Pre-term premature rupture of the fetal membranes (PPROM) occurs commonly after amniocentesis and fetoscopic surgery. However, membrane healing is poor making attempts to seal the defect ineffective. Intra-amniotic infusion with platelet-rich serum successfully seals membrane defects in two-thirds of cases but is associated with stillbirth in 16%. The mechanisms which promote fetal membrane healing are poorly understood and this is preventing development of new therapies.
We have identified an important stretch-sensitive protein which influences inflammation and the healing response. This project will utilise a human ex-vivo approach to investigate the role of the stretch sensitive protein connexin-43 in inflammation and membrane healing in collaboration with Dr Anna David (UCLH) and Prof David Becker (Singapore). Our 2014 publication in Placenta (http://authors.elsevier.com/sd/article/S0143400414007826) demonstrates that repetitive strain of the human AM, similar to that occurring in preterm labour, leads to increased expression of Cx43. This was associated with enhanced production of prostaglandins, important inflammatory factors that cause AM rupture. In addition, human AM samples following fetoscopic laser surgery for twin-to-twin transfusion syndrome (provided by Co-I Deprest) showed enhanced Cx43 expression and reduced collagen levels close to the wound edge when compared to control samples taken from the same AM but away from the wound site. This is the first demonstration that enhanced Cx43 expression will influence AM integrity and is altered when the AM has a wound.
The project will utilise a multi-disciplinary bioengineering/clinical approach to develop a pharmacological therapy that has tissue modifying activities and prevent PPROM. The project was previoulsy funded by Wellbeing of Woman (2011-14) and the project team have been awarded funds by the RoseTrees Trust to support David Barrett during his PhD studentship (2014-17).
Sam Howard, CEO at Rosetrees Trust, said,“The findings are extremely encouraging and show the value of conducting early stage research into biological mechanisms. This piece in the puzzle may lead to novel treatment strategies to reduce pre-term birth, the main cause of infant death world-wide. Rosetrees Trust is delighted to be able to support such cutting edge research carried out by outstanding researchers such as Dr Tina Chowdhury and Dr Anna David, which has a direct human impact.”
Liz Campbell, Director at Wellbeing of Women, said, “Wellbeing of Women is committed to funding research which looks at the possible causes of premature birth and offers safe and effective solutions. Premature birth can be very dangerous for mother and baby; and is particularly devastating when babies die. Almost half of premature births occur as a result of waters breaking too early and up until now doctors have not been able to say why this happens.
“This study, co funded by Wellbeing of Women, helps explain why some amniotic sacs, which protect the baby as it grows inside the womb, are more prone to breaking too early – which can lead to premature birth. Going forward, we can now focus on new treatments to address this weakness in the womb tissue and help women who have had previous preterm births feel more confident about their pregnancies and their ability to carry a pregnancy to full term.”