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    Original Investigation
    Obstetrics and Gynecology
    June 17, 2020

    Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
    • 2Wilhelmina Children’s Hospital, Department of Obstetrics, University Medical Center Utrecht, Gynecology and Neonatology, Utrecht, the Netherlands
    • 3Department of Obstetrics and Gynecology, University Medical Center Groningen, Groningen, the Netherlands
    • 4Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands
    • 5Department of Obstetrics and Gynecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
    • 6Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands
    • 7Department of Obstetrics and Gynecology, Maxima Medical Center, Veldhoven, the Netherlands
    • 8Department of Obstetrics and Gynecology, Isala Hospital, Zwolle, the Netherlands
    • 9Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, the Netherlands
    • 10Department of Obstetrics and Gynecology, Leiden University Medical Center, Leiden, the Netherlands
    • 11Department of Obstetrics and Gynecology, Medical Center Leeuwarden, Leeuwarden, the Netherlands
    • 12Emma Children’s Hospital, Amsterdam UMC, Department of Neonatology, University of Amsterdam, Amsterdam, the Netherlands
    • 13The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
    • 14Department of Cardiology, Holbæk Hospital, Holbæk, Denmark
    • 15Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
    JAMA Netw Open. 2020;3(6):e205323. doi:10.1001/jamanetworkopen.2020.5323
    Key Points español 中文 (chinese)

    Question  Does sildenafil reduce the risk of perinatal mortality or morbidity in children of pregnant women with severe early onset fetal growth restriction?

    Findings  In this randomized clinical trial including 216 pregnant women, perinatal mortality or major morbidity was not statistically different and occurred in the offspring of 60.2% of participants allocated to sildenafil vs 54.2% of those allocated to placebo. Pulmonary hypertension occurred in 18.8% of neonates in the sildenafil group compared with 5.1% of neonates in the placebo group, which was statistically significantly different.

    Meaning  These findings suggest that treatment of severe early onset fetal growth restriction by maternal sildenafil did not reduce the risk of perinatal mortality or major neonatal morbidity, but increased neonatal pulmonary hypertension was observed.

    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 early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.

    Interventions  Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.

    Main Outcomes and Measures  The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.

    Results  Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).

    Conclusions and Relevance  These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02277132

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