The efficacy of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction: the STRIDER RCT

Article history

The research reported in this issue of the journal was funded by the EME programme as award number 12/62/109. The contractual start date was in March 2014. The draft manuscript began editorial review in February 2023 and was accepted for publication in December 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

Copyright statement

Copyright © 2024 Sharp et al. This work was produced by Sharp et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 Sharp et al.

Study design and participants

The STRIDER study was a Phase III clinical trial to quantify the effects of administration of sildenafil on pregnancy outcome in severe early‐onset IUGR. A total of 135 women with affected pregnancies were recruited and randomised to receive one of two treatment arms, sildenafil or placebo. The study received funding from the National Institute of Health and Care Research (NIHR) and Medical Research Council (MRC). It was co-sponsored by the University of Liverpool and Liverpool Women’s NHS Foundation Trust and co-ordinated through the Liverpool Clinical Trials Unit (LCTU, which is part of the Liverpool Trials Collaborative, UKCRC Registration 12).

All participants were recruited from one of the 19 STRIDER research sites located in the UK. All sites were leading obstetric units within the UK and successfully completed site feasibility during the green light phase of the trial set-up. Suitable collaborating sites and investigators were therefore assessed on the level of fetal medicine and neonatal service they provide and their ability to conduct the trial. Ahead of the trial starting at a site the Principal Investigators were required to agree to adhere to the good clinical practice (GCP) guidelines. In addition, all relevant regulatory and ethics approvals were required.

The study was designed as a randomised double-blind, placebo-controlled trial with sildenafil or placebo prescribed orally at a dose of 25 mg three times per day (Figure 1). This dosage regime was based on previous studies by the collaborators on the project. All participants recruited had a singleton pregnancy between 22⁺⁰ weeks’ gestation and 29⁺⁶ weeks’ gestation with a diagnosis of IUGR and had agreed to expectant management. For the purpose of study, IUGR was defined as a fetus with an estimated fetal weight or abdominal circumference below the 10th centile using local charts and absent or reversed end-diastolic flow in the umbilical artery on Doppler velocimetry.

FIGURE 1.

STRIDER trial flow chart.

Gestational age was confirmed by first trimester ultrasound and in each case, the diagnosis of severe early-onset IUGR was confirmed by a fetal medicine expert having excluded fetal anatomical abnormalities. Following diagnosis and informed consent, a full history, measurements of maternal cardiovascular parameters (BP and pulse rate), fetal biometry and Doppler velocimetry were taken. Maternal venepuncture for angiogenic biomarkers was also performed.

All participants had further BP and pulse rate measurements and blood sampling 2 hours after receiving the first dose of the study drug. Subsequently, participants were followed up within 3–4 days and at weekly intervals thereafter, or earlier if clinically indicated. The remainder of clinical care was at the discretion of the local fetal medicine experts and included regular ultrasound assessment of growth and Doppler blood flow and antenatal cardiotocography.

Study medication was over-encapsulated (Sharp Clinical Services, Crickhowell, UK) to ensure that participants, clinicians and pharmacists were masked to the study drug. 26 Medication was dispensed in 10-day supplies with a new supply being provided weekly to ensure there was no period where medication was missed. Treatment ended at 31⁺⁶ weeks’ gestation or delivery, whichever came first. All participants were advised of the potential side effects.

Data on pregnancy outcome were collected prospectively from clinical maternity notes and entered onto a secure electronic case report form (eCRF) platform at research sites. Data quality and protocol compliance were monitored regularly by central and on-site monitoring methods.

The STRIDER UK study protocol v7.0 is available as Appendix 1

Start of study

Prior to the start of recruitment on 11 November 2014, the following approvals were obtained on the respective dates: Sponsorship – 9 October 2013, Research Ethics Committee (REC; North East – Newcastle and North Tyneside 2, Chair Dr Alasdair MacSween) – 20 March 2014, Clinical Trial Authority (CTA) – 18 July 2014 and Trial Greenlight Approval – 6 November 2014. All approvals for participating research sites were in place within 12 months of opening. The trial protocol (Appendix 1) was first registered on 31 July 2014, 4 months prior to the first participant being recruited. The first participant was recruited and randomised on 21 November 2014.

End-of-study definition

As defined in the protocol, the end of phase 1 of the STRIDER study was ‘when the last recruited woman/baby is discharged from hospital, or the baby has reached expected date of birth, whichever is later’. The last participant to be recruited to the study was on 6 July 2016 and the last infant to be discharged from hospital was on 13 February 2017. Therefore, the end of study for the STRIDER trial was reported as 13 February 2017.

Inclusion and exclusion criteria

The study inclusion criteria were as follows:

• singleton pregnancy with severe, early‐onset IUGR between 22⁺⁰ and 29⁺⁶ weeks’ gestation AND a clinical decision to manage expectantly

• IUGR defined as an estimated fetal weight < 10th centile OR abdominal circumference < 10th centile AND absent or reversed end-diastolic flow in the umbilical artery

• 16 years of age or older

• consent to take part in the trial

The exclusion criteria for the study were as follows:

• multiple pregnancy

• known or suspected structural or chromosomal fetal abnormality

• maternal illness (such as pre‐eclampsia) expected to require delivery for maternal reasons within 72 hours

• maternal wish not to have active management of the pregnancy, such as a decision to have a termination of pregnancy

• inability to give informed consent

• cocaine use in the current pregnancy

• contraindication to sildenafil therapy

  • known maternal cardiac disease

  • left ventricular outflow tract obstruction

  • concomitant treatment with nitrates, nitrate drugs for chest pains/heart problems including nitro-glycerine (glyceryl trinitrate, GTN), isosorbide dinitrate, isosorbide mononitrate

  • nitrates – some recreational drugs contain amyl nitrate (‘poppers’)

  • previous allergy to sildenafil, including hives, difficulty breathing, swelling of the face, lips or tongue

Sample size estimation

Internal audits of early‐onset IUGR cohorts revealed an average diagnosis to delivery interval of around 20 days with a SD of 11 days. In order to confirm that sildenafil could prolong pregnancy by 1 week (7 days), a total recruitment of 104 women (alpha 5%, power 90%) was required. Although loss to follow‐up was not anticipated, recruitment of 135 women was planned in order to account for any possible post‐randomisation withdrawal of consent or missing data.

