Fetal Growth Restriction: A Failure of Placental Adaptation In Response To Fetal Nutrient Demand?

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

Babies that are born small (they fail to reach the size their genetics would suggest) are at greater risk of being stillborn. Should these babies survive, they are then at a greater risk of disability in childhood (e.g. cerebral palsy, developmental delay). There are now well defined links between being born small, termed Fetal Growth Restriction (FGR), and an increased risk of adulthood diseases such as high blood pressure (and subsequent risk of heart attack) or diabetes. Thus, FGR is responsible for a significant emotional and financial burden on families and the NHS, both before and after birth. Despite this, there are no new drugs currently being designed specifically for use in pregnancy-related diseases such as FGR.
For growth of the baby to proceed as normal, a placenta that functions as normal is crucial. The placenta supplies oxygen and other nutrients to the growing baby and eliminates waste products via mother. When the placenta fails to function as normal, FGR may ensue. Despite it being acknowledged that a poorly functioning placenta may result in FGR, the mechanisms behind this are still not well understood. Most research thus far has focused on how signals from mother are able to cause changes in how the placenta transfers nutrients to the mother and how this is altered in FGR. This study aims to examine the signals that baby produces in more detail. Evidence suggests that in normal pregnancy, baby is able to signal to mother to alter the amount of nutrients getting across, via the placenta, to baby. This helps baby's growth to proceed as normal. In FGR, there is evidence that this signaling between baby and mother fails; thus the transfer of nutrients by the placenta is insufficient for normal growth and FGR occurs. This study shall assess human placentas from both normal and FGR-affected pregnancies to assess what these important fetal signals may be. This includes the use of cutting-edge technologies to identify key markers within umbilical artery blood (which flows from the baby back to the placenta) and the fetal-facing side of the placenta (where these signals would bind). Important signals would then be administered to the placenta after delivery of the baby (in a system that mirrors pregnancy). This would examine whether these signals altered placental transfer of nutrients in a manner that would be beneficial for baby.
This study will shed new light onto how baby is able to signal back to mother and how these signals cause changes in the delivery of nutrients back to baby by the placenta. This information will allow exploitation of these signals with an ultimate aim of improving baby's growth in at-risk pregnancies. This work will take place within the Maternal and Fetal Health Research Centre (MFHRC), University of Manchester. The MFHRC is the largest pregnancy-based research group in Europe and has a deserved reputation as a world-class research facility. The MFHRC consists of scientists, clinicans and midwives, all of whom work together with a combined aim of making pregnancy safer for both mum and baby.

Technical Summary

Fetal growth restriction (FGR), the inability of a fetus to achieve its genetic growth potential, is a major clinical problem. FGR significantly increases the risk of stillbirth and childhood morbidity, whilst being born `small' increases the risk of diseases such as hypertension in adulthood. Whilst placental dysfunction is known to be a major causative factor in FGR, there are multiple aetiologies, many of which are still poorly understood. In normal pregnancy, there is evidence that placentas of differing size alter their nutrient supply capacity, to maintain normal fetal growth. In FGR, this adaptation appears to fail. I hypothesise that in pregnancies leading to appropriate growth of the fetus, there are fetal signals that adapt placental nutrient transfer capacity in order for the fetus to achieve its genetic growth potential. I also hypothesise that in FGR, fetuses either no longer produce these signals or the placenta is unable to respond to fetal signals. This study aims to test these hypotheses and determine the identity of some of the fetal signals that adapt nutrient transfer in normal pregnancies and whether these signals are lacking in FGR pregnancies. In order to meet the aims, metabolomic analysis will be carried out on blood collected from umbilical arteries together with proteomic analysis of placental tissue. This will enable the identification of candidate fetal signals that drive alterations in placental nutrient transport. In addition, candidate fetal signals will be administered specifically on the fetal side of the normal or FGR placenta in an ex-vivo perfused placenta model and their effect on maternofetal nutrient (calcium, amino acid) transport measured. Human studies will be complemented with work on mouse genetic models of abnormal fetal growth.This study will provide the first comprehensive profile of candidate fetal signals that drive placental adaptation and whether these are altered in FGR.

