{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:22:50Z","timestamp":1788916970536,"version":"build-2803163510"},"reference-count":44,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>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.<\/jats:p><\/jats:sec>Objective<\/jats:title>To determine whether sildenafil reduces perinatal mortality or major morbidity.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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.<\/jats:p><\/jats:sec>Interventions<\/jats:title>Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.<\/jats:p><\/jats:sec>Results<\/jats:title>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<\/jats:italic>\u2009=\u2009.38). 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<\/jats:italic>\u2009=\u2009.008).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT02277132<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2020.5323","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T12:09:55Z","timestamp":1592395795000},"page":"e205323","source":"Crossref","is-referenced-by-count":121,"title":["Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction"],"prefix":"10.1001","volume":"3","author":[{"given":"Anouk","family":"Pels","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Derks","sequence":"additional","affiliation":[{"name":"Wilhelmina Children\u2019s Hospital, Department of Obstetrics, 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