The secondary hypothesis was that sildenafil will improve utero‐placental circulation and therefore delay the development of fetal cardiovascular changes (reduced short-term heart rate variability, deterioration of fetal Doppler indices) that lead to the indication for iatrogenic delivery. With a complete data set for approximately 100 participants, it was predicted that a clinically meaningful 20% difference in mean Doppler Pulsatility Index (PI) values of uterine arteries (0.86, SD 0.20), middle cerebral artery (2.21, SD 0.39) and ductus venosus (0.62, SD 0.22) would be detectable (alpha 5%, power > 80%).

Randomisation

Randomisation was performed using a web‐based randomisation service operating at the Clinical Trials Unit (CTU), British Columbia Women’s Hospital (Vancouver, Canada). Passwords and login details were provided to each STRIDER research site at the point of site ‘green light’ authorisation by the LCTU.

Treatments were allocated with equal probability by means of computer generated random permuted blocks of size two and four in equal proportions. The randomisation was stratified by two factors, the participating research sites and the gestational age at diagnosis: < 26⁺⁰ and ≥ 26⁺⁰ weeks of gestation.

As STRIDER was a double-blind placebo-controlled trial, both the participant and any clinical staff were blinded to the treatment allocation. It was a requirement that any unbinding that occurred during the running of the study was reported as a major protocol deviation. Unblinded participants would then be retained in the intention to treat (ITT) population, but removed from any per-protocol analyses.

Study end points

The primary end point for the study was the difference in length of gestation (days), defined as the time from estimated gestation until birth.

The secondary end points were divided into subgroups for fetal, infant and maternal safety and were as follows.

Statistical analysis

Participants’ groups for analysis were defined on an ITT basis. Unadjusted estimates with Kaplan–Meier estimates were presented and analysed with linear regression techniques, including the stratification factor as a main effect. The treatment effect was reported as the mean difference between groups. Statistical significance was determined as p = 0.05 or less and participants randomised before 26⁺⁰ weeks and at 26⁺⁰ weeks or later were included in the subgroup analyses.

For continuous data, the analysis of secondary end points matched the analysis for the primary end point. Binary data were compared across treatment groups using a chi-squared (χ²) test or Fisher’s exact test as appropriate and reported using RR with 95% confidence intervals (95% CI). All analyses were performed using the statistical software package, R (version 3.3.3).

A Statistical Analysis Plan (SAP) was not produced prior to the analysis being undertaken.

Quality control and data validation

The STRIDER study was subject to regular data checks and reviews as set out in the trial-specific Data Management Plan. The study was also subject to both central and on-site monitoring as set out in the trial-specific Monitoring Plan. Regular Central Monitoring Reports were produced and reviewed by the Trial Management Team. In addition, on-site monitoring visits were carried out for each research site following the hospital discharge of the first participant and surviving infant. All visits were completed and any outstanding issues identified were actioned and closed accordingly.

An Independent Trial Steering Committee (TSC – Chair Professor Alan Cameron) and Safety and Data Monitoring Committee (ISDMC – Chair Professor Ed Juszczak) were established to provide oversight for the study. These committees met prior to the study opening, twice yearly while it was running and then one final time at the end of the study to review and approve the results. No significant issues relating to the management of the study or the safety of the participants were escalated.

The STRIDER randomisation list was reviewed to ensure provision of the correct number of strata, adequate randomisation numbers per stratum, appropriate block sizes and treatment allocations, and balanced allocation of treatments for various cumulative totals. This was found to be accurate. In line with the regular safety and efficacy review of the data by the ISDMC, checks were carried out for omitted, or, out of sequence allocations and balanced in treatment allocations.

At the end of the trial, a multiple logistic regression model with treatment arm as response and baseline variables as explanatory variables was used to confirm whether the best-fitting (minimum AIC) model was the one with no explanatory variables – that is, the baseline variable was uninformative as to treatment allocation.

All statistical coding relating to the analysis of the STRIDER data deriving the primary outcome variable was reviewed by an independent statistician who performed checks to ensure that the number of participants from the database matched the number in the analyses. A random check of at least 10% of participants was also performed to ensure that the derived gestational time and birth date was correct.

Adverse events and compliance

Adverse events (AEs) and treatment adherence were assessed and recorded at weekly clinical visits from recruitment to delivery. Participants were encouraged to record any side effects or AEs, which were then reviewed and documented during each clinical visit. Adherence was assessed weekly during clinical review, with any temporary discontinuation in treatment being recorded. Treatment adherence was considered to be good if the reported intake of tablets was 90% or more of the total expected to have been taken between randomisation and the visit date.

Phase 2 – 2-year follow-up

All surviving children of mothers recruited to the STRIDER UK study were eligible and invited for follow-up. Nominated members of the core research team were responsible for accessing the original confidential trial data in order to determine the contact details of all potential participants. As part of the original STRIDER UK trial, an audit of all consent forms took place to ensure that all participants had consented to further contact in relation to future research. In addition, a check was also made to ensure that the infants of all such participants survived. This was carried out via a number of methods including a thorough audit of all SAEs (which detail all fetal and neonatal deaths) and a final check at the local research site on the child’s health status. All participants received newsletters which provided information on the trial and also give the option of opting out of any further contact. Any participant who contacted the trial management team and requested to opt out of future correspondence and participation in further research was removed from the list of potential participants for the follow-up study.

A study invitation pack was sent to all parents/carers of surviving children. This included an invitation letter, participant information sheet and informed consent form. Participants were asked to read the information carefully and discuss their child’s participation in the study with either close friends, family and/or a relevant health professional. A named contact, telephone number and e-mail address were included on all correspondence so that parents/carers were able to contact the research team and discuss their child’s participation further, if required. If they were interested in taking part, they were asked to contact the research team in order to give verbal consent to take part in the study and to arrange a convenient date and time for their child’s assessment. Those participants who did not contact the research team within 2 weeks of the invitation pack being sent were contacted by a member of the core research team. For those participants who wanted to take part, an assessment date and time was arranged. Once an assessment date and time had been confirmed, an assessment pack was sent to the participant, as detailed below who have given expressed verbal consent to take part in the study.

