- Why is the BBB project needed and who will benefit?
Fetal growth restriction, pre-eclampsia, and preterm birth are three of the four main complications of pregnancy. They affect up to 60,000 families in the UK every year. The fourth main complication, recurrent miscarriage, affects 1% of all couples trying to conceive – with an estimated 1,000 new cases every year. Each complication presents significant health risks to both mother and baby, has enormous emotional impact on those affected, and carries a high cost burden for the NHS.
Fetal growth restriction affects 20,000 babies in the UK every year and this condition accounts for 50% of all stillbirths. Growth restricted babies are at increased risk of intrauterine oxygen restriction, which can cause serious disability, and death.
Pre-eclampsia is a form of very high blood pressure and is one of the two leading causes of maternal death. It is responsible for a considerable proportion of the 500,000 infant deaths per year worldwide and affects up to 14,000 pregnancies in the UK every year.
Preterm birth is responsible for 80% of all neonatal deaths, and affects 30,000 babies in the UK annually. The rate of cerebral palsy in preterm babies is up to 30 times higher than in babies born at term. This incidence has not changed significantly in recent years, and prematurity represents a major health issue and challenge for modern obstetric care.
Recurrent miscarriage, the loss of 3 or more consecutive pregnancies, affects 1% of couples trying to conceive. While the actual number is difficult to quantify because of the nature of this complication, experts estimate there are at least 1,000 families newly affected every year.
This will be the most detailed ‘whole family’ analysis to be undertaken anywhere in the world. The Baby Bio Bank will be available for experts to access from anywhere in the world, forming a unique resource which will greatly help with both prevention and treatment of pregnancy complications
- Causes of Complications in Pregnancy
These four complications may be caused by many factors, including the environment in the womb, and external environmental factors such as the health of the mother, and genetic anomalies. This complexity explains why there has been limited progress in understanding exactly why they occur.
These complications can and do occur in isolation but Professor Regan and Professor Moore hypothesise that they are also interrelated in many cases, particularly by underlying genetic defects, which are established at the point the maternal, paternal, and fetal genes come together (Figure 1).
Figure 1: DNA is the blueprint for every cell, but defects can occur as DNA sends a signal to the cells RNA, or as RNA sends a message to the cells protein. The Baby Bio Bank samples will be analysed for defects at each point
Evidence indicates that the four complications are a biological continuum with different end-points – a ‘spectrum of pregnancy complications’ (Figure 2)
§ The association between fetal growth restriction and preterm labour is greater than would be expected by chance alone. Women who have a preterm baby in one pregnancy are more likely than average to have a growth restricted baby in their next pregnancy, and vice versa.
§ Pre-term labour is associated with an elevated level of a specific inflammatory protein, similar to that seen in pre-eclampsia.
§ Recent studies indicate that fetal growth restriction is associated with impaired circulation in the fetus, as is pre-eclampsia.
§ Successful pregnancies in women who have experienced recurrent miscarriage are at increased risk of pre-eclampsia, fetal growth restriction and premature birth.
Figure 2. The Spectrum of Pregnancy Complications
- Aims and Objectives
A greater understanding of the human genome and advanced scientific technology means this type of analysis can now be more easily undertaken. The Baby BioBank project will help establish:
§ why these pregnancy complications occur
§ who is at greatest risk
§ medical interventions to save lives of women and their babies
The short-term aim of this project (within five years) is to generate a unique database of DNA samples from families in the UK to further research into the four major complications of pregnancy, which may be related by particular genetic anomalies and other underlying causes. Research into complications of pregnancy has yet to pinpoint these causes because a large enough cohort has not been available to come up with conclusive results.
Another aim of the project is to speed up research, as a bigger collection of samples will allow researchers to pose targeted questions and find answers much more quickly. As well as facilitating future research, this will fast track research already being undertaken, as individual researchers will no longer have to spend years collecting the samples they need.
The project will also encourage greater scientific collaboration. Access to this data will be made available to both national and international researchers whose research proposal has been approved on the grounds of scientific validity and clinical impact by an appointed Committee of experts. The project leaders hope that this resource will encourage more research studying these complications collectively.
The long-term (within ten years) aim of this project is to save the lives of mothers and their babies and to protect families from the grief and distress that these conditions can cause. A reduction in the cost burden on the NHS would also follow – for example, the cost of preterm birth is thought to amount to £939 million in extra costs linked to neo-natal care and hospital readmissions.
