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Visual Abstract. Maternal Sildenafil vs Placebo for Severe Early-Onset Fetal Growth Restriction
Maternal Sildenafil vs Placebo for Severe Early-Onset Fetal Growth Restriction
Figure.  CONSORT Flow Diagram
CONSORT Flow Diagram
Table 1.  Baseline Characteristics
Baseline Characteristics
Table 2.  Fetal or Neonatal Outcomes (Intention-to-Treat Analysis)a
Fetal or Neonatal Outcomes (Intention-to-Treat Analysis)a
Table 3.  Maternal Outcomes (Intention-to-Treat Analysis)a
Maternal Outcomes (Intention-to-Treat Analysis)a
Table 4.  Prespecified Sensitivity and Subgroup Analyses on the Primary Outcome According to Treatment
Prespecified Sensitivity and Subgroup Analyses on the Primary Outcome According to Treatment
1.
Perined. Yearbooks Healthcare in the Netherlands [in Dutch]. Accessed April 22, 2020. https://www.perined.nl/producten/jaarboeken
2.
Spencer  R, Rossi  C, Lees  M,  et al; EVERREST Consortium.  Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.   BJOG. 2019;126(9):1157-1167. doi:10.1111/1471-0528.15590PubMedGoogle ScholarCrossref
3.
Severi  FM, Rizzo  G, Bocchi  C, D’Antona  D, Verzuri  MS, Arduini  D.  Intrauterine growth retardation and fetal cardiac function.   Fetal Diagn Ther. 2000;15(1):8-19. doi:10.1159/000020969PubMedGoogle ScholarCrossref
4.
Pels  A, Beune  IM, van Wassenaer-Leemhuis  AG, Limpens  J, Ganzevoort  W.  Early-onset fetal growth restriction: a systematic review on mortality and morbidity.   Acta Obstet Gynecol Scand. 2020;99(2):153-166. doi:10.1111/aogs.13702PubMedGoogle ScholarCrossref
5.
Levine  TA, Grunau  RE, McAuliffe  FM, Pinnamaneni  R, Foran  A, Alderdice  FA.  Early childhood neurodevelopment after intrauterine growth restriction: a systematic review.   Pediatrics. 2015;135(1):126-141. doi:10.1542/peds.2014-1143 PubMedGoogle ScholarCrossref
6.
Murray  E, Fernandes  M, Fazel  M, Kennedy  SH, Villar  J, Stein  A.  Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review.   BJOG. 2015;122(8):1062-1072. doi:10.1111/1471-0528.13435PubMedGoogle ScholarCrossref
7.
Nardozza  LM, Caetano  AC, Zamarian  AC,  et al.  Fetal growth restriction: current knowledge.   Arch Gynecol Obstet. 2017;295(5):1061-1077. doi:10.1007/s00404-017-4341-9PubMedGoogle ScholarCrossref
8.
Paauw  ND, Terstappen  F, Ganzevoort  W, Joles  JA, Gremmels  H, Lely  AT.  Sildenafil during pregnancy: a preclinical meta-analysis on fetal growth and maternal blood pressure.   Hypertension. 2017;70(5):998-1006. doi:10.1161/HYPERTENSIONAHA.117.09690PubMedGoogle ScholarCrossref
9.
Sharp  A, Cornforth  C, Jackson  R,  et al; STRIDER group.  Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.   Lancet Child Adolesc Health. 2018;2(2):93-102. doi:10.1016/S2352-4642(17)30173-6PubMedGoogle ScholarCrossref
10.
Choudhary  R, Desai  K, Parekh  H, Ganla  K.  Sildenafil citrate for the management of fetal growth restriction and oligohydramnios.   Int J Womens Health. 2016;8:367-372. doi:10.2147/IJWH.S108370 PubMedGoogle ScholarCrossref
11.
Dastjerdi  MV, Hosseini  S, Bayani  L.  Sildenafil citrate and uteroplacental perfusion in fetal growth restriction.   J Res Med Sci. 2012;17(7):632-636.PubMedGoogle Scholar
12.
Samangaya  RA, Mires  G, Shennan  A,  et al.  A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia.   Hypertens Pregnancy. 2009;28(4):369-382. doi:10.3109/10641950802601278PubMedGoogle ScholarCrossref
13.
Trapani  A  Jr, Gonçalves  LF, Trapani  TF, Franco  MJ, Galluzzo  RN, Pires  MM.  Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices.   Ultrasound Obstet Gynecol. 2016;48(1):61-65. doi:10.1002/uog.15673PubMedGoogle ScholarCrossref
14.
Trapani  A  Jr, Gonçalves  LF, Trapani  TF, Vieira  S, Pires  M, Pires  MM.  Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial.   Obstet Gynecol. 2016;128(2):253-259. doi:10.1097/AOG.0000000000001518PubMedGoogle ScholarCrossref
15.
von Dadelszen  P, Dwinnell  S, Magee  LA,  et al; Research into Advanced Fetal Diagnosis and Therapy (RAFT) Group.  Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.   BJOG. 2011;118(5):624-628. doi:10.1111/j.1471-0528.2010.02879.xPubMedGoogle ScholarCrossref
16.
Russo  FM, Conings  S, Allegaert  K,  et al.  Sildenafil crosses the placenta at therapeutic levels in a dually perfused human cotyledon model.   Am J Obstet Gynecol. 2018;219(6):619.e1-619.e10. doi:10.1016/j.ajog.2018.08.041PubMedGoogle ScholarCrossref
17.
Ganzevoort  W, Bloemenkamp  K, von Dadelszen  P,  et al.  Dutch STRIDER: Data Monitoring Committee Charter.   Zenodo. June 21, 2016. doi:10.5281/zenodo.56147Google Scholar
18.
Webster  LM, Gill  C, Seed  PT,  et al.  Chronic hypertension in pregnancy: impact of ethnicity and superimposed preeclampsia on placental, endothelial, and renal biomarkers.   Am J Physiol Regul Integr Comp Physiol. 2018;315(1):R36-R47. doi:10.1152/ajpregu.00139.2017 PubMedGoogle ScholarCrossref
19.
Escouto  DC, Green  A, Kurlak  L,  et al.  Postpartum evaluation of cardiovascular disease risk for women with pregnancies complicated by hypertension.   Pregnancy Hypertens. 2018;13:218-224. doi:10.1016/j.preghy.2018.06.019 PubMedGoogle ScholarCrossref
20.
Dröge  LA, Höller  A, Ehrlich  L, Verlohren  S, Henrich  W, Perschel  FH.  Diagnosis of preeclampsia and fetal growth restriction with the sFlt-1/PlGF ratio: diagnostic accuracy of the automated immunoassay Kryptor.   Pregnancy Hypertens. 2017;8:31-36. doi:10.1016/j.preghy.2017.02.005 PubMedGoogle ScholarCrossref
21.