The assessment pack included confirmation of the (already agreed) assessment date, time and location, a map (if necessary), details of what will take place during the assessment, who will carry out the assessment and a study questionnaire pack.

Assessments took place at either a local outpatient facility or in the home. A preference was made to carry out all assessments in a controlled setting (i.e. clinical research setting), however, where necessary assessments also took place in the child’s home after the researcher had assessed the home environment for suitability. Where assessments were planned to take place in the child’s home, further information was provided to parents on how to prepare their home (e.g. clearing an open space on the floor, providing a small table/work surface and turning off any distractions such as the television and or radio). Every effort was made to ensure that assessment dates were booked to suit the needs of the participant; however, it was preferred that assessments took place in the morning as this is a time that children are often well rested, fed and able to concentrate.

Participants were given contact details should they need to cancel or rearrange their assessment. Furthermore, they received a reminder telephone call 3 days prior to the assessment date and a text reminder the day before.

All assessments were performed by a suitably trained senior research psychologist with expertise in developmental assessment techniques in young infants. This researcher was also suitably trained in the specific cardiovascular assessment techniques used within this study and blinded to treatment allocation for the main STRIDER UK study. Additional oversight and supervision were provided by co-investigator, Professor Brigitte Vollmer for neurodevelopmental assessment techniques and Dr Andrew Sharp for cardiovascular assessment procedures.

Initially, the researcher facilitated introductions between all present, following on from this the study was explained and the child and parent/carer were given the opportunity to ask any questions relating to their child’s participation. Once this was complete and informed written consent had been received, the research assessment began. The researcher explained to the parent/carer the importance of allowing the child to complete all activities independently. The parent/carer was allowed to remain in the room while the assessment took place; however, they were asked not to interrupt or assist the child with these tasks unless otherwise invited to by the researcher.

The questionnaires sent to parents/carers in the assessment pack were reviewed by the researcher and any missing items were highlighted and discussed. If the parent/carer had any questions relating to the completion of the questionnaires, this was addressed so that the parent/carer could complete them during the assessment. Other factors were determined from the core STRIDER UK data set and where necessary neonatal records including gestational age, birthweight, APGAR (Activity, Pulse, Grimace, Appearance, Respiration) scores, duration of ventilation, chronic lung disease, persistent arterial ductus, neonatal sepsis, retinopathy of prematurity, necrotising enterocolitis and focal brain injury.

Once this was complete, the researcher played with the child to build a rapport so the child was relaxed and at ease during the assessment activities. Once the researcher deemed that the child was ready, the formal assessments were introduced to the child in the order set out in Table 1. These included the Cognitive, Language and Motor Subscales of the Bayley Scales of Infant and Toddler Development – III (BSID-III);27 Hempel’s Neurological Examination for Toddler Age28 which was used to identify major neurological impairment (cerebral palsy; CP) and to detect subtle deviations from typical neurological and neuromotor function and a cardiovascular assessment which included brachial systolic BP and diastolic BP and arterial stiffness, assessed as aortic (central) augmentation index (AIx).

The assessments took approximately 2.5 hours, excluding rest breaks (Table 1). Additional data were collected by the parental questionnaire and completed prior to the follow-up assessment. The assessment included well-established, valid and reliable standardised measures selected to provide a comprehensive neurodevelopmental and cardiovascular assessment together with the collection of core information on the child’s general health and well-being.

Once the assessments were complete, the researcher thanked the child and their parent/carer for their participation and parents/carers and children were given the opportunity to ask any further questions. They were advised that once the results of the assessment had been scored and interpreted, they would receive a report which would summarise the neurodevelopmental findings. Where specifically requested, a more detailed report was sent to the child’s GP and/or paediatrician who they would be able to contact if they should require any further information regarding these outcomes. The children were given a pack for participating in the study which included a certificate and a small gesture of thanks (e.g. age appropriate book) and parents/carers were given a voucher to the value of £10 to reimburse them for their time and any travel expenses.

Where potential participants cancelled or failed to attend follow-up appointments on more than three occasions, they were invited to participate remotely. All such participants received a follow-up questionnaire pack which included all questionnaires detailed as part of the main study in addition to the Ages and Stages Questionnaire-3 (in place of the BSID-III, neurodevelopmental assessment). A separate participant information sheet and consent form was also included in this pack, which had been modified to reflect the changes for remote participation in the study. This pack was also sent to potential participants who were hard-to-reach in the initial contact phase. Those participants invited to take part remotely who did not respond within 4 weeks of the remote participation pack being sent were contacted by telephone by a member of the core research team. This was to check whether the participant had received their pack and if they would like to discuss their potential participation further. During this telephone contact, participants interested in taking part were given the option to provide consent and complete the follow-up questionnaires via the paper-based method or verbally over the telephone.

Assessment methods

Trial population

One hundred and thirty-five participants were recruited to the STRIDER trial between 21 November 2014 and 6 July 2016 from 19 fetal medicine units within the UK (Figure 2). A number of 75 participants were recruited before 26⁺⁰ weeks’ gestation and 60 between 26⁺⁰ and 29⁺⁶ weeks’ gestation. A number of 70 participants were randomly assigned to receive sildenafil and 65 to receive the placebo. None of the participants withdrew their consent nor were lost to follow-up; therefore, additional ‘per-protocol’ analysis was not performed.

FIGURE 2.

Cumulative monthly recruitment to the STRIDER trial.

There were no clinically important differences found between the sildenafil arm and the placebo arm for ethnicity, age, body mass index (BMI), parity and pre-existing pre-eclampsia, but more participants self-reported smoking in pregnancy in the sildenafil arm (17% compared 3%; Table 2).