- Plan of Investigation
The minimum requirement for a sample size sufficient to begin to detect inheritance patterns and underlying causes is 2,500 families: 500 families from each one of the four complications of pregnancy and 500 families with normal pregnancies. Together these London units have 23,000 births per year and it is expected that the total number of deliveries will be 92,000 over the four and a half year collection period. Within this total there will be, sadly, an ample number of families affected by one of the four complications in order to achieve the minimum sample size The above targets are dependent on samples being collected at a rate of one family per day. However, the more samples we can collect, the more effective the Baby Bio Bank will be, and the only limit on the success of the project is funding for extra staff to achieve greater numbers. Further maternity units from across the UK would be able to take part with additional funding beyond the scope of the current project timescale.
Recruitment of families
Any family having a baby at one of the above units can contribute. Where possible, families will be recruited at the antenatal clinic or when a complication presents itself.
They will be counselled and given consent forms and information leaflets and will be given time to decide if they want to take part.
Collection will involve taking blood from the mother, father and cord blood and placenta from the baby after he or she is born. Detailed information about the family will also be recorded, for example, weight and height of the mother and father and their pregnancy history and medical history.
Sample transfer and storage
Each maternity unit will temporarily store each sample until it can be moved to the Baby Bio Bank, which will be housed in duplicate at the Institute of Child Health, University College London, and Imperial College, in order to provide a back up according to HTA (Human Tissue Authority) regulations. The samples will then be carefully catalogued using the Asset Performer database (link will be requested) and stored in the Baby Bio Bank.
Each sample can then be used for up to 50,000 individual experiments – so there will be no need for this collection to be repeated in our lifetimes.
Given the emerging evidence that recurrent miscarriage, fetal growth restriction, pre-eclampsia and preterm birth may have overlapping causes, the project leaders propose that the following strategies can be used to investigate the role played by maternal, paternal, grandparental and fetal genes.
1. Genes that have been shown to be associated with each pregnancy complication in other DNA banks can be confirmed or refuted using this expansive resource. Their role in each of the pregnancy complications can also be investigated in more detail.
2. Genes shown to be important in early fetal development and growth will be tested for mutations in these families and their matched tissue samples.
3. Availability of matched RNA and protein samples will be an invaluable unique resource for verification of biological function. Placental samples collected from cases and controls will act as sources of RNA for both confirmatory and exploratory profiling studies.
4. Identification and characterisation of differentially-expressed and/or modified proteins.
- Project Leaders
The project will be led by Professor Lesley Regan (St Mary’s Hospital, Imperial College London), internationally acclaimed Obstetrician and Gynaecologist and recurrent miscarriage expert, and Professor Gudrun Moore (Institute of Child Health, University College London), one of the world’s leading scientific experts on the genetics of pregnancy complications, with a special interest in fetal growth restriction. Imperial College London and the Institute of Child Health are two of the UK’s leading scientific research centres.
Researchers in Professor Regan’s group at Imperial College aim to integrate research activity in human reproductive medicine and biology, focusing on infertility, fetal loss, fetal development, preterm birth and neonatal brain damage.
Professors Gudrun Moore and Lesley Regan
At the Institute of Child Health, Professor Moore and her colleagues work to understand the molecular, genetic and developmental aetiology of a range of single gene disorders, syndromes and complex traits in humans and translate research findings into improved care for children, adults and families. Both institutions have state-of-the-art research centres, capable of processing the large number samples required to make the project a success.
At each maternity unit a Principal Collaborator will oversee co-ordination with the project. They are:
- Professor Catherine Williamson, Consultant in Obstetric Medicine
- Queen Charlotte’s and Chelsea Hospital
- Professor Lesley Regan, Consultant in Obstetrics and Gynaecology
- St Mary’s Hospital
- Professor Mark Johnson, Consultant in Obstetrics and Gynaecology
- Chelsea and Westminster Hospital
- Professor Donald Peebles, Consultant in Obstetrics and Gynaecology
- University College London Hospital
- Professor Kypros Nicolaides, Head of Academic Obstetrics and Gynaecology
- King’s College Hospital
The BBB Research Manager
The Research Manager, Dr Sayeda Abu-Amero, was appointed in March 2009 and is the overall project co-ordinator, overseeing all five collecting maternity units to ensure that sample storage and processing are carried out correctly. Duties include the supervision and co-ordination of the BBB team, management of the database, ethical approval and co-ordination of the Clinical Steering Committee and the Resource Management Board.
