, the group also reported on the use of near-infrared spectroscopy in a very small subset of newborn patients, which revealed that sildenafil-treated patients had lower renal but not cerebral oxygenation during the first 72 h of life [ 90 ].…”

Fetal Biometric Assessment and Infant Developmental Prognosis of the Tadalafil Treatment for Fetal Growth Restriction

“…These are candidates for new therapeutic agents to improve uteroplacental perfusion, and their efficacy and safety have been reported in several studies. The Sildenafil Therapy in Dismal Prognosis Early-onset Fetal Growth Restriction (STRIDER) consortium has been trying to provide evidence of the benefit of sildenafil citrate for FGR treatment [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. The STRIDER UK study reported no benefits of sildenafil for pregnancy prolongation, survival, or short-term neonatal outcomes [ 18 ].…”