The Lancet Child & Adolescent Health February 01, 2018

Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial

Andrew Sharp, Christine Cornforth, Richard Jackson, Jane Harrold, Mark A Turner, Louise C Kenny, Philip N Baker, Edward D Johnstone, Asma Khalil, Peter von Dadelszen, Aris T Papageorghiou, Zarko Alfirevic

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Bottom Line

In pregnancies complicated by severe early-onset fetal growth restriction, maternal administration of sildenafil did not prolong pregnancy or improve perinatal outcomes compared to placebo.

Key Findings

1. Among 135 randomized pregnant women, there was no significant difference in the median time from randomization to delivery between the sildenafil and placebo groups (17 days [IQR 7–24] vs. 18 days [IQR 8–28]; p=0.23).

2. Livebirth rates were comparable across both study arms, occurring in 73% (51 of 70) of women assigned to sildenafil and 75% (49 of 65) of women assigned to placebo.

3. There were no significant differences in fetal deaths (26% [18 of 70] with sildenafil vs. 23% [15 of 65] with placebo) or neonatal deaths (14% [7 of 51] vs. 10% [5 of 49]).

4. Median birthweight did not significantly differ between the intervention and control groups (450 g [IQR 365–595] vs. 460 g [IQR 395–600]).

Study Design

Design

RCT

Double-Blind

Sample

135

Patients

Duration

Until hospital discharge

Median

Setting

19 UK centers

Population Pregnant women with severe early-onset fetal growth restriction.

Intervention Sildenafil 25 mg orally three times daily.

Comparator Matching placebo orally three times daily.

Outcome Time from randomization to delivery, measured in days.

Study Limitations

• The study was primarily powered to detect a 1-week prolongation in pregnancy and may have been underpowered to detect smaller differences in rare perinatal morbidities or survival.

• The extreme severity of the enrolled cohort's condition suggests that placental damage might have already been too advanced and irreversible at the time of randomization for any vasodilator to provide meaningful clinical benefit.

• The high baseline rates of fetal and neonatal mortality highlight the hostile intrauterine environment of severe early-onset FGR, potentially overshadowing modest pharmacological effects.

• The primary report was limited to outcomes up to hospital discharge, preventing immediate conclusions on long-term childhood neurodevelopmental or cardiovascular effects.

Clinical Significance

The STRIDER UK trial definitively demonstrated that sildenafil offers no clinical benefit in prolonging gestation or improving neonatal outcomes for severe early-onset fetal growth restriction. These findings directly informed global obstetrical guidelines, strongly discouraging the off-label use of PDE5 inhibitors for placental insufficiency. The trial reinforced that careful fetal monitoring and timely iatrogenic delivery remain the cornerstones of managing severe FGR.

Historical Context

Severe early-onset fetal growth restriction (FGR) lacks effective medical treatments and frequently results in extreme prematurity, severe morbidity, or perinatal death. Because nitric oxide pathways mediate uteroplacental vasodilation, phosphodiesterase type 5 (PDE5) inhibitors like sildenafil were hypothesized to improve uteroplacental blood flow. To rigorously test this, the international STRIDER consortium was formed. The STRIDER UK trial (2018) was the first to report, demonstrating striking futility. Subsequently, the Dutch STRIDER trial (Pels et al., 2020) was halted prematurely by its Data Safety Monitoring Board due to safety concerns—an unexpected increase in neonatal pulmonary hypertension and neonatal deaths in the sildenafil arm. The Canadian and NZAus trials were similarly halted. Together, these consortium trials represent a landmark example of rigorous multi-center collaboration ultimately preventing the widespread adoption of a futile and potentially harmful off-label therapy.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Sildenafil was investigated as a potential treatment for fetal growth restriction (FGR) due to its vasodilatory properties. What is the molecular mechanism of sildenafil, and how was it theoretically expected to improve fetal growth in the setting of early-onset FGR?

Key Response

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor. It prevents the degradation of cyclic GMP (cGMP), leading to prolonged smooth muscle relaxation and vasodilation. In early-onset FGR, which is typically characterized by high-resistance, low-flow uteroplacental circulation, vasodilation was hypothesized to improve placental perfusion, enhance nutrient and oxygen delivery, and subsequently improve fetal growth.

Resident

Given that the STRIDER trial demonstrated no benefit of sildenafil in prolonging pregnancy or improving perinatal outcomes, what remains the standard-of-care medical management strategy and criteria for delivery in severe early-onset FGR?

Key Response

Without effective pharmacological therapies to improve placental function, management relies entirely on close fetal surveillance (umbilical artery and ductus venosus Doppler ultrasound, biophysical profiles, and cardiotocography) to optimize the timing of delivery. Delivery is indicated when the risks of ongoing intrauterine hypoxia outweigh the risks of extreme prematurity, often triggered by absent or reversed end-diastolic velocity in the umbilical artery, combined with administering maternal corticosteroids for fetal lung maturity.