Planned Impact

Since insufficient transport of nutrients has been identified as a causative factor in the development of fetal growth restriction (FGR), approaches to rectify this clearly present an attractive therapeutic strategy in the future. Growing evidence suggests that in normal pregnancies, the fetus is able to 'detect' when nutrient supply is inadequate and thus signal back to the placenta to normalize maternofetal nutrient transfer across the placenta, thus maintaining normal growth. Two hugely important questions remain; (i) what are these signals and (ii) are these absent in FGR or is it the placenta that is no longer able to respond to these signals? By the end of this 5-year Fellowship, a small, but specific, list of candidate fetal signals will have been drawn up. In addition, it will be known whether these specific signals are lacking in FGR or if the pathologies of FGR placentas prevent a response to these signals from occurring.
These data will be of interest to pharmaceutical companies; candidate fetal signals that are lacking in FGR would provide a direct therapeutic target in FGR pregnancies. Even though these signals are targeted to the fetal facing basal plasma membrane (BM) of the placental syncytiotrophoblast (transporting epithelium), an increase in maternofetal nutrient transport may also be observed following administration into the mother. Also, studies exist in our group that are looking at novel-targeting peptides that permit delivery of a drug to a specific target within the body. This would allow signals to be delivered specifically to the syncytiotrophoblast (and ideally the BM) thus preventing adverse outcomes in the fetus. This is achievable within 5-10 years.
To facilitate translation of this basic scientific research into an effective biotechnological application, the University of Manchester runs a system for the early filing of patents on exploitable findings, and the Research to Enterprise Centre aids researchers with business plans and marketing strategies, and interfaces with the commercial sector (http://www.rte.manchester.ac.uk/). These resources will provide me with the support and guidance to effectively exploit my research. In addition, scientists and clinicians within The Maternal and Fetal Health Research group have worked closely with pharmaceutical companies including Pfizer and Ardana Biosciences in the past, thus I will capitalize on these existing links at an appropriate time.
 
Description MRC dTP awarded to Kirsty McIntyre
Amount £96,000 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 08/2018
 
Description Manchester-Melbourne Mobility fund
Amount £2,000 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 09/2014
 
Description Physiological society travel award scheme
Amount £700 (GBP)
Organisation Physiological Society 
Sector Charity/Non Profit
Country Global
Start 08/2014 
End 09/2014
 
Description The Physiological Society Travel Award
Amount £500 (GBP)
Organisation Physiological Society 
Sector Charity/Non Profit
Country Global
Start 03/2018 
End 03/2018
 
Description USDA/NIH 2016 Aspen/Snowmass Perinatal Biology Travel Award
Amount $500 (USD)
Organisation North Dakota State University 
Sector Academic/University
Country United States
Start 08/2016 
End 08/2016
 
Description Y.W. Loke New Investigator Travel Award
Amount $500 (USD)
Organisation International Federation of Placenta Associations (IFPA) 
Sector Academic/University
Country Global
Start 09/2016 
End 09/2016
 
Description Collaboration with Dr Julian Christians 
Organisation Simon Fraser University
Country Canada 
Sector Academic/University 
PI Contribution We are interested in whether fetal:placental weight ratio is an accurate marker of placental efficiency. As such, we collaborated with Dr Julian Christians and provided intellectual input into design of studies and the key research questions.
Collaborator Contribution Dr Julian Christians and Dr David Grynspan assessed the effectiveness of fetal:placental weight ratio as a marker of placental efficiency by accessing the National Collaborative Perinatal Project dataset.
Impact PMID 30055670
Start Year 2017
 
Description Collaboration with University of Melbourne 
Organisation University of Melbourne
Country Australia 
Sector Academic/University 
PI Contribution We have been carrying out some in vivo studies to test a compound for its effectiveness at improving fetal growth and reducing blood pressure in mouse models of FGR/preeclampsia.
Collaborator Contribution These partners are supplying the compounds and kits to measure downstream processing of samples.
Impact - See publications list. PMID: 28115513. Onda et al (2017), Hypertension, 69(3), 457-468.
Start Year 2014
 
Description Collaboration with University of Riyadh 
Organisation King Saud University
Country Saudi Arabia 
Sector Academic/University 
PI Contribution I have helped with the design of experiments and analysis of data for the assessment of sex on placental size/shape and potential consequences for nutrient transport
Collaborator Contribution King Saud University collect and analyse all samples (including clinical data) from multi centres
Impact See publication by Alwasel SH et al. Sex differences in regional specialisation across the placental surface.
Start Year 2013
 
Description A day in my life as a placenta scientist 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I made a video about 'a day in my life' as a scientist. It has been viewed more than 4,500 times and was awarded Best Research Film for it at the University of Manchester Postgraduate Summer Research Showcase.
Year(s) Of Engagement Activity 2017
URL https://www.facebook.com/tommys/videos/10155445635117329/
 
Description Animal Research Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The Animal Research Day provided an unique opportunity for students to understand why the humane use of animals is essential in some circumstances to alleviate human suffering through scientific and medical research.
The Animal Research Day has recently been nominated for a University of Manchester 'Making a Difference Award 2017'.
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Before You Were Born event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Over 230 members of the public attended the 'Before you were born' event, which I co-organised, to showcase and explain the research done in the Maternal and fetal research centre, and the benefit it has to the wider public. Attendees reported that they found it enjoyable, had greater knowledge of the centre's research and that they understood more about placental research.
Year(s) Of Engagement Activity 2017
URL https://blogs.bmh.manchester.ac.uk/doctoralacademy/2017/10/before-you-were-born/
 
