The efficacy of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction: the STRIDER RCT
Bibliographic record
Abstract
Background Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.003 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".