1.0 Background - ANZCTR
Research ProtocolReducing the risk of fetal distress with sildenafil (RIDSTRESS Study)PI:Professor Sailesh KumarAI:Prof Vicki FlenadyDr Liam DunnDr Jessica TurnerMain Sponsor: Mater Health ServiceFunders: Mater FoundationStudy Coordination centre: Mater Research Institute/University of QueenslandHREC/15/MHS/33Study Management GroupPrincipal Investigator: Professor Sailesh Kumar Mater Research Institute/University of QueenslandAubigny Place, Raymond TerraceSouth Brisbane QLD 4101 AustraliaCo-Investigators: Prof Vicki FlenadyDirector, Translating Research into Practice (TRIP) Institute Mater Research Institute/University of QueenslandAubigny Place, Raymond TerraceSouth Brisbane QLD 4101 AustraliaDr Liam Dunn Mater Research Institute/University of QueenslandAubigny Place, Raymond TerraceSouth Brisbane QLD 4101 AustraliaDr Jessica TurnerMater Research Institute/University of QueenslandAubigny Place, Raymond TerraceSouth Brisbane QLD 4101 AustraliaStudy Coordination centreFor general enquires and supply of trial documentation please contactName:Dr Jessica TurnerAddress: MMRI, Level 3, Aubigny Place, Raymond Terrace, South Brisbane. QLD 4101, AustraliaEmail:jessica.turner@uq.edu.auTel:0476614033Fax:07 3163 1890FunderMater Foundation, Aubigny Place, Raymond Terrace, South Brisbane, QLD 4101, AustraliaTable of Contents TOC \o "1-3" \h \z \u 1.0 Background PAGEREF _Toc15031799 \h 42.0 Study Objectives: PAGEREF _Toc15031800 \h 53.0 Study Design and sample size PAGEREF _Toc15031801 \h 54.0 Participant entry PAGEREF _Toc15031802 \h 54.1 Inclusion and Exclusion criteria PAGEREF _Toc15031803 \h 54.2 Withdrawal criteria PAGEREF _Toc15031804 \h 65.0 Methods PAGEREF _Toc15031805 \h 66.0 Study outcome measures PAGEREF _Toc15031806 \h 77.0 Adverse Events PAGEREF _Toc15031807 \h 77.1 Safety Reporting PAGEREF _Toc15031808 \h 87.2 Stopping criteria PAGEREF _Toc15031809 \h 98.0 Lost to follow up PAGEREF _Toc15031810 \h 99.0 Trial Closure PAGEREF _Toc15031811 \h 910.0 Statistics and data analysis PAGEREF _Toc15031812 \h 911.0 Regulatory issues PAGEREF _Toc15031813 \h 911.1 Clinical Trial Authorisation PAGEREF _Toc15031814 \h 911.2 Ethics PAGEREF _Toc15031815 \h 912.0 Consent PAGEREF _Toc15031816 \h 913.0 Confidentiality PAGEREF _Toc15031817 \h 914.0 Indemnity PAGEREF _Toc15031818 \h 1015.0 Sponsor PAGEREF _Toc15031819 \h 1016.0 Funding PAGEREF _Toc15031820 \h 1017.0 Audits and inspection PAGEREF _Toc15031821 \h 1018.0 Publication Policy PAGEREF _Toc15031822 \h 1019.0 Ethical Considerations PAGEREF _Toc15031823 \h 10References PAGEREF _Toc15031824 \h 11Appendix I PAGEREF _Toc15031825 \h 13Appendix III PAGEREF _Toc15031826 \h 19Appendix IV PAGEREF _Toc15031827 \h 201.0 BackgroundLabour is perhaps the most hazardous time in pregnancy for the fetus. Uterine contractions are associated with an up to 60% decline in uterine blood flow ADDIN EN.CITE <EndNote><Cite><Author>Janbu</Author><Year>1987</Year><RecNum>43</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="s2e9pvxsow2rznex2035xszrf2tsw992etze">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Janbu, T</author><author>Nesheim, BL</author></authors></contributors><titles><title>Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure</title><secondary-title>Br J Obstet Gynaecol</secondary-title></titles><periodical><full-title>Br J Obstet Gynaecol</full-title></periodical><pages>1150-5</pages><volume>94(12)</volume><number>Dec</number><dates><year>1987</year></dates><urls></urls></record></Cite></EndNote>1, and this in turn may lead to fetal decompensation. Up to 63% of babies who become distressed and suffer oxygen deprivation in labour have no prior risk factors ADDIN EN.CITE <EndNote><Cite><Author>Low</Author><Year>2001</Year><RecNum>10</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="avtrz5tr6aesazeprww5xsaffzx9sp0pvfep" timestamp="1551754518">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Low, James A</author><author>Pickersgill, Heather</author><author>Killen, Helen</author><author>Derrick, E Jane</author></authors></contributors><titles><title>The prediction and prevention of intrapartum fetal asphyxia in term pregnancies</title><secondary-title>American journal of obstetrics and gynecology</secondary-title></titles><periodical><full-title>American journal of obstetrics and gynecology</full-title></periodical><pages>724-730</pages><volume>184</volume><number>4</number><dates><year>2001</year></dates><isbn>0002-9378</isbn><urls><related-urls><url>(01)76505-2/fulltext</url></related-urls></urls></record></Cite></EndNote>2. 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ADDIN EN.CITE.DATA 5,6. Cerebral redistribution is an adaptive response to sub-optimal placental function ADDIN EN.CITE <EndNote><Cite><Author>Baschat</Author><Year>2004</Year><RecNum>378</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="s2e9pvxsow2rznex2035xszrf2tsw992etze">378</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baschat, Dr Ahmet Alexander</author></authors></contributors><titles><title>Fetal responses to placental insufficiency: an update</title><secondary-title>BJOG: An International Journal of Obstetrics & Gynaecology</secondary-title></titles><periodical><full-title>BJOG: An International Journal of Obstetrics & Gynaecology</full-title></periodical><pages>1031-1041</pages><volume>111</volume><number>10</number><dates><year>2004</year></dates><publisher>Blackwell Science Ltd</publisher><isbn>1471-0528</isbn><urls><related-urls><url>, and occurs prior to obvious deterioration in growth velocity. Previous work from our group has shown that changes in fetal blood flow, detected by ultrasound scan were highly predictive of identifying fetuses at risk of compromise in labour as well as reliably excluding those that were not at riskPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmlvcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 5,6. We have shown that the ratio of the pulsatility index of the fetal middle cerebral and umbilical arteries (cerebro-umbilical (CU) ratio) were predictive of intrapartum compromise. Fetuses with a CU ratio <10th percentile were six times more likely to be delivered by caesarean for fetal compromise than those with a CU ratio ≥10th percentile. Furthermore, a CU ratio >90th percentile was protective for fetal compromise with a negative predictive value of 100%. These results suggest that there exists a population of fetuses at term which, though appropriately grown, still display circulatory evidence of reduced placental function. We have also identified abnormalities in umbilical venous flow ADDIN EN.CITE <EndNote><Cite><Author>Prior</Author><Year>2013</Year><RecNum>389</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="s2e9pvxsow2rznex2035xszrf2tsw992etze">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Prior, Tomas</author><author>Mullins, Edward</author><author>Bennett, Phillip</author><author>Kumar, Sailesh</author></authors></contributors><titles><title>Umbilical venous flow rate in term fetuses: can variations in flow predict intrapartum compromise?