Hinojosa-Rodríguez  M, Harmony  T, Carrillo-Prado  C,  et al.  Clinical neuroimaging in the preterm infant: diagnosis and prognosis.   Neuroimage Clin. 2017;16:355-368. doi:10.1016/j.nicl.2017.08.015 PubMedGoogle ScholarCrossref
22.
Papile  LA, Burstein  J, Burstein  R, Koffler  H.  Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.   J Pediatr. 1978;92(4):529-534. doi:10.1016/S0022-3476(78)80282-0 PubMedGoogle ScholarCrossref
23.
Towbin  A.  Cerebral intraventricular hemorrhage and subependymal matrix infarction in the fetus and premature newborn.   Am J Pathol. 1968;52(1):121-140.PubMedGoogle Scholar
24.
Chen  CC, Huang  CB, Chung  MY, Huang  LT, Yang  CY.  Periventricular echogenicity is related to delayed neurodevelopment of preterm infants.   Am J Perinatol. 2004;21(8):483-489. doi:10.1055/s-2004-835966 PubMedGoogle ScholarCrossref
25.
Grunnet  ML.  Periventricular leukomalacia complex.   Arch Pathol Lab Med. 1979;103(1):6-10.PubMedGoogle Scholar
26.
Bancalari  E, Claure  N.  Definitions and diagnostic criteria for bronchopulmonary dysplasia.   Semin Perinatol. 2006;30(4):164-170. doi:10.1053/j.semperi.2006.05.002 PubMedGoogle ScholarCrossref
27.
Finer  NN, Bates  R, Tomat  P.  Low flow oxygen delivery via nasal cannula to neonates.   Pediatr Pulmonol. 1996;21(1):48-51. doi:10.1002/(SICI)1099-0496(199601)21:1<48::AID-PPUL8>3.0.CO;2-M PubMedGoogle ScholarCrossref
28.
Jobe  AH, Bancalari  E.  Bronchopulmonary dysplasia.   Am J Respir Crit Care Med. 2001;163(7):1723-1729. doi:10.1164/ajrccm.163.7.2011060 PubMedGoogle ScholarCrossref
29.
Walsh  MC, Wilson-Costello  D, Zadell  A, Newman  N, Fanaroff  A.  Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia.   J Perinatol. 2003;23(6):451-456. doi:10.1038/sj.jp.7210963PubMedGoogle ScholarCrossref
30.
Walsh  MC, Yao  Q, Gettner  P,  et al; National Institute of Child Health and Human Development Neonatal Research Network.  Impact of a physiologic definition on bronchopulmonary dysplasia rates.   Pediatrics. 2004;114(5):1305-1311. doi:10.1542/peds.2004-0204 PubMedGoogle ScholarCrossref
31.
Bell  MJ, Ternberg  JL, Feigin  RD,  et al.  Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging.   Ann Surg. 1978;187(1):1-7. doi:10.1097/00000658-197801000-00001PubMedGoogle ScholarCrossref
32.
Hintz  SR, Kendrick  DE, Stoll  BJ,  et al; NICHD Neonatal Research Network.  Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis.   Pediatrics. 2005;115(3):696-703. doi:10.1542/peds.2004-0569PubMedGoogle ScholarCrossref
33.
Heath  P.  Pathology of the retinopathy of prematurity: retrolental fibroplasia.   Am J Ophthalmol. 1951;34(9):1249-1259. doi:10.1016/0002-9394(51)91859-4PubMedGoogle ScholarCrossref
34.
Hellström  A, Smith  LE, Dammann  O.  Retinopathy of prematurity.   Lancet. 2013;382(9902):1445-1457. doi:10.1016/S0140-6736(13)60178-6PubMedGoogle ScholarCrossref
35.
Tranquilli  AL, Brown  MA, Zeeman  GG, Dekker  G, Sibai  BM; Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP).  The definition of severe and early-onset preeclampsia.   Pregnancy Hypertens. 2013;3(1):44-47. doi:10.1016/j.preghy.2012.11.001PubMedGoogle ScholarCrossref
36.
Bayley  N.  Bayley Scales of Infant and Toddler Development. 3rd ed. Pearson Assessments; 2006.
37.
Healy  P, Gordijn  SJ, Ganzevoort  W,  et al.  A core outcome set for the prevention and treatment of fetal growth restriction: developing endpoints: the COSGROVE study.   Am J Obstet Gynecol. 2019;221(4):339.e1-339.e10. doi:10.1016/j.ajog.2019.05.039PubMedGoogle ScholarCrossref
38.
Pels  A, Jakobsen  JC, Ganzevoort  W,  et al.  Detailed statistical analysis plan for the Dutch STRIDER (Sildenafil Therapy in Dismal Prognosis Early-Onset Fetal Growth Restriction) randomised clinical trial on sildenafil versus placebo for pregnant women with severe early onset fetal growth restriction.   Trials. 2019;20(1):42. doi:10.1186/s13063-018-3136-zPubMedGoogle ScholarCrossref
39.
Sharp  A, Cornforth  C, Jackson  R,  et al; STRIDER group.  Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.   Lancet Child Adolesc Health. 2018;2(2):93-102. doi:10.1016/S2352-4642(17)30173-6PubMedGoogle ScholarCrossref
40.
Groom  KM, McCowan  LM, Mackay  LK,  et al.  STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.   BJOG. 2019;126(8):997-1006. doi:10.1111/1471-0528.15658PubMedGoogle Scholar
41.
Ganzevoort  W, Alfirevic  Z, von Dadelszen  P,  et al.  STRIDER: Sildenafil Therapy in Dismal Prognosis Early-Onset Intrauterine Growth Restriction—a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis.   Syst Rev. 2014;3:23. doi:10.1186/2046-4053-3-23PubMedGoogle ScholarCrossref
42.
European Medicines Agency. Guideline on multiplicity issues in clinical trials. Accessed April 22, 2020. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-issues-clinical-trials_en.pdf
43.
US Food and Drug Administration. FDA Drug Safety Communication: FDA clarifies warning about pediatric use of Revatio (sildenafil) for pulmonary arterial hypertension. Updated January 2016. Accessed April 22, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-clarifies-warning-about-pediatric-use-revatio-sildenafil-pulmonary
44.
Martin  A, Lines  A. 'Viagra saved my baby's life': Mum's 11-week premature child still alive thanks to anti-impotence drug. Mirror. October 9, 2015. Accessed April 22, 2020. https://www.mirror.co.uk/news/uk-news/viagra-saved-babys-life-mums-6606806
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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