The median gestation at randomisation was 24.4 weeks [interquartile range (IQR) 24.0–27.5; see Table 2]. At randomisation, a reversed Doppler umbilical artery end-diastolic flow was detected in 44 (33%) participants (see Table 2). An absent umbilical artery end-diastolic flow was detected in all of the remaining participants. The fetal ductus venosus a-wave was found to be absent or reversed in 8 (6%) participants (see Table 2). The estimated fetal weight at randomisation was 445 g (IQR 344–608; Table 2). A total of 69 (51%) fetuses had an estimated fetal weight below 500 g (see Table 2). Two babies were postnatally diagnosed with Down syndrome (one allocated to the sildenafil arm and the other to the placebo arm) and two had confirmed cytomegalovirus infection (one allocated to the sildenafil arm and the other to placebo arm); all four babies were included in the ITT analysis.

The phase 2 follow-up study of surviving infants (aged 2–3 years corrected), born to mothers who took part in STRIDER UK, included the 75 babies discharged alive from the neonatal unit. One baby died after discharge and before follow-up (treatment arm – placebo). After extensive attempts to contact participants, 3 declined further involvement and 10 were uncontactable; therefore, 61 babies were included in the follow-up phase. Core descriptive statistics of the study sample can be found in Table 4. The mothers of 32 of the babies assessed had received sildenafil when pregnant and 29 had received placebo. There was no difference in the sex, birthweight, gestation at delivery (median 29.214 weeks vs. 29.857 weeks), mode of delivery or oxygen usage between babies whose mothers had received sildenafil or placebo.

Primary end point

The median time between randomisation and delivery was 18 days (IQR 8–27); 17 days (7–24) in the sildenafil arm and 18 days (8–28) in the placebo arm (p = 0.23; Table 3 and Figure 3). Linear regression showed that time to delivery did not differ between the two treatment arms for all participants (2.7 days, 95% CI −1.3 to 6.8; p = 0.19; Figure 3).

FIGURE 3.

Kaplan–Meier plot of interval from randomisation to birth. (a) < 26 weeks’ gestational age. (b) ≥ 26 weeks’ gestational age.

Secondary end points

Of the 135 participants recruited to the STRIDER trial, 98 (73%) had at least two separate umbilical artery Doppler measurements with a minimum 48 hours apart, 93 (69%) for ductus venosus, 90 (67%) for middle cerebral artery and 87 (64%) for uterine arteries (see Table 3). Ductus venosus a-wave deteriorated over time in more participants treated with sildenafil than with placebo (Table 5). Eighteen (95%) of the 19 babies in whom the ductus venosus deteriorated were randomly assigned before 26⁺⁰ weeks’ gestation (see Table 4). Between-group differences were not observed in the pattern of Doppler changes for any of the other fetal vessels examined (middle cerebral artery, umbilical artery and uterine arteries; see Table 4).

The exposure to antenatal corticosteroids and magnesium sulphate, given for neuroprotection, was similar in both treatment arms (see Table 4). There was also no difference in the caesarean section rate between the arms (see Table 4), with 98% (90 of 92) of all livebirths being delivered by caesarean section (Table 5).

Livebirth rates and neonatal deaths did not differ between the treatment arms (see Table 5). Forty-three (72%) of the 60 deaths reported occurred in utero and 48 (80%) deaths occurred in the subgroup randomly assigned before 26⁺⁰ weeks’ gestation (see Table 5). No clinically significant differences were observed between the two treatment arms for any of the other pre-specified secondary end points (see Table 5).

Serious adverse events and adherence

Adverse events (AEs) were recorded as part of routine medical data review. AEs were not graded.

A total of eight SAEs, graded as per medDRA, were reported during the course of the study; none of these were attributed to sildenafil. Three (38%) were maternal hospital admissions in the placebo arm; one antepartum haemorrhage, one general malaise (unwell, dizzy and light-headed), and one hospital admission following a stillbirth with drowsiness. There were two reported neonatal SAEs in the sildenafil arm; a baby with Down syndrome with an atrioventricular septal defect and a fetal intracranial haemorrhage grade 1, which was detected on an antenatal MRI performed in the context of a separate research study. In the placebo arm, three neonatal SAEs were reported; a baby with Down syndrome, a fetal intracranial haemorrhage grade 1 and a baby with bone fractures that were postnatally attributed to osteopenia/metabolic bone disease.

Overall, 42 women reported 94 side effects: 24 (34%) in the sildenafil arm and 18 (28%) in the placebo arm (RR 1.24, 95% CI 0.74 to 2.06; p = 0.41). The majority of the side effects reported were for facial flushing [45 of 94 (48%)]. Other reported side effects included nasal congestion, a dry mouth and headaches.

Good treatment adherence was reported; of the 265 recorded cycles of therapy, 257 (97%) reported that drug adherence was at least 90%. At a participant level, 130 (96%) of the 135 participants had study drug compliance of at least 90% for all cycles of therapy.

Phase 2 end points

Child neurodevelopmental assessments were performed on all eligible infants in their home setting or a local hospital at the parents request as described above. Demographic data are presented in Table 6.

The Bayley assessment of child neurodevelopment at 2 years of age (corrected) is shown in Table 7. No significant differences in cognitive, language (including receptive and expressive language) or motor (including fine and gross motor) subscales were found between children of sildenafil- and placebo-treated mothers. Total scores reveal a trend of being lower than expected across all three domains compared with standard population norms (i.e. 100, SD = 15); however, this was not found to be statistically significant. No difference was found between the sildenafil and placebo groups for presence of CP at 2 years, as reported by the parent.

Table 8 shows the physical characteristics of the population. There was no difference in height or weight. Head circumference was slightly larger in those treated with sildenafil (49.25, 46.4–50.262) versus placebo (47.175, 44.713–48.95). There was no difference between systolic and diastolic BP between those children treated with sildenafil or placebo. Median values were appropriate for children aged 2 years.

The BRIEF-P (Table 9) demonstrated no difference in adjusted T-scores between sildenafil and placebo for any of the assessed domains. The median total CBCL scores and adjusted T-scores (Table 10) showed no difference between infants whose mothers were treated with sildenafil versus placebo for any of the assessed domains.

