BACKGROUND AND PURPOSE:

• Sildenafil, a phosphodiesterase type 5 inhibitor, has been proposed as a potential treatment for fetal growth restriction
  • Sildenafil involved in a biochemical pathway that may improve uteroplacental circulation
• Pels et al. (JAMA Network Open, 2020) investigated whether sildenafil reduced perinatal mortality or morbidity in the context of fetal growth restriction

METHODS:

• Placebo-controlled randomized clinical trial (RCT)
• Sildenafil Therapy in Dismal Prognosis Early Onset Fetal Growth Restriction (STRIDER) consortium
• Participants
  • Pregnant women between 20w0d and 27w6d with severe FGR
• Intervention
  • Sildenafil group: 25 mg, 3 times a day
  • Placebo group
• FGR definition
  • AC <3rd percentile or EFW <5th percentile combined with either
    • Abnormal Dopplers (unilateral or bilateral notching of the uterine artery, PI >95th percentile, MCA PI <5th percentile) or a maternal hypertensive disorder
• Statistical analysis
  • Sample size requirement 180 participants per group based on
    • Relative risk (RR) reduction of 21% | Assume 10% loss to follow-up | Type I error of 5% | 80% power
  • The trial was stopped early when benefit on the primary outcome was determined to be unlikely
• Primary outcome
  • A composite of perinatal mortality or major neonatal morbidity until hospital discharge

RESULTS:

• 216 pregnant women included
• Sildenafil group: 108 women
  • Median (IQR) gestational age: 24 weeks 5 days (23w3d to 25w5d)
  • Mean (SD) estimated fetal weight: 458 (160) g
• Placebo group: 108 women
  • Median (IQR) gestational age: 25 weeks 0 days (22 weeks 5 days to 26 weeks 3 days
  • Mean (SD) estimated fetal weight: 464 (186) g
• The trial was halted in due to increased incidence of neonatal pulmonary hypertension (a predefined outcome for safety monitoring)
  • Primary outcome benefit was unlikely even if the study continued to completion
  • Nor was benefit seen for secondary and exploratory outcomes
  • The committee took in to account other published and unpublished reports by the STRIDER consortium
• The primary outcome did not differ between groups
  • Sildenafil group: 60.2%
  • Placebo group: 54.2%
  • RR 1.11 (95% CI, 0.88 to 1.40, P = 0.38)
• Neonatal pulmonary hypertension occurred more frequently in the sildenafil group
  • Sildenafil group: 18.8% (16 neonates)
  • Placebo group: 5.1% (4 neonates)
  • RR 3.67 (95% CI, 1.28 to 10.51, P = 0.008)

CONCLUSION:

• Sildenafil
  • Does not appear to improve severe fetal growth restriction
  • May increase the risk for neonatal pulmonary hypertension

Learn More – Primary Sources:

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

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