    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 early-onset fetal growth restriction is also 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.8-16 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.8-16 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.

    Methods

    We conducted this placebo-controlled randomized clinical trial in 10 tertiary care centers and 1 general hospital in the Netherlands. Ethical approval was granted by Amsterdam UMC. All participating women provided written informed consent. The protocol was registered on September 29, 2014 (Trial Protocol in Supplement 1), before the first participant was randomized. This study is reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Study Design

    An independent data safety monitoring board (DSMB) monitored the safety of the participants after data were available for each 50 participants, as well as the efficacy after the outcomes were known for half of the participants.17 The DSMB charter included the provision to recommend stopping the trial in case the safety of current or future participants was considered to be compromised. Furthermore, a stopping rule was included, indicating that the trial would be stopped if a significant difference between the 2 treatment groups was observed at interim analysis (according to the O’Brien-Fleming spending function, P < .005).

    Participants

    Pregnant women were eligible if they were between 20 weeks 0 days and 27 weeks 6 days of gestation and if the fetal abdominal circumference was below the 3rd percentile or the estimated fetal weight (EFW) below the 5th percentile, combined with either unilateral or bilateral notching of the uterine artery, Pulsatility Index (PI) of the umbilical artery above the 95th percentile, PI of the middle cerebral artery below the 5th percentile, or a maternal hypertensive disorder. Participants with gestation between 28 weeks 0 days and 29 weeks 6 days were eligible if the EFW was less than 700 g, combined with the aforementioned Doppler anomalies or a maternal hypertensive disorder, to select the patients with unfavorable prognosis. Gestational age estimation was based on a first trimester ultrasound. Exclusion criteria were anticipated imminent termination of pregnancy for maternal or fetal indications, multifetal pregnancy, identified congenital anomalies (affecting outcomes), identified congenital infection, maternal age younger than 18 years, cocaine use, current use of sildenafil, current use of cytochrome P450 3A5 isozyme inhibitors, and recent myocardial infarction or stroke.

    Maternal race/ethnicity was collected because maternal race/ethnicity is associated with placental dysfunction and pregnancy outcomes.18,19 Whether the maternal race/ethnicity was European descent, African descent, or Asian descent was indicated by the investigator. In case of doubt, the patient was asked to report her race/ethnicity.

    In participating centers, samples of maternal blood were collected at randomization by venipuncture and stored at −80 °C for batch testing of placental growth factor (PGF) level. Measurement of PGF level was performed on the Kryptor immunoassay (Thermo Fisher Scientific) and compared with the fifth percentile of a reference population (ie, 106.54 pg/mL).20

    Randomization and Masking

    The web-based randomization had a 1:1 ratio, random block sizes of 2 to 6, and was stratified per participating center. Participants, clinicians, investigators, and outcome assessors were blinded for the treatment allocation.

    Procedures

    Trial medication was manufactured specifically for this trial by Tiofarma, and tablets contained either sildenafil 25 mg or placebo and were taken orally 3 times daily. Active and placebo medications were matching in color, size, weight, and taste. The dosage regimen was based on previous studies by the collaborators on this project.12,15

    Participants used the trial medication until fetal death, 32 weeks of gestation, or birth. Adherence was participant-reported at each antenatal outpatient clinic visit, Additionally, at the end of the exposure period, medication bottles were collected, and the remaining number of tablets was counted. Participants kept a record of adverse effects. Trial medication was ended at the discretion of the patient. The fetal monitoring (ultrasonography and cardiotocography) and interventions other than the trial medication were at the discretion of the attending gynecologist and in line with Dutch national guidelines and local protocols, depending on the gestational age and EFW. In most participating centers, active management was installed after extensive counseling of parents by a gynecologist and neonatologist and at a minimum gestational age of 26 weeks 0 days combined with an EFW of 500 g. Data were collected from the patient’s electronic health record and entered into a secure electronic database (REDCAP).

    Outcomes

    The primary outcome was a composite of either perinatal mortality or major neonatal morbidity before the neonate was discharged from the hospital. Major neonatal morbidity was defined as intraventricular hemorrhage grade 3 or more,21-23 periventricular leukomalacia grade 2 or more,24,25 moderate or severe bronchopulmonary dysplasia,26-30 necrotizing enterocolitis Bell stage 2 or more,31,32 or retinopathy of prematurity requiring laser therapy.33,34 We defined the neonatal period as the time until hospital discharge. Mortality after hospital discharge was considered not to be the mortality of interest in the primary outcome, since the chance of this mortality being associated with the intervention was considered small.