Description Before you were born public engagement event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact As part of our hosting of the International Federation of Placental Associations (IFPA) annual conference, we decided to host a large-scale public engagement event called 'Before you were born' which took place on Saturday 2nd September 2017 at Manchester Central Convention Complex. I was on the organising committee for this event. This event covered all aspects of pregnancy from trying to conceive through to delivery, with a particular emphasis on the role of the placenta during pregnancy. The event was family-themed and delivered by 50 members of the Maternal and Fetal Health Research Centre (MFHRC) including scientists, clinicians and midwives and collaborators from the University of Southampton. 230 members of the public were in attendance. The event used interactive displays including 'the little lab', lay talks in a 'meet the scientist' session and information stands based on our specialist pregnancy clinics. 86% of attendees thought the event was enjoyable, and 83% felt they knew more about how lifestyle can affect the baby and placenta allowing the event. During this event, we were also able to recruit members of the public to our patient advisory group which gives feedback on grant applications and strategic priorities within the MFHRC.
Year(s) Of Engagement Activity 2017
URL https://research.cmft.nhs.uk/news-events/before-you-were-born
 
Description British Science Week - interactive table 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Held tabletop demonstrations on our centre's research as part of British Science Week Science Fair.
Over 1109 pupils attended over 4 event days; the feedback from teachers and pupils so far was overwhelmingly positive.
Year(s) Of Engagement Activity 2017
 
Description Charlotte Beswick Medicine Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I devised and delivered an interactive presentation on John Charnley - the man, surgeon and his multidisciplinary team - to approximately 55 year 8/9 pupils from several schools in the local area. The presentation was a part of the 'Charlotte Beswick day' and I was also involved in facilitating workshops and supporting other members of the organising team. Students were given an insight into careers in healthcare that they had not previously been aware of and the need for collaboration in science! Compared to the beginning of the day, there were more pupils interested in a career in healthcare then at the beginning (assessed by red/yellow/green cards - held up).
Year(s) Of Engagement Activity 2015
 
Description Connecting Researchers with School Students 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was invited to be interviewed for a short Youtube video discussing the benefits of connecting researchers with school students. I was able to draw upon my own experiences as a researcher to communicate this.
Year(s) Of Engagement Activity 2016
URL https://www.youtube.com/watch?v=_SEJd7Gfglo
 
Description Discover day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I ran a lab based workshop with 16 year 11/12 students. The session consisted of short presentations and mini-experiments that I facilitated, giving the students the opportunity to both understand, and carry out studies using Drosophila as animal models. Students reported a change in perspective and understanding in relation to how scientists develop novel ideas and therapeutics.
Year(s) Of Engagement Activity 2015
URL http://www.flyfacility.ls.manchester.ac.uk/
 
Description Gateways 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I devised and delivered interactive workshops to groups of up to 20 year 9 students. The sessions included an icebreaker, interactive presentation, a mini-experiment (carrying out tests to determine sensitivity of the skin at various points of the body) and plenary/reflection. Pupils found the sessions fun, different and engaging.
Year(s) Of Engagement Activity 2016
URL http://www.gateways.manchester.ac.uk/programme/
 
Description Have You Heard? 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Have You Heard? is a project that I co-founded at the University of Manchester with the aim of clearing the haze that often surrounds scientific discoveries and connecting the line between the science and the headline.
At tailored sessions with adult community groups real examples from experiment to news story are discussed, along with what can go wrong along the way.
We have been on local radio to discuss the project and have also produced an infographic with some top tips on how to interpret science in the news.
Year(s) Of Engagement Activity 2017,2018,2019
 
Description Maternal and Fetal Health Research Centre - Research Shaping Group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I co-facilitated a patient panel meeting with members of the public who have attended St Mary's Hospital during their/their partner's pregnancy recently to help shape our research.
Year(s) Of Engagement Activity 2017
URL https://www.facebook.com/groups/1881317052118391/
 
Description Minute Lecture: The placenta the inside story of pregnancy 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I wrote and narrated a minute lecture video all about my research on the placenta. It has been viewed nearly 7,000 times and has been shared widely on social media (including by research funders Tommy's, the baby charity), disseminating the work that our research group do on a daily basis.
Year(s) Of Engagement Activity 2017
URL https://www.facebook.com/bmhuom/videos/1824097561254277/
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Approx 50 people attended a themed Pint of Science event, entitled 'Womb 101' in which both Mark Dilworth and Kirsty McIntyre spoke at. This engaged the general public regarding the placenta and its vital role in pregnancy. This sparked general discussion afterwards and we also had stalls at which we were able to speak to the public at an individual level.
Year(s) Of Engagement Activity 2018
URL https://pintofscience.co.uk/event/the-glam-life-in-utero-
 