</title><secondary-title>American journal of obstetrics and gynecology</secondary-title></titles><periodical><full-title>American journal of obstetrics and gynecology</full-title></periodical><number>0</number><keywords><keyword>fetal compromise</keyword><keyword>fetal Doppler</keyword><keyword>labor</keyword><keyword>umbilical venous flow</keyword></keywords><dates><year>2013</year></dates><isbn>0002-9378</isbn><urls><related-urls><url> in this same group of fetuses. Further recent work from our group has shown that levels of placental growth factor (PlGF) are significantly lower in women who develop fetal distress in labour supporting the case for reduced placental function in this cohort. Having developed a technique for prediction of intrapartum compromise we now wish to translate this into the clinical setting in a pilot randomised controlled trial using sildenafil to reduce the risk of fetal distress in labour. The rationale for the use of sildenafil to reduce intrapartum fetal compromise in this study comes from its effect in improving pelvic and uteroplacental blood flow seen in pregnancies complicated by pre-eclampsia or fetal growth restriction. Given that the cardiovascular adaptations in fetuses with growth restriction are similar to that seen in term appropriately grown babies who develop intrapartum fetal compromise; it is reasonable to suppose that sildenafil, via its ability to improve uteroplacental perfusion could potentially reduce the risk of intrapartum compromise and the need for emergency delivery. Much of the evidence to support the use of sildenafil in pregnancy comes from its use in severe fetal growth restriction. There is evidence from ex vivo, animal and human models of growth restriction that the phosphodiesterase-5 inhibitor sildenafil citrate increases average pup birth weight and improves uteroplacental blood flow (umbilical artery, uterine artery)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWx3b3J0aDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA 9-14. Sildenafil may therefore be a potential therapeutic option to improve uteroplacental blood flow in human pregnancies complicated by severe fetal growth restriction ADDIN EN.CITE <EndNote><Cite><Author>Herraiz</Author><Year>2012</Year><RecNum>357</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>357</rec-number><foreign-keys><key app="EN" db-id="avtrz5tr6aesazeprww5xsaffzx9sp0pvfep" timestamp="1559521771">357</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herraiz, S.</author><author>Pellicer, B.</author><author>Serra, V.</author><author>Cauli, O.</author><author>Cortijo, J.</author><author>Felipo, V.</author><author>Pellicer, A.</author></authors></contributors><auth-address>Fundacion IVI-Instituto Universitario IVI, University of Valencia, Paterna, Spain.</auth-address><titles><title>Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats</title><secondary-title>BJOG</secondary-title></titles><periodical><full-title>BJOG</full-title></periodical><pages>1394-402</pages><volume>119</volume><number>11</number><keywords><keyword>Animals</keyword><keyword>Blood Pressure/drug effects</keyword><keyword>Female</keyword><keyword>Fetus/blood supply</keyword><keyword>Phosphodiesterase 5 Inhibitors/pharmacology/*therapeutic use</keyword><keyword>Piperazines/pharmacology/*therapeutic use</keyword><keyword>Pre-Eclampsia/blood/*drug therapy</keyword><keyword>Pregnancy</keyword><keyword>Purines/pharmacology/therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Sildenafil Citrate</keyword><keyword>Sulfones/pharmacology/*therapeutic use</keyword><keyword>Treatment Outcome</keyword><keyword>Ultrasonography, Doppler</keyword></keywords><dates><year>2012</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1471-0528 (Electronic)
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ADDIN EN.CITE.DATA 17 showed a tendency towards more live-born children that survived intact to primary discharge after sildenafil intervention. A recent systematic review has demonstrated the safety profile and tolerability of Sildenafil Citrate use in pregnancy and demonstrated that it is not associated with maternal or fetal toxicity or teratogenicity. We have summarised all available publications relevant to sildenafil in pregnancy in Table 1 (APPENDIX I). Currently there is an international multicentre randomised controlled trial (NZAus STRIDER study), of which the Mater Mothers’ Hospital is a participating centre, evaluating the benefit of sildenafil therapy versus placebo in severe early onset fetal growth restriction. This study has recently been assessed and approved by the Mater HREC and Governance committees and participant recruitment is in progress. This study involves the use of sildenafil for a much longer duration than that proposed in the RIDSTRESS study. PlGF and placental functionPlGF is a member of the vascular endothelial growth factor (VEGF) family and is predominantly expressed by the placenta and also present in low levels in heart, lung, muscle and adipose tissue. It binds specifically to the VEGFR-1 receptor and whilst PlGF’s precise physiological actions are not clear, it has a pivotal role in placental angiogenesis and induces vasodilation of uterine, myometrial, mesenteric, and subcutaneous arteriesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pc29sPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 21,22. There are however no data relating to PlGF and intrapartum compromise at term. Markers of hypoxia and mRNAThere is growing evidence that hypoxic insults within the placenta result in measurable changes in several hypoxic markers in maternal blood including sFLT-1, mRNA and microRNAs. Intermittent hypoxia and reperfusion results in oxidative stress, resulting in the generation of reactive oxygen species as well as trophoblast apoptosis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaW5kcm92YS1EYXZpZXM8L0F1dGhvcj48WWVhcj4yMDA3