    The secondary outcomes were (1) the proportion of mothers experiencing either pre-eclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome35; (2) PI of umbilical artery. the first PI measured at the ultrasound performed more than 24 hours after start trial medication; (3) birth weight, with birth weight of live born neonates and birth weight of stillborn fetuses described separately; (4) gestational age at birth or fetal death; and (5) the proportion of neonates with neurodevelopmental impairment at age 2 years, assessed on the 2-year Bayley Scales of Infant Development, Third Edition (BSID-III)36 and its cognitive and motor subscales. The latter secondary outcome is not reported here because the 2-year follow-up is not yet complete. When possible, we reported outcomes according to the core outcome set for fetal growth restriction that was developed after the start of the trial.37

    Statistical Analysis

    We aimed to find a decrease in the incidence of the primary outcome from 71%15 in the control group to 56% in the experimental group, which is equal to a relative risk reduction of 21%. Allowing for 10% loss to follow-up and interim analysis for efficacy according to the O’Brien-Fleming spending function (P < .005), and with an accepted type I error of 5% and type II error of 80%, we needed to randomize 180 women per group.

    The statistical analysis plan, published elsewhere and available in Supplement 1),38 provides the details of the statistical analysis. In short, the prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Additionally, several prespecified sensitivity analyses were conducted for the primary outcome: adjusting for gestational age and EFW at randomization; only including participants who had a fetus or neonate without any congenital anomaly that could either explain the small fetal size in hindsight or would have a likely effect on the primary outcome (originally defined as a subgroup analysis, since not all congenital anomalies can be known antenatally); and a per-protocol analysis for the primary outcome that included only participants who used at least 1 tablet of trial medication. Relative risks were calculated using generalized linear models (log link function), and continuous outcomes were analyzed using linear regression.38

    Predefined subgroup analyses were conducted for participants with a serum level of PGF (categorized as less than the fifth percentile and fifth percentile or higher), gestational age at randomization (categorized as <25 weeks of gestation and ≥25 weeks of gestation), and EFW at randomization (categorized as <300 g, 300 to 599 g, and ≥600 g).

    All statistical analyses were conducted independently by 2 researchers (C.N. and R.G.D., supervised by J.C.J.) using R statistical software version 3.5.1 (R Project for Statistical Computing) and SAS statistical software version 9.4 (SAS Institute). P values were 2-sided, and statistical significance was set at P < .05. Data were analyzed from January 20, 2015, to January 18, 2019.

    Results

    Between January 20, 2015 and July 16, 2018, 281 women were eligible, of whom 216 were randomized (Figure). Among these, 108 women were 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] estimate fetal weight, 458 [160] g) and 108 women were randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimate fetal weight 464 [186] g). On July 19, 2018, the DSMB recommended to discontinue the trial based on the findings at the interim analysis on the data from the first 183 participants (eAppendix 1 in Supplement 2). The main consideration for the DSMB to recommend stopping was an increased incidence of neonatal pulmonary hypertension (a predefined outcome important for monitoring safety), 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. Moreover, no positive effects on the primary, secondary, or exploratory outcomes, as defined in the statistical analysis plan,38 were seen. The results of the recently published STRIDER UK trial39 as well as the (at that time unpublished) data of the STRIDER New Zealand/Australia trial40 were included in the DSMB deliberations, as was foreseen in the DSMB charter.17 The trial leadership stopped the trial immediately on July 19, 2018, at which point 7 remaining participants using trial medication were advised to stop using the trial medication, and drug allocation of all participants was unblinded for the participants and the researchers. Owing to the unforeseen stopping of the trial, we were not able to carry out all analyses as planned (eAppendix 2 in Supplement 2).

    Of 216 participants randomized at the time of halting the trial, 1 participant was lost to follow-up for all outcomes after having moved abroad, and 12 participants did not start trial medication and were therefore excluded from the per-protocol analysis. The mean (SD) adherence in the per-protocol group was 91% (23%) of the tablets taken.

    Baseline characteristics are shown in Table 1. There were no clinically relevant differences between the sildenafil and placebo groups in the maternal or fetal baseline characteristics, other than a slight imbalance in fetal sex (sildenafil: 51 [47.2%] boys; placebo: 59 [54.6%] boys).

    No difference was observed in the composite primary outcome of perinatal mortality or major neonatal morbidity until hospital discharge: 65 participants (60.2%) in the sildenafil-group and 58 participants (54.2%) in the placebo-group experienced perinatal death or major neonatal morbidity (relative risk [RR], 1.11; 95% CI, 0.88-1.40; P = .38) (Table 2). Bayes factor analysis indicated that the results on the primary outcome were 3.7-fold more likely compatible with no effect than with the risk reduction hypothesized in the sample size calculation. No differences were observed in the subcomponents of the primary outcome. Perinatal mortality was comparable (sildenafil: 44 deaths [40.7%]; placebo: 40 deaths [37.4%]; RR, 1.09; 95% CI, 0.78-1.52; P = .61). Two more children in the sildenafil group died after hospital discharge: 1 died 1 day after hospital discharge owing to sepsis resulting from necrotizing enterocolitis; another died at age 18 months owing to cardiogenic shock resulting from sepsis. Trial sequential analysis on the data from this trial showed that the boundary for futility was crossed for the primary outcome (eAppendix 3 in Supplement 2).

    The proportion of mothers experiencing either pre-eclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome was 46 mothers (42.6%) in the sildenafil group vs 48 mothers (44.9%) in the group allocated to placebo (RR, 0.95; 95% CI, 0.70-1.29) (Table 3). The mean PI of the maternal uterine artery or the fetal umbilical and middle cerebral artery arteries after treatment with study medication did not differ between groups (eTable 1 in Supplement 2).

    No difference in birth weight was observed between the treatment groups. Mean (SD) birth weight of the neonates who were stillborn was 414 (143) g in the sildenafil group vs 362 (115) g in the placebo group (P = .15). Mean (SD) gestational age of birth or fetal death was 29 weeks 3 days (4 weeks 0 days) in the sildenafil group vs 29 weeks 3 days (4 weeks 3 days) in the placebo group (P > .99).