The HSCS-PS scores are shown as a total score by domain and as individual components (Table 11). There was no difference between infants who had received sildenafil and those who had received placebo for any of the domains assessed.

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.

Acknowledgements

The researchers would like to thank all the women who participated in this study during such a distressing time for them and their families. They would also like to thank the members of the Trial Steering Committee (Professor Alan Cameron – Chair, Professor Elizabeth Draper, Professor Paul Clarke, Dr Laura Price, Dr Laura Bonnett, Mr Alex Astor, Ms Louise Hardman, and Miss Karen Wilding), Independent Safety and Data Monitoring Committee (Professor Ed Juszczak – Chair, Professor Christoph Lees and Professor Ben Stenson) and all the individuals who helped with the management and conduct of the STRIDER UK study. The researchers are also grateful to Sharp Clinical Services and The University of British Columbia (UBC), Canada for supporting the provision of blinded drug to research sites and to staff of pharmacy and research and development departments in all of the participating hospitals. The researchers would like to thank UBC for the development and support of the STRIDER randomisation and electronic data capture systems.

The researchers would like to thank the NIHR who funded this programme of work.

Contributions of authors

Andrew Sharp (https://orcid.org/0000-0003-3396-7464) (Senior lecturer in Obstetrics, Obstetrician) wrote the initial submission for funding, wrote the submission for phase 2 funding for the study, supervised the conduct of the RCT and wrote the manuscript.

Christine Cornforth (https://orcid.org/0000-0002-6047-8634) (Director of Partnerships & Programmes, Senior Trial Manager) wrote the submission for Phase 2 funding for the study, supervised the conduct of the RCT, performed neurodevelopmental assessments, reviewed the neurodevelopmental data and wrote the manuscript.

Richard Jackson (https://orcid.org/0000-0002-7814-5088) (Senior Lecturer in Statistics, Statistician) performed statistical analysis.

Jane Harrold (https://orcid.org/0000-0002-9281-1446) (Doctor, Trial Manager) collated trial data.

Mark A Turner (https://orcid.org/0000-0002-5299-8656) (Professor of Neonatology, Neonatologist) supervised neonatal outcomes.

Louise Kenny (https://orcid.org/0000-0002-9011-759X) (Professor of Obstetrics and Executive Pro-Vice-Chancellor, Obstetrician) developed the STRIDER study consortium.

Philip N Baker (https://orcid.org/0000-0002-4592-6427) (Professor of Obstetrics and Pro Vice-Chancellor, Research and Enterprise, Obstetrician) conceived the idea for the study and developed the STRIDER study consortium.

Edward D Johnstone (https://orcid.org/0000-0001-9732-8544) (Professor of Obstetrics, Obstetrician) reviewed trial data.

Asma Khalil (https://orcid.org/0000-0003-2802-7670) (Professor of Fetal Medicine, Obstetrician) assessed the cardiovascular results.

Peter von Dadelszen (https://orcid.org/0000-0003-4136-3070) (Professor of Global Women’s Health, Obstetrician) developed the STRIDER study consortium.

Aris T Papageorghiou (https://orcid.org/0000-0001-8143-2232) (Professor of Fetal Medicine, Obstetrician) developed the STRIDER study consortium.

Brigitte Vollmer (https://orcid.org/0000-0003-4088-5336) (Professor of Perinatal Neurology) provided oversight relating to the neurodevelopmental outcomes assessment and interpretation, reviewed the neurodevelopmental data and wrote the manuscript.

Zarko Alfirevic (https://orcid.org/0000-0001-9276-518X) (Emeritus Professor of Fetal Medicine, Obstetrician) developed the STRIDER study consortium, wrote the initial submission for funding, wrote the submission for phase 2 funding for the study, supervised the conduct of the RCT and wrote the manuscript.

All authors reviewed the final manuscript and prepared the results for publication.

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the NIHR Journals Library report publication page at https://doi.org/10.3310/WAKV3677.

Primary conflicts of interest: Andrew Sharp, Asma Khalil, Richard Jackson, Edward D Johnstone, Jane Harrold, Louise Kenny, Peter von Dadelszen, Zarko Alfirevic, Christine Cornforth, Mark A Turner, Brigitte Vollmer declare no conflicts of interest.

Philip N Baker is a minority shareholder of Metabolomic Diagnostics, a spin out company which seeks to develop screening tests for pregnancy complications.

Aris T Papageorghiou is a co-founder of and shareholder of Intelligent Ultrasound, a University spin out company.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to available anonymised data may be granted following review.

Ethics statement

Ethical approval for phase 1 of this study was obtained on 20 March 2014, Research Ethics Committee (REC; North East – Newcastle and North Tyneside 2, REC Ref: 14/NE/0011) and for phase 2 was obtained on 21 December 2016 (REC; London – Brent Research Ethics Committee, REC Ref: 16/LO/2225).

Information governance statement

The University of Liverpool and Liverpool Women’s Hospital have a steadfast commitment to adhering to the UK Data Protection Act (2018) and the General Data Protection Regulation (EU GDPR) 2016/679 when it comes to managing personal information. As per the Data Protection legislation, the University of Liverpool serves as the Data Controller. For detailed information on how personal data is handled, including guidance on exercising individual rights and contacting the Data Protection Officer, please refer to this link (legal@liverpool.ac.uk).

Disclaimers

This article presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the EME programme or the Department of Health and Social Care.

STRIDER UK: phase 2 follow-up

Version 7.0, 11 October 2022

SPONSORS: The University of Liverpool

SPONSOR REFERENCE: UoL001286

FUNDERS: National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME)

FUNDING REFERENCE: 12/62/109

RESEARCH ETHICS COMMITTEE: London – Brent Research Ethics Committee

REC REFERENCE: 16/LO/2225

Study summary

This protocol describes the STRIDER UK: phase 2 follow-up study and provides information about procedures for participants. Every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to investigators in the study. Problems relating to this study should be referred, in the first instance, to the Chief Investigator.

