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Randomized Controlled Trial
. 2025 Jul 8;334(2):149-159.
doi: 10.1001/jama.2025.7710.

Intrapartum Sildenafil to Improve Perinatal Outcomes: A Randomized Clinical Trial

Sailesh Kumar  1   2   3 , William Tarnow-Mordi  4 , Ben W Mol  5 , Vicki Flenady  1   2 , Helen G Liley  1 , Nadia Badawi  6   7 , Susan Walker  8 , Jonathan Hyett  9   10 , Anna Lene Seidler  4   11   12 , Emily Callander  13 , John Simes  4 , Rachel L O'Connell  4 ; iSEARCH Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Intrapartum Sildenafil to Improve Perinatal Outcomes: A Randomized Clinical Trial

Sailesh Kumar et al. JAMA. .

Abstract

Importance: Sildenafil citrate may increase uteroplacental blood flow. Its ability to reduce perinatal complications related to fetal hypoxia during labor is uncertain.

Objective: To compare the effectiveness of intrapartum maternal oral sildenafil citrate vs placebo in improving perinatal outcomes potentially related to intrapartum hypoxia in term pregnancies.

Design, setting, and participants: This pragmatic, multicenter, investigator-initiated, placebo-controlled randomized clinical trial including 3257 women was conducted in 13 Australian hospitals from September 6, 2021, to June 28, 2024. The last date of follow-up (28-day neonatal mortality) was July 26, 2024. Women aged 18 years or older with singleton or dichorionic twin pregnancies, planning vaginal birth at term by either spontaneous labor or induction of labor, were recruited.

Interventions: Women were assigned to 50 mg oral sildenafil citrate every 8 hours up to 150 mg or equivalent placebo.

Main outcome and measures: The primary composite outcome was intrapartum stillbirth, neonatal death, Apgar score less than 4 at 5 minutes (a score of <4 at 5 minutes is indicative of severe neonatal depression at birth, with scores ranging from 0 to 10), acidosis at birth (umbilical cord artery pH <7.0), hypoxic ischemic encephalopathy, neonatal seizures, neonatal respiratory support for greater than 4 hours, neonatal unit admission for greater than 48 hours, persistent pulmonary hypertension of the newborn, or meconium aspiration syndrome. Secondary outcomes were the individual components of the primary composite and emergency cesarean delivery or instrumental birth for intrapartum fetal distress.

Results: A total of 3257 women were randomized to sildenafil citrate (n = 1626 women and 1634 infants) or placebo (n = 1631 women and 1641 infants). Mean (SD) maternal age and gestation at randomization were similar in both groups (31.7 [5.1] vs 31.5 [5.0] years and 39.5 [1.2] vs 39.5 [1.1] weeks, respectively). A total of 868 participants (53.4%) vs 874 participants (53.6%) were of Australia/New Zealand ethnicity and 315 participants (19.4%) vs 311 participants (19.1%) were of European ethnicity. Most participants were nulliparous (944 of 1624 [58.1%; 2 missing values] vs 966 of 1630 [59.3%; 1 missing value]). Induction of labor occurred in 1353 of 1621 women (83.5%) in the sildenafil citrate group and 1348 of 1627 women (82.9%) in the placebo group. The primary outcome occurred in 83 of 1625 women (5.1%) in the sildenafil citrate group and 84 of 1625 (5.2%) in the placebo group (relative risk, 1.02; 95% CI, 0.75-1.37). Sildenafil citrate had no significant effect on emergency cesarean delivery or instrumental vaginal birth for fetal distress (relative risk, 1.12; 95% CI, 0.98-1.29) or on any of the individual components of the primary outcome. Subgroup analyses showed no evidence of heterogeneity of treatment effect.

Conclusions and relevance: Sildenafil citrate did not result in a lower incidence of adverse perinatal outcomes potentially related to intrapartum hypoxia.

Trial registration: anzctr.org.au Identifier: ACTRN12621000231842.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kumar reported grants from the National Health and Medical Research Council (NHMRC) during the conduct of the study. Dr Tarnow-Mordi reported grants from NHMRC during the conduct of the study. Dr Mol reported consultancy fees, travel support, and grants from Merck KGaA; and consultancy fees from Ferring, Organon, and Norgine outside the submitted work. Dr Flenady reported serving as chief investigator for the Stillbirth Centre of Research Excellence, funded by NHMRC. Dr Simes reported grants from Roche, Merck Sharp & Dohme, Bayer, Bristol Myers Squibb, and Amgen to his institution outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Randomization, Delivery, and Assessment of Patients in a Clinical Trial of Sildenafil
aReasons women were excluded are not shown because this information was not routinely recorded by participating sites.
Figure 2.
Figure 2.. Prespecified Subgroup Analyses According to Maternal and Neonatal Characteristics
The forest plot shows relative risks and 95% CIs in a comparison of sildenafil citrate with placebo on the composite primary end point. The size of the squares is proportional to the amount of statistical information in that category (ie, the inverse of the variance). Interaction tests between treatment and subgroup were not significant (P > .05). aThe overall treatment effect is based on a generalized estimating equation log-binomial model. Effects within subgroups were estimated using a generalized linear log-binomial model because the analysis was exploratory and because of the small number of twins within subgroups.
See this image and copyright information in PMC

References

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