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ADDIN EN.CITE.DATA 23 In-vitro studies have demonstrated that exposure to exposed to repeated ischaemia-reperfusion injuries, as may occurs in labour, increases trophoblast apoptosis, reduces differentiation of the cytotrophoblasts reduces PlGF transcription and production.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcmViczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 27,28 2.0 Study Objectives:The primary aims of this randomised controlled trial is:To ascertain if the use of sildenafil in labour is associated with a reduction in the incidence of intrapartum fetal compromise requiring emergency delivery. For the purposes of this study emergency delivery is defined as either caesarean section or instrumental vaginal delivery where the primary indication for delivery is concern for fetal wellbeing (non-reassuring fetal status).To assess the effect of sildenafil on fetal and uteroplacental blood flow in term appropriately grown foetuses.Secondary aims are:To ascertain if sildenafil is associated with an improvement in neonatal outcomes as defined by a composite neonatal outcome score (admission to neonatal intensive care unit, APGAR <7 at 5 minutes, cord pH<7.1 or lactate >6mmol/L, neonatal encephalopathy).To ascertain if sildenafil is associated with a reduction in intrapartum fetal heart rate abnormalities or meconium stained liquor.To ascertain if sildenafil is associated with a reduction in the need for intrapartum fetal blood samplingTo establish to extent to which sildenafil crosses the placenta into the fetal circulation by measuring umbilical cord blood levels of sildenafil.3.0 Study Design and sample sizeThis is a double blinded, randomised controlled trial (Phase II trial). The sample size calculation was based on our previous data which showed that the incidence of emergency operative delivery (caesarean section or instrumental vaginal delivery) for fetal compromise at the Mater Mother’s Hospital was approximately 18.9% ADDIN EN.CITE <EndNote><Cite><Author>Bligh</Author><Year>2018</Year><RecNum>1207</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>1207</rec-number><foreign-keys><key app="EN" db-id="rrpr55trws29pvet0t1prd5y0zfzftp5d9wr" timestamp="1525390777">1207</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bligh, L.</author></authors></contributors><titles><title>Pre-labour screening for intrapartum fetal compromise in low risk pregnancies at term: cerebroplacental ratio and placental growth factor</title></titles><dates><year>2018</year></dates><urls><related-urls><url>.* If sildenafil is successful in halving the rate of caesarean section in this cohort to 9.5%, a total sample size of 288 women per group (>90% power, alpha of 0.05) would be required. Assuming a 10% drop out rate, a sample of 320 women per group should be sufficient to adequately address the research objectives. 4.0 Participant entry4.1 Inclusion and Exclusion criteriaInclusion criteria:Aged between 18-50 who are able to give informed consentSingleton pregnancy between 37+0 – 42+0 weeks gestationCephalic presentationAppropriately grown fetus without any known structural, chromosomal or genetic abnormalityPlanning a vaginal deliveryExclusion criteriaWomen <18 years old and those unable to give informed consentWomen with pre-existing heart disorders, stroke, hypotension or hypertension, retinitis pigmentosa, kidney or liver abnormalities, sickle cell anaemia, stomach ulcers or any other bleeding disorderWomen taking any anti-hypertensive medication, alpha-adrenergic blocking agents, calcium channel blockers (verapamil), amyl nitrate, nicorandil, nitrates (including glyceryl trinitrate or isosorbide salts), sodium nitroprusside, bosentan, fosamprenavir and ritonavir combination, hepatic enzyme inhibitors CYP3A4 (including itraconazole, ketoconazole, ritonavir, cimetidine, erythromycin, saquinavir, darunavir), hepatic enzyme substrates (CYP3A4 and beta-adrenergic blocking agents), medications used to treat pulmonary arterial hypertension, and other phosphodiesterase type 5 inhibitors.All participants must be able to understand the study information sheet, and provide informed consent of their desire to participate in the research study. 4.2 Withdrawal criteriaParticipants are at liberty to withdraw at any stage of the study and need only to inform any member of the trial team of their intention. Once they have withdrawn from the study no further involvement will be sought. However, all data collected up to the point of their withdrawal will still be used for final analysis of outcomes.5.0 MethodsPatients at MMH, who satisfy the inclusion criteria will be invited to participate either a) from the antenatal clinic or Pregnancy assessment centre from 37+0 weeks gestation, prior to presenting for induction of labour or in early labour or b) when they are admitted either in early labour (cervical dilatation <4cm) or for scheduled induction of labour. The aim is to recruit women who have had apparently “normal” low risk pregnancies and who will deliver within 72 hours of commencement of the study processes as outlined below. Appendix III provides a flowchart of the timeline of study processes for each participant.Women who meet the entry criteria detailed above will be initially approached and recruited by either Professor Kumar or Dr Turner who will provide the study information and obtain written consent. Recruitment will take place predominantly in the Early Labour Ward (Level 9, MMH), although it may also be undertaken in the Antenatal Clinic (Level 7, MMH), Pregnancy Assessment Centre (Level 5, MMH) or Birth Suite (Level 5, MMH). It will be emphasized that the use of sildenafil in labour is experimental and that it is not currently licensed for use for any obstetric indication. Sufficient time will be afforded to potential participants to ensure they, and their support person (where applicable), can make an informed decision about their participation. After all questions are answered written consent will be obtained. If they are recruited and written consent obtained antenatally (in advance of admission for induction of labour or in early labour) then consent will be re-confirmed verbally prior to commencement of trial processes.Following consent, information about the maternal age, ethnicity, parity, booking blood pressure, gestation at onset of labour, Body Mass Index (BMI), smoking history, pre-existing maternal medical or obstetric disorders, previous fetal growth restriction, stillbirth or neonatal death will be recorded on a pro-forma sheet.Where possible participants will undergo an obstetric ultrasound scan (performed by either Dr Turner or an obstetric sonographer) either when they present in early labour or have been admitted for induction of labour. For participants who are being induced, the ultrasound scan will take place as early as possible in the induction process that is convenient to the woman to avoid interfering with her induction. For women admitted in early labour the ultrasound scan will be performed after admission to either the birth suite or the early labour