This study will adhere to the principles outlined in the NHS Research Governance Framework for Health and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as appropriate.

List of abbreviations

Keywords Neonate, preterm, intrauterine growth restriction, neurodevelopment, cardiovascular, sildenafil

Table of contents

Introduction

Research outcomes

The primary research outcomes for this study are:

• survival free of neurodevelopmental delay at 2–3 years corrected age, defined by absence of cerebral palsy, deafness, blindness, developmental delay (BDAI-III cognitive, language or motor score < 85), and

• survival free of cardiovascular impairment as defined by normal (similar to that in controls) systolic, diastolic BP or AIx (arterial stiffness) at 2–3 years corrected age.

The secondary research outcomes for this study are:

• brachial pulse pressure (PP), brachial mean arterial pressure, heart rate, central systolic BP, central PP, aortic augmentation pressure, peripheral Alx and pulse wave velocity,

• presence of MND, categorised as MND1 and MND2,

• delay defined as a CBCL, internalising, externalising and overall subscale score > 2 SD, and

• difference in mean BRIEF-P scores overall subscale score > 2 SD.

Study design/assessment procedure

This is a follow-up study of surviving infants (aged 2–3 years corrected) born to mothers who took part in STRIDER UK, a multicentre double-blind randomised placebo-controlled trial. Infants were born between December 2014 and July 2016. Core descriptive statistics of the study sample will be available upon completion of the main trial analyses.

Study procedure

Participants

All surviving children of mothers recruited to the STRIDER UK study will be eligible and invited for follow-up. Prior to contacting participants and inviting them to take part in the study, a thorough review of the child’s medical records will be carried out by designated members of the core research team to ensure the infant has survived. Contact information will be available for all mothers who took part in the main STRIDER UK trial (Figure 1).

Nominated members of the core research team will request access to the original confidential trial data in order to determine the contact details of all potential participants. As part of the original STRIDER UK trial, an audit of all consent forms will take place to ensure that all participants have consented to further contact in relation to future research. In addition, a check will also be made to ensure that the infants of all such participants survived. This will be carried out via a number of methods including a thorough audit of all serious adverse events (SAEs; which detail all fetal and neonatal deaths) and a final check at the local research site on the child’s health status. All participants receive newsletters which provide information on the trial and also give the option of opting out of any further contact regarding the trial. Any participant who has made contact with the trial management team and requested to opt out of future correspondence and participation in further research will also be removed from the list of potential participants for the follow-up study.

FIGURE 1.

Data access process for the identification of eligible participants for the follow-up study.

Pre-contact

STRIDER UK participants receive regular newsletters which provide an update on the STRIDER UK trial together with information on the follow-up. This will give participants the opportunity to contact the research team and get more information about the follow-up, if required. Potential participants will then be contacted again prior to their child reaching the age of 2 years corrected. This contact will be made by sending the parent/carer an invitation pack, detailed below. Additional efforts will be made by the research team to contact participants using a wide range of methods, including a letter, telephone call, e-mail and a newsletter. This will be carried out by experienced research staff who have a proven track record of working on longitudinal follow-up within this study population.

Invitation pack

A study invitation pack will be sent to all parents/carers of surviving children. This will include an invitation letter, participant information sheet and informed consent form. Participants will be asked to read the information carefully and discuss their child’s participation in the study with either close friends, family and/or a relevant health professional. There will also be a named contact, telephone number and e-mail address included on all correspondence so that parents/carers are able to contact the research team and discuss their child’s participation further, if required. If the parents are interested in taking part they will be asked to contact the research team in order to give verbal consent to take part in the study and to arrange a convenient date and time for their child’s assessment. Those participants who do not make contact with the research team within 2 weeks of the invitation pack being sent, will be contacted by a member of the core research team. This will be to check whether the participant has received their invitation pack and if they would like to discuss their potential participation further. For participants who do wish to take part an assessment date and time will be made (between the age of 2 and 3 years corrected ±3 months), additional time will be given to participants who would like to seek further advice about their child’s participation and a note will be made for those participants who are not contactable or who do not wish to take part in this phase of the study. Once an assessment date and time has been confirmed an assessment pack will be sent to the participant, as detailed below.

Assessment pack

Once an assessment date and time has been agreed, an assessment pack will be sent to participants who have given expressed verbal consent to take part in the follow-up. This pack will include confirmation of the (already agreed) assessment date, time and location, a map (if necessary), details of what will take place during the assessment, who will carry out the assessment, and a study questionnaire pack.

Location of assessments

Assessments will take place at either a local outpatient facility or in the home. A preference will be made to carry out all assessments in a controlled setting (i.e. clinical research setting), however, where necessary assessments will take place in the child’s home. However, under such circumstances, the researcher will need to assess the home environment for suitability beforehand. Where assessments are planned to take place in the child’s home, further information will be provided to parents on how to prepare their home (e.g. clearing an open space on the floor, providing a small table/work surface and turning off any distractions such as the television and or radio). Every effort will be made to ensure that assessment dates are booked to suit the needs of the participant; however, it is preferred that assessments take place in the morning as this is a time that children are often well rested, fed and able to concentrate.

Participants will be provided with contact details should they need to cancel or rearrange their assessment. Furthermore, they will receive a reminder telephone call 3 days prior to the assessment date and a text reminder the day before. Where the participant does not have access to a mobile phone number and the research team have been unable to make contact by telephone 3 days prior to the assessment date, further telephone calls by landline will be made to confirm the appointment is going ahead.

The follow-up assessment

The assessment will be performed by a suitably trained senior research psychologist with expertise in developmental assessment techniques in young infants. They will also be suitably trained in the specific cardiovascular assessment techniques used within this study and blinded to treatment allocation for the main STRIDER UK study.

Initially, the researcher will facilitate introductions between all present, following on from this the study will be explained and the child and parent/carer will be given the opportunity to ask any questions relating to their/their child’s participation. Once this is complete and informed written consent has been received, the research assessment will begin. The researcher will explain to the parent/carer the importance of allowing the child to complete all activities independently. The parent/carer is allowed to remain in the room while the assessment is taking place; however, they are asked not to interrupt or assist the child with these tasks unless otherwise invited to by the researcher.