Fellow

The international STRIDER consortium consisted of multiple distinct trials. While the UK trial showed a lack of efficacy, the Dutch STRIDER trial was halted early due to safety concerns. What was the major adverse neonatal outcome observed in the Dutch cohort, and what is a potential pathophysiological explanation for this paradoxical finding?

Key Response

The Dutch trial reported an increased incidence of persistent pulmonary hypertension of the newborn (PPHN) and neonatal mortality in the sildenafil group. While sildenafil is used postnatally to treat PPHN, prenatal exposure may disrupt normal vascular remodeling in the developing fetal lung or cause a rebound pulmonary vasoconstriction upon withdrawal of the drug after birth, highlighting the complex and sometimes paradoxical effects of transplacental pharmacology.

Attending

The STRIDER trials serve as a prime example of promising preclinical and small observational studies failing to translate into RCT success. How should attendings use this trial to counsel highly anxious patients presenting with severe early-onset FGR who request 'off-label' experimental therapies?

Key Response

Attendings should use this trial to emphasize that biological plausibility and preclinical success do not guarantee clinical efficacy or safety. The STRIDER trial is a vital teaching point: off-label sildenafil not only failed to improve outcomes but, in associated cohorts, caused harm (PPHN). Counseling must focus on shared decision-making, explaining that current evidence-based care maximizes safety through precise surveillance and timed delivery rather than experimental in-utero pharmacological rescue.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The STRIDER initiative utilized an international consortium of coordinated, independent RCTs using a core outcome set rather than a single global multicenter trial. What are the methodological vulnerabilities of this 'federated' trial design, particularly regarding Data and Safety Monitoring Board (DSMB) early stopping rules?

Key Response

A federated design allows for region-specific funding and cultural adaptations but suffers from disparate DSMB thresholds. When the Dutch trial halted due to safety signals (PPHN), it compromised the blinding and equipoise of the other ongoing international trials (e.g., UK, ANZ, Canada). This forces complex statistical and ethical dilemmas regarding whether to halt enrollment prematurely, adjust power calculations mid-study, or modify protocols, which can threaten the statistical validity of the remaining independent trials.

Journal Editor

As an editor reviewing the STRIDER UK manuscript, what critical appraisal would you apply regarding the choice of the primary outcome (prolongation of pregnancy) versus a composite of severe neonatal morbidity and mortality, particularly concerning statistical power?

Key Response

Prolongation of pregnancy (time from randomization to delivery) is a surrogate outcome. While clinically relevant, it is only meaningful if it translates to improved intact neonatal survival. A rigorous reviewer would flag whether the trial was adequately powered to detect clinically significant differences in the rarer, but more critical, composite neonatal outcomes. Relying on a surrogate primary outcome risks a Type II error for the true clinical endpoints, though the overwhelmingly null and potentially harmful signals across the consortium validate the ultimate conclusion of no benefit.

Guideline Committee

In light of the STRIDER trial results and the associated international cohorts, how should national guidelines (e.g., ACOG or SMFM) formulate their recommendations regarding the use of vasodilators like sildenafil for early-onset FGR?

Key Response

Guidelines must issue a strong recommendation against the use of sildenafil for FGR (Level of Evidence: 1A, based on high-quality RCTs). Current SMFM and ACOG guidelines emphasize that there are no proven pharmacological therapies for FGR. Given the lack of benefit in the UK STRIDER and the severe signal for harm (PPHN) in the Dutch STRIDER, the committee should explicitly warn against the off-label use of PDE5 inhibitors for this indication to prevent iatrogenic harm, reinforcing that management must remain focused solely on surveillance and indicated delivery.

Clinical Landscape

Noteworthy Related Trials

2003

GRIT Trial

n = 548 · Lancet

Tested

Immediate delivery

Population

Pregnancies with suspected preterm fetal growth restriction

Comparator

Expectant management (delayed delivery)

Endpoint

Perinatal mortality or severe disability at 2 years of age

Key result: There was no significant difference in survival without severe disability at 2 years between the immediate and delayed delivery groups.

2015

TRUFFLE Trial

n = 503 · Lancet

Tested

Delivery timing based on ductus venosus Doppler changes

Population

Women with early-onset severe fetal growth restriction

Comparator

Delivery timing based on computerized cardiotocography alone

Endpoint

Survival without neurodevelopmental impairment at 2 years of age

Key result: Timing delivery based on late ductus venosus changes significantly improved survival without neurodevelopmental impairment compared to standard cardiotocography.

2018

Dutch STRIDER Trial

n = 216 · Lancet

Tested

Sildenafil 25mg three times daily

Population

Pregnant women with severe early-onset fetal growth restriction

Comparator

Placebo

Endpoint

Intact neonatal survival to hospital discharge

Key result: The trial was halted early due to an increased incidence of persistent pulmonary hypertension of the newborn and neonatal mortality in the sildenafil group, with no survival benefit.

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