    The results of all exploratory outcomes are reported in Table 2 and Table 3. Because the DSMB based their advice to stop the trial on the increased occurrence of neonatal pulmonary hypertension in the sildenafil group, we composed an expert adjudication committee of 4 neonatologists (W.O., A.F.J.v.H., I.K.M.R., and E.L.) experienced in treating neonates who are preterm and growth restricted and a pediatric cardiologist (R.M.F.B.) knowledgeable on the subject of neonatal and pediatric pulmonary hypertension to carefully review this outcome. The committee, blinded for treatment allocation, reviewed all neonatal records with the purpose of consensus validation of this diagnosis after discontinuation of the trial. Persistent pulmonary hypertension was defined as either confirmed by cardiac ultrasonagraphic examination or as a difference in oxygen saturation between the right upper extremity and either lower extremity (ie, postductal) of more than 10%. There was an increase of neonates in the sildenafil group who experienced pulmonary hypertension vs the placebo group (16 of 85 neonates [18.8%] vs 4 of 78 neonates [5.1%]; RR, 3.67; 95% CI, 1.28-10.51; P = .008). The adjudication committee observed that 2 different forms of pulmonary hypertension had occurred (eTable 2 in Supplement 2), including persistent pulmonary hypertension in the neonate and later-onset pulmonary hypertension associated with either sepsis or bronchopulmonary dysplasia. Neonatal death was attributable to pulmonary hypertension in 4 infants, 2 in each group (eTable 2 and eTable 3 in Supplement 2). We plan to publish a separate article on the diagnosis of pulmonary hypertension and the validation process within the trial.

    No subgroup differences were detected when assessed by adding interaction terms to the models, and the sensitivity analyses did not lead to statistically significant results on the primary outcome (Table 4). However, the RR slightly increased when analyses were adjusted for gestational age and EFW at inclusion (RR, 1.23; 95% CI, 0.69-2.23; P = .48) and in a post hoc analysis that explored the potential effect of the imbalance of sex at inclusion (RR, 1.33; 95% CI, 0.77-2.30; P = .31).

    We observed 10 maternal and 2 fetal or neonatal serious adverse events in the sildenafil group vs 8 maternal and 2 fetal or neonatal serious adverse events in the placebo group that could be directly attributed to the high-risk nature of the study population (eg, hospitalization of the neonate) (eTable 4 in Supplement 2). Other than pulmonary hypertension, there were no differences in the other serious adverse events. Several adverse effects of the trial medication with different frequencies were reported by the participants and are presented in eTable 5 in Supplement 2. The primary causes of neonatal death and the congenital anomalies observed are described in eTable 6 and eTable 7 in Supplement 2.

    Discussion

    This randomized clinical trial found that sildenafil compared with placebo did not reduce the risk of perinatal mortality or major neonatal morbidity. This finding is in line with 2 other published STRIDER trials from the UK39 and from New Zealand and Australia,40 and is confirmed by trial sequential analysis of this outcome that includes all 3 trials.

    Our present finding of an increased incidence of pulmonary hypertension after antenatal sildenafil administration was not observed in the 2 other STRIDER trials.39,40 This difference may be explained by definition differences, diagnostic strategies, or thresholds of suspicion. Our finding may indicate an important safety signal, and causality is a possibility because sildenafil targets the pulmonary vasculature. We hypothesize that the causal mechanisms might be rebound vasoconstriction (or lack of dilatation) of the pulmonary arteries to structural changes within the pulmonary vasculature.

    The Canadian STRIDER trial (NCT02442492) was terminated based on the results of this STRIDER trial. The planned individual patient data analysis that combines our data with all other STRIDER trials will have more power to draw conclusions based on all available data and hopefully to allow meaningful subgroup analysis to identify if there are specific participant groups that experience harm or benefit from the intervention.41

    Limitations

    Our trial has limitations. First, the trial was stopped before the planned sample size was reached because of an increased incidence of pulmonary hypertension in the sildenafil group, as well as indications of futility in our primary outcome. Pulmonary hypertension was predefined as an important safety outcome to monitor, but it was neither defined as a primary or secondary outcome, and pulmonary hypertension is a nonvalidated surrogate outcome regarding more patient-centered outcomes. Although each adverse event should be seriously regarded,42 it might be argued that the pulmonary hypertension result should only be regarded as hypothesis-generating and should be tested in the planned individual patient data analysis.41 Second, when assessing the primary outcome of perinatal mortality or major neonatal morbidity, the trial sequential analysis showed that the boundary for futility was crossed, indicating that we could reject that sildenafil reduces the risk of the primary outcome by 20%. However, we cannot reject that sildenafil reduces the risk of the primary outcome by smaller and perhaps clinically important margins, or that sildenafil reduces the risk of any of the secondary outcomes.

    It could be argued that the trial was stopped too soon owing to the lack of robustness on the findings of harm. However, the advice of the independent DSMB was not only based on potential harms but also on lack of benefits. In addition to the increase in pulmonary hypertension observed at the interim analysis, it became evident that it was unlikely that benefit of sildenafil treatment would be shown on the primary outcome if the trial were continued to its completion. This was also demonstrated in the trial sequential analysis on the primary outcome that showed that the boundary for futility was crossed when taking the results of the UK39 and Australian/New Zealand40 STRIDER trials into account.

    It could also be argued that the STRIDER trials were premature. However, there was extensive evidence in appropriate animal models of fetal growth restriction and increasing human evidence suggesting potential for a positive effect on fetal growth.8 The dosage used in this study (ie, 25 mg 3 times daily) was based on a previous trial15 and is slightly higher than the dosage used for the treatment of pulmonary hypertension in adults. A meta-analysis of animal studies8 suggested that a higher dosage than the current study used might be necessary to reach adequate serum levels of sildenafil. Sildenafil is approved to improve exercise ability and delay clinical worsening of pulmonary arterial hypertension in adult patients (World Health Organization Group I). In 2012, the US Food and Drug Administration recommended that sildenafil should not be prescribed to children ages 1 through 17 years for pulmonary arterial hypertension.43 However, there were no reported safety concerns for the use of sildenafil in fetal growth restriction. In contrast, there was an ongoing inclusion of this drug into clinical practice in this at-risk patient category.44 Adequately powered randomized clinical trials are necessary to assess the validity of an intervention before it is implemented. The concerted approach of the STRIDER trials aimed to prevent premature implementation of sildenafil based a few underpowered trials and sought to thoroughly test the beneficial claims before implementation.12,14,15

    Conclusions

    This randomized clinical trial found that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal death or major neonatal morbidity. Our results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.

