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. Furthermore, events in labour account for as many as 20% of cases of cerebral palsy in term infantsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0ludHlyZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0ludHlyZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE.DATA 3. It is estimated that worldwide, of the 7.6 million deaths of children under 5 years of age, almost 700,000 (9.4%) are as a consequence of intrapartum related complicationsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaHV0dGE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaHV0dGE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 4 and that almost 45% of stillbirths occur during labour are usually due to hypoxiaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0ludHlyZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0ludHlyZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE.DATA 3. In many pregnancies placental function is sufficient to allow adequate growth of the fetus throughout pregnancy, but may be not be adequate enough to meet the extra demands required during labour thereby potentially predisposing these babies to hypoxic insults which are clinically manifested by fetal heart rate abnormalities and meconium stained liquor. In extreme cases, these babies can be born acidotic or suffer hypoxic ischaemic encephalopathy. If severe enough these insults not only result in short term morbidity but also significant long term neurodevelopmental issues. There is increasing evidence that amongst appropriately grown fetuses at term there exists a cohort with evidence of relatively altered umbilical and cerebral blood flow (i.e. cerebral redistribution) similar to that seen in growth restricted fetusesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmlvcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmlvcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl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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 PEVuZE5vdGU+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 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)
1470-0328 (Linking)</isbn><accession-num>22827567</accession-num><urls><related-urls><url>. It has been used in several human studies to improve perinatal outcome in pregnancies complicated by fetal growth restriction or pre-eclampsiaPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 12,13,15-17. A recent small cohort studyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj52b24gRGFkZWxzemVuPC9BdXRob3I+PFllYXI+MjAxMTwv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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52b24gRGFkZWxzemVuPC9BdXRob3I+PFllYXI+MjAxMTwv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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 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pc29sPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 18. This effect is particularly pronounced in uterine arteries during pregnancy, suggesting that PlGF contributes to uterine vascular remodelling during gestation. Maternal levels of PlGF are lower in pregnancies that develop early onset pre-eclampsia and/or fetal growth restrictionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwcGVsbDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwcGVsbDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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==
ADDIN EN.CITE.DATA 19,20. The low levels of PlGF in both clinical situations likely reflect the underlying pathophysiology whereby defective trophoblast invasion leads to altered expression of angiogenic-related factorsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc3ZvbGQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc3ZvbGQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
ZWNOdW0+MzY3PC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+
MjEsMjI8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNjc8L3JlYy1u
dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJhdnRyejV0cjZhZXNhemVw
cnd3NXhzYWZmeng5c3AwcHZmZXAiIHRpbWVzdGFtcD0iMTU1OTUyMjM5NSI+MzY3PC9rZXk+PC9m
b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl
Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Bc3ZvbGQsIEIuIE8uPC9hdXRob3I+PGF1
dGhvcj5WYXR0ZW4sIEwuIEouPC9hdXRob3I+PGF1dGhvcj5Sb211bmRzdGFkLCBQLiBSLjwvYXV0
aG9yPjxhdXRob3I+SmVudW0sIFAuIEEuPC9hdXRob3I+PGF1dGhvcj5LYXJ1bWFuY2hpLCBTLiBB
LjwvYXV0aG9yPjxhdXRob3I+RXNraWxkLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1
dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUHVibGljIEhlYWx0aCwgTm9yd2VnaWFu
IFVuaXZlcnNpdHkgb2YgU2NpZW5jZSBhbmQgVGVjaG5vbG9neSwgVHJvbmRoZWltLCBOb3J3YXku
