The STRIDER RCT (randomised controlled trial) of sildenafil versus placebo, for the treatment of women carrying a singleton pregnancy affected by severe early-onset IUGR, was a pragmatic design to ensure that clinically relevant findings were assessed. The study was based on good laboratory and animal evidence of benefits of treatment with sildenafil to recover placental function. In addition, there were emerging human data showing a beneficial effect on both placental function and fetal growth as demonstrated by improvements in some assessments of fetal weight and fetal Dopplers. Sildenafil was also known to be safe in women and while not advised for use in pregnancy, there was no evidence of harm.
Of greater concern was the emerging anecdotal evidence that clinicians across the world were already beginning to prescribe sildenafil for the treatment of growth restriction with no RCT evidence of benefit. The pragmatic design to use a mixed population from across the UK and to have a primary outcome of prolongation of pregnancy by 1 week was chosen to ensure that any positive findings would be immediately translatable to clinical practice.
The study was completed on time and within budget for the RCT with good engagement from clinicians and women. Recruitment was excellent with > 80% of screened women randomised, which is particularly noticeable as this was a CTIMP (Clinical Trial of an Investigational Medicinal Product) study in pregnancy. The subsequent extended funding for the follow-up phase allowed us to ensure that any benefits or harms from treatment with sildenafil would be identified in the perinatal period and in infancy.
The STRIDER UK study showed no beneficial effect for any perinatal outcome for mother or baby from treatment with 25 mg sildenafil TDS for severe early-onset IUGR. In fact, the interval between randomisation and delivery was on average 2.7 days shorter in the sildenafil arm, although this difference did not reach conventional statistical significance in the gestational age adjusted logistic regression analysis (p = 0.19). The study also showed no clinically important differences in mortality or short-term neonatal morbidity, although the trial was not adequately powered for these secondary end points.
It was anticipated that, if sildenafil was effective, there may be a beneficial effect on placental function, as assessed by uteroplacental and fetal Doppler studies, even in the absence of a clear benefit on substantive clinical outcomes. The observed higher proportion of babies in whom Doppler findings in ductus venosus deteriorated with sildenafil treatment may have been a chance finding, but is also potentially worrying, particularly if linked to the somewhat shorter randomisation to delivery interval in this treatment arm. Interestingly, no such adverse effect from sildenafil on the blood flow in uterine arteries, umbilical artery or middle cerebral artery was found. It was not possible to obtain two separate measurements for all babies, but in this placebo-controlled study, it is very unlikely that Doppler measurements were somehow systematically biased. At present, a plausible pathophysiological explanation cannot be offered for the possible adverse effect of sildenafil on the fetal blood flow in the STRIDER cohort.
The findings of the study are in contrast with animal and several previously reported clinical studies.16–19,21,35–40 The sildenafil dose used was based on the consensus from researchers with most experience in clinical evaluation of sildenafil in pregnancy at the time17,20 and a higher dose could possibly have been more effective. A recent systematic review identified 16 studies of sildenafil in human pregnancies, of which only four exceeded our daily dose of 75 mg in three divided doses. Three reports of improved uteroplacental perfusion in IUGR pregnancies used a 50-mg dose once daily and recruited participants at later gestations with umbilical end-diastolic flow present in most cases.21,35,36 As pharmacokinetic studies of sildenafil in pregnancy are currently not available, it would be difficult to determine an ideal dosing schedule for future studies although other dosing regimens of sildenafil have been proposed. More importantly, a possibility that the current dose of 25 mg three times daily may have a deleterious effect on blood flow in the ductus venosus and would require extreme caution in any future studies with a higher dose, particularly in fetuses with absent or reversed end-diastolic flow in the umbilical artery.
Another possibility is that the study’s definition of growth restriction included fetuses with such advanced disease that it was not possible to improve or reverse the process. The STRIDER study recruited more than half of the IUGR babies before 26 weeks’ gestation and all fetuses had severely compromised umbilical circulation with absent or reversed end-diastolic flow; overall mortality was around 45%. In comparison, the average gestational age at randomisation in the study by Dastjerdi et al. was 35 weeks. The authors did not report the proportion of babies with absent or reversed umbilical artery blood flow, but given the reported gestation, it is likely that these babies would have been delivered rather than recruited.21 El-Sayed et al.35 reported that only 11 (20%) of 54 babies developed absent or reversed end-diastolic umbilical artery blood flow at some point after randomisation, whereas in the study by Trapani et al.,36 reversed umbilical artery blood flow was, in fact, an exclusion criterion. None of the studies reported any perinatal deaths or long-term follow-up data and it is, therefore, far too early to speculate that the reported improvements in uteroplacental perfusion in less severe IUGR at later gestation would lead to improved survival and better long-term outcomes.
Although there was no firmly agreed fetal monitoring protocol, or uniform triggers for the delivery of compromised babies in this study, all participating units had access to fetal medicine experts, detailed Doppler assessment of fetal and uteroplacental circulation and antenatal cardiotocography. It is therefore not surprising that the overall survival observed is broadly in agreement with other recent studies that included severe early-onset IUGR with abnormal umbilical artery Doppler.3,41
The phase 2 follow-up STRIDER study had good retention and engagement in a very high-risk population with complex needs with > 80% of liveborn babies having neurodevelopmental and behavioural assessment at 2 years of age.
