Sildenafil in Pregnancy – background information

1. The history of research into sildenafil for fetal growth restriction in pregnancy

2. Ongoing related research by Gravida researchers, including Dr Charlotte Oyston

3. Detail of the STRIDER NZAus trial

 1. Fifteen years of evidence inform today’s trial

The STRIDER NZAus clinical trial is the culmination of more than fifteen years of international research.

Professor Phil Baker started investigating the use of sildenafil (Viagra) in pregnancy in 1998; the first study to suggest that the drug might increase the blood supply to the uterus was published in 2000.[1]

In 2005, Prof Baker and a research team in the UK published a study of biopsies taken at the time of Caesarean section, comparing the behaviour of arteries in uterine tissues from normal pregnancies to those taken from pregnancies complicated by growth restriction. They showed that sildenafil significantly reduced constriction and significantly improved the relaxation of small arteries.[2] Several subsequent studies confirmed theses beneficial effects on blood vessels from women suffering pregnancy complications.[3,4]

In 2011, Prof Baker worked with Canadian colleagues on a small case-control study of 11 women who had been given a dire prognosis of their severe case of IUGR, and who opted to take the chance to enter a special programme run by British Columbia Provincial Health Services Authority that offered people innovative therapies when they felt they had no other avenues. The course of sildenafil changed these babies’ odds of survival for the better – results showed the growth of the babies increased markedly and 10 of the 11 babies survived, a much greater proportion than the norm expected without intervention.[5]

Alongside tissue studies, animal studies are a routine part of clinical drug development, helping researchers find consistent answers that provide a body of evidence before human trials can be approved.

A strong body of evidence from these models has also been published, including research by Dr Joanna Stanley (Gravida and University of Auckland), who has looked at mice models and demonstrated that sildenafil improves the blood supply to the placenta, enhances development of the placenta, increases growth of pups, and reduces adverse pregnancy signs.[6]

Based on all this research, last year Gravida provided funding for Prof Baker, paediatrician Professor Frank Bloomfield, Dr Katie Groom and researcher Dr Charlotte Oyston to extend their various studies, design a framework for the STRIDER randomised control (RCT) clinical trial, and gain ethics approval. This ground work, alongside other current Gravida projects, then led to Dr Groom’s application for the new STRIDER NZAus clinical trial’s funding from the Health Research Council of grant 2013 (see HRC release here).

 2. Other Gravida research projects continue in parallel with the trial

A network of other research projects are continuing in tandem with the trial.

Dr Charlotte Oyston, a trainee obstetrician and Gravida-funded PhD student, is amongst the first in the world to shift from studying small-size animals to large-size animals, and is studying effects of sildenafil on lamb growth at the Ngapouri farm. Her focus is to record the wider effects of sildenafil in both the ewe and lamb, in pregnancies affected by growth restriction. Her research seeks to see if sildenafil can improve fetal growth, uterine and umbilical artery blood flow (measured by Doppler ultrasound), and development of the placenta. She is also investigating the placental tissue after a lamb is born, looking at placental growth, structure, and vascular function, to scientifically document differences and changes.

Other relevant Gravida research projects include:

  • Following the effects of sildenafil on offspring of animals assisted in their pregnancy with this treatment;
  • Vascular physiology studies and Doppler waveform studies to provide further insight into the pathophysiology of placental ischaemic conditions;
  • Studies to see if sildenafil can improve triplet lamb growth;
  • Modelling of the mechanisms of novel therapies such as sildenafil for fetal growth restriction;
  • Continued work by Dr Joanna Stanley at the Liggins Institute, also looking at other therapies.

 3. Details of the clinical trial

The STRIDER NZAus trial is a bi-national, multicentre, double-blind randomised placebo-controlled trial. Women will be recruited in Auckland, Wellington and Christchurch as well as Australia (Melbourne, Sydney, Brisbane, Adelaide and Perth).

The Auckland centre and team will lead and coordinate the trial across all sites. Recruitment will take place over a three-year period and involve more than 120 participants.

Eligible women will be identified by their obstetrician prior to 30 weeks of pregnancy. They will receive a low dose of sildenafil (lower than the recommended adult dose) or an identical placebo tablet until they deliver their baby or until 32 weeks, whichever is first. The key measure of the trial is if sildenafil improves fetal growth velocity. Mothers will be under specialist care and monitored very regularly.

A second measure will try to identify if sildenafil can improve the rates of neonatal survival, free of major long term morbidity. This second measure is an important part of the international STRIDER collaborative trial monitoring.

The STRIDER NZAus trial will be run by Dr Groom with co-investigators Prof Phil Baker, Prof Lesley McCowan, Prof Peter Stone and Dr Arier Lee, all from the Department of Obstetrics and Gynaecology or wider departments within .

If the trial proves successful in the ‘’early-onset’’ window of pregnancy, the researchers hope there is scope for an extension of the therapy to later gestations, where outcomes linked to disease prevalence are higher and the overall number of cases of pregnancies eligible to be treated may be greater. At a population level, adoption in clinical practice of sildenafil for all pregnancies diagnosed with growth restriction or pre-eclampsia could result in major societal and financial savings for families and the healthcare system. It could reduce a huge emotional and financial burden for our population as a whole.

It is anticipated findings from the trial will be published in 2017.

References:

1. Sher G, Fisch JD. . Hum Reprod 2000 Apr;15(4):806-9.

2. Wareing M, Myers JE, O'Hara M, Baker PN. . J Clin Endocrinol Metab 2005;90:2550-5.

3. Samangaya RA, Wareing M, Skillern L, Baker PN.Phosphodiesterase inhibitor effect on small artery function in preeclampsia. Hypertens Pregnancy 2011;30(2):144-52.

4. Wareing M, Myers JE, O'Hara M, Kenny LC, Taggart MJ, Skillern L, Machin I, Baker PN. . Eur J Obstet Gynecol Reprod Biol 2006 Jul;127(1):41-9.

5. von Dadelszen P, Dwinnell S, Magee LA, Carleton BC, Gruslin A, Lee B, Lim KI, Liston RM, Miller SP, Rurak D, Sherlock RL, Skoll MA, Wareing MM, Baker PN, and for the Research into Advanced Fetal Diagnosis and Therapy (RAFT) Group. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-8.

6. Stanley JL, Andersson IJ, Poudel R, Rueda-Clausen CF, Sibley CP, Davidge ST, Baker PN. Sildenafil citrate rescues fetal growth in the catechol-o-methyl transferase knockout mouse model. Hypertension 2012;59:1021-8.