EVERREST Developing a Therapy for Fetal Growth Restriction
Condition: Fetal Growth Retardation
MeSH terms: Fetal Growth Retardation
Study type: Observational

Summary: 
      Fetal Growth Restriction (FGR) is a major obstetric problem, affecting 1.46 million fetuses
      worldwide each year and contributing to 50% of stillbirths. Severe early onset FGR affects 1
      in 500 pregnancies, leading to stillbirth or the need for delivery before 28 weeks gestation.
      The combination of FGR and prematurity is associated with a significant risk of neonatal
      mortality and short and long-term complications. Even modest increases in birthweight (e.g
      from 500 to 600g) and gestation at delivery (e.g from 26 to 27 weeks) are associated with
      significantly better outcomes but there are currently no treatments.

      The EVERREST Clinical Trial, funded by the European Commission, aims to develop a treatment
      which will increase fetal growth in severe early onset FGR. It will use gene therapy injected
      into the uterine arteries of the mother to increase the levels of vascular endothelial growth
      factor (VEGF) and so increase uterine artery blood flow and fetal growth.

      The EVERREST prospective study aims to form a clinical database and biobank of pregnancies
      affected by severe early onset FGR to improve understanding of the condition and serve as a
      comparison to assess the safety and efficacy of this intervention.

      The prospective study will take place across four European centers who will later take part
      in the EVERREST Clinical Trial. Women with singleton fetuses with early onset FGR will be
      approached to take part in the study. Participating women will provide blood samples, details
      of their clinical condition, samples of umbilical cord blood, placenta and myometrial and
      placental bed biopsies at the time of Caesarean section (if needed). Data on short and
      long-term outcomes of the babies will be collected. All data will be entered onto a central
      database for eventual use as a comparator for treated women on the EVERREST Clinical Trial,
      for which separate ethical approval will be sought.
    

Detailed description: 
      Fetal Growth Restriction (FGR) is a major obstetric problem, affecting 1.46 million fetuses
      worldwide each year and contributing to 50% of stillbirths. Severe early onset FGR affects 1
      in 500 pregnancies, leading to stillbirth or the need for delivery before 28 weeks gestation.
      The EVERREST prospective study plans to clinically and biochemically characterise a cohort of
      pregnancies affected by severe early onset FGR across the four European centres. A database
      will be created containing information about antenatal investigations, maternal
      complications, fetal outcome and neonatal progress. This will be linked to a biobank
      containing samples of maternal blood, umbilical cord, umbilical cord blood, placenta,
      placental bed and myometrium.

      There are three aims to this study:

        1. To provide data from pregnancies affected by severe early onset FGR with which to
           compare outcomes from a group of pregnancies that will undergo treatment using maternal
           Ad.VEGF gene therapy.

        2. To provide important information about the likely prognosis for babies born after
           affected pregnancies in the short and long term. These are data which are currently
           lacking.

        3. To provide samples that will be used to investigate the biological mechanisms that
           underlie the condition, which subsequently may be used to provide biomarkers of outcome.

      The design of the project has involved consultation with leading European fetal medicine
      specialists, neonatologists, pathologists and biomedical scientists who form part of the
      EVERREST consortium. The multicenter nature of the project raises issues of confidentiality
      and data protection but also allows for a larger data set from which to draw more meaningful
      conclusions. Furthermore it means that the findings are applicable not just in the United
      Kingdom but also in Europe. It also provides a larger group of patients from which to recruit
      to the EVERREST trial. The project has also been given approval by the National Institute for
      Health Research, funded Fetal Medicine Clinical Study Group at the Royal College of
      Obstetrician and Gynecologists, of which the PI is a member. Other leading Fetal Medicine
      centres across the United Kingdom will be involved in recruiting to the prospective study so
      that a wider picture of severe FGR and samples from affected pregnancies are available in the
      UK.

      Recruitment Women referred to the Fetal Medicine Unit for suspected severe early onset Fetal
      Growth Restriction will be given a Participant Information Sheet (PIS) to read. If the
      diagnosis of severe early onset FGR is made women will be asked if they are interested in
      taking part in the study. Interested eligible women will meet with a member of the research
      team who will read through the PIS with them and answer any questions they have. If the woman
      would like more time to decide they can meet with a member of the research team at a
      subsequent hospital appointment.

      Risks, burdens and benefits Women may be distressed by discussing the study at what will
      already be a worrying and upsetting time following the diagnosis of severe early onset FGR.
      If this is the case it will not be pursued, and can be discussed at a future appointment if
      the woman wishes. Within the University College London Hospital Fetal Medicine Unit women are
      frequently given information about research at the time of their appointments and the
      investigators have not found this to be distressing to them.

      Women may be concerned that declining to be involved in the study will affect the care that
      they receive. The Participant Information Sheet will make it clear that this will not be the
      case.

      There is a risk of breach of confidentiality with data sharing. This will be minimised by
      holding data in a central secure database, which will be password protected and can only be
      accessed by authorised members of the team, and by creating a unique pseudoanonymised
      Participant Identification Number which will be used on the database. Participant
      identifiable data, including name, address and hospital ID number, will not be entered onto
      the central database.

