Intrapartum Sildenafil to Improve Perinatal Outcomes: A Randomized Clinical Trial

Uterine contractions during labor reduce placental perfusion, which limits fetal oxygenation. Intrapartum fetal hypoxia and acidemia occur when there is insufficient reperfusion time between contractions or when placental dysfunction restricts oxygen transfer. The risks of hypoxic-ischemic injury during labor include intrapartum stillbirth, neonatal death, and neonatal encephalopathy. Emergency cesarean or instrumental deliveries are often required when fetal acidemia is suspected, though these interventions carry increased maternal and neonatal risk. Despite widespread use of electronic fetal heart rate monitoring to detect fetal compromise, rates of cerebral palsy, perinatal mortality, and other neonatal well-being measures have not improved. This highlights the need for more effective strategies to prevent adverse perinatal outcomes related to hypoxic injury. Phosphodiesterase type 5 inhibitors may be used to improve uteroplacental perfusion and enhance vasoconstriction in uterine and spinal arteries. Sildenafil citrate, a PDE5 inhibitor, has been used for indications related to placental dysfunction, to treat maternal hypertension, or both. A previous phase II randomized clinical trial (RCT) found that oral sildenafil reduced operative birth for fetal distress by 51% compared with placebo, but was underpowered to assess perinatal outcomes. The aim of this study was to assess whether oral sildenafil citrate during labor improves perinatal outcomes related to intrapartum hypoxia.The iSEARCH trial was a placebo-controlled, double-blind RCT conducted at 14 Australian hospitals from September 2021 to June 2024. Included were adult women with singleton or dichorionic twin pregnancies attempting vaginal birth at term, either by spontaneous labor or induction of labor. Excluded were those with monochorionic twins, triplets, higher-order multifetal gestation, or severe hepatic or kidney impairment. Also excluded were those taking nitrate-containing medications or other PDE inhibitors. Study participants were randomized 1:1 to receive 50 mg sildenafil citrate or a placebo every 8 hours for a maximum of 3 doses. The primary outcome was a composite of 10 intrapartum or neonatal events, including intrapartum stillbirth, 28-day neonatal death, Apgar score