PC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QW5naW9nZW5pYyBmYWN0b3JzIGluIG1hdGVy
bmFsIGNpcmN1bGF0aW9uIGFuZCB0aGUgcmlzayBvZiBzZXZlcmUgZmV0YWwgZ3Jvd3RoIHJlc3Ry
aWN0aW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogRXBpZGVtaW9sPC9zZWNvbmRhcnkt
dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0gSiBFcGlkZW1pb2w8L2Z1
bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz42MzAtOTwvcGFnZXM+PHZvbHVtZT4xNzM8L3Zv
bHVtZT48bnVtYmVyPjY8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+
PGtleXdvcmQ+QW50aWdlbnMsIENELypibG9vZDwva2V5d29yZD48a2V5d29yZD5DYXNlLUNvbnRy
b2wgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Db25maWRlbmNlIEludGVydmFsczwva2V5d29y
ZD48a2V5d29yZD5FbmRvZ2xpbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+RmV0YWwgR3Jvd3RoIFJldGFyZGF0aW9uLypibG9vZDwva2V5d29yZD48a2V5d29yZD5H
ZXN0YXRpb25hbCBBZ2U8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk
PkluZmFudCwgTmV3Ym9ybjwva2V5d29yZD48a2V5d29yZD4qSW5mYW50LCBTbWFsbCBmb3IgR2Vz
dGF0aW9uYWwgQWdlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4tMSBS
ZWNlcHRvci1MaWtlIDEgUHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5MaW5lYXIgTW9kZWxzPC9r
ZXl3b3JkPjxrZXl3b3JkPk9kZHMgUmF0aW88L2tleXdvcmQ+PGtleXdvcmQ+UGxhY2VudGEgR3Jv
d3RoIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5QcmVnbmFuY3k8L2tleXdvcmQ+PGtleXdvcmQ+
UHJlZ25hbmN5IFByb3RlaW5zLypibG9vZDwva2V5d29yZD48a2V5d29yZD5QcmVnbmFuY3kgVHJp
bWVzdGVycy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIENlbGwgU3VyZmFjZS8q
Ymxvb2Q8L2tleXdvcmQ+PGtleXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+
PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXIgMTU8L2RhdGU+PC9w
dWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDc2LTYyNTYgKEVsZWN0cm9uaWMpJiN4RDswMDAyLTky
NjIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIxMzE3MjIwPC9hY2Nlc3Npb24tbnVt
Pjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1
Ym1lZC8yMTMxNzIyMDwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv
dXJjZS1udW0+MTAuMTA5My9hamUva3dxMzczPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3Jl
Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5OZXNzPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48
UmVjTnVtPjM2ODwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MzY4PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iYXZ0cno1dHI2YWVzYXplcHJ3dzV4c2Fm
Znp4OXNwMHB2ZmVwIiB0aW1lc3RhbXA9IjE1NTk1MjI0MDkiPjM2ODwva2V5PjwvZm9yZWlnbi1r
ZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJp
YnV0b3JzPjxhdXRob3JzPjxhdXRob3I+TmVzcywgUi4gQi48L2F1dGhvcj48YXV0aG9yPlNpYmFp
LCBCLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl
cGFydG1lbnQgb2YgRXBpZGVtaW9sb2d5LCBVbml2ZXJzaXR5IG9mIFBpdHRzYnVyZ2gsIEdyYWR1
YXRlIFNjaG9vbCBvZiBQdWJsaWMgSGVhbHRoLCBQaXR0c2J1cmdoLCBQQSAxNTI2MSwgVVNBLiBy
ZXByb0BwaXR0LmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNoYXJlZCBhbmQgZGlz
cGFyYXRlIGNvbXBvbmVudHMgb2YgdGhlIHBhdGhvcGh5c2lvbG9naWVzIG9mIGZldGFsIGdyb3d0
aCByZXN0cmljdGlvbiBhbmQgcHJlZWNsYW1wc2lhPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFt
IEogT2JzdGV0IEd5bmVjb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48
ZnVsbC10aXRsZT5BbSBKIE9ic3RldCBHeW5lY29sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48
cGFnZXM+NDAtOTwvcGFnZXM+PHZvbHVtZT4xOTU8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48
a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DYXJkaW92YXNjdWxh
ciBEaXNlYXNlcy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29tb3JiaWRpdHk8L2tl
eXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RW5k
b3RoZWxpdW0sIFZhc2N1bGFyLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVt
YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZldGFsIEdyb3d0aCBSZXRhcmRhdGlvbi9ibG9vZC8qcGh5
c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5I
eXBveGlhLUluZHVjaWJsZSBGYWN0b3IgMS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPklu
c3VsaW4gUmVzaXN0YW5jZS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBsYWNlbnRhLypw
aHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJlLUVjbGFtcHNpYS9ibG9vZC9lcGlk
ZW1pb2xvZ3kvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmVnbmFuY3k8L2tl
eXdvcmQ+PGtleXdvcmQ+VHJvcGhvYmxhc3RzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jk
cz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1
Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTctNjg2OCAoRWxlY3Ryb25pYykmI3hEOzAwMDItOTM3
OCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTY4MTM3NDI8L2FjY2Vzc2lvbi1udW0+
PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi
bWVkLzE2ODEzNzQyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291
cmNlLW51bT4xMC4xMDE2L2ouYWpvZy4yMDA1LjA3LjA0OTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1u