- Recruitment Team
The recruiting team are very experienced and highly motivated. They are fully equipped to counsel parents as to why their samples are needed, explain the ethics consent form to them, take them through the information sheets and answer any questions they may have. The team is led by Ms Katherine Rogers, who has had previous experience in large cohort studies, and has established a working protocol for Drs Anita Solanky and Ana Maria Perez Miranda, who are Research Associates, with international experience in recruitment and research.
The BBB Recruiting Team: Katherine Rogers, Nita Solanky and Ana Maria Perez Miranda
They BBB recruiting team are responsible for:
§ collection of the blood samples
§ detailing and recording parents medical histories and family histories
§ obtaining parent’s consent to take blood from the placenta and cord after birth, liaising with the Research Technicians to ensure swift and safe delivery to the Baby Bio Bank
The BBB recruiting team are at the frontline of this project and they are crucial to its success. They will be required to collect the baby’s samples as soon as he or she is born – which can be at anytime: day or night, weekday or weekend.
- Sample Management Team
Drs Shawnelle White and Anna Thomas, are two highly skilled Research Associates responsible for the production of DNA and RNA and will be based at the Institute of Child Health and St Mary’s Hospital. They
will also be responsible for DNA and RNA quality control and will help with distribution to external researchers once their projects have received ethical approval.
BBB Sample Management Team: Shawnelle White and Anna Thomas
The BBB team are a dynamic group of individuals, who are all capable of recruiting participants, collecting and processing samples and developing research strategies and are committed to working as a team to ensure the completion of the BBB as a resource and to lead in the research into complications of pregnancy.
- Wellbeing of Women
Wellbeing of Women is a charity dedicated to improving the health of women and babies, to make a difference to people’s lives today, tomorrow and in the future. They provide information to raise awareness of health issues to keep women and babies well today; they fund pioneering medical research which has and will continue to develop better treatments tomorrow; and they fund training grants for midwives and doctors to nurture and secure expertise in women’s health for the future.
Since its founding in 1964, every person born in the UK and many worldwide will have benefitted from its work. Their researchers developed the science leading to the cervical cancer screening programme, ultrasound scans to enable safer pregnancy and projects helping premature babies to survive and live healthy lives
- Ethical Issues
All data will be anonymous and confidential and will only be accessible by the BBB Recruiting Team and the pertinent consultant at the participant’s site.. At birth all personal identifiers will be removed and each study participant will have a unique number relevant only to the study group. The Baby Bio Bank will be under the ownership and joint custodianship of London, Imperial, Wellbeing of Women and the five Hospital Trusts.
- Monitoring and Evaluation
Clinical Steering Committee
At the outset a Clinical Steering Committee will be appointed made up of the Principal Collaborators from each site. Any clinical queries raised during recruitment will be referred to this committee. As an additional quality control measure, there will be annual site visits by the Committee to review the data collection.
The Resource Management Board
A Resource Management Board (RMB) will be appointed to oversee management of the Baby Bio Bank and it will have the following responsibilities:
§ To maintain and demonstrate confidentiality of the data and sample resource
§ To maintain and demonstrate quality control for data entry and sample collection/storage and dispatch
§ To maintain and demonstrate audit of the use of the resource collection
§ To assess applications for access and provision of samples from the resource centre
§ To hold responsibility for communications of decisions regarding sample use
Reports are presented twice a year to the RMB detailing recruitment progress, site visits and costings-to-date.
The BBB has ethical approval for the duration of the project from Trent Research Ethics Committee (REC) which is renewable on application (09/H0405/30). Annual reports are required by Trent REC to assess that the project is adhering to ethical guidelines.
- Benefits and Outcomes
§ A global resource for research into complications of pregnancy
§ Information held in the bank will yield improved care and treatment for women at risk of complications at every stage of pregnancy
§ New methods to track markers of pregnancy complications by taking a blood sample and to closely monitor those at risk in order to intervene if necessary e.g. with a simple drug treatment
§ More successful, healthy pregnancies will mean more healthy babies
§ Genetic information collected will potentially provide information about and solutions to other obstetric and gynaecological health problems
§ Each individual DNA sample set can be used up to 50,000 times so there will be no need to repeat this project in our lifetimes