STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials

An estimated 0.4% of pregnancies worldwide are complicated by severe early-onset (<28 weeks gestation) fetal growth restriction (FGR) caused by placental insufficiency. This patient group utilises disproportionate amounts of obstetric care and has a high likelihood of premature birth, both for fetal and for secondary maternal indications such as the development of the maternal syndrome of pre-eclampsia. As these growth-restricted infants are usually born very preterm, they carry additional significant risks of major and minor neonatal morbidity, and long-term health sequelae if they survive. These risks are not only related to gestational age at birth, but also to the degree of FGR. Survival proportions for severely growth-restricted fetuses very remote from term (<28 weeks’ gestation) vary between 7 and 33% [1‐3] and less than one third of these fetuses will survive their neonatal intensive care unit (NICU) stay without significant neurodevelopmental sequelae [4].

The diagnosis of early onset FGR is often missed but even when diagnosed based on growth parameters below the normal range (<10th, <5th, or <3rd centile) with or without evidence of abnormal fetal and maternal Doppler waveforms there are currently no specific evidence-based therapies available. Non-specific interventions may include lifestyle modifications such as reducing or stopping work, stopping aerobic exercise, rest at home, and hospital admission for rest and surveillance. These interventions are used in the belief that rest will reduce the steal from the utero-placental circulation to the glutei and quadriceps muscles but are not based on any good quality evidence. In the absence of proven therapeutic interventions, standard clinical management consists of counselling, intensive monitoring, and timely delivery once a fetus has reached a viable gestation and size but often results in extreme preterm birth.

Doppler waveform analysis of pregnancies complicated by severe FGR suggests compromised utero-placental circulation and placental hypo-perfusion [5, 6]. Sildenafil, a phosphodiesterase inhibitor, potentiates the action of nitric oxide thus causing vasodilatation [7]. It is therefore possible that sildenafil may affect utero-placental circulation and perfusion resulting in improved gaseous and nutrient exchange and improved fetal growth and well-being. Animal and preclinical studies support this concept [8‐13].

Although the number of women using sildenafil in pregnancy is low, it is increasingly used in pregnancy for maternal cardiac indications with no reports of adverse maternal or fetal effects [14‐21]. In a small randomised clinical trial in women with early onset pre-eclampsia, sildenafil use had no demonstrable effect on prolongation of pregnancy, but provided further reassurance on drug safety profile in pregnancy [16]. Sildenafil has been used in a small cohort of women in the setting of early onset FGR. In an observational study by STRIDER collaborators in Vancouver, Canada, there was a tendency towards more live-born children with survival intact to primary discharge for women treated with sildenafil when compared to women with pregnancies at similar risk but not receiving sildenafil [17]. From the limited observations to date there are no concerns of adverse maternal, fetal, neonatal, or infant effects associated with sildenafil use in pregnancy [14‐21].

On the basis of this preliminary research, some centres have already adopted treatment with sildenafil [18, 19]. However, there is no clear evidence of true health benefits and, more significantly, potential harm has not yet been excluded. Use of sildenafil for other indications in clinical trials and in post-market reporting has highlighted adverse drug reactions including headache, flushing, nasal congestion, and impaired vision and, rare, serious consequences such as myocardial infarction, arrhythmias, and stroke [7]. More specific to pregnancy and FGR, sildenafil’s vasodilatory properties may cause a transient decrease in blood pressure with potential to adversely affect the most at risk fetuses (those with absent or reversed end diastolic flow on Doppler waveform analysis), via a reduction in critical utero-placental flow or by a direct effect on fetal vasculature. Prolonging pregnancy in FGR has the potential to shift the survival curve but will not necessarily have the same positive impact on short term outcomes and long term well-being. Well-designed, appropriately powered randomised placebo-controlled trials are required before implementation into clinical practice should be considered.

The overarching hypothesis of this collaboration of clinical trials is that sildenafil citrate compared with placebo will improve fetal growth and wellbeing, allowing prolongation of pregnancy leading to a decrease in the rate of fetal and neonatal mortality and severe morbidity.

The STRIDER trials were conceived and designed through international collaboration. The trials are competitively funded at a national level by government funded research agencies within each country. Each individual trial protocol was developed independently by local groups of investigators but all trial designs are similar and all outcomes will be collected in all trials. Each trial will be conducted autonomously, but in close co-operation across the six countries involved. There is a central trial management service hosted at the University of British Columbia, Canada, providing a central randomisation service as well as a central electronic data collection system for each trial. The randomisation service and data collection systems have been designed collaboratively and, although each trial will use its own independent randomisation service and data collection systems these shared resources have reduced overall trial costs and will ensure data compatibility for future analysis in the prospectively planned IPD meta-analyses.

The research teams for all STRIDER trials have regular communication via e-mail, teleconferencing, face-to-face meetings, and a newsletter. Collaboration between the groups is strong with all teams committed to securing funding for long-term infant and childhood outcome studies. These data will contribute to further the systematic review and IPD meta-analysis.

The STRIDER trials are all conducted in order to reduce bias by employing central, stratified randomisation; blinding of all parties through use of matching placebos; central data management focusing on few missing data and dropouts; blinded drawing of conclusions; transparent uploading of IPD data after the trials have been published; no involvement of the pharmaceutical industries selling the product; as well as planning for systematic review of all trials including meta-analyses of individual patient data. These bias eliminating or reducing actions have all been conducted to minimize any risks of systematic errors, that is overestimation of benefits and underestimation of harms [33‐40].

The STRIDER trials have all calculated their sample sizes taking into consideration a projected drop-out rate. This gives sample sizes that are inflated according to the assumed risks. We acknowledge this methodology should no longer be undertaken as there is now international consensus to analyse data with multiple imputation [41, 42]. Such analyses will be used for the individual trials, however, we have not amended the sample size calculations as the projected drop-out is small in all trials.

In medicine, a single randomised clinical trial is unlikely to be able to change clinical practice [38]. Therefore, the STRIDER trials have from inception been planned to be systematically reviewed together with any other randomised trials addressing the same topic [22]. Furthermore, in order to better evaluate benefits and harms, the STRIDER trials are planned to be included alone or together with any other trial providing data into individual patient data meta-analyses [22]. The STRIDER Consortium is presently writing up a detailed statistical analysis plan for the systematic review and individual patient data meta-analyses.

The STRIDER Collaboration will ensure the assessment of sildenafil use for the treatment of early onset FGR occurs in a safe and timely manner and should ensure sildenafil is only introduced into clinical practice if reliable data on safety and efficacy supports its use. The extensive IPD data will also provide opportunities to broaden our knowledge of severe early onset FGR, and to explore other applications for sildenafil use if safety and efficacy are established.