However, the follow-up phase encountered delays due to the significant impact of the COVID-19 pandemic on the availability of research staff and the challenges in accessing patients, which may have contributed to some women declining participation in this phase of the study.
Although the study was not specifically designed to assess neurodevelopmental or behavioural outcomes between 2 and 3 years of age in the surviving infants, the findings revealed that maternal treatment with sildenafil did not yield any statistically significant beneficial effects in the parameters studied, compared to the placebo. Importantly, no harmful effects were observed either. There was a statistically significant increase in head circumference in those babies treated with sildenafil. Given that there were no other clinically important differences in clinical outcomes between the two groups, and that due to follow-up issues and perinatal deaths the children assessed can no longer be deemed to be randomised this increase of 2.1 cm on average is likely to be a chance finding. There was also no effect on infant BP from treatment with sildenafil. Given these results, further investigation is warranted to explore the potential long-term effects and outcomes of maternal treatment with sildenafil. Future research could delve into assessing subtle neurodevelopmental and behavioural phenotypes as the children progress into school age and beyond. This could involve evaluating aspects such as attention, emotional regulation, and various cognitive functions. Additionally, it is crucial to emphasise the value of continuing to follow this well-characterised cohort into the school years, with access to linked data encompassing health and school records. Such comprehensive follow-up would provide invaluable insights into the potential benefits or risks associated with maternal sildenafil treatment, contributing to a deeper understanding of its implications.
After the conclusion of the UK and the New Zealand/Australia STRIDER trials, the Dutch STRIDER trial was halted early due to evidence from a planned interim review of increased perinatal mortality in the Sildenafil-treated group.42 Further assessment deemed this to be predominantly due to persistent pulmonary hypertension of the neonate (PPHN), which has been proposed to be a pathophysiological mechanism of ‘rebound’ vasoconstriction after cessation of sildenafil.43
Both the UK and the New Zealand/Australia STRIDER Phase I trials reviewed their data using the same criteria for PPHN as the Dutch STRIDER trial and did not find an increased mortality.44 This will be the subject of a planned IPD of all the international STRIDER studies.24
The STRIDER RCT, and its international collaborating studies, has shown no beneficial effect for mothers or babies affected by severe early-onset IUGR from treatment with 25 mg sildenafil 8 hourly. On current evidence, the researchers do not believe that there is likely to be any beneficial effect on fetal growth or perinatal outcomes in this patient group and would advise that further use of sildenafil in this population should be stopped. Prior to any further studies using PDE5 inhibitors to treat IUGR being performed, pharmacokinetic and pharmacodynamic experiments specific to pregnancy should be performed to establish an efficacious therapeutic dose.
Therefore, as sildenafil was neither beneficial nor harmful to these infants, the cohort could now be interpreted as a study of a population of severe early-onset IUGR which would be beneficial to clinicians and families for counselling. Furthermore, when combined with less severe cohorts from the TRUFFLE3,22 and POPS45 studies, it would give a counselling picture for fetuses affected with growth restriction from 22 weeks to term.
In conclusion, when sildenafil was administered to pregnant women carrying a severely growth-restricted fetus, it did not prolong pregnancy, improve survival or reduce short-term neonatal morbidity.
Implications for decision-makers
This study has demonstrated that there is no benefit from the use of oral sildenafil given to mothers carrying a fetus affected by severe early-onset IUGR. Therefore, the study recommend that future guidance on the management of the IUGR fetus should declare that sildenafil should not be used for this condition outside of a research study.
Recommendations for future research
The study recommend that future research should focus on the use of differing doses of sildenafil and the use of sildenafil in less severe cohorts of IUGR. Further assessment of the long-term implications of severe early-onset IUGR on neurodisability and behaviour could also be gained from studying the surviving children from the STRIDER study.
Study registration
ISRCTN Ref: ISRCTN39133303
EudraCT Ref: 2013-005398-32
MHRA CTA Ref: 04196/0032/001-0001
REC Ref: 14/NE/0011 (phase 1)
REC Ref: 16/LO/2225 (phase 2)
Patient and public involvement
The study incorporated patient and public involvement (PPI) through various key contributors. The Stillbirth and Neonatal Death Society (SANDS) played a pivotal role in shaping and informing the study, as they were actively involved in its design and served as members of the study steering committee. Additionally, the antenatal results and choice (ARC) charity played a crucial role in facilitating PPI efforts throughout the study’s duration.
Antenatal results and choice, in particular, was instrumental in the development of patient information and played a significant part in disseminating the study findings. Their involvement in the STRIDER study began from its initial design stages and continued all the way through to the study’s execution and the subsequent dissemination of its results.
Equality, diversity and inclusion
Promoting equality, diversity and inclusion (EDI) was a fundamental principle embedded in the STRIDER UK study. Although the rarity of severe early-onset IUGR posed challenges in conducting specific diversity characterisations, the researchers made concerted efforts to ensure that the selection of recruiting sites encompassed a comprehensive geographical representation across the UK. By embracing this approach, our recruitment was able to encompass diverse populations from both rural and urban areas, which inherently exhibit distinct demographic compositions across recruiting sites.