      Performing the ultrasound assessments of uterine artery blood flow will add 2-5 minutes to a
      30 minute ultrasound scan. At these appointments women will often need to wait for their
      ultrasound scan and may need blood pressure monitoring, urine checks and fetal heart beat
      monitoring (cardiotocograph) as part of their routine care. This can mean they are at the
      hospital for an hour or more, or which the uterine blood flow assessment would be a small
      fraction.

      The maternal blood samples may involve temporary pain and/or bruising. This will be minimised
      by having the samples taken by trained healthcare professionals. During a low risk pregnancy
      two routine blood samples are recommended at booking and 28 weeks gestation. In pregnancies
      complicated by severe early onset FGR several additional blood samples will be needed as part
      of clinical care. Investigators plan to take the investigators first sample at the same time
      as blood tests needed to look for maternal infections (toxoplasmosis, cytomegalovirus,
      rubella) and the investigators second at the same time as pre-operative blood tests taken
      before Caesarean section.

      The myometrial biopsy and placental bed biopsy will each add an estimated 1 minute to the
      Caesarean section. Generally the surgical time for a Caesarean is about 45 minutes but when
      anesthetic time and patient transfer are included the overall procedure takes approximately 2
      hours. They are not associated with a significant risk of hemorrhage or post-operative
      complications. Biopsies would not be taken if there were a clinical contra-indication e.g.
      excessive uterine bleeding or maternal medical conditions meaning the duration of the surgery
      had to be limited.

      The umbilical cord, umbilical cord blood and placental samples will be taken after the baby
      has been delivered, the cord cut and the placenta delivered so will not involve any pain or
      inconvenience for the mother or baby.

      At the moment there is no treatment for severe early onset FGR. This can leave parents
      feeling helpless in the face of the diagnosis. It may help them to feel their participation
      could contribute to a better understanding of the condition and a potential treatment in the
      future. Women who have a pregnancy affected by severe early onset FGR are at higher risk of
      having a future affected pregnancy, so there may also be the potential for a direct benefit
      to their future reproductive health.

      Babies born from pregnancies affected by severe early onset FGR are routinely followed up in
      all four EU countries to two years of age, corrected for prematurity, since it is well known
      that many have severe morbidity for which medical input is required. Investigators will
      collect data about clinical blood results, investigations and neurodevelopmental assessments,
      which are performed routinely as part of their standard care.

      Confidentiality The EVERREST consortium will be collecting demographic and clinical data
      about participants from four European countries which will be combined in a central database.

      Within each centre participants will be given a unique study Participant Identification
      Number (PIN). Data will be entered under this identification number onto the central database
      stored on the servers based at the University College London. The database will be password
      protected and only accessible to members of the EVERREST Consortium, UCL Clinical Trials
      Unit, the participating hospitals and external regulators, including the European Commission.
      The servers are protected by firewalls and are patched and maintained according to best
      practice. The physical location of the servers is protected by Closed-circuit television and
      security door access. The database and coding frames will be developed by the Trial Manager
      in conjunction with the CTU.

      The information linking participant identifiable data to the pseudoanonymised Participant
      Identification Number will be held locally by the research sites. This will either be held in
      written form in a locked filing cabinet or electronically in password protected form on
      hospital computers. After completion of the study the data linking participant identifiable
      data to the PIN will be destroyed and the database will be retained on the servers of
      University College London for on-going analysis in conjunction with the bio bank.

      All members of the research team will receive training in the regulations surrounding
      confidentiality and data handling and their responsibilities in this area. It will be made
      clear to participants in the PIS and during the process of consent that data will be obtained
      from their medical records and the medical records of their baby. It will be explained that
      this data will be stored in a form in which they are not directly identifiable and will be
      shared within the European Union for the purposes of the study. Electronic data will be
      transferred in encrypted and password protected form.

      It is not anticipated that the results of analysing the tissue samples will have any direct
      clinical significance for the participants. If, however, results were to be obtained which
      would have a serious impact on the participant's current or future health these would be fed
      back to the recruiting study centre under the Participant Identification Number. Within the
      recruiting centre the results could be linked back to the participant without them being
      identified to the rest of the research team.

      Use of tissue samples in future research At the conclusion of the study, stored samples will
      be transferred to a site with national regulatory approval, for retention as a bio bank.
      Participant consent will be obtained in advance for this retention. Separate ethical
      application will be made for research using these samples. Samples will be stored until they
      are fully used or become unusable, which is anticipated to be a maximum of 10 years for
      frozen samples.

      If participants do not give their consent for retention for future research then UK samples
      will be disposed of in accordance with the Human Tissue Authority's Code of Practice and
      European samples will be disposed of according to local and national guidelines.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Pregnant women with FGR
      
Biospecimen description: 
      Plasma, serum, whole blood, fixed placenta, frozen placenta, fixed placenta bed.
    
Keywords: Severe early onset Fetal Growth Restriction