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    Article Information

    Accepted for Publication: March 16, 2020.

    Published: June 17, 2020. doi:10.1001/jamanetworkopen.2020.5323

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Pels A et al. JAMA Network Open.

    Corresponding Author: Wessel Ganzevoort, MD, PhD, Department of Obstetrics and Gynecology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (j.w.ganzevoort@amsterdamumc.nl).

    Author Contributions: Dr Ganzevoort had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Pels, Ganzevoort.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Pels, Naaktgeboren, Jacobsen, Gluud, Ganzevoort.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Naaktgeboren, Jakobsen, Gluud, Duijnhoven.

    Obtained funding: Ganzevoort.

    Administrative, technical, or material support: All authors.

    Supervision: Ganzevoort.

    Conflict of Interest Disclosures: Dr Ganzevoort reported receiving grants from Netherlands Organization for Health Research and Development(ZonMW) during the conduct of the study. No other disclosures were reported.

    Funding/Support: The trial was funded by the Netherlands Organization for Health Research and Development (project No. 836021023).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    The Dutch STRIDER Trial Group: Joris A. M. van der Post, MD, PhD (Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands); Katayoun Taghavi, MD (Department of Obstetrics and Gynecology, Inselspital Bern, Frauenklinik, Bern, Switzerland); Ben W. Mol, MD, PhD (Department of Obstetrics and Gynecology, Monash University, Monash Medical Centre, Clayton, Australia); Harry van Goor, MD, PhD (Department of Pathology and Medical Biology, section Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands); Rolf M. F. Berger, MD, PhD (Department of Pediatric Cardiology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands); Willem P. de Boode, MD, PhD (Department of Neonatology, Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children’s Hospital, Nijmegen, The Netherlands); Danilo Gavilanes, MD, PhD (Department of Neonatology, Maastricht University Medical Center, Maastricht, The Netherlands); Arno F. J. van Heijst, MD, PhD (Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands); Elisabeth M. W. Kooi, MD, PhD (Division of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands); Petra Lemmers, MD, PhD (Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands); Enrico Lopriore, MD, PhD (Leiden University Medical Center, Department of Neonatology, Leiden, The Netherlands); Susanne M. Mulder-de Tollenaer, MD, PhD (Department of Pediatrics, Isala Hospital, Zwolle, the Netherlands); Hendrik Niemarkt, MD, PhD (Department of Neonatology, Maxima Medisch Centrum, Veldhoven, The Netherlands); Irwin K.M. Reiss, MD, PhD (Department of Pediatrics, Division of Neonatology, Erasmus UMC Rotterdam, the Netherlands); Sinno H.P. Simons, MD, PhD (Department of Pediatrics, Division of Neonatology, Erasmus UMC Rotterdam, Sophia Children’s hospital, the Netherlands); and Mirjam M. van Weissenbruch, MD, PhD (Department Pediatrics/Intenive Care Neonatology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands).

    Additional Contributions: Marleen Kemper, PhD, PharmD (Department of Pharmacy, Amsterdam UMC, University of Amtserdam, The Netherlands) and all pharmacy staff of the participating hospitals provided support regarding the process of the provision of trial medication according to the high required standards. Carrie Ris-Stalpers, PhD, and Marjolein Spiering (Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands) provided help on the organization of the trial. Katie M. Groom, MD, PhD (Department of Obstetrics and Gynecology, Auckland University, Auckland, New Zealand); Ken Lim, MD, PhD (Division of Maternal Fetal Medicine, BC Women’s Hospital, Vancouver, Canada); Zarko Alfirevic, MD, PhD (Department of Obstetrics and Gynecology, University of Liverpool, Liverpool, United Kingdom); and Louise C. Kenny, MD, PhD (University College Cork, Cork, Ireland) provided support for the international collaboration of the STRIDER Consortium. Chirag T. Kariya, Larry Li, and Tang Lee, MSc (Division of Maternal Fetal Medicine, BC Women’s Hospital, Vancouver, Canada), provided support of the STRIDER randomization and electronic data capture systems. Kit C. B. Roes, MD, PhD (Department of Biostatistics, Radboud University Medical Center, Nijmegen, The Netherlands); Hayo I. J. Wildschut, MD, PhD (Department of Obstetrics and Gynecology, Westfries Gasthuis, Hoorn, The Netherlands); Hein W. Bruinse, MD, PhD (Department of Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands); Hanneke van der Lee, MD, PhD (Department of Clinical Biostatistics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands); David P. van der Ham, MD, PhD (Department of Obstetrics and Gynecology, Martini Hospital, Groningen, The Netherlands); and Timo R. de Haan, MD, PhD (Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands), served as the data safety monitoring board.

    Data Sharing Statement: See Supplement 3.