ward as soon as practicable and convenient for the woman. Women who are recruited antenatally will undergo their initial ultrasound scan either when they present for induction of labour or when they are admitted in early labour as above. The initial ultrasound scan will be performed by Dr Turner or a research sonographer and will take approximately 35 minutes to complete. Parameters measured will include fetal biparietal diameter, head circumference, abdominal circumference and femur length thereby allowing calculation of estimated fetal weight as well as measurement of the amniotic fluid index. Doppler indices (Pulsatility Index, Resistance Index and maximum velocity flow) for various fetal (umbilical artery, middle cerebral artery, ductus venosus, umbilical vein, renal artery, femoral artery etc.) and maternal (uterine arteries) will be measured. Where possible participants will have a blood sample (10ml) to measure Placental Growth Factor (PlGF) levels and other markers of inflammation, hypoxic stress and angiogenesis. This will be performed at two time points. 1) Immediately prior to administration of the first dose of study medication (in the majority of women this sample will be taken at the time of routine venous cannulation as per standard obstetric practice) and 2) between 2-4hours after the first dose of study treatment. Plasma and serum will be separated and stored at -80°C by Mater Pathology. By obtaining maternal blood samples prior to and after administration of study medication we will be able to assess a) the correlation between these markers and the development of IFC and b) whether the administration of SC alters these biomarkers to any extent.Once the initial ultrasound scan is completed, participants will then be randomized. Each participant will receive a unique, sequentially ordered, participant number (001, 002 etc.). Computer random allocation software (STATA 13) will be used to generate a random sequence table prior to the start of the trial using the two groups and the adequate sample size. A printed and electronic copy of this table will be retained by the MMRI statisticians. Participants will be allocated to either the sildenafil or placebo arm using this table using appropriate block sizes of up to 6 to yield an appropriate sample size with equal numbers (1:1) allocated to each study arm.Each participant number will correlate to sequentially numbered, non-transparent envelopes prepared by Mater Pharmacy, according to the randomization table. Each envelope will contain 3 capsules of the either sildenafil or placebo, instructions for the attending clinicians including a list of possible side effects for which to observe and document, recommended observations, contact details for the Principal and Associate Investigators and guidelines for AE and SAE reporting. In the event of a SAE requiring unblinding of the allocation this will be immediately possible via the on-call Mater Pharmacist or Professor Kumar or Dr Turner. The dose regimen of sildenafil will be 50mg taken orally every 8 hours for a maximum of 24 hours (total dose 150mg; i.e. 3 doses only)The first dose of sildenafil or placebo will be administered by the attending midwife after the participant has been transferred to the Birth Suite for management of labour. Commencement of labour is defined as the transfer of the participant to Birth Suite at 4cm dilatation, for artificial rupture of membranes and/or commencement of syntocinon infusion. After the first dose of sildenafil or placebo is administered a repeat ultrasound scan will be performed within 3 hours measure the previously described vascular parameters. This scan will be performed in Birth Suite and should not take longer than 20 minutes. The purpose of the second ultrasound scan is to ascertain the changes (if any) in fetal blood flow as a result of the intervention (i.e. sildenafil or placebo). Clinicians managing the pregnancy will be blinded as to the results of the ultrasound scan and the blood tests with labour being managed as per institutional protocols and guidelines to ensure that obstetric care is consistent across both groups of women. However, in the event that either of the ultrasound scans detects any significant abnormalities including fetal malpresentation (breech, transverse lie etc.), significant oligohydramnios (deepest pool <1cm) or abnormal umbilical artery Dopplers (absent or reversed end diastolic flow), the on call obstetric registrar and/or consultant will be informed and the woman then excluded from the study. However, the data collected will still be analysed according to the intention to treat principle. After the birth of the baby and once the umbilical cord has been clamped and cut, umbilical cord gases will be performed and 10ml sample of cord blood will be obtained for analysis of sildenafil and PlGF levels. This is to ascertain the degree (if any) of transfer of sildenafil across the placenta. After delivery the following outcome data will be recorded – mode of delivery (caesarean section, instrumental delivery or normal vaginal delivery), the indication for assisted or operative delivery, length of labour, fetal heart rate abnormalities, intrapartum haemorrhage, meconium stained liquor, post-partum haemorrhage, serious intrapartum maternal complications (abruption, prolapse, collapse, preeclampsia, HELLP etc), any fetal blood sampling, cord blood analyses and Apgar scores. If admission to the neonatal unit occurs, the indication for admission, length of stay and details of any complications (sepsis, respiratory, necrotizing enterocolitis, encephalopathy, need for ionotropic and/or chronotropic support, length of hospital stay, death) will be recorded. Telephone follow up of the participant will also be conducted within 2 weeks after discharge from MMH to ascertain if there any issues relating to the study that require additional follow up. Women will also be consented for future contact (within a 5 year timeframe from closure of RIDSTRESS) to participate in growth and development studies of their babies to enable longer term data as to the safety of sildenafil to be obtained. All obstetric or neonatal adverse events will be investigated as per the hospital’s clinical risk policies. These may involve a root cause analysis of the event which will also assess the involvement of the woman in this study to ascertain if their participation was a factor in the adverse event. Written information about this study will be provided to women booked for delivery at MMH at an antenatal appointment. It is intended that information about this study will appear on the Mater Facebook page and other official Mater communication mediums. No response to