Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium
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Notice bibliographique
Résumé
No therapy exists for fetal growth restriction (FGR) due to poor placental function. Current management centers around timing of delivery, balancing the risks of intrauterine demise with those of prematurity due to indicated early birth. Pharmacological intervention to improve placental function may be a way to overcome this dilemma. The international Sildenafil TheRapy In Dismal prognosis Early-onset intrauterine growth Restriction (STRIDER) Consortium was established in 2011 as a group of investigators committed to exploring the effects of the phosphodiesterase-5 inhibitor, sildenafil, for the treatment of FGR in the first randomized placebo-controlled trial in humans. Previously, animal1 and preclinical2 studies, as well as a small case–control series in humans3, supported the hypothesis that this selective vasodilator may enhance uteroplacental blood flow and, hence, ameliorate impaired fetal growth and improve fetal wellbeing, allowing safe prolongation of pregnancy. Not only was early-onset FGR identified as the condition that poses the highest risk for poor perinatal outcome, but women whose pregnancy is affected by this condition constitute the group in which any treatment effect was likely to be most significant, and therefore the best target of investigation. After careful consideration, the Consortium proceeded to undertake a series of independent Phase-II/early Phase-III national/binational trials, as opposed to a single worldwide trial. This allowed for broader access to funding, variations in regional approval and faster recruitment for a condition with such a low prevalence. All four trials within the Consortium have been funded independently by national peer-reviewed funding bodies and executed independently, with a plan for independent publication4-7. All trials were designed in collaboration across the Consortium; thus, although there were variations in inclusion criteria and primary outcome measures, these were clearly defined a priori to ensure compatibility for assessment, in prospectively planned individual participant data (IPD) and trial-level meta-analyses8, 9. It has been estimated that this IPD meta-analysis will have sufficient power to assess the effects of sildenafil on infant survival and risk of serious adverse neonatal outcome. Given these two facts of possible (but currently unproven) harm and likely lack of benefit, the decision was made to stop the trial, to allow detailed review and validation of the findings before any further exposure of women and their fetuses to sildenafil. It is important to note that these findings in the Dutch trial do not seem to be consistent with those of the completed STRIDER trials in the UK10 and New Zealand/Australia (reported and submitted for publication). These previous trials, using almost identical methods, did not find any beneficial effect of sildenafil therapy in FGR, but also found no evidence of an association with persistent pulmonary hypertension of the newborn or neonatal death. These findings are of concern and are being taken very seriously. The STRIDER Consortium is currently exploring the data fully to elucidate the mechanisms of the findings within the Dutch trial. In order to do this comprehensively, all outstanding data must be collected, findings validated and trial data analysis completed; in addition, the planned IPD meta-analysis will be undertaken. During this time and until clarity on the effects of sildenafil treatment in FGR emerges, we reiterate our strong recommendation that sildenafil should not be prescribed for FGR outside the setting of high-quality randomized clinical trials. The STRIDER Consortium comprises: Z. Alfirevic, W. Ganzevoort, K. M. Groom, K. Lim, P. Baker, P. von Dadelszen, C. Gluud, J. Jakobsen, A. T. Papageorghiou, L. Kenny, L. Magee, C. Kariya, T. Lee, L. Li and A. Pels.
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