Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction

Abstract

IMPORTANCE Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. OBJECTIVE To determine whether sildenafil reduces perinatal mortality or major morbidity. DESIGN, SETTING, AND PARTICIPANTS This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped

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

“…Likewise, a lack of difference in cerebrorenal oxygenation status combined with absence of any observable increase in cerebroplacental ratio or birth weight, suggests that sildenafil did not improve placental function and fetal hemodynamics in this cohort. This is in line with the findings of the individual STRIDER studies, which reported no improvement of uteroplacental perfusion, fetal hemodynamics and growth after sildenafil treatment ( 12 – 14 ). While this lack of effect questions the general use of sildenafil, it may also relate to insufficient power or underdosage of sildenafil, since in animal studies, higher sildenafil dosages resulted in greater effects on fetal growth ( 10 ).…”

“…The STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset fetal growth Restriction) collaboration set up aligned RCTs allocating pregnant women with FGR to either sildenafil or placebo (11). The individual trials demonstrated lack of improved fetal growth and other maternal and perinatal outcomes (12)(13)(14). However, the Dutch STRIDER was halted due to futility and higher rates of persistent pulmonary hypertension (PPHN) and mortality in sildenafil-exposed neonates (14).…”

“…The individual trials demonstrated lack of improved fetal growth and other maternal and perinatal outcomes (12)(13)(14). However, the Dutch STRIDER was halted due to futility and higher rates of persistent pulmonary hypertension (PPHN) and mortality in sildenafil-exposed neonates (14). The hemodynamic mechanisms of sildenafil underlying either benefit or harm are unknown.…”

Phosphodiesterase type 5 inhibitor use among pregnant and reproductive‐age women in the United States

“…In July 2018, the Dutch STRIDER trial was terminated prematurely because of excessive neonatal deaths in babies whose mothers were treated with sildenafil for EO-FGR. 7,8 At the time of trial termination, 183 women were enrolled. The neonatal mortality rate was 27% (19/71) in the sildenafil group compared to 14% (9/63) in the placebo group (risk ratio = 1.87, 95% confidence interval: 0.91-3.84).…”

“…9 During preparation of this manuscript, further investigation including the planned IPD meta-analysis is underway to understand whether the increased neonatal mortality observed in the Dutch STRIDER trial was caused by sildenafil treatment or other maternal or child health conditions and the inconsistency of neonatal birth outcomes in STRIDER across centers. 8 Phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil are both approved by the US Food and Drug Administration (FDA) to treat pulmonary arterial hypertension (PAH) in adults, and erectile dysfunction in men. Although current guidelines recommend that women with PAH should avoid pregnancy due to high maternal mortality, 10 some women may choose to carry a pregnancy.…”