any participant’s queries will be made via social media or by anyone outside the research group. All potential participants will be informed by Mater clinicians or Mater social media to contact the study investigators either by telephone or via email if they are interested in participating or would like more information. Contact details of the investigators will be provided. “Cold calling” by the investigators will not be performed. Mater Marketing will be involved in facilitating social media publicity of this study once Ethical, Governance and Privacy approvals have been obtained. The study period will be 6 years (01.05.2015-01.05.2021).6.0 Study outcome measuresPrimary Outcome – Incidence of obstetric intervention (Emergency caesarean section or instrumental vaginal birth) for intrapartum fetal compromise (non-reassuring fetal status) in the two groups (sildenafil and placebo).Secondary Outcomes – Incidence of fetal heart rate abnormalities, meconium stained liquor, need for intrapartum fetal blood sampling and a composite neonatal outcome score between the two cohorts.7.0 Adverse EventsAn adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom or disease temporally associated with the use of a medicinal (investigational/experimental) product, whether or not related to this product. An Adverse Drug Reaction (ADR) for sildenafil, in this study to reduce intrapartum fetal compromise (unapproved purpose), is a noxious and unintended response to the medicinal product related to any dose. The phrase ‘responses to a medicinal product’ means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. AEs/ADRs in this study include:More frequentLess frequent DiarrhoeaAnaemiaDizzinessBronchitisFlushingCellulitis/Skin rashGastro-oesophageal reflux/dyspepsia* (15.8%) ADDIN EN.CITE <EndNote><Cite><Author>Dunn</Author><Year>2017</Year><RecNum>75</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>75</rec-number><foreign-keys><key app="EN" db-id="rrpr55trws29pvet0t1prd5y0zfzftp5d9wr" timestamp="0">75</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dunn, L.</author><author>Greer, R.</author><author>Flenady, V.</author><author>Kumar, S.</author></authors></contributors><auth-address>Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.</auth-address><titles><title>Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes</title><secondary-title>Fetal Diagn Ther</secondary-title></titles><periodical><full-title>Fetal Diagn Ther</full-title><abbr-1>Fetal diagnosis and therapy</abbr-1></periodical><pages>81-88</pages><volume>41</volume><number>2</number><dates><year>2017</year></dates><isbn>1421-9964 (Electronic)
1015-3837 (Linking)</isbn><accession-num>27926905</accession-num><urls><related-urls><url> arterial pH 7.0-7.1Headache* (45%)EpistaxisMyalgia/Limb painDyspnoea*Vision changes (blurred, coloured, increased sensitivity)* (17.3%)FeverVomiting*Hypo/paraesthesiaVaginal itch*Migraine-like headacheOedemaPostpartum haemorrhage ≤1500mLsTremor* - additional reported side effects (extracted from literature review) of pregnant women who have taken sildenafil (see APPENDIX I)A Serious Adverse Event (SAE) defined as: MaternalMaternal Intensive Care Unit admissionMaternal hypotension (<80/50mmHg x 3 episodes) requiring medical interventionMajor postpartum haemorrhage >1,500mlsPersistent visual changes requiring ophthalmic reviewMaternal death prior to discharge from hospitalNeonatalAdmission to Neonatal Intensive Care Unit for >24hoursCord arterial pH <7.0Hypoxic ischaemic encephalopathy or neonatal seizureStillbirth or fetal or neonatal death prior to discharge from hospital7.1 Safety ReportingThe Principal and Associate Investigators will be responsible for all safety reporting. All data regarding AEs/SAEs will be collected from the electronic patient record and documented in the participant’s CRF and followed up for satisfactory resolution. Each participant’s record will be reviewed within 96 hours of delivery, for collection of outcome data. This will also allow rapid identification of any AEs/SAEs. There will be ongoing monitoring of AEs/SAEs on a twice-weekly basis to ensure early and comprehensive detection of any complications. All SAEs will be reported to the PI, DMSC chair, Sponsor and HREC, with both entities being notified within 24 hours after identifying an SAE. After this initial notification, an initial report of the SAE will be provided within 7 business days and a complete, comprehensive report within 15 business days if additional information is required. The investigators will review all of the known information about the SAE and define it as:Expected eventExpected unrelated event (Expected SAE) – the SAE is expected in the clinical setting in which it occurred and with reference to the study medication AND is not considered related to the study medication. Expected related event (Serious Adverse Reaction, SAR) – the investigator considers the SAE possibly, probably or definitely related to the study medication.Unexpected EventUnexpected unrelated event (Unexpected SAE) – the SAE is unexpected based on the existing information and data on the study medication and the underlying conditions AND is not considered related to the study medication. Unexpected related event (Suspected Unexpected Serious Adverse Reaction, SUSAR) – the SAE is unexpected based on the known information about the study medication and the underlying conditions AND is possible, probably or definitely related to the study medication. Additionally, there will be a follow up phone call to the participant within 2 weeks of discharge from hospital to ascertain if there any issues relating to the study that require additional follow up. Up to date reports on safety will be provided to the Sponsor and HREC upon request.Protocol Violations will be reported to the DSMC within two weeks of occurring (to allow for review of scanned case notes). See Appendix IV for a list of what constitutes a protocol violation.7.2 Stopping criteriaParticipants who satisfy the below criteria will, in the interest of their safety, have their treatment ceased:Acute severe maternal hypotension (<80/50 mmHg x 3 episodes) sufficient to cause maternal and/or fetal compromise Participant requests discontinuation from studyInvestigative team believes it is in the best interest of the participant on grounds of safety or side effect tolerability that discontinuation take place (due to Adverse or Serious Adverse Event)In the event of a SAE requiring unblinding of the allocation this will be immediately possible via Professor Kumar or Dr Turner.8.0 Lost to follow upWhat data that has already been collected from cases “lost to follow up” will still be included for analysis where appropriate.9.0 Trial ClosureRecruitment into this study will take place over a period of 6 years. Patient data will remain stored in a protected electronic format at Mater Research Institute/University of Queensland for up to 15 years for maternal data and 33 years for neonatal data to allow continued data analysis. The information collected may be used for another purpose by the research team in the future. If this is deemed necessary then further ethical approval will be sought.10.0 Statistics and data analysisAnalysis of this study will be on an intention to treat (ITT) basis. Based on current birthing rates at the Mater Mothers’ Hospital the proposed number of participants required is pragmatic and should be easily achievable within the study period (3 years). 