The questionnaires sent to parents/carers in the assessment pack will be reviewed by the researcher and any missing items will be highlighted and discussed. If the parent/carer has any questions relating to the completion of the questionnaires, this will be addressed so that the parent/carer can complete them during the assessment. The researcher will also complete a general questionnaire with the parent/carer to determine information on a core set of variables that may affect research outcomes including, general health, since discharge from the neonatal unit and socio economic status. Other factors will be determined from the core STRIDER UK data set and where necessary neonatal records including gestational age, birthweight, APGAR scores, duration of ventilation, chronic lung disease, persistent arterial ductus, neonatal sepsis, retinopathy of prematurity, necrotising enterocolitis and focal brain injury. For the cardiovascular parameters, the study will collect information on systolic BP, diastolic BP and AIx adjusted for sex, weight and height. The study will also correct AIx for heart rate in view of the inverse linear relationship between AIx and heart rate.

Once this is complete, the researcher will play with the child to build a rapport so the child is relaxed and at ease during the assessment activities. Once the researcher deems that the child is ready, the formal assessments will be introduced to the child in the order set out in Table 1. These include the Cognitive, Language and Motor Subscales of the Bayley Scales of Infant and Toddler Development – III (BDAI-III);31 Hempel’s Neurological Examination for Toddler Age32 which will be used to identify major neurological impairment (cerebral palsy; CP) and to detect subtle deviations from typical neurological and neuromotor function and a cardiovascular assessment which includes brachial systolic BP and diastolic BP and arterial stiffness, assessed as aortic (central) AIx.

TABLE 1 - Assessment schedule

Assessment/procedure	Completed by	Time to complete
Introduction/consent	Parent/researcher	15–20 minutes
Questionnaire review	Parent/researcher	5–10 minutes
General health and well-being	Parent/researcher	5–10 minutes
Break
Introductory play session	Child/researcher	10–15 minutes
BDAI: mental/cognitive assessment	Child/researcher	10–15 minutes
BDAI: fine motor assessment	Child/researcher	10–15 minutes
Break
BDAI: gross motor assessment	Child/researcher	10–15 minutes
Hempel neuromotor assessment	Child/researcher	20–30 minutes
Break
Cardiovascular assessment	Child/researcher	15 minutes
Thank you and assessment summary	Parent/child/researcher	5 minutes

All participants will be asked to consent to the assessment being recorded for the purpose of assessing rater-reliability. For those consenting participants, all recordings will be labelled by the participant ID, date and time of assessment. These recordings will be stored electronically on a secure, password protected drive within the University of Liverpool. This drive will only be accessed by members of the core research team.

The assessments will take a total of 2.5 hours, excluding rest breaks (see Table 1). Additional data will be collected by parental questionnaire and completed prior to the follow-up assessment. The assessment includes well-established valid and reliable standardised measures selected to provide a comprehensive neurodevelopmental and cardiovascular assessment together with the collection of core information on the child’s general health and well-being. It is planned that all assessments will be completed by one trained and experienced senior researcher; however other researchers will also be trained if the situation arises where additional support is required. All assessors will be blinded to treatment allocation, formally trained in assessment techniques prior to commencing data collection and rater-reliability will be assessed throughout the study.

Once the assessments are complete, the researcher will thank the child and their parent/carer for their participation and parents/carers and children will be given the opportunity to ask any further questions. They will be advised that once the results of the assessment have been scored and interpreted, they will receive a report which will summarise the neurodevelopmental findings. With their consent, a more detailed report will be sent to the child’s GP and/or paediatrician who they will be able to contact if they should require any further information regarding these outcomes. The children will be given a pack for participating in the study which will include a certificate and a small gesture of thanks (e.g. age appropriate book) and parents/carers will be given a voucher to the value of £10 to reimburse them for their time and travel expenses.

Thanks and feedback pack

Approximately 2 weeks after the assessment date, participants will receive a Thank you/Feedback pack which will include a general letter and the participant’s version of the assessment feedback report. As outlined previously, a more detailed version of this report will be sent to the child’s GP and/or paediatrician.

As this is a research activity, it will be in addition to standard neonatal follow-up which should normally take place between the ages of 2 and 3 years (corrected for prematurity), though we will endeavour to co-ordinate appointments to both maximise recruitment and make attendance easier for parents. Consent will be requested for data from this assessment to be made available to clinicians carrying out the routine standard neonatal, aged 2–3 years, follow-up and the child’s GP and/or paediatrician.

Where potential participants cancel or fail to attend follow-up appointments, they will be invited to participate remotely. All such participants will receive a follow-up questionnaire pack which will include all questionnaires detailed as part of the main study in addition to the Ages and Stages Questionnaire (in place of the BDAI-III, neurodevelopmental assessment). A separate participant information sheet and consent form will also be included in this pack, which have been modified to reflect the changes for remote participation in the study. This pack will also be sent to potential participants who have been hard-to-reach in the initial contact phase. Those participants invited to take part remotely who do not respond within 4 weeks of the remote participation pack being sent will be contacted by telephone by a member of the core research team. This will be to check whether the participant has received their pack and if they would like to discuss their potential participation further. During this telephone contact, participants interested in taking part will be given the option to provide consent and complete the follow-up questionnaires via the paper-based method or verbally over the telephone.

Participant entry

Participants in this study are children of women who took part in the STRIDER UK trial.

Assessment methods

The assessment includes well-established valid and reliable standardised measures selected to provide a comprehensive neurodevelopmental, cardiovascular and general health assessment at age 2–3 years corrected. Assessment measures are detailed overleaf.

The Bayley Scales of Infant and Toddler Development – III (BDAI-III)27 will be used as a standard measure of neurological Cognitive, Language and Motor Scales. This is an individually administered instrument designed to measure the developmental functioning of infants and toddlers. Other specific purposes of the BDAI-III are to identify possible developmental delay, inform professionals about specific areas of strength or weakness when planning a comprehensive intervention, and provide a method of monitoring a child’s developmental progress. The BDAI-III is appropriate for administration to children between the ages of 1 month and 42 months (although norms extend downward to age 16 days).