    References
    1.
    Perined. Yearbooks Healthcare in the Netherlands [in Dutch]. Accessed April 22, 2020. https://www.perined.nl/producten/jaarboeken
    2.
    Spencer  R, Rossi  C, Lees  M,  et al; EVERREST Consortium.  Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.   BJOG. 2019;126(9):1157-1167. doi:10.1111/1471-0528.15590PubMedGoogle ScholarCrossref
    3.
    Severi  FM, Rizzo  G, Bocchi  C, D’Antona  D, Verzuri  MS, Arduini  D.  Intrauterine growth retardation and fetal cardiac function.   Fetal Diagn Ther. 2000;15(1):8-19. doi:10.1159/000020969PubMedGoogle ScholarCrossref
    4.
    Pels  A, Beune  IM, van Wassenaer-Leemhuis  AG, Limpens  J, Ganzevoort  W.  Early-onset fetal growth restriction: a systematic review on mortality and morbidity.   Acta Obstet Gynecol Scand. 2020;99(2):153-166. doi:10.1111/aogs.13702PubMedGoogle ScholarCrossref
    5.
    Levine  TA, Grunau  RE, McAuliffe  FM, Pinnamaneni  R, Foran  A, Alderdice  FA.  Early childhood neurodevelopment after intrauterine growth restriction: a systematic review.   Pediatrics. 2015;135(1):126-141. doi:10.1542/peds.2014-1143 PubMedGoogle ScholarCrossref
    6.
    Murray  E, Fernandes  M, Fazel  M, Kennedy  SH, Villar  J, Stein  A.  Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review.   BJOG. 2015;122(8):1062-1072. doi:10.1111/1471-0528.13435PubMedGoogle ScholarCrossref
    7.
    Nardozza  LM, Caetano  AC, Zamarian  AC,  et al.  Fetal growth restriction: current knowledge.   Arch Gynecol Obstet. 2017;295(5):1061-1077. doi:10.1007/s00404-017-4341-9PubMedGoogle ScholarCrossref
    8.
    Paauw  ND, Terstappen  F, Ganzevoort  W, Joles  JA, Gremmels  H, Lely  AT.  Sildenafil during pregnancy: a preclinical meta-analysis on fetal growth and maternal blood pressure.   Hypertension. 2017;70(5):998-1006. doi:10.1161/HYPERTENSIONAHA.117.09690PubMedGoogle ScholarCrossref
    9.
    Sharp  A, Cornforth  C, Jackson  R,  et al; STRIDER group.  Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.   Lancet Child Adolesc Health. 2018;2(2):93-102. doi:10.1016/S2352-4642(17)30173-6PubMedGoogle ScholarCrossref
    10.
    Choudhary  R, Desai  K, Parekh  H, Ganla  K.  Sildenafil citrate for the management of fetal growth restriction and oligohydramnios.   Int J Womens Health. 2016;8:367-372. doi:10.2147/IJWH.S108370 PubMedGoogle ScholarCrossref
    11.
    Dastjerdi  MV, Hosseini  S, Bayani  L.  Sildenafil citrate and uteroplacental perfusion in fetal growth restriction.   J Res Med Sci. 2012;17(7):632-636.PubMedGoogle Scholar
    12.
    Samangaya  RA, Mires  G, Shennan  A,  et al.  A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia.   Hypertens Pregnancy. 2009;28(4):369-382. doi:10.3109/10641950802601278PubMedGoogle ScholarCrossref
    13.
    Trapani  A  Jr, Gonçalves  LF, Trapani  TF, Franco  MJ, Galluzzo  RN, Pires  MM.  Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices.   Ultrasound Obstet Gynecol. 2016;48(1):61-65. doi:10.1002/uog.15673PubMedGoogle ScholarCrossref
    14.
    Trapani  A  Jr, Gonçalves  LF, Trapani  TF, Vieira  S, Pires  M, Pires  MM.  Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial.   Obstet Gynecol. 2016;128(2):253-259. doi:10.1097/AOG.0000000000001518PubMedGoogle ScholarCrossref
    15.
    von Dadelszen  P, Dwinnell  S, Magee  LA,  et al; Research into Advanced Fetal Diagnosis and Therapy (RAFT) Group.  Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.   BJOG. 2011;118(5):624-628. doi:10.1111/j.1471-0528.2010.02879.xPubMedGoogle ScholarCrossref
    16.
    Russo  FM, Conings  S, Allegaert  K,  et al.  Sildenafil crosses the placenta at therapeutic levels in a dually perfused human cotyledon model.   Am J Obstet Gynecol. 2018;219(6):619.e1-619.e10. doi:10.1016/j.ajog.2018.08.041PubMedGoogle ScholarCrossref
    17.
    Ganzevoort  W, Bloemenkamp  K, von Dadelszen  P,  et al.  Dutch STRIDER: Data Monitoring Committee Charter.   Zenodo. June 21, 2016. doi:10.5281/zenodo.56147Google Scholar
    18.
    Webster  LM, Gill  C, Seed  PT,  et al.  Chronic hypertension in pregnancy: impact of ethnicity and superimposed preeclampsia on placental, endothelial, and renal biomarkers.   Am J Physiol Regul Integr Comp Physiol. 2018;315(1):R36-R47. doi:10.1152/ajpregu.00139.2017 PubMedGoogle ScholarCrossref
    19.
    Escouto  DC, Green  A, Kurlak  L,  et al.  Postpartum evaluation of cardiovascular disease risk for women with pregnancies complicated by hypertension.   Pregnancy Hypertens. 2018;13:218-224. doi:10.1016/j.preghy.2018.06.019 PubMedGoogle ScholarCrossref
    20.
    Dröge  LA, Höller  A, Ehrlich  L, Verlohren  S, Henrich  W, Perschel  FH.  Diagnosis of preeclampsia and fetal growth restriction with the sFlt-1/PlGF ratio: diagnostic accuracy of the automated immunoassay Kryptor.   Pregnancy Hypertens. 2017;8:31-36. doi:10.1016/j.preghy.2017.02.005 PubMedGoogle ScholarCrossref
    21.
    Hinojosa-Rodríguez  M, Harmony  T, Carrillo-Prado  C,  et al.  Clinical neuroimaging in the preterm infant: diagnosis and prognosis.   Neuroimage Clin. 2017;16:355-368. doi:10.1016/j.nicl.2017.08.015 PubMedGoogle ScholarCrossref
    22.
    Papile  LA, Burstein  J, Burstein  R, Koffler  H.  Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.   J Pediatr. 1978;92(4):529-534. doi:10.1016/S0022-3476(78)80282-0 PubMedGoogle ScholarCrossref