10.1 Interim analysisAn interim analysis will be performed after the first 200 participants have been recruited, although the calculated sample size is 1012. Ongoing interim analyses will be performed after each subsequent 100 participants have been recruited.10.2 MonitoringA Data Safety and Monitoring Committee (DSMC) comprising an independent obstetrician, neonatologist, pharmacist and statistician will be established to oversee all AEs and SAEs arising in this study. All members of the DSMC will be external to and independent of the research group. All AEs will be tabulated and provided to the DSMC for review at DSMC meetings. The AE reports will be available for HREC review upon request. All SAEs will be reported to the DSMC within 96 hours after identifying an SAE. An initial report of the SAE will be provided within the following 7 days and a complete, comprehensive report within 15 days if additional information is required.11.0 Regulatory issuesThere are no regulatory issues (other than Ethical and Governance approvals) relevant to this study.11.1 Clinical Trial AuthorisationThis study is registered as a clinical trial with the Australian New Zealand Clinical Trials Registry (ANZCTRN12615000319572).11.2 EthicsAn application for ethical approval for this study has been made to the Mater Human Research Ethics Committee.12.0 ConsentConsent to enter the study will be sought from each participant only after a full explanation has been given, an information leaflet offered (with the latest version of PICF) and time allowed for consideration. Signed participant consent will only be obtained by a member of the study team. The right of women to decline participation without giving reasons will be respected. All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment. Women will receive no financial incentive to participate in this study.13.0 ConfidentialityParticipants’ unique identification data will be required for the registration and recruitment process. It will then however be stored in a de-identified but subsequently re-identifiable manner to enable pregnancy outcome data to be collected and matched for each participant.14.0 IndemnityThe Sponsor, Mater Health Services has made arrangements to hold insurances for harm caused by the trial that could not have been anticipated and holds insurance policies which apply to this study.15.0 SponsorThe Mater Health Services will act as the main Sponsor for this study. 16.0 FundingThe Mater Foundation is funding this study. 17.0 Audits and inspectionThis study is being conducted in compliance with full Good Clinical Practice (GCP) and may be subject to inspection and audit by Mater Health Service under their remit as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to GCP.18.0 Publication PolicyThe results from this study will be published in peer reviewed journals, and presented at scientific meetings, both nationally and internationally. This project is also the basis for the PhD project of the associate investigators, Dr Jessica Turner and Dr Liam Dunn.19.0 Ethical ConsiderationsUltrasound has been used as an imaging modality in obstetrics for over 30 years. It utilises high frequency sound waves to create real time images of the fetus and placenta. The risks associated with medical ultrasound are minimal and include heating and cavitation, although these effects are negligible with modern machines. A World Health Organisation meta-analysis published in 2009 ADDIN EN.CITE <EndNote><Cite><Author>Torloni</Author><Year>2009</Year><RecNum>369</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="avtrz5tr6aesazeprww5xsaffzx9sp0pvfep" timestamp="1559522437">369</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Torloni, M. R.</author><author>Vedmedovska, N.</author><author>Merialdi, M.</author><author>Betran, A. P.</author><author>Allen, T.</author><author>Gonzalez, R.</author><author>Platt, L. D.</author><author>Isuog-Who Fetal Growth Study Group</author></authors></contributors><auth-address>Department of Obstetrics, Sao Paulo Federal University and Brazilian Cochrane Center, Sao Paulo, Brazil. ginecologia@.br</auth-address><titles><title>Safety of ultrasonography in pregnancy: WHO systematic review of the literature and meta-analysis</title><secondary-title>Ultrasound Obstet Gynecol</secondary-title></titles><periodical><full-title>Ultrasound Obstet Gynecol</full-title></periodical><pages>599-608</pages><volume>33</volume><number>5</number><keywords><keyword>Female</keyword><keyword>Fetal Development/*physiology</keyword><keyword>Functional Laterality/*physiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Odds Ratio</keyword><keyword>Pregnancy</keyword><keyword>Risk Factors</keyword><keyword>Ultrasonography, Prenatal/*adverse effects</keyword></keywords><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><isbn>1469-0705 (Electronic)
0960-7692 (Linking)</isbn><accession-num>19291813</accession-num><urls><related-urls><url>, confirmed that according to the available evidence, the use of B mode and Doppler ultrasound during pregnancy (techniques that will be used in this study) was not associated with adverse maternal outcome, adverse perinatal outcome, abnormal childhood growth and neurological development, childhood malignancy or intellectual performance and mental disease. The only positive finding was a weak association (only with multiple scans) with non-right-handedness in boys. Ultrasound causes no pain or discomfort to women during imaging and requires no special preparation prior to the scan.Sildenafil is a rapidly acting, pharmacological agent that has been used primarily for the treatment of erectile dysfunction in males. It is also used for the treatment of pulmonary hypertension both in women and men. More recently it has been used in pregnancy for a variety of indications without any reported significant maternal or fetal toxicity. The ongoing STRIDER study at the Mater Mothers’ Hospital is an international multicentre trial evaluating the efficacy of Sildenafil to improve perinatal outcome for pregnancies complicated by severe growth restriction. In the STRIDER study women will be taking Sildenafil for a variable period but potential several days or weeks. In contrast, in this study women will be taking Sildenafil for a much shorter duration (i.e. only during labour). References ADDIN EN.REFLIST 1.Janbu T, Nesheim B. Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure. Br J Obstet Gynaecol 1987; 94(12)(Dec): 1150-5.2.Low JA, Pickersgill H, Killen H, Derrick EJ. The prediction and prevention of intrapartum fetal asphyxia in term pregnancies. American journal of obstetrics and gynecology 2001; 184(4): 724-30.3.McIntyre S, Taitz D, Keogh J, Goldsmith S, Badawi N, Blair E. A systematic review of risk factors for cerebral palsy in children born at term in developed countries. Dev Med Child Neurol 2013; 55(6): 499-508.4.Bhutta ZA, Black RE. Global maternal, newborn, and child health--so near and yet so far. N Engl J Med 2013; 369(23): 2226-35.5.Prior T, Mullins E, Bennett P, Kumar S. Prediction of intrapartum fetal compromise using the cerebroumbilical ratio: a prospective observational study. Am J Obstet Gynecol 2013; 208(2): 124 e1-6.6.Prior T, Mullins E, Bennett P, Kumar S. Umbilical venous flow rate in term fetuses: can variations in flow predict intrapartum compromise? Am J Obstet Gynecol 2014; 210(1): 61 e1-8.7.Baschat DAA. Fetal responses to placental insufficiency: an update. BJOG: An International Journal of Obstetrics & Gynaecology 2004; 111(10): 1031-41.8.Prior T, Mullins E, Bennett P, Kumar S. Umbilical venous flow rate in term fetuses: can variations in flow predict intrapartum compromise? American journal of obstetrics and gynecology 2013; (0).9.Dilworth MR, Andersson I, Renshall LJ, et al. Sildenafil citrate increases fetal weight in a mouse model of fetal growth restriction with a normal vascular phenotype. PLoS One 2013; 8(10): e77748.10.George EM, Palei AC, Dent EA, Granger JP. Sildenafil attenuates placental ischemia-induced hypertension. Am J Physiol Regul Integr Comp Physiol 2013; 305(4): R397-403.11.Herraiz S, Pellicer B, Serra V, et al. Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats. BJOG 2012; 119(11): 1394-402.12.Lin TH, Su YN, Shih JC, Hsu HC, Lee CN. Resolution of high uterine artery pulsatility index and notching following sildenafil citrate treatment in a growth-restricted pregnancy. Ultrasound Obstet Gynecol 2012; 40(5): 609-10.13.Stanley JL, Andersson IJ, Poudel R, et al. Sildenafil citrate rescues fetal growth in the catechol-O-methyl transferase knockout mouse model. Hypertension 2012; 59(5): 1021-8.14.Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab 2005; 90(5): 2550-5.15.Samangaya RA, Mires G, Shennan A, et al. A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia. Hypertens Pregnancy 2009; 28(4): 369-82.16.Samangaya RA, Wareing M, Skillern L, Baker PN. Phosphodiesterase inhibitor effect on small artery function in preeclampsia. Hypertens Pregnancy 2011; 30(2): 144-52.17.von Dadelszen P, Dwinnell S, Magee LA, et al. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011; 118(5): 624-8.18.Osol G, Celia G, Gokina N, et al. Placental growth factor is a potent vasodilator of rat and human resistance arteries. Am J Physiol Heart Circ Physiol 2008; 294(3): H1381-7.19.Chappell LC, Duckworth S, Seed PT, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation 2013; 128(19): 2121-31.20.Herraiz I, Droge LA, Gomez-Montes E, Henrich W, Galindo A, Verlohren S. Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction. Obstet Gynecol 2014; 124(2 Pt 1): 265-73.21.Asvold BO, Vatten LJ, Romundstad PR, Jenum PA, Karumanchi SA, Eskild A. Angiogenic factors in maternal circulation and the risk of severe fetal growth restriction. Am J Epidemiol 2011; 173(6): 630-9.22.Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol 2006; 195(1): 40-9.23.Cindrova-Davies T, Yung HW, Johns J, et al. Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol 2007; 171(4): 1168-79.24.Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JC. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996; 175(6): 1534-42.25.Yuan HT, Haig D, Ananth Karumanchi S. Angiogenic factors in the pathogenesis of preeclampsia. Curr Top Dev Biol 2005; 71: 297-312.26.Mizuuchi M, Cindrova-Davies T, Olovsson M, Charnock-Jones DS, Burton GJ, Yung HW. Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6beta: implications for the pathophysiology of human pregnancy complications. J Pathol 2016; 238(4): 550-61.27.Dunn L, Flatley C, Kumar S. Changes in maternal placental growth factor levels during term labour. Placenta 2018; 61: 11-6.28.Many A, Roberts JM. Increased xanthine oxidase during labour--implications for oxidative stress. Placenta 1997; 18(8): 725-6.29.Bligh L. Pre-labour screening for intrapartum fetal compromise in low risk pregnancies at term: cerebroplacental ratio and placental growth factor. 2018.30.Dunn L, Greer R, Flenady V, Kumar S. Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes. Fetal diagnosis and therapy 2017; 41(2): 81-8.31.Torloni MR, Vedmedovska N, Merialdi M, et al. Safety of ultrasonography in pregnancy: WHO systematic review of the literature and meta-analysis. Ultrasound Obstet Gynecol 2009; 33(5): 599-608.Appendix ISummary of relevant published literature from Embase, PubMed (MeSH terms: sildenafil citrate; pregnancy), CINAHL and Google Scholar. REFERENCEINDICATIONSAMPLE SIZEGESTATIONAL AGEDOSE AND REGIMENOUTCOMESubbaiah M, et al. Pregnancy outcome in women with pulmonary arterial hypertension: single-center experience from India. Arch Gynecol Obstet, 2013 288:305–309.Idiopathic pulmonary arterial hypertension (IPAH) and patients with Eisenmenger syndrome throughout pregnancy.Four patients with severe PAH, which included two patients with idiopathic PAH (IPAH). ‘Throughout’ pregnancy.Sildenafil (20 mg three times daily)There were no thrombotic complications, severe anemia, postpartum hemorrhage or infections in the study population.There was no stillbirth, neonatal mortality or congenital malformation.Tacoy G, Ekim NN, Cengel A. Dramatic response of a patient with pregnancy induced idiopathic pulmonary arterial hypertension to sildena?l treatment. J Obstet Gynaecol Res, 2010;36(2):414–417.Pregnancy induced IPAH16 months pre-conception, 2 months from conception.50mg dailyPregnancy terminated at ~k8.Duarte AG, et al. Management of Pulmonary Arterial Hypertension During Pregnancy A Retrospective, Multicenter Experience. Chest, 2013; 143(5):1330–1336.PAH12 – 4 of whom were on Sildenafil.1xk6; 1xk29; 1xk24; 1xk2725mg; 20mg; 20mg; 20mg. regimen not specified.Intrapartum maternal complications:hypotension in four patients (33%) of the 12 total requiring IV norepinephrine – not specified what treatment these women were on.No neonatal deaths.Goland S, et al. Favorable Outcome of Pregnancy with an Elective Use of Epoprostenol and Sildenafil in Women with Severe Pulmonary Hypertension. Cardiology, 2010;115:205–208.PAH21xk32; 1xk3650mg PO TDS until 36+3; 50mg PO TDS until 37.No maternal/fetal AE described. Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K: Eisenmenger’s syndrome in a 27 week pregnancy – management with bosentanand Sildenafil. Ir Med J, 2005; 98: 87–88.PAH1k28+Not specified.Case StudyNo maternal or neonatal concerns described.Lacassie HJ, Germain AM, Valdes G, Fernandez MS, Allamand F, Lopez H: Management of Eisenmenger syndrome in pregnancy with Sildenafil and L arginine. Obstet Gynecol 2004; 103: 118–120.Eisenmenger 1Peri-conception and third trimester150mg/day until k9 -> restarted at k31 ->k36 deliveryCase StudyNo maternal or neonatal concerns described. Lin TH, Su YN, Shih JC, Hsu HC and Lee CN. Resolution of high uterine artery pulsatility and notching following Sildenafil citrate treatment in a growth-restricted pregnancy. Ultrasound Obst Gyn, 2012;40:607-611.FGR1k2625mg PO TDS until 32+6Decrease in uterine artery pulsatility index and resolution of uterine artery notching. Normal growth interval. No reported maternal or fetal adverse events.Ng WPK, Yip WLJ. Successful maternal-foetal outcome using nitric oxide and Sildenafil in pulmonary hypertension with atrial septal defect and HIV infection. Singap Med J, 2012; 53(1): e3–e5.PAH1k3525mg PO TDS for 24/24.Maternal: haemodynamically stable.Neonatal: Apgar 9.Von Dadelszen P, et al. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. Brit J Obstet Gynaec, 2011;118:624-628.FGR27 (10x Sildenafil arm, 17xSildenafil na?ve) Case-controlled. GA (Median=22+4) at recruitment25mg PO TDS until delivery (median=27+1)Sign. growth in AC with Sildenafil.1xstillbirth 48/24 after recruitment in Sildenafil arm (had pre-existing REDF).No adverse maternal effects.Samangaya RA, et al. A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor Sildenafil for the treatment of preeclampsia. Hypertens Pregnancy, 2009;28(4):369-82.PE35 (17xSildenafil, 18xplacebo) Double blinded RCT.k24 – 34Incremental dose: 20mg PO TDS for 3/7 -> 40mg PO TDS for 3/7 -> 80mg PO TDSNo prolongation of gestationSildenafil achieved maximum drug concentrations of 48 ng/ml, 88 ng/ml, and 271 ng/ml after 3 days of 20 mg TDS, 40 mg TDS and 80 mg TDS, respectively.No major maternal of fetal morbidity or mortality documented. Mild ADRs.Sher G, Fisch JD. Vaginal Sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF.Hum Reprod, 2000;15:806 – 809.Poor endometrial development in ART4Pre-embryo transfer (ceased at least >5/7)25mg PV QID for 7/7+oestradiol valerate; improved uterine blood flow and endometrial thickness.No patient reported side effects.Sher G, Fisch JD. Effect of vaginal Sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril, 2002;78:1073 – 1076.Poor endometrial development in ART105Pre-embryo transfer (ceased at least >5/7)25mg PV QID for 3-10/7Enhanced endometrial development in 70% participants.Higher implantation and ongoing pregnancy rates. No patient reported side effects.Paulus WE, Strehler E, Zhang M, Jelinkova L, El-Danasouri I, Sterzik K. Benefits of vaginal Sildenafil citrate in assisted reproduction therapy. Fertil Steril, 2002;77:846 – 847.Decreased uterine artery blood flow and poor endometrial development10Not specified.25mg PV QID for 9-10/7No incr. ut. Art. Vasodilation but increased endometrial thickness.Check JH, Graziano V, Lee G, Nazari A, Choe JK, Dietterich C. Neither Sildenafil nor vaginal estradiol improves endometrial thickness in women with thin endometria after takingoral estradiol in graduating dosages. Clin Exp Obstet Gyn, 2004;31:99 – 102.Poor endometrial development in ART?Not specified.25mg PV QIDNo increase in blood flow or endometrial thicknessEl-Far M, et al. Biochemical role of intravaginal Sildenafil citrate as a novel antiabortive agent in unexplained recurrent spontaneous miscarriage: first clinical study of four case reports from Egypt. Clin Chem Lab Med, 2009;47(11):1433–1438unexplained recurrent spontaneousmiscarriage4Commenced 24/7 of Sildenafil immediately post threatened miscarriage25 mg intravaginally, 4 times/day for24 daysIncreased vasodilation and blood flowVulval irritation in one patient Jerzak M, et al. Sildenail citrate decreased natural killer cell acitivty and enhanced chance of successful pregnancy in women with a history of recurrent miscarriage. Fertil Steril, 2008;90(5):1848-1853Recurrent miscarriage38Not specified.25mg PV QID for 36/7Improved endometrial increased, NK cells decreasedSE not reported.Lacassie H, et al. Management of Eisenmenger Syndrome in Pregnancy with Sildenafil and L-Arginine. Obstet Gynecol 2004;103:1118-20Eisenmenger Syndrome150mg Daily some time prior to k7 -> changed to 150mg until k9 (ceased due to cost) -> recommenced 150mg PO k31 through until night before IOL at k36.Significant improvement in Maternal condition, no fetal abnormality. Review ArticlesBédard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonaryarterial hypertension? Eur Heart J, 2009;30: 256–265.PAH5Not specifiedNot specifiedFive (7%) parturients in this review received Sildenafil, four with CHD-PAH, and one with IPAH; no adverse effects reported.Huang S, DeSantis ER: Treatment of pulmonaryarterial hypertension in pregnancy. Am J Health Syst Pharm, 2007; 64: 1922–1926.PAH2 (Reviews two previous case reports)Case study - Not availableVallaneuva-Garcai D, Mota-Rojas D, Hernandez-Gonzalez R, et al. A systematic review of experimental and clinical studies of siuldenafil citrate for intrauterine growth restriction and pre-term labour. J Obstet Gynaecol,2007;27(3):255-259.IUGR and PTL3 x in vitro studies5 x experimental animal studies4 x human pregnancy fertility/sterility studies (100mg/day Sildenafil vaginally)2 x case reports of pregnant women receiving Sildenafil for pulmonary arterial hypertension (1 x report of 150mg/day)No teratogenic/fetotoxic effects reported.Appendix IIIFlowchart of study processes for each participantAppendix IVDefinitions of Protocol ViolationsParticipant receives wrong study medication (i.e. not the pack no. corresponding with the trial number of that participant)The study medication is given at the wrong time, for example not at the time when the midwife deems her to be in active labour or not when she undergoes an ARM.Failure of the study team to report SAEs in the appropriate timeline to the DSMC, HREC and RGO ................
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