Hempel’s Neurological Examination for Toddler Age28 will be used to identify major neurological impairment (CP) and to detect subtle deviations from typical neurological and neuromotor function. The Hempel examination has been developed to evaluate MND at preschool age. It assesses MND in five domains of functions: fine motor function, gross motor function, posture and muscle tone, reflexes, and visuo-motor function. 30 Each of the domains can be scored as typical or deviant. Findings are classified as major neurological dysfunction, complex MND, simple MND, or neurologically normal. Major neurological dysfunction implies the presence of a distinct neurological syndrome, such as CP. Complex MND implies the presence of two or more deviant domains; simple MND implies the presence of one deviant domain. Neurologically normal implies the absence of deviant domains or the presence of only deviant reflexes. 30 Simple MND has limited clinical significance and reflects the presence of a normal, but non-optimally wired brain. On the other hand, complex MND represents the clinically relevant form of MND and is associated with behavioural and learning disorders. 31 The reliability of the Hempel examination is satisfactory (κ scores for various items: 0.62–1.00).

Where it is not feasible to calculate the Hempel scores owing to difficulties/lack of consent in recording the session, the assessment will continue to be completed with the following core variables collected: limb tone and reflexes, ankle and foot (e.g. clonus right and left ankle, Babinski reflex), presence and severity of cerebral palsy. These variables form part of the 2 to 3-years neurological outcomes for the STRIDER IPD analysis.

Child Behaviour Checklist 1.5–5 Parent Form (CBCL)33 will be used to assess emotional and behavioural difficulties. The CBCL includes 100 items that address emotional and behavioural problems, which are scored by parents on a three-point scale: not true, somewhat or sometimes true, and very true or very often true. The sum of all questions results in the TPS, an internalising problem score (IPS: emotionally reactive, anxious or depressed, somatic complaints and withdrawn), and an externalising problem score (EPS: attention problems and aggressive behaviour). Raw scores are normalised into T-scores (mean: 50, SD: 10). Higher T-scores represent more problematic behaviour. T-scores below 60 are in the normal range, T-scores of 60–63 (84th to 90th percentile) are in the borderline range, and T-scores above 63 (above 90th percentile) are in the clinical range. The T-scores are dichotomised into typical (scores in the normal range) and atypical (scores in the borderline and clinical range). The reliability and validity of the CBCL are good. 33 Where a child is attending nursery or daycare, the Caregiver–Teacher Report Form for Ages 1.5–5 will also be requested by post.

Behaviour Rating Inventory of Executive Function – Preschool version (BRIEF-P)34 is a parent questionnaire for early assessment of executive function. The BRIEF is a standardised questionnaire completed by the primary caregiver or parent that has been widely used in research and clinical settings to assess the presence and severity of executive dysfunction in day-to-day situations. 34 It is composed of three broad indices (General Executive Composite, the Metacognitive Index and the Behaviour Regulation Index) and eight subscales. The Metacognitive Index is comprised of five subscales: initiate (how well an individual independently initiates tasks), working memory (holding information in mind, manipulating information in mind), planning/organisation (using systematic, well planned approaches to tasks), organisation of materials and monitor (monitoring one’s behaviour or task approach). The Behaviour Regulation Index is comprised of three subscales, including inhibit (an index of impulsive behaviour or acting before thinking), shift (the ability to maintain a flexible approach to problem solving or behaviour) and emotional control (the ability to manage and regulate emotional responses). Age-based T-scores are computed for each subscale and index, and a score of 65 or higher is considered a clinically significant problem.

Cardiovascular assessments will be carried out using standard BP equipment. Prior to the assessments being carried out, the researcher will ensure that the following is controlled: (1) room temperature – environment kept at 22°C ± 1°C; (2) participants will be asked to be in a recumbent, supine position; and (3) the researcher must be aware of the effect of cardiac arrhythmia, white coat hypertension on measurements. Where children are fearful or distressed, a note will be made in the assessment notes and if necessary the assessment will be stopped and the most recent information will be used from the child’s medical notes (where applicable).

Statistical analyses

The main STRIDER UK trial recruited a total of 135 participants. It is estimated that approximately 86 participants (43 per group: 80% response rate) will take part in this follow-up phase. This could vary depending upon the final number of neonatal deaths reported for the study.

Regulatory issues

Project management

The Project Management Group will be responsible for overseeing progress of the project on a day-to-day basis; this will consist of the Chief Investigator, Principal Investigators and core research staff.

A Project Steering Committee will be set up consisting of members of the main STRIDER UK trial oversight committees. This committee will oversee the progress of the project and will meet when required unless otherwise requested by the Project Management Group. This committee will formally meet once all data has been collected to review the study findings.

End of study

The study will be complete when all participating infants have had their notes retrospectively audited for the IPD data outcomes and completed their age 2–3-year (corrected) assessment.

Substudies

The main STRIDER UK trial protocol (EudraCT Ref: 2013-005398-32) included four ancillary studies linked to additional analyses. These were: (1) vascular profiling, (2) placental biobanking, (3) IPD meta-analysis and (4) cardiovascular profiling. Detailed below are the substudies that will be linked to this follow-up study and possible subsequent analyses.

Archiving

Data and all appropriate documentation should be stored for a minimum of 10 years after the completion of the study, including the follow‐up period, unless otherwise directed by the funder/sponsor/regulatory bodies.

Publication

STRIDER UK and this follow-up study will be published in peer-reviewed scientific journals and presented at clinical and academic conferences. In addition, the STRIDER IPD collaboration is in place to ensure that longer-term outcomes are assessed in the most efficient way so that if sildenafil is safe and effective, timely change in clinical practice and subsequent improvements in health will be achieved. Dissemination of results will be aided by the IPD collaboration (part of the Global Obstetric Network). Full details on publication will be defined following the first Project Oversight Meeting.

Protocol amendments