    23.
    Towbin  A.  Cerebral intraventricular hemorrhage and subependymal matrix infarction in the fetus and premature newborn.   Am J Pathol. 1968;52(1):121-140.PubMedGoogle Scholar
    24.
    Chen  CC, Huang  CB, Chung  MY, Huang  LT, Yang  CY.  Periventricular echogenicity is related to delayed neurodevelopment of preterm infants.   Am J Perinatol. 2004;21(8):483-489. doi:10.1055/s-2004-835966 PubMedGoogle ScholarCrossref
    25.
    Grunnet  ML.  Periventricular leukomalacia complex.   Arch Pathol Lab Med. 1979;103(1):6-10.PubMedGoogle Scholar
    26.
    Bancalari  E, Claure  N.  Definitions and diagnostic criteria for bronchopulmonary dysplasia.   Semin Perinatol. 2006;30(4):164-170. doi:10.1053/j.semperi.2006.05.002 PubMedGoogle ScholarCrossref
    27.
    Finer  NN, Bates  R, Tomat  P.  Low flow oxygen delivery via nasal cannula to neonates.   Pediatr Pulmonol. 1996;21(1):48-51. doi:10.1002/(SICI)1099-0496(199601)21:1<48::AID-PPUL8>3.0.CO;2-M PubMedGoogle ScholarCrossref
    28.
    Jobe  AH, Bancalari  E.  Bronchopulmonary dysplasia.   Am J Respir Crit Care Med. 2001;163(7):1723-1729. doi:10.1164/ajrccm.163.7.2011060 PubMedGoogle ScholarCrossref
    29.
    Walsh  MC, Wilson-Costello  D, Zadell  A, Newman  N, Fanaroff  A.  Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia.   J Perinatol. 2003;23(6):451-456. doi:10.1038/sj.jp.7210963PubMedGoogle ScholarCrossref
    30.
    Walsh  MC, Yao  Q, Gettner  P,  et al; National Institute of Child Health and Human Development Neonatal Research Network.  Impact of a physiologic definition on bronchopulmonary dysplasia rates.   Pediatrics. 2004;114(5):1305-1311. doi:10.1542/peds.2004-0204 PubMedGoogle ScholarCrossref
    31.
    Bell  MJ, Ternberg  JL, Feigin  RD,  et al.  Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging.   Ann Surg. 1978;187(1):1-7. doi:10.1097/00000658-197801000-00001PubMedGoogle ScholarCrossref
    32.
    Hintz  SR, Kendrick  DE, Stoll  BJ,  et al; NICHD Neonatal Research Network.  Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis.   Pediatrics. 2005;115(3):696-703. doi:10.1542/peds.2004-0569PubMedGoogle ScholarCrossref
    33.
    Heath  P.  Pathology of the retinopathy of prematurity: retrolental fibroplasia.   Am J Ophthalmol. 1951;34(9):1249-1259. doi:10.1016/0002-9394(51)91859-4PubMedGoogle ScholarCrossref
    34.
    Hellström  A, Smith  LE, Dammann  O.  Retinopathy of prematurity.   Lancet. 2013;382(9902):1445-1457. doi:10.1016/S0140-6736(13)60178-6PubMedGoogle ScholarCrossref
    35.
    Tranquilli  AL, Brown  MA, Zeeman  GG, Dekker  G, Sibai  BM; Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP).  The definition of severe and early-onset preeclampsia.   Pregnancy Hypertens. 2013;3(1):44-47. doi:10.1016/j.preghy.2012.11.001PubMedGoogle ScholarCrossref
    36.
    Bayley  N.  Bayley Scales of Infant and Toddler Development. 3rd ed. Pearson Assessments; 2006.
    37.
    Healy  P, Gordijn  SJ, Ganzevoort  W,  et al.  A core outcome set for the prevention and treatment of fetal growth restriction: developing endpoints: the COSGROVE study.   Am J Obstet Gynecol. 2019;221(4):339.e1-339.e10. doi:10.1016/j.ajog.2019.05.039PubMedGoogle ScholarCrossref
    38.
    Pels  A, Jakobsen  JC, Ganzevoort  W,  et al.  Detailed statistical analysis plan for the Dutch STRIDER (Sildenafil Therapy in Dismal Prognosis Early-Onset Fetal Growth Restriction) randomised clinical trial on sildenafil versus placebo for pregnant women with severe early onset fetal growth restriction.   Trials. 2019;20(1):42. doi:10.1186/s13063-018-3136-zPubMedGoogle ScholarCrossref
    39.
    Sharp  A, Cornforth  C, Jackson  R,  et al; STRIDER group.  Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.   Lancet Child Adolesc Health. 2018;2(2):93-102. doi:10.1016/S2352-4642(17)30173-6PubMedGoogle ScholarCrossref
    40.
    Groom  KM, McCowan  LM, Mackay  LK,  et al.  STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.   BJOG. 2019;126(8):997-1006. doi:10.1111/1471-0528.15658PubMedGoogle Scholar
    41.
    Ganzevoort  W, Alfirevic  Z, von Dadelszen  P,  et al.  STRIDER: Sildenafil Therapy in Dismal Prognosis Early-Onset Intrauterine Growth Restriction—a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis.   Syst Rev. 2014;3:23. doi:10.1186/2046-4053-3-23PubMedGoogle ScholarCrossref
    42.
    European Medicines Agency. Guideline on multiplicity issues in clinical trials. Accessed April 22, 2020. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-issues-clinical-trials_en.pdf
    43.
    US Food and Drug Administration. FDA Drug Safety Communication: FDA clarifies warning about pediatric use of Revatio (sildenafil) for pulmonary arterial hypertension. Updated January 2016. Accessed April 22, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-clarifies-warning-about-pediatric-use-revatio-sildenafil-pulmonary
    44.
    Martin  A, Lines  A. 'Viagra saved my baby's life': Mum's 11-week premature child still alive thanks to anti-impotence drug. Mirror. October 9, 2015. Accessed April 22, 2020. https://www.mirror.co.uk/news/uk-news/viagra-saved-babys-life-mums-6606806
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