Description Pint of Science: Womb 101 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Mark Dilworth and Kirsty McIntyre gave talks relating to their research as part of the international Pint of Science festival.
Year(s) Of Engagement Activity 2018
 
Description Science Uncovered at Manchester Museum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I gave a Lightening talk on my research as part of the Science Uncovered event at Manchester Museum - this sparked discussion and interaction with the audience (general public)
Year(s) Of Engagement Activity 2016
 
Description Science fair launch - Manchester Grammar School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I was invited by Manchester Grammar School to give a talk to 200 year 8's to promote enthusiasm and interest for the launch of their science fair. I used questioning as part of my presentation to assess the level of aptitude and related content in my talk to the projects that they will be designing this term.
I will be returning in 3 weeks to judge the pupils projects and award prizes to the best in class, and year.
Year(s) Of Engagement Activity 2016
URL https://www.mgs.org/
 
Description Team member, coordinating Pint of Science events 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Between 30-60 members of the public attended an evening of talks by academics and postgraduate students in a local pub sparking interest and discussion in topics such as cell biology, cancer and cosmetics. We held 3 consecutive evenings in 6 separate venues with Q&A sessions and activities at each. These were well received and helped communicate science with members of the general public.
Additionally, I helped organise one-off event as part of Manchester Science Festival, brining together different areas of science (physiology, astronomy, mechanical engineering) to members of the public.
Year(s) Of Engagement Activity 2015,2016
URL https://pintofscience.co.uk/events/manchester/
 
Description The Brilliant Club (Thornleigh Salesian College) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I developed and delivered 6 tutorial sessions to 8 year 12 students at Thornleigh Salesian College. The students completed weekly homework assignments leading up to their Final Assessment - a 2,000 word essay that explored the content covered in tutorials and . I then graded these assignments, awarding Undergraduate level marks (ie. 2.1; 1st class). All students then attended a graduation ceremony at the University of Manchester. I received excellent formative, and summative feedback from the pupils. The school were very pleased with the progress and engagement of the students.
Consequently, 2 of the students asked for some work experience in my department. I arranged 2 afternoons shadowing me in my laboratory at the Maternal Fetal Health Research Centre at the University of Manchester. At the end, one of the students wrote a piece for The Brilliant Club blog about her experience.
Year(s) Of Engagement Activity 2015
URL https://medium.com/@BrilliantClub/blog-the-brilliant-club-work-experience-at-st-mary-s-hospital-685d...
 
Description Workshop delivery at Cheadle Hulme High School (School-University Partnership Initiative) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I developed and subsequently delivered 2 workshops to 56 year 9 students at Cheadle Hulme High School. The pupils reported learning about what 'research science' really is, and that they enjoyed the session. Stereotypes were 'busted' and we discussed the various ways in which the scientific method can help us solve problems. At the end of the session the pupils presented their research plans/experimental ideas to the class.
The school gave very positive feedback on the event.
Year(s) Of Engagement Activity 2015
URL http://www.supi.manchester.ac.uk/projectlistingportal/generalsciences/researchscience/
 
Description Workshop with Schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I delivered an academic session to 36 year 7/8 students from 3 different schools. This comprised of a short interactive presentation followed by a challenge where the students came up with their own 'research problem' and discussed how they would tackle it (using the scientific method). They presented their ideas to the group at the end of the session.
Pupils reported that they learnt more about what being a scientist means, including how to formulate a hypothesis and understanding that science may apply to many different subjects/themes.
Year(s) Of Engagement Activity 2016
 
Description Workshop with patient involvement panel 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact At the Maternal and Fetal Health Research Centre, we have started a patient involvement panel who feedback on future grant ideas/applications and strategic priorities of the centre. This panel largely includes pregnant women, and those women that may have had previous pregnancy problems (e.g. preeclampsia, stillborn baby). For this particular workshop, I engaged with this panel who read a lay summary of a proposed grant based upon advanced maternal age. As part of this workshop, the patients were encouraged too input ideas into the feasibility of the study including their willingness to attend hospital for an increased number of appointments. This information is being used to help shape a project grant application the MRC.
Year(s) Of Engagement Activity 2017
 
Description Young Scientists Journal Conference: Science communication workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I was invited to co-run a workshop on science communication: what it is, why do it and how to do it at the Young Scientists Journal Conference held at Bolton School in February 2018.
Year(s) Of Engagement Activity 2018
URL https://events.ysjournal.com/programme/