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

Jim Van Eyck,Sanne J Gordijn ,J Van Drongelen ,Titia Lely,Marieke Sueters,Judith Van Laar,Aleid Van Wassenaer-Leemhuis,Wes Onland,Marjon A De Boer ,Anouk Pels,Wessel Ganzevoort,Janus Christian Jakobsen ,Jan Derks,Christiana Naaktgeboren,Marinka S Post ,Salwan Al‐Nasiry ,Ayten Elvan-Taşpınar ,Ruben G Duijnhoven,Christian Gluud,Hans Duvekot

doi:10.1001/jamanetworkopen.2020.5323

Abstract

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. To determine whether sildenafil reduces perinatal mortality or major morbidity. 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. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. 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). 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. ClinicalTrials.gov Identifier: NCT02277132.

Highlights

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction. 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
The main consideration for the data safety monitoring board (DSMB) to recommend stopping was an increased incidence of neonatal pulmonary hypertension, whereas it was considered unlikely that benefit would be shown on the primary outcome of perinatal mortality or major neonatal morbidity until hospital discharge if the trial were continued to its completion

Summary

Introduction

Severe early onset fetal growth restriction is a rare condition, complicating approximately 0.4% of all pregnancies.[1,2] It is associated with a high risk of fetal death, iatrogenic preterm birth, long-lasting stay at the neonatal intensive care unit, neonatal mortality, and long-term morbidity.[3,4] Severe earlyonset fetal growth restriction is strongly associated with neurodevelopmental impairment later in childhood.[5,6] To our knowledge, no effective treatment to promote fetal growth has been identified, and management consists of intensive monitoring to determine the best moment to deliver the fetus, balancing the consequences of prematurity vs undernutrition and hypoxia.[7]Recently, phosphodiesterase type 5 inhibitors, most often sildenafil, have been investigated as potential treatment for fetal growth restriction.[8,9,10,11,12,13,14,15,16] The Sildenafil Therapy in Dismal Prognosis Early Onset Fetal Growth Restriction (STRIDER) consortium designed and conducted in synchrony 4 randomized clinical trials to study sildenafil’s hypothesized improvement of placental circulation through its effects on the uteroplacental circulation.[8,9,10,11,12,13,14,15,16] In the Dutch STRIDER trial, the hypothesis that sildenafil reduces the chance of perinatal mortality and morbidity was tested using a composite outcome of perinatal mortality and major neonatal morbidity.

Results

Discussion

Conclusion