dW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
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
PC9ZZWFyPjxSZWNOdW0+MTIxPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBl
cnNjcmlwdCI+MjM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMjE8
L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJhdnRyejV0cjZh
ZXNhemVwcnd3NXhzYWZmeng5c3AwcHZmZXAiIHRpbWVzdGFtcD0iMTU1MTc1NDUyMyI+MTIxPC9r
ZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3Jl
Zi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5DaW5kcm92YS1EYXZpZXMsIFQu
PC9hdXRob3I+PGF1dGhvcj5ZdW5nLCBILiBXLjwvYXV0aG9yPjxhdXRob3I+Sm9obnMsIEouPC9h
dXRob3I+PGF1dGhvcj5TcGFzaWMtQm9za292aWMsIE8uPC9hdXRob3I+PGF1dGhvcj5Lb3JvbGNo
dWssIFMuPC9hdXRob3I+PGF1dGhvcj5KYXVuaWF1eCwgRS48L2F1dGhvcj48YXV0aG9yPkJ1cnRv
biwgRy4gSi48L2F1dGhvcj48YXV0aG9yPkNoYXJub2NrLUpvbmVzLCBELiBTLjwvYXV0aG9yPjwv
YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUGh5c2lv
bG9neSwgRGV2ZWxvcG1lbnQsIGFuZCBOZXVyb3NjaWVuY2UsIFVuaXZlcnNpdHkgb2YgQ2FtYnJp
ZGdlLCBEb3duaW5nIFN0LiwgQ2FtYnJpZGdlIENCMiAzRFksIFVLLjwvYXV0aC1hZGRyZXNzPjx0
aXRsZXM+PHRpdGxlPk94aWRhdGl2ZSBzdHJlc3MsIGdlbmUgZXhwcmVzc2lvbiwgYW5kIHByb3Rl
aW4gY2hhbmdlcyBpbmR1Y2VkIGluIHRoZSBodW1hbiBwbGFjZW50YSBkdXJpbmcgbGFib3I8L3Rp
dGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl
cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFBhdGhvbDwvZnVsbC10aXRsZT48L3Blcmlv
ZGljYWw+PHBhZ2VzPjExNjgtNzk8L3BhZ2VzPjx2b2x1bWU+MTcxPC92b2x1bWU+PG51bWJlcj40
PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFwb3B0
b3Npcy9nZW5ldGljczwva2V5d29yZD48a2V5d29yZD5DeWNsb294eWdlbmFzZSAyL2dlbmV0aWNz
L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzL2dlbmV0aWNzL21ldGFib2xp
c208L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPipHZW5lIEV4cHJl
c3Npb248L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkxhYm9yLCBP
YnN0ZXRyaWMvKmdlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk5lb3Zhc2N1
bGFyaXphdGlvbiwgUGh5c2lvbG9naWMvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+T2xpZ29u
dWNsZW90aWRlIEFycmF5IFNlcXVlbmNlIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPipPeGlk
YXRpdmUgU3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRvcmVkdWN0YXNlcy9nZW5ldGljcy9t
ZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBsYWNlbnRhLyptZXRhYm9saXNtPC9rZXl3b3Jk
PjxrZXl3b3JkPlByZWduYW5jeTwva2V5d29yZD48a2V5d29yZD5UcmFuc2NyaXB0aW9uLCBHZW5l
dGljPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDc8L3llYXI+PHB1Yi1kYXRl
cz48ZGF0ZT5PY3Q8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDAyLTk0NDAgKFBy
aW50KSYjeEQ7MDAwMi05NDQwIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4xNzgyMzI3
NzwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3d3dy5uY2Jp
Lm5sbS5uaWguZ292L3B1Ym1lZC8xNzgyMzI3NzwvdXJsPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5u
bG0ubmloLmdvdi9wbWMvYXJ0aWNsZXMvUE1DMTk4ODg2Ny9wZGYvSlBBVEgxNzEwMDExNjgucGRm
PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBNQzE5ODg4Njc8L2N1c3RvbTI+
PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjIzNTMvYWpwYXRoLjIwMDcuMDcwNTI4PC9lbGVj
dHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE 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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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcmViczwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl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 EN.CITE.DATA 24-26 This is supported by in-vivo data demonstrating a decline in PlGF and a rise in xanthine oxidase (a marker of oxidative stress) over the course of labour.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdW5uPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdW5uPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj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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 ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related download
Related searches
- 1 or 2 374 374 1 0 0 0 1 168 1 1 default username and password
- 1 or 3 374 374 1 0 0 0 1 168 1 1 default username and password
- 1 or 2 711 711 1 0 0 0 1 168 1 1 default username and password
- 1 or 3 711 711 1 0 0 0 1 168 1 1 default username and password
- 1 or 2 693 693 1 0 0 0 1 168 1 1 default username and password
- 1 or 3 693 693 1 0 0 0 1 168 1 1 default username and password
- 1 or 2 593 593 1 0 0 0 1 or 2dvchrbu 168 1 1 default username and password
- 1 or 3 593 593 1 0 0 0 1 or 2dvchrbu 168 1 1 default username and password
- 1 or 2 910 910 1 0 0 0 1 168 1 1 default username and password
- 1 or 3 910 910 1 0 0 0 1 168 1 1 default username and password
- 192 1 or 2 33 33 1 0 0 0 1 1 1 default username and password
- 1 or 2 364 364 1 0 0